DRAFT TOXICOLOGICAL PROFILE FOR 1,4-DICHLOROBENZENE Prepared by: Research Triangle Institute Under Contract No. 205-93-0606 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry September 1997 1,4-DICHLOROBENZENE DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. ZAT. FOR ” pUBLIC HEA! TH ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE UPDATE STATEMENT A Toxicological Profile for 1,4-Dichlorobenzene was released in April 1993. This edition supersedes any previously released draft or final profile. Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 ***DRAFT FOR PUBLIC COMMENT*** } § FOREWORD This toxicological profile is prepared in accordance with guidelines developed by the Agency for Toxic Substances and Disease Registry (ATSDR) and the Environmental Protection Agency (EPA). The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile succinctly characterizes the toxicologic and adverse health effects information for the hazardous substance described therein. Each peer-reviewed profile identifies and reviews the key literature that describes a hazardous substances toxicologic properties. Other pertinent literature is also presented, but is described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. The focus of the profiles is on health and toxicologic information; therefore, each toxicological profile begins with a public health statement that describes, in nontechnical language, a substance's relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance's health effects is described in a health effects summary. Data needs that are of significance to protection of public health are identified by ATSDR and EPA. Each profile includes the following: (A) The examination, summary, and interpretation of available toxicologic information and epidemiologic evaluations on a hazardous substance to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects; (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure that present a significant risk to human health of acute, subacute, and chronic health effects; and (C) Where appropriate, identification of toxicologic testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. The principal audiences for the toxicological profiles are health professionals at the Federal, State, and local levels; interested private sector organizations and groups; and members of the public. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E-29 Atlanta, Georgia 30333 vi The toxicological profiles are developed in response to the Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) which amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed ATSDR to prepare toxicological profiles for hazardous substances most commonly found at facilities on the CERCLA National Priorities List and that pose the most significant potential threat to human health, as determined by ATSDR and the EPA. The availability of the revised priority list of 275 hazardous substances was announced in the Federal Register on April 29, 1996 (61 FR 18744). For prior versions of the list of substances, see Federal Register notices dated April 17, 1987 (52 FR 12866); October 20, 1988 (53 FR 41280); October 26, 1989 (54 FR 43619); October 17,1990 (55 FR 42067); October 17, 1991 (56 FR 52166); October 28, 1992 (57 FR 48801); and February 28, 1994 (59 FR 9486). Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the list. This profile reflects ATSDR’s assessment of all relevant toxicologic testing and information that has been peer-reviewed. Staff of the Centers for Disease Control and Prevention and other Federal scientists have also reviewed the profile. In addition, this profile has been peer-reviewed by a nongovernmental panel and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. David Satcher, M.D., Ph.D Administrator Agency for Toxic Substances and Disease Registry 1,4-DICHLOROBENZENE Vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHORS(S): Malcolm William, DVM, Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Wayne Spoo, DVM, DABT, DABVT Research Triangle Institute, Research Triangle Park, NC THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying end points. 2. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to substance-specific minimal risk levels (MRLs), reviews the health effects database of each profile, and makes recommendations for derivation of MRLs. 3. Data Needs Review. The Research Implementation Branch reviews data needs sections to assure consistency across profiles and adherence to instructions in the Guidance. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE ix PEER REVIEW A peer review panel was assembled for 1,4-dichlorobenzene. The panel consisted of the following members: 1. Dr. Arthur Gregory, 1 Gregory Lane, Luray, VA; 2. Dr. James Withey, Environmental Health Centre, Ottawa, Ontario, Canada; and 3. Dr. Norman Trieff, Department of Preventive Medicine and Community Health, University of Texas Medical Branch, Galveston, Texas. These experts collectively have knowledge of 1,4-dichlorobenzene's physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers' comments and determined which comments will be included in the profile. A listing of the peer reviewers' comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile's final content. The responsibility for the content of this profile lies with the ATSDR. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE xi CONTENTS FOREWORD .....vvnivmrmermssmmr mr emins shes das hui Nas od Ms ans ans wus mgs uw v CONTRIBUTORS . © vii PEER REVIEW civ vivmemmemmr moms mm smd 3d IBA AE HME SASHES MEI Hes Ao bb ix LISTOFP FIGURES incon inn:onl sng ams un comnts dis nies menags Bes nssnntnapmessn XV LIST OF TABLES ©. © Xvii 1. PUBLIC HEALTH STATEMENT on: vv: ous mei noons in sna moos ome mmessusrgs ses 1 1.1 WHAT IS 1,4-DICHLOROBENZENE? ..... i. 1 1.2 WHAT HAPPENS TO 1,4-DICHLOROBENZENE WHEN IT ENTERS THE ENVIRONMENT? . vv inv ss sms smismimsssias abs ssaisan ani ust ums ews ses 2 1.3 HOW MIGHT I BE EXPOSED TO 1,4-DICHLOROBENZENE? .................. 3 1.4 HOW CAN 1,4-DICHLOROBENZENE ENTER AND LEAVE MY BODY? .......... 4 1.5 HOW CAN 1,4-DICHLOROBENZENE AFFECT MY HEALTH? . ................. 5 1.6 1S THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,4-DICHLOROBENZENE? ..... 6 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TOPROTECT HUMAN HEALTH? . cnissinsanisnsanminnsmsrmesgssnstmonmes 7 1.8 WHERE CAN I GET MORE INFORMATION? .............................. 8 2. HEALTHEPPECTS ... vo iviimiinainainssoism isi SMI Ne Rens Nmss meso ams 11 2.1 INTRODUCTION . . 11 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE .............. 11 221 Inhalation BXPOSUIE =. oc scr i nisntnas mus smevs sm sums ame nes ons ns 13 22.1.1 Death . oe 13 2212 SystemicEBffects .........;co os tnstvsnnrs uns macnn tutes 14 2.2.1.3 Immunological and Lymphoreticular Effects . .................. 34 2.2.1.4 Neurological Effects ...................................35 221.5 ReproductiveEffects .........coivvsnrvnsniincsonsnmonns 36 2216 Developmental BIfectS = . v.50 av ncaonsmramesmssnmsnes mas 37 2.2.1.7 Genotoxic Effects ........ 38 22.0.8 CANCET . oot 39 222 Oral BXpOstire ... wc coi mn imu san inst $2 HL ARE HME IR a HAE ERE HAE 39 2221 Dell o:nsioncun inmomeinas nn: 9s pm NI eR IME IHR MAL wy a 39 2222 Systemic Effects ............ 41 2.2.2.3 Immunological and Lymphoreticular Effects . .................. 71 2224 Newological Bffects ......c..oisnsnnsmsewranssnstnromes 72 2225 Reproductive Effects «.. iss: ssoncsmrvsvmsvumssvrsmes wes 72 2226 Developme Effects « vcr rsntsnsvntmenncnnsmmesnsvmes 73 2.22.7 Genotoxic Effects ........ 74 2328 Cancer ....uvvowrrm mmr mmr sma mm tC RF INARI AR I REE RES By 75 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 223 to [ 2.4 2.7 2.8 29 2.10 CHEMICAL AND PHYSICAL INFORMATION CHEMICAL IDENTITY 3.1 2232 Systiemie Bffects ...u:un:upivmesn nm inminmivas mesos nn; 2.2.3.3 Immunological and Lymphoreticular Effects . .................. 2.23.4 Neurological Effects ....... 2.23.5 Reproductive Effects ......... 2236 Developmental Effects . ... ci numa nssmenmasmasmsmossisa 2237 CenotoXic Effects ..c:vcivicvusmnisosmpmeswiowimmens a 2.23.8 CANCEI «ott TOXICOKINETICS ©. eee 2.3.1 ADSOIPUON © oot 23.1.1 Inhalation BXposure . ...:.s isis mes a smsnasnmimasmssms ns 2.3.1.2 Oral Exposure . ...... 2.3.1.3 Dermal Exposure . . ......e 2.32 Distribution Lo... 232.1 Inhalation BXposure . : sc cons om enmesms mpi amsnme wenn wsdnn 2.32.2 Oral EXposure . . .. 2.3.23 Dermal EXposure . . ... 233 MotabollSl . svn ros mir mimesis HEI ME HB SE TE BAI HA BERBER EE #3 2.34 Elimination and EXCretion . . . .... 2.3.4.1 Inhalation Exposure ........... 2342 OralEBXposSUIC . cuss ssmtsomsnainmsme smibmsnmedesssans 2.3.43 Dermal Exposure . . ...... 2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic MECHANISMS OF ACTION 24.1 242 243 RELEVANCE TO PUBLIC HEALTH 2.6.1 2.62 INTERACTIONS WITH OTHER CHEMICALS POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE METHODS FOR REDUCING TOXIC EFFECTS 29.1 29.2 293 ADEQUACY OF THE DATABASE 2.10.1 2.10.2 2.10.3 Ongoing Studies (PD) Models Pharmacokinetic Mechanisms Mechanisms of Toxicity . ..... Animal-to-Human Extrapolations . ....................... .. .. ...... Biomarkers Used to Identify or Quantify Exposure to 1,4-Dichlorobenzene Biomarkers Used to Characterize Effects Caused by 1,4-Dichlorobenzene Reducing Peak Absorption Following Exposure Redveing Body Burden . «co sums ss smn rmme mms mes ua smo smi BE 2 HE 25 4 Interfering with the Mechanism of Action for Toxic Effects .............. Existing Information on Health Effects of 1,4-Dichlorobenzene Identification of Data Needs “**DRAFT FOR PUBLIC COMMENT*** xii 77 77 77 77 77 77 77 77 78 78 78 78 79 79 80 80 80 81 82 84 84 85 86 1,4-DICHLOROBENZENE xiii 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ....................... 141 4.1 PRODUCTION oo 141 42 IMPORT/EXPORT .. oot tints osmm ram sansa ts as omime sams nmerms unis 144 3 USE . vo mmr mes mer ms ion ih is NEbBI URI RAINE ISL EMI UWS Bs Sim HEE HE 144 4.4 DISPOSAL 145 5. POTENTIAL FOR HUMAN EXPOSURE . . . . eee 147 S01 OVERVIEW rir mr icant mmr sss me sme mmr hi bamts is mis mss masvssn 147 52 RELEASES TO THE ENVIRONMENT ..: ic omomus ons nis mes minnmsspmptnsess 149 5.2.1 AIT oo 149 522 WALEr © © ee 152 52.3 SOU oe 153 5.3 ENVIRONMENTAL FATE . . ee eee es 154 5.3.1 Transport and Partitioning : «= . sus vss nsscevas tin sunssmmonss va suns ns 154 5.3.2 Transformation and Degradation ................................. 156 S321 AIT «oe 156 BI2Z WBC. vs vos mms mm mia Bi bi AUS I RA SHE HES HE I MEE HEPES 156 5.3.2.3 Sediment and Soil . ... 158 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............ 158 5.4.1 BAIT i + ve ro econ ens mei ss we en mr me bea Ra REE REE RE RE 160 542 WALLET vv vs mrs mass be Me tm End a Ns MSH 23% § 5d SHIH PMG 3 DRESS DSS 163 543 Sediment and Soil... . 166 544 Other Environmental Media . ...... 168 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ............... 168 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .................. 170 5.7 ADEQUACY OF THE DATABASE .................. nsw es muame amet Bes 172 5.7.1 Identification of Data Needs . ... 5 cos omiumsnss nes wen ntmuss@ssmss 172 572 Ongoing SAIS ....u:sxsivssvisnsuntuvsnsrmspnrsrnsmvssmsnnsn 175 6. ANALYTICAL METHODS =. . . oo io vim n ems saints sis moans nis mus shssmssnss 177 6.1 BIOLOGICAL SAMPLES . . . ee ee 177 6.2 ENVIRONMENTAL SAMPLES ©... eee 181 63 ADEQUACYOFTHEDATABASE ........ 0.6. evevssnninnsnnsnmemess 185 6.3.1 Identification of Data Needs . . . . . eee 186 6.3.2 Ongoing Studies ......... 187 7. REGULATIONS AND ADVISORIES . eee 189 8. REFERENCES . . . «oo 201 0. GLOSSARY oo 229 APPENDICES A. MINIMAL RISK LEVEL (MRL) WORKSHEETS .......................... A-1 B. USER'S GUIDE . . . B-1 C. ACRONYMS, ABBREVIATIONS, AND SYMBOLS ........................ C-1 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE XV 5-1 5-2 5-3 LIST OF FIGURES Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation . . ................. 22 Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral ....................... 54 Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance ................................. 88 Existing Information on Health Effects of 1,4-Dichlorobenzene . .................... 126 Frequency of NPL Sites with 1,4-Dichlorobenzene Contamination .................. 148 The Decomposition of 1,4-Dichlorobenzene in Air. ............................ 157 The Decomposition of 1,4-Dichlorobenzene in Soil and Water ..................... 159 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE xvii 2-1 2-2 3-1 3-2 4-1 5-1 5-2 5-3 5-4 6-2 7-1 LIST OF TABLES Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation . .................. 15 Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral . ...................... 42 Genotoxicity of 1,4-Dichlorobenzene In Vivo . ................................ 114 Genotoxicity of 1,4-Dichlorobenzene In Vitro . ......................... Lh. 115 Chemical Identity of 1,4-Dichlorobenzene ................................... 138 Physical and Chemical Properties of 1,4-Dichlorobenzene ........................ 139 Facilities That Manufacture or Process 1,4-Dichlorobenzene . ...................... 142 Releases to the Environment from Facilities That Manufacture or Process 1,4-Dichlorobenzene . . . . «o.oo ot 150 Levels of 1,4-Dichlorobenzene in Indoor Air... ................. 161 Levels of 1,4-Dichlorobenzene in Outdoor Air .............. en .. 164 Levels of 1,4-Dichlorobenzene Detected in Workplace Air. ...................... 176 Analytical Methods for Determining 1,4-Dichlorobenzene in Biological Materials . ....... 178 Analytical Methods for Determining 1,4-Dichlorobenzene in Environmental Samples... . . 182 Regulations and Guidelines Applicable to 1,4-Dichlorobenzene . .................... 192 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 1 1. PUBLIC HEALTH STATEMENT This public health statement tells you about 1,4-dichlorobenzene and the effects of exposure. The Environmental Protection Agency (EPA) has identified 1,445 hazardous waste sites as the most serious in the nation. These sites make up the National Priorities List (NPL) and are targeted for long-term federal clean-up. 1,4-Dichlorobenzene has been found in at least 281 NPL sites. However, it's unknown how many NPL sites have been evaluated for this substance. As EPA looks at more sites, the sites with 1,4-dichlorobenzene may increase. This is important because exposure to this substance may harm you and because these sites may be sources of exposure. When a substance is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. This release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it by breathing, eating, touching, or drinking. If you are exposed to 1,4-dichlorobenzene, many factors determine whether you'll be harmed. These factors include the dose (how much), the duration (how long), and how you come in contact with it. You must also consider the other chemicals you're exposed to and your age, sex, diet, family traits, lifestyle, and state of health. 1.1 WHAT IS 1,4-DICHLOROBENZENE? The chemical 1.4-dichlorobenzene is usually called para-DCB or p-DCB, but there are about 20 additional names for it, including para crystals and paracide. It is also called paramoth because it is one of two chemicals commonly used to make mothballs. 1,4-Dichlorobenzene is used to make deodorant blocks used in garbage cans and restrooms, as well as to help control odors in animal-holding facilities. 1,4-Dichlorobenzene has also been used as an ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 2 1. PUBLIC HEALTH STATEMENT insecticide on fruit and as an agent to control mold and mildew growth on tobacco seeds, leather, and some fabrics. At room temperature, 1,4-dichlorobenzene is a white solid with a strong odor that you would probably recognize as the smell of mothballs. When a package of 1,4-dichlorobenzene is opened, it slowly changes from a solid into a vapor and is released into the atmosphere. The released vapor acts as a deodorizer and insect killer. Most of the 1,4-dichlorobenzene that is released to the general environment is present as a vapor. 1,4-Dichlorobenzene can burn, but does not burn easily. Most people begin to smell 1,4-dichlorobenzene when it is present in the air at a concentration of 0.18 parts per million (ppm) and in water at a concentration of 0.011 ppm. 1,4-Dichlorobenzene does not occur naturally, but is produced by chemical companies to make products for home use and other chemicals such as resins. More information on the properties and uses of 1,4-dichlorobenzene may be found in Chapters 3 and 4. 1.2 WHAT HAPPENS TO 1,4-DICHLOROBENZENE WHEN IT ENTERS THE ENVIRONMENT? Most of the 1,4-dichlorobenzene enters the environment as a result of its uses in moth- repellant products and in toilet-deodorizer blocks. Because it changes from a solid to a gas easily, almost all of what is produced is released into the air. Some 1,4-dichlorobenzene is released to the air by factories that make or use it, and minor amounts are released to soil and water. Very little 1,4-dichlorobenzene enters the environment from hazardous waste sites. Because 1,4-dichlorobenzene does not dissolve easily in water, the small amounts that enter bodies of water quickly evaporate into the air. If it is released to groundwater, it may be transported to surface water. Some may cling to soil and sediment, but this is not certain. 1,4-Dichlorobenzene in soil is not usually easily broken down by soil organisms. There is evidence that plants absorb 1,4-dichlorobenzene, and fish have also been shown to absorb this compound. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 1. PUBLIC HEALTH STATEMENT More information on how 1,4-dichlorobenzene behaves in the environment may be found in Chapters 4 and 5. 1.3 HOW MIGHT | BE EXPOSED TO 1,4-DICHLOROBENZENE? Humans are exposed to 1,4-dichlorobenzene mainly by breathing vapors from 1.,4-dichloro- benzene products used in the home, such as mothballs and toilet-deodorizer blocks. Reported levels of 1,4-dichlorobenzene in some homes and public restrooms have ranged from 0.29 to 272 parts of 1,4-dichlorobenzene per billion parts (ppb) of air. Outdoor levels of 1.4-dichlorobenzene are much lower, and reported levels in cities range from 0.02 to 20 ppb. Even levels in the air around hazardous waste sites are low; reported levels range from 0.03 to 4.25 ppb. 1,4-Dichlorobenzene has also been found in 13% of the drinking water samples from U.S. surface water sources. The surface water samples measured contain about 0.008—154 ppb of 1,4-dichlorobenzene. 1,4-Dichlorobenzene is less likely to be found in drinking water from wells. Levels of 1,4-dichlorobenzene in soil measured around hazardous waste sites in the United States average about 450 ppb. However, background levels of 1,4-dichlorobenzene in soil that is not around waste sites are not known. 1.4-Dichlorobenzene has also been detected in foods such as pork, chicken, and eggs. This is because 1,4-dichlorobenzene is sometimes used as an odor-control product around animal stalls. 1,4-Dichlorobenzene has been found in fish; levels of 1-4 ppb were measured in trout caught in the Great Lakes. Babies can receive 1,4-dichlorobenzene in their mothers’ milk, as demonstrated by its detection in human breast milk at 5 locations in the United States. These levels were 0.04—68 ppb. It has also been detected in the fat of people and of animals. The average daily adult intake of this chemical is estimated to be about 35 micrograms (ug), which comes mainly from breathing vapors of 1,4-dichlorobenzene that are released from products in the home. These levels would not be expected to result in harmful effects. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 1. PUBLIC HEALTH STATEMENT Workers may be exposed to 1,4-dichlorobenzene in the workplace air at much higher levels than those to which the general public is exposed. Levels measured in the air of factories that make or process 1,4-dichlorobenzene products have ranged from 5.6 to 748 ppm of air. About 35,000 people in the United States are exposed to 1,4-dichlorobenzene in the workplace. More information on how you might be exposed to 1,4-dichlorobenzene is given in Chapter 5. 1.4 HOW CAN 1,4-DICHLOROBENZENE ENTER AND LEAVE MY BODY? The main way that 1,4-dichlorobenzene enters your body is through the lungs when you breathe in 1,4-dichlorobenzene vapors released in the workplace or from home use of products that contain 1,4-dichlorobenzene. When you breathe in this chemical for a few hours, as much as 20% of the 1,4-dichlorobenzene that has entered your body will get into your bloodstream. 1,4-Dichlorobenzene can also get into your body if you drink water that contains this chemical or if you eat certain foods that contain 1,4-dichlorobenzene, such as meat, chicken, eggs, or fish. Most of the 1,4-dichlorobenzene that enters your body from food and water will get into your bloodstream. It is not known if 1,4-dichlorobenzene can enter your body through the skin if you touch products that contain it. There is also a possibility that 1,4-dichlorobenzene used in the home can be accidentally swallowed, especially by young children. When 1,4-dichlorobenzene is used in mothballs or deodorant blocks, these products may be freely available in closets or bathrooms. Of the 1.,4-dichlorobenzene that enters your body, most of it (perhaps more than 95%) leaves through the urine in less than a week. Another 1-2% leaves in the feces, and about 1-2% leaves in the air that you breathe out. Tiny amounts remain in your fat and may stay there for a long time. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 1. PUBLIC HEALTH STATEMENT In your body, most 1,4-dichlorobenzene is changed to the chemical 2,5-dichlorophenol. Tt is not known if this breakdown product is more or less harmful than 1,4-dichlorobenzene itself. More information on how 1,4-dichlorobenzene enters and leaves the body is found in Chapter 2. 1.5 HOW CAN 1,4-DICHLOROBENZENE AFFECT MY HEALTH? Inhaling the vapor or dusts of 1,4-dichlorobenzene at very high concentrations (much higher than you would be exposed to in the home) can be very irritating to your lungs. It may also cause burning and tearing of the eyes, coughing, difficult breathing, and an upset stomach. There is no evidence that the moderate use of common household products that contain 1,4-dichlorobenzene will result in any problems to your health. There are some medical reports of patients who have developed some health effects, such as dizziness, headaches, and liver problems as a result of very high levels of 1.4-dichlorobenzene in the home. However, these were reports of extremely high usage of 1,4-dichlorobenzene products, and the persons continued to use the products for months or even years, even though they felt ill. There are also cases of people who have eaten 1,4-dichlorobenzene products regularly for long periods (months to years) because of its sweet taste. This has caused skin blotches and problems with red blood cells, such as anemia. There is no direct evidence that 1,4-dichlorobenzene causes cancer or birth defects or affects reproduction in humans. Workers breathing high levels of 1,4-dichlorobenzene (80-160 ppm) have reported painful irritation of the nose and eyes. There is very little information on the effects of skin contact with 1,4-dichlorobenzene. 1,4-Dichlorobenzene can cause a burning feeling in your skin if you hold a block of 1,4 dichlorobenzene against your skin for a long time. To protect the public from the harmful effects of toxic chemicals and to find ways to treat people who have been harmed, scientists use many tests. One way to see if a chemical will hurt people is to learn how the chemical is absorbed, used, and released by the body; for some chemicals, animal testing may be necessary. Animal ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 1. PUBLIC HEALTH STATEMENT testing may also be used to identify health effects such as cancer or birth defects. Without laboratory animals, scientists would lose a basic method to get information needed to make wise decisions to protect public health. Scientists have the responsibility to treat research animals with care and compassion. Laws today protect the welfare of research animals, and scientists must comply with strict animal care guidelines. In laboratory animals, breathing or eating 1,4-dichlorobenzene can cause harmful effects in the liver, kidneys, and blood. Rats and mice given oral doses of 1,4-dichlorobenzene in lifetime studies had increased rates of liver cancer when compared with animals that did not receive 1,4-dichlorobenzene. We do not definitely know if 1,4-dichlorobenzene plays a role in the development of cancer after ordinary exposure. The Department of Health and Human Services (DHHS) has determined that 1,4-dichlorobenzene may reasonably be anticipated to be a carcinogen in humans. The International Agency for Research on Cancer (IARC) has determined that 1,4-dichlorobenzene is possibly carcinogenic to humans. The EPA has determined that 1,4-dichlorobenzene is a possible human carcinogen. More information on how 1.4-dichlorobenzene can affect your health is given in Chapter 2. 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO 1,4-DICHLOROBENZENE? There are tests that can be used to find out if you have been exposed to 1,4-dichlorobenzene. The most commonly used test measures its breakdown product, 2,5-dichlorophenol, in urine and blood. These tests require special equipment that is not routinely available in a doctor's office, but they can be performed in a special laboratory. The presence of the compound 2,5-dichlorophenol in the urine indicates that the person has been exposed to 1,4-dichlorobenzene within the previous day or two. This test has been used in industrial settings in surveys of workers exposed to 1,4-dichlorobenzene. Another test measures levels of 1,4-dichlorobenzene in your blood, but it is less commonly used. Neither ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE S 1. PUBLIC HEALTH STATEMENT of these tests can be used to find out how high the level of 1,4-dichlorobenzene exposure was or to predict whether harmful health effects will follow. More information on how 1,4-dichlorobenzene can be measured in exposed humans is presented in Chapters 2 and 6. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? The federal government develops regulations and recommendations to protect public health. Regulations can be enforced by law. Federal agencies that develop regulations for toxic substances include the Environmental Protection Agency (EPA), the Occupational Safety and Health Administration (OSHA), and the Food and Drug Administration (FDA). Recommendations provide valuable guidelines to protect public health but cannot be enforced by law. Federal organizations that develop recommendations for toxic substances include the Agency for Toxic Substances and Disease Registry (ATSDR) and the National Institute for Occupational Safety and Health (NIOSH). Regulations and recommendations can be expressed in not-to-exceed levels in air, water, soil, or food that are usually based on levels that affect animals, then they are adjusted to help protect people. Sometimes these not-to-exceed levels differ among federal organizations because of different exposure times (an 8-hour workday or a 24-hour day), the use of different animal studies, or other factors. Recommendations and regulations are also periodically updated as more information becomes available. For the most current information, check with the federal agency or organization that provides it. Some regulations and recommendations for 1,4-dichlorobenzene include the following: The federal government has taken a number of steps to protect humans from excessive 1,4-dichlorobenzene exposure. EPA has listed 1,4-dichlorobenzene as a hazardous waste and ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 8 1. PUBLIC HEALTH STATEMENT has subjected it to hazardous waste regulations. EPA has set a maximum level of 75 pg of 1,4-dichlorobenzene per liter of drinking water. In addition, 1,4-dichlorobenzene is a pesticide registered with EPA, and its manufacturers must provide certain kinds of information to EPA in order for it to be registered for use as a pesticide. OSHA has set a maximum level of 75 ppm for 1,4-dichlorobenzene in workplace air for an 8-hour day, 40-hour work week. More information on federal and state regulations regarding 1,4-dichlorobenzene is presented in Chapter 7. 1.8 WHERE CAN | GET MORE INFORMATION? If you have any more questions or concerns, please contact your community or state health or environmental quality department or Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, Mailstop E-29 Atlanta, GA 30333 * Information line and technical assistance Phone: (404) 639-6000 Fax: (404) 639-6315 or 6324 ATSDR can also tell you the location of occupational and environmental health clinics. These clinics specialize in recognizing, evaluating, and treating illnesses resulting from exposure to hazardous substances. ***DRAFT FOR PUBLIC COMMENT"*** 1,4-DICHLOROBENZENE 1. PUBLIC HEALTH STATEMENT * To order toxicological profiles, contact National Technical Information Service 5285 Port Royal Road Springfield, VA 22161 Phone: (800) 553-6847 or (703) 487-4650 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 11 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of 1,4-dichloro- benzene. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure—inhalation, oral, and dermal; and then by health effect—death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods—acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELs) or lowest- observed-adverse-effect levels (LOAELSs) reflect the actual doses (levels of exposure) used in the studies. LOAELS have been classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious” effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 12 2. HEALTH EFFECTS at distinguishing between "less serious” and "serious" effects. The distinction between "less serious” effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user's perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAELSs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of 1,4-dichloro- benzene are indicated in Table 2-2 and Figure 2-2. Because cancer effects could occur at lower exposure levels, (the) figure(s) (provide specific figure number if only one range is given) also show a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10 to 107), as developed by EPA. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for 1,4-dichlorobenzene. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 13 2. HEALTH EFFECTS development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. A User's Guide has been provided at the end of this profile (see Appendix B). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 2.2.1 Inhalation Exposure Descriptive data are available from reports of humans exposed to 1,4-dichlorobenzene via inhalation (and possibly dermal contact). It is important to note that the case studies discussed in this section should be interpreted with caution since they reflect incidents in which individuals have reportedly been exposed to 1,4-dichlorobenzene, and they assume that there has been no other exposure to potentially toxic or infectious agents. There is usually little or no verification of these assumptions. Case studies in general are not scientifically equivalent to carefully designed epidemiological studies or to adequately controlled and monitored laboratory experiments. Thus, the case studies described below should be considered only as providing supplementary evidence that 1,4-dichlorobenzene may cause the reported effects. 2.2.1.1 Death Only one report of human death attributed to 1,4-dichlorobenzene exposure has been located in the literature. A 60-year-old man and his wife died within months of each other due to acute yellow atrophy of the liver (also known as massive hepatic necrosis or fulminant hepatitis) (Cotter 1953). Their home had been "saturated" with 1,4-dichlorobenzene mothball vapor for a period of about 3—4 months, but no air measurements were available. Clinical symptoms included severe headache, diarrhea, numbness, clumsiness, slurred speech, weight loss (50 pounds in 3 months in the case of the husband), and jaundice. The wife died within a year of the initial exposure; however, it was not clear if 1,4-dichlorobenzene was the primary cause of death. This case study did not address whether these individuals consumed excessive amounts of alcohol or had previous medical problems. Several studies were located regarding death in animals after inhalation exposure to 1,4-dichloro- benzene. In an acute-duration study, 2 of 6 male CD-1 mice exposed to 1,4-dichlorobenzene at an air ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 14 2. HEALTH EFFECTS concentration of 640 ppm, 6 hours a day for 5 days died on the fifth day; no deaths were reported at an exposure level of 320 ppm (Anderson and Hodge 1976). Mortality data were also reported in intermediate-duration studies using rats, guinea pigs, and rabbits. In studies performed by Hollingsworth et al. (1956), rats, guinea pigs, and rabbits were exposed to 1,4-dichlorobenzene vapors for 9-12 weeks at an air concentration of 798 ppm, 8 hours a day, 5 days a week. In that study, 4 of 34 rats, 2 of 23 guinea pigs, and 4 of 16 rabbits died during the study period. The exact number of exposures that resulted in death was not specified. In a chronic-duration study, there was no evidence of a treatment effect on mortality in Wistar rats exposed to 1,4-dichlorobenzene at concentrations up to 490-499 ppm for 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). LOAEL values for death in each species and duration category are listed in Table 2-1 and plotted in Figure 2-1. 2.2.1.2 Systemic Effects The limited information available regarding systemic effects in humans and animals after inhalation exposure to 1,4-dichlorobenzene is discussed below. The highest NOAEL values and all reliable LOAEL values for these systemic effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Respiratory Effects. A case of pulmonary granulomatosis was reported to have occurred in a 53-year-old woman who for 12-15 years had been inhaling 1,4-dichlorobenzene crystals that were scattered on a weekly basis on the carpets and furniture of her home. A lung biopsy revealed the presence of 1,4-dichlorobenzene crystals with the surrounding lung parenchyma being distorted by fibrosis, thickening of the alveolar walls, and marked infiltrates of lymphocytes and mononuclear phagocytes. Also, there was some thickening of the muscular walls of small arteries and focal fibrous thickening of the pleura (Weller and Crellin 1953). These effects are most likely related to the physical interaction of 1,4-dichlorobenzene crystals (or any crystals when inhaled) with lung tissue, rather than to chemical toxicity. This conclusion by the authors of the study was based on exposure history of the patient, radiography, and histological examination of the lung tissue which showed the “**DRAFT FOR PUBLIC COMMENT*** «»LNIWNOD O178Nd HOH 14VHA... Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation a Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference ACUTE EXPOSURE Systemic 1 Rat 10d Resp 508.4 F Hodge et al. (Alderley- Gd 6-15 1977 Park) 6 hr/d Cardio 508.4 F Hepatic 508.4 F Renal 508.4 F Bd Wt 508.4 F 2 Rabbit 13d Hepatic 800 F Hayes et al. (New Gd 6-18 1985 Zealand) 6 hr/d Renal 800 F Reproductive 3 Rat 10d 500 F Hodge et al. (Alderley- Gd 6-15 1977 Park) 6 hr/d 4 Rat 16d 173 M Hollingsworth et (NS) 5 d/iwk al. 1956 7 hrid 5 Gn Pig 16d 173 M Hollingsworth et (NS) 5 diwk al. 1956 7 hr/d 6 Rabbit 13d 800 Hayes et al. (New Gd 6-18 1985 Zealand) 6 hr/d S103443 HIV3H 2 IN3IZN3IBOHOTHOIQ-v'L St ««LNFJWWNOD 2118Nd HOL 14VHAus Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (continued) 7 Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference Developmental 7 Rat 10d 508.4 Hodge et al. (Alderley- Gd 6-15 1977 Park) 6 hr/d 8 Rabbit 13d 300° 800F (increased incidence of Hayes et al. (New Gd 6-18 retroesophageal right 1985 Zealand) 6 hr/d subclavian artery) INTERMEDIATE EXPOSURE Death 9 Rat 9-12 wk 798 (2/19 males and 2/15 Hollingsworth et (NS) 5 diwk females died) al. 1956 8 hr/d 10 Gn Pig 4-4.5 wk 798 M (2/16 died) Hollingsworth et 8 hr/d 11 Rabbit 12 wk 798 (3 males and 1 female died) Hollingsworth et (NS) 5 d/iwk al. 1956 8 hr/d S103443 HLV3H 2 3IN3IZN3IGOHOTHOIa-¥'t 9 «+LNIJWNOD O1N8Nd HOH 14VHQA... Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (continued) a Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference Systemic 12 Rat 2-12 wk Resp 798 F 173 M (slight interstitial edema, Hollingsworth et (NS) 5 diwk alveolar hemorrhage) al. 1956 7or8hrid Cardio 173 Hepatic 173F (slight liver congestion 798 (cloudy swelling and central and granular necrosis) degeneration) Renal 173 (increased relative kidney weight) Ocular 798 (eye irritation) Bd Wt 173 798 (unquantitated weight loss) 13 Rat 51-71 mo Hemato 96 Hollingsworth et (NS) 5 d/wk al. 1956 7 hr/d Hepatic 96° 158 (increased relative liver weight; cloudy swelling or degeneration of parenchyma) Renal 96 158 M (increased relative kidney weight) Bd Wt 341 S103443 H1VaH 2 3INIZN38OHOTHOIa-v't LL «LNIJWWOD O118Nd HOH 14VHA... Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (continued) a Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference 14 Rat 2 generation Resp 211 538 (encrustation of the Tyl and (Sprague- perinasal area) Neeper-Bradley Dawley) 1989 Hepatic 66.3 M 211 M (signif. incr. in liver wt.) 211 F 538 F Renal 538 F 66.3 M (incr. incidence of hyaline droplets, tubular protein, granular cast formation, & interstitial nephritis in Fo generation) Ocular 211 538 (encrustation of periocular region; lacrimation) Bd Wt 66.3 M 211M (decr. body weight in the 211 F 538 F male Fo group and in the F1 male and females in the 5-week recovery study) Other 21 538 (decreased grooming; unkempt appearance; decr. food consumption) 15 Mouse 5.1-7.1mo Hepatic 158 M Hollingsworth et (NS) 5 diwk 96 F al. 1956 7 hr/d Renal 158 M 96 F Bd Wt 158 M 96 F S103443 HIVaH 2 3JN3IZN380HOTHOIA-v'L 8l «INIWWNOD 01N8Nd HOH 14VHA... Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (continued) a Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference 16 Gn Pig 5.1-7.1 mo Hepatic 96 158F (increased relative liver 341 (focal necrosis, slight Hollingsworth et (NS) 5 diwk weight) cirrhosis in males) al. 1956 7 hr/d Renal 341 Bd Wt 96 158 (slight depression in final body weight) 17 Gn Pig 2-4.5 wk Resp 173F (alveolar hemorrhage and Hollingsworth et (NS) 5 diwk edema) al. 1956 7or8hrid Cardio 798 Hepatic 173 798 (cloudy swelling in the liver and central necrosis) Renal 798 Ocular 173 798 (eye irritation) Bd Wt 173 798 (body weight loss, but not quantified) 18 Rabbit 2-12 wk Resp 173F (lung congestion and 798 (emphysema in 2/8) Hollingsworth et (NS) 5 diwk interstitial edema) al. 1956 7or8hr/d Hepatic 173 798 (cloudy swelling in the liver and central necrosis) Renal 798 Ocular 798 (eye irritation; reversible nonspecific eye changes) Bd Wt 173 798 (body weight depression, but not quantitated) Neurological 19 Rat 9-12 wk 798 (tremors, weakness, Hollingsworth et (NS) 5 diwk unconsciousness) al. 1956 8 hr/d S103443 H1V3H 2 3N3IZN3GOHOTHOIA vt 61 ~LN3IWWOD O118Nd HOH 14VHAuus Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (continued) a Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference 20 Gn Pig 4-4.5 wk 798 (tremors, weakness, Hollingsworth et (NS) 5 diwk unconsciousness) al. 1956 8 hr/d 21 Rabbit 12 wk 798 (tremors, weakness, Hollingsworth et (NS) 5 diwk unconsciousness) al. 1956 8 hr/d Reproductive 22 Rat 5.1-7.1 mo 158 M Hollingsworth et (NS) 5 d/iwk al. 1956 7 hr/d 23 Rat 2 generation 66.3 211 (decreased maternal 538 (decreased average litter ~~ Tyland (Sprague- body weight) size & survival) Neeper-Bradley Dawley) 1989 24 Gn Pig 5.1-7.1 mo 158 M Hollingsworth et (NS) 5 d/wk al. 1956 7 hr/d Developmental 25 Rat 2 generation 211 538 (decreased survival; Tyland (Sprague- decreased body weight) Neeper-Bradley Dawley) 1989 CHRONIC EXPOSURE Systemic 26 Human 4.75yr Resp 80M (nose irritation) Hollingsworth et al. 1956 Hemato 725M Dermal 725 M Ocular 80M (eye irritation) S103443 H1TV3H 2 3IN3IZNIBOHOTHOIA +} 0c «INIWWOD 2118Nd HOS L4vHdQ... Table 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (continued) a Exposure/ LOAEL Key to Species duration/ NOAEL Less serious Serious figure (strain) frequency System (ppm) (ppm) (ppm) Reference 27 Rat 76 wk Resp 75 490-499 (increased lung weight at Riley et al. 1980 (Wistar) 5 d/iwk week 112) 5 hr/d Cardio 75 490-499 (increased heart weight at week 112) Gastro 490-499 Hemato 490-499 Musc/skel 490-499 Hepatic 7549 490-499 (incr. liver wt throughout the study in males; at wks 27 and 112 in females) Renal 75 490-499 (incr. kidney wt. throughought study in males; at wks 27 & 112 in females) Endocr 490-499 Ocular 490-499 Bd Wt 490-499 Other 490-499 *The number corresponds to entries in Figure 2-1. ®Used to derive an acute inhalation MRL of 0.8 ppm. Concentration adjusted for intermittent exposure, converted to an equivalent concentration in humans, and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Used to derive an intermediate inhalation MRL of 0.2 ppm. Concentration adjusted for intermittent exposure, converted to an equivalent concentration in humans, and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). “Used to derive a chronic inhalation MRL of 0.1 ppm. Concentration adjusted for intermittent exposure, converted to an equivalent concentration in humans, and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Bd Wt = body weight; Cardio = cardiovascular; d = day(s); Endocr = endocrine; F = female; Gd = gestational day; Hemato = hematological; hr = hour(s); LOAEL = lowest-observable-adverse-effect level; M = male; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observable-adverse-effect level; NS = not specified; Resp = respiratory; wk = week(s); yr = year(s) S103443 H1TV3H 2 3N3ZN380HOTHOIQ-v' Le «««LNJWWOO 0118Nd HOH L4VHQ.us Figure 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation Acute (<14 days) Systemic 5 Q Q - © 0 x < 2 & § g 5 g £ F 3 © _ 3 g Ss (ppm) & ° 3 3 2 £ ® & S 3 & @ & 3 1000 9 1 O 1 O 1 3 3 7 3 r r r 2h r 2h r r 6h r 8h oO oO oO Oo Oo oO oO oh oO ar 5g 1 oO O | 100 1 I | I I | I I 1 10 I I I I Key I " 2 ee @ LOAEL for serious effects (animals) Minimal risk level | 1 : . ( LOAEL for less serious effects (animals) , for effects other | g guinea pig ] w than cancer i h rabbit O NOAEL (animals) “ . The number next to A LOAEL for less serious effects (humans) 80h DOA COTERpUTS A NOAEL (humans) to entries in Table 2-1. 0.1 S103443 H1V3H 2 JIN3IZN3ISOHOTHOIA-¥'L ce + LNTFWWOD 2178Nd HOH 14VHuus Figure 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (cont.) Intermediate (15-364 days) 3N3IZN3IBOHOTHOIQ-v't Systemic 3 T > .Q I Z 8 3 sg 2 © £ .Q © oT (ppm) 5 a 5 £ 8 3 7] © 7} (3) 1000 - o x 2 = = ® Oo © \ ® oO @ ® © or 10g 11h > 18h 179 12r 179 18h 16g 14r o var 18h 12r 137 QQ 15m 16g 179 18h Qo 0 Qo Oo 0 12r O 179 13r Ter 13r 0 o 100} Oo O&O Oo i O 16g 1 1 1 1 1 | 1 10} ! 1 1 1 I 1 1 Key 1 1 1L " 1B @® LOAEL for serious effects (animals) Minimal risk level ; uinea pig @ LOAEL for less serious effects (animals) for effects other ! g gumneapyg } w than cancer ! h rabbit O NOAEL (animals) ! ; The number next to ! A LOAEL for less serious effects (humans) gach OIL ELIEs ONS ! A NOAEL (humans) to entries in Table 2-1. w 0.1L S103443 H1TV3H 2 1% «+LNJWWOD 2178Nd HO4 14VHA.. Figure 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (cont.) Intermediate (15-364 days) Systemic % © 8 Q [©] > - pom) : 5 g 2 i £3 1000 ~ @ oO @ oO 2 @ Q © O o 3 Q Qo 2 0 uw @ eo © 230 251 17 18h r 17g 18h 12r 17g 18h 19 20 21h 169 ’ ao 13r ao A 9 & @ O 14r 12r 17 12 > 17g 18h 23r 251 13r 15m 9 r 16g 9 14r 22r (24g O 2 o O o © © oO 0 O00 o O 14r 15m 100} O 1a the O 23r 13 0 169 oO 10f Key 1} . . ‘ ee @® LOAEL for serious effects (animals) Minimal risk level , . LOAEL for less serious effects (animals) , for effects other 3 ‘guineas pg than cancer h rabbit O NOAEL (animals) A LOAEL for less serious effects (humans) | é number next to each point corresponds A NOAEL (humans) to entries in Table 2-1. 0.1L S103443 H1TV3aH ¢ 3N3ZN38OHOTHOIQ-v'} ve «LNIWWOD O1N8Nd HOH 14VH0... Figure 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation (cont.) Chronic (>365 days) Systemic § 3 g z > = J) Ss § £8 3 Q $ £ 3 Ss 2 Ss © - 5 5 . < (ppm) sg FF £ g g 2 Sg 5 S 3 $ a § a 2 S £ @ Gq ag S 5 S 1000 r 27r 27r 27r A 27r 27r 27r 27r 27r A 27r 27r 27r Oo % OQ Oo Qo Qo Oo 28 oO O Oo 100 F 26 7 27r 27r 27r 26 Oo O Oo A | I 1 I 1 1 1 10 | 1 I I 1 | I 1 I Key I 1} ! r rat @® LOAEL for serious effects (animals) ; Minimal risk level m mouse . . for effects other ; g guinea pig ® LOAEL for less serious effects (animals) ! than CONCar h rabbit O NOAEL (animals) 1 . The number next to A LOAEL for less serious effects (humans) each point corresponds to | A NOAEL (humans) entries in Table 2-1. 01 Lb uv S103443 HIV3H 2 3INIZNIGOHOTHOIQ-¥'t Se 1,4-DICHLOROBENZENE 26 2. HEALTH EFFECTS presence of birefringent crystals and a clear granulatomous reaction. A study of 58 men occupationally exposed for 8 hours a day, 5 days a week, continually or intermittently, for 8 months to 25 years (average: 4.75 years) to 1,4-dichlorobenzene found painful irritations of the nose at levels ranging from 80 to 160 ppm. At levels greater than 160 ppm, the air was considered not breathable for unacclimated persons (Hollingsworth et al. 1956). In pregnant Alderley-Park rats, whole-body exposure to 1,4-dichlorobenzene at air concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours a day on gestation days (Gd) 6-15 produced no adverse clinical or pathological signs in the lung tissues of the dams (Hodge et al. 1977). Mild histopathological changes of interstitial edema, congestion, and alveolar hemorrhage were observed in the lungs of male (but not female) rats, female guinea pigs, and 1 female rabbit after 16 days of exposure to 1,4-dichlorobenzene at 173 ppm (Hollingsworth et al. 1956). Congestion and emphysema were also reported in the lungs of 2 rabbits exposed to 798 ppm for 12 weeks (Hollingsworth et al. 1956). These observations were derived from a large study using several species of laboratory animals; however, interspecies comparisons are difficult to make due to the various experimental designs used in this study. For example, at 798 ppm, 10 male rats, 15 female rats, 16 male guinea pigs, 7 female guinea pigs, and 8 rabbits of each sex were exposed up to 62 times; at 173 ppm, 5 rats of each sex, 5 guinea pigs of each sex, and 1 rabbit of each sex were exposed for 16 days. These reported observations provide only qualitative evidence of respiratory effects as a result of intermediate-duration inhalation exposure to 1,4-dichlorobenzene. In a chronic-duration study, male and female Wistar rats were exposed to 1,4-dichlorobenzene at air concentrations of 75 or 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). Rats in the high-exposure group showed a small but significant increase in absolute lung weight at termination of the study (112 weeks). This response was not observed in rats sacrificed on week 76 or in rats exposed to 75 ppm 1,4-dichlorobenzene for 112 weeks. In addition, no treatment-related histological alterations were observed in the larynx, trachea, or lungs in this study. Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans following inhalation exposure to 1,4-dichlorobenzene. Limited information is available regarding cardiovascular effects in animals. No alterations in relative heart weight were observed in rats or guinea pigs exposed to 1,4-dichlorobenzene at an air ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 27 2. HEALTH EFFECTS concentration of 173 ppm, 7 hours a day, 5S days a week for up to 12 exposures (Hollingsworth et al. 1956). Similar results were reported after approximately 130 exposures to 1,4-dichlorobenzene at an air concentration of 96 ppm using the same exposure protocol (Hollingsworth et al. 1956); no other cardiovascular end points were evaluated in this study. In pregnant Alderley-Park rats, whole-body exposure to 1,4-dichlorobenzene at air concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours a day from Gd 6 to 15 produced no adverse clinical or pathological signs in the heart tissues of the dams (Hodge et al. 1977). A significant increase in absolute heart weight was reported in male and female rats exposed to 1,4-dichlorobenzene at air concentrations of 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks and allowed to recover until week 112 (Riley et al. 1980). This effect was not seen at the 76-week interim sacrifice or at the lower-exposure concentration of 75 ppm. Examination of the heart and aorta at interim sacrifices or at termination of the study revealed no significant histological alterations related to 1,4-dichlorobenzene treatment. Gastrointestinal Effects. Two case reports provide evidence of gastrointestinal effects in humans after exposure to unknown concentrations of 1,4-dichlorobenzene. A 60-year-old male who had been exposed to vapors of 1,4-dichlorobenzene in his home for 3-4 months reported having several bowel movements a day with loose tarry stools for 10 days before being admitted to a hospital (Cotter 1953). The second case is that of a 34-year-old woman who had been exposed to vapors of 1,4-dichloro- benzene at work and became acutely ill with nausea and vomiting, and was hospitalized with hemorrhage from the gastrointestinal tract (Cotter 1953). The physical and chemical findings led to the diagnosis of subacute yellow atrophy and cirrhosis of the liver from 1,4-dichlorobenzene exposure. No further information was located. Limited information regarding gastrointestinal effects in animals is provided in a chronic-duration study. In that study (Riley et al. 1980), the investigators found no effect on the organ weight or on gross and histopathological appearance of the caecum, colon, duodenum, jejunum, esophagus, pancreas, and stomach in male and female Wistar rats exposed to 1,4-dichlorobenzene at air concentrations of up to 490-499 ppm, 5S hours a day, 5 days a week for 76 weeks. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 28 2. HEALTH EFFECTS Hematological Effects. Two reports of hematological effects in humans after inhalation exposure to 1,4-dichlorobenzene were located in the literature. Based on results from blood counts, anemia was diagnosed in two men; one had been exposed to unknown concentrations of 1,4-dichlorobenzene vapors at home for 3-4 months and the other had been in a storage plant saturated with 1,4-dichloro- benzene vapor. A woman exposed in a similar manner was diagnosed with borderline anemia (Cotter 1953). Early industrial hygiene surveys found no evidence of adverse hematological effects attributable to exposure to 1,4-dichlorobenzene in workers at air concentrations ranging from 10 to 550 ppm for 8 months to 25 years (average 4.75 years) (Hollingsworth et al. 1956). Information regarding hematological effects in animals is scant. No hematologic effects (specific tests not provided) were observed in rats and rabbits exposed to 1,4-dichlorobenzene vapors at concentrations of 96 or 158 ppm, respectively, dosed for durations of 7 hours a day, 5 days a week for 5-7 months (Hollingsworth et al. 1956). A chronic-duration study reported that some changes in blood chemistry and hematologic parameters were seen in rats exposed 5 hours per day, 5 days per week to 1,4-dichlorobenzene at air concentrations of up to 490-499 ppm for 76 weeks; however, the reported changes showed no consistent trend with dose, sex, or exposure duration that would indicate treatment-related effects (Riley et al. 1980). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after inhalation exposure to 1,4-dichlorobenzene. One study was located which examined the musculoskeletal effects in laboratory animals after inhalation exposure to 1,4-dichlorobenzene. No gross or histological alterations in skeletal muscle (unspecified parameters) were detected in rats exposed to 1,4-dichlorobenzene at air concentrations of up to 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). Hepatic Effects. Hepatic effects have been reported in humans following long-term exposure to 1,4-dichlorobenzene via inhalation. A 60-year-old man and his wife who were exposed to mothball vapor that "saturated" their home for 3-4 months both died of liver failure (acute liver atrophy) within a year of the initial exposure (Cotter 1953). Yellow atrophy and cirrhosis of the liver were reported in a 34-year-old woman who demonstrated 1,4-dichlorobenzene products in a department store and in a 52-year-old man who used 1,4-dichlorobenzene occupationally in a fur storage plant for about 2 years (Cotter 1953). Duration of exposure was not estimated for the 34-year-old woman, but was indicated “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 29 2. HEALTH EFFECTS in the report to be more than 1 year. No estimates of the 1,4-dichlorobenzene exposure levels (other than the use of the term “saturated”) were provided in any of the studies, nor was it verified that 1,4-dichlorobenzene exposure was the only factor associated with the observed effects. History of alcohol consumption was not mentioned for any of the cases reported by Cotter (1953). These case studies indicate that the liver is a target organ for 1,4-dichlorobenzene in humans, but they do not provide quantitative information. In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-dichloro- benzene at air concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours a day from Gd 6 to 15 produced no adverse clinical or pathological signs in the hepatic tissues of the dams (Hodge et al. 1977). In a similar study, New Zealand White rabbits exposed whole-body to 1,4-dichlorobenzene 6 hours a day on Gd 6-18 experienced no adverse effects on absolute or relative maternal liver weights at air concentrations up to 800 ppm (Hayes et al. 1985). In a cross-species comparative study, exposure to 1,4-dichlorobenzene at air concentrations up to 158 ppm, 7 hours a day, 5 days a week for 5-7 months produced no treatment-related effects on liver weight or microscopic appearance in male and female mice; in contrast, various hepatic effects were noted in rats, guinea pigs, and rabbits exposed to 1,4-dichlorobenzene at various levels and durations of exposure (Hollingsworth et al. 1956). There was considerable variability in the species of animals exposed at each dose, the number of animals exposed, and the total number of exposures. When rats and rabbits inhaled 173-798 ppm of 1,4-dichlorobenzene intermittently for 2—12 weeks, several hepatic effects were observed. Relative liver weight was increased in rats exposed to 173 ppm; histopathological examination at this exposure level revealed slight congestion and granular degeneration in female rats; at 798 ppm, liver changes included cloudy swelling and central necrosis in both sexes of rats and rabbits. In the same study, when rats inhaled 158-341 ppm 1,4-dichlorobenzene intermittently for 5-7 months, male and female rats displayed cloudy swelling and central zone degeneration of the hepatic parenchymal cells in the liver, and increased relative liver weights at 158 ppm. These changes were not seen at a concentration of 96 ppm. Based on the NOAEL of 96 ppm, an intermediate-duration MRL of 0.2 ppm was calculated as described in the footnote to Table 2-1 and in Appendix A. In the same study, guinea pigs that were exposed to 341 ppm for a comparable duration or to 798 ppm for 2-4.5 weeks had focal necrosis and slight cirrhosis (in some animals) as well as hepatocyte swelling and degeneration. “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 30 2. HEALTH EFFECTS In a 2-generation study of the effects of inhalation exposure to 1,4-dichlorobenzene in Sprague-Dawley rats, males and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-dichlorobenzene 6 hours a day for 10 weeks prior to mating. The females were also exposed during mating, and on Gd 0-19 and postnatal days 5-27; males were exposed throughout the study. Marked hepatocellular hypertrophy, localized in the centrilobular area, was noted in Fj, and F, males and females in the 538 ppm dose group; no such effects were seen in the low- and mid-dose groups. Liver weights were significantly elevated in F( males at the 211 and 538 ppm doses and in F;, females at the 538 ppm dose; liver weights were also significantly elevated in F; males and females at the 538 ppm dose (Tyl and Neeper-Bradley 1989). In a long-term inhalation study in rats, exposure to 1,4-dichlorobenzene at air concentrations of 490-499 ppm 5 hours per day, 5 days per week for 76 weeks resulted in an increase in absolute liver weight throughout the study in males and at weeks 27 and 112 in females (Riley et al. 1980). This effect was not accompanied by histological alterations or by increased serum transaminase activities. No hepatic effects were noted at 75 ppm. None of the adverse hepatic effects reported at lower concentrations of 1,4-dichlorobenzene for shorter durations (Hollingsworth et al. 1956), as described above, were identified in the 76-week study. Based on the NOAEL of 75 ppm for lack of hepatic effects, a chronic-duration MRL of 0.1 ppm was calculated as described in the footnote to Table 2-1 and in Appendix A (Hollingsworth et al. 1956). Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 1,4-dichlorobenzene. In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-dichloro- benzene at air concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours a day from Gd 6 to 15 produced no adverse clinical or pathological signs in the kidney tissues of the dams (Hodge et al. 1977). In a similar study, pregnant New Zealand White rabbits exposed whole-body to 1,4-dichlorobenzene 6 hours a day on Gd 6-18 experienced no adverse effects with regard to either absolute or relative maternal kidney weights at air concentrations up to 800 ppm (Hayes et al. 1985). In mice, rats, and rabbits exposed by inhalation to 1,4-dichlorobenzene at air concentrations ranging from 96 to 798 ppm, 7 or 8 hours per day, for periods as long as 7 months, no renal effects were noted in mice or rabbits, while both male and female rats experienced increased relative kidney ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 31 2. HEALTH EFFECTS weights at the 173 ppm dose level. In addition, a slight cloudy swelling of the tubular epithelium was noted in female rats exposed to 798 ppm. In the same study, inhalation of 1,4-dichlorobenzene at 158 or 341 ppm intermittently for 5-7 months by rats caused a slight increase in relative kidney weight in males but not females (Hollingsworth et al. 1956). This effect was not observed in groups of guinea pigs, in one monkey, or in two rabbits under the same experimental conditions (Hollingsworth et al. 1956). The findings in this study are consistent with those reported by Riley et al. (1980) in a 76-week study in rats, described below. In a 2-generation study of the effects of inhalation exposure to 1,4-dichlorobenzene in Sprague-Dawley rats, males and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-dichlorobenzene 6 hours a day for 10 weeks prior to mating. The females were also exposed during mating, and on Gd 0-19 and postnatal days 5-27; males were exposed throughout the study. An increased incidence of nephrosis was seen in F,, males of all dose groups and in F, males of the 211 and 538 ppm dose groups; lesions consisted of hyaline droplets, tubular protein nephrosis, granular cast formation, and interstitial nephritis. No renal lesions were noted in Fj or F; females. Kidney weights were significantly elevated in F, males at all doses and in F, males at the 538 ppm dose. In females, kidney weights were significantly elevated in the F, generation at the 538 ppm dose, but were not elevated in the F, generation (Tyl and Neeper-Bradley 1989). In a chronic-duration inhalation study in rats, exposure to 1,4-dichlorobenzene at air concentrations of 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks resulted in an increase in absolute kidney weight in males throughout the study and in females at weeks 27 and 112 weeks. Exposure to 75 ppm 1 4-dichlorobenzene had no effect on kidney weight, and neither exposure level caused histopathological alterations in the kidneys (Riley et al. 1980). It is of interest to note that the renal effects observed in inhalation studies using 1,4-dichlorobenzene are mild in contrast with the severe renal effects observed in oral studies as described in Section 2.2.2.2. Endocrine Effects. No studies were located regarding endocrine effects in humans following inhalation exposure to 1,4-dichlorobenzene. The only information regarding endocrine effects in animals after inhalation exposure to 1,4-dichloro- benzene is from a chronic-duration study in rats. In that study (Riley et al. 1980), no gross or histopathological effects were observed in the adrenal, thyroid, or pituitary glands of male or female ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 3 2. HEALTH EFFECTS rats exposed to 1,4-dichlorobenzene at air concentrations up to 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks. No further information regarding endocrine effects was located. Dermal Effects. Dermal effects resulting from 1,4-dichlorobenzene exposure were reported to have occurred in a 69-year-old man who had been exposed for approximately 3 weeks to 1,4-dichloro- benzene used in his home, including on a chair on which he had been sitting. He gradually developed petechiae (small red spots), purpura (purple or brownish-red spots), and swelling of his hands and feet. His sensitivity to 1,4-dichlorobenzene was established by an indirect basophil degranulation test which showed a strongly positive reaction (degenerative changes in 62% of his basophils when tested with 1,4-dichlorobenzene, compared with a 6% reaction of normal serum with 1,4-dichlorobenzene) (Nalbandian and Pearce 1965). The authors suggested that these effects were probably immunologically mediated. In a study of 58 men occupationally exposed to up to 725 ppm I,4-dichlorobenzene, 8 hours a day, 5 days a week continually or intermittently for 8 months to 25 years (average: 4.75 years), medical examinations revealed no evidence of dermatological effects (Hollingsworth et al. 1956). No studies were located regarding dermal effects in animals after inhalation exposure to 1,4-dichloro- benzene. Ocular Effects. In a report on 58 men who had worked for 8 months to 25 years (average = 4.75 years) in a plant that used 1,4-dichlorobenzene, painful irritation of the nose and eyes were reported to have occurred at levels ranging from 80 to 160 ppm (Hollingsworth et al. 1956). At levels greater than 160 ppm, the air was considered unbreathable by unacclimated persons. Neither cataracts nor any other lens changes were found upon examination of their eyes. There is no clear, quantitative evidence of ocular effects resulting from inhalation exposure to I.4-dichlorobenzene in animal studies. Ocular effects, described as reversible, nonspecific eye ground changes (changes in the fundus or back of the eye), were seen in 2 rabbits exposed to 1,4-dichloro- benzene at 798 ppm 8 hours a day, 5 days a week for 12 weeks (Hollingsworth et al. 1956). In the same study, no lens changes were observed in rats or guinea pigs exposed to 798 ppm 1,4-dichloro- benzene, but eye irritation was reported in the three species tested. It should be noted that ocular effects occurring during and/or after exposure to chemicals in the air are likely to be due to direct contact of the chemical with the eye. “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 33 2. HEALTH EFFECTS A chronic-duration inhalation study in male and female Wistar rats reported no histopathological alterations in the eyes of rats exposed to 1,4-dichlorobenzene at air concentrations up to 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). No further data were located. Body Weight Effects. A 60-year-old man who was exposed to vapors of 1,4-dichlorobenzene in his home for 3-4 months was reported to have lost approximately 50 pounds in body weight in 3 months (Cotter 1953). His wife, who received similar exposure, also lost weight. A third case reported by the same author (Cotter 1953) is that of a 52-year-old man who was exposed to 1.4-dichlorobenzene by using the chemical for preserving raw furs. On examination, this individual was described as being emaciated. Information regarding food consumption was not available in any of these cases. In the case of the 60-year-old man, persistent diarrhea may have contributed to the weight loss. In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-dichloro- benzene at air concentrations of 74.7, 198.6, or 508.4 ppm, 6 hours a day from Gd 6 to 15 had no effect on maternal body weight gain (Hodge et al. 1977). Body weight data are available for various animal species after exposure to 1,4-dichlorobenzene 7-8 hours a day, 5 days a week, for periods ranging from 2 weeks to 6 months (Hollingsworth et al. 1956). Rats, rabbits, and guinea pigs experienced weight loss when exposed to 798 ppm, 8 hours a day, 5 days a week. Rats exposed to up to 341 ppm 1,4-dichlorobenzene for 5-7 months grew at a rate similar to that of unexposed controls. Similar results were obtained in rabbits exposed to 173 ppm for 16 days or to 158 ppm for about 200 days. Slight growth depression was observed in male and female guinea pigs exposed to 158 ppm 1,4-dichlorobenzene for 157 days, but only males showed a slight delay in growth when the exposure level was 341 ppm for 6 months. In male and female mice and in one female monkey there were no effects on body weight after exposure to 1.4-dichlorobenzene at air concentrations up to 158 ppm for as long as 7.1 months. In a 2-generation study of the effects of inhalation exposure to 1,4-dichlorobenzene in Sprague-Dawley rats, males and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-dichlorobenzene 6 hours a day for 10 weeks prior to mating. The females were also exposed during mating, and on Gd 0-19 and postnatal days 5-27; males were exposed throughout the study. Male F,, body weight and body weight gain were significantly reduced in the 538 ppm group. Body weight gain was also significantly ***DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 34 2. HEALTH EFFECTS reduced in the 211 ppm group; however, the effect was seen at fewer observation periods. Female F, body weights were equivalent across all treatment groups during the entire prebreeding period. The F, generation males and females exposed to 538 ppm 1,4-dichlorobenzene had lower body weights than did controls; however, these decreases were accompanied by decreased food consumption (Tyl and Neeper-Bradley 1989). A chronic-duration inhalation study in male and female Wistar rats found that body weight was not significantly altered after exposure to 1,4-dichlorobenzene at air concentrations up to 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). Other Systemic Effects. No studies were located regarding other effects in humans following inhalation exposure to 1,4-dichlorobenzene. Ascites, esophageal varices, hemorrhoids, and tarry stools are all secondary effects of subacute, yellow atrophy and cirrhosis of the liver (Cotter 1953). A chronic-duration inhalation study in male and female Wistar rats found that food and water consumption was not significantly altered after exposure to 1,4-dichlorobenzene at air concentrations up to 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). In a 2-generation study of the effects of inhalation exposure to 1,4-dichlorobenzene in Sprague-Dawley rats, males and females were exposed to 0, 66.3, 211, or 538 ppm 1,4-dichlorobenzene 6 hours daily for 10 weeks prior to mating. The females were also exposed during mating, and on Gd 0-19 and postnatal days 5-27; males were exposed throughout the study. Exposure of the F, and F, generations to 538 ppm 1,4-dichlorobenzene resulted in clinical signs of toxicity such as decreased grooming, unkempt appearance, decreased food consumption, and dehydration (Tyl and Neeper-Bradley 1989). 2.2.1.3 Immunological and Lymphoreticular Effects As mentioned in Section 2.2.1.2, dermal effects observed in a 69-year-old man who had been exposed to 1,4-dichlorobenzene in his home for approximately 3 weeks (Nalbandian and Pearce 1965) may have been mediated by immunological mechanisms. In addition to petechiae, purpura, and swelling of his hands and feet, his serum showed a strong positive reaction to 1,4-dichlorobenzene in an indirect basophil degranulation test. The authors stated that, to their knowledge, this was the first reported case of allergic (anaphylactoid) purpura induced by exposure to 1,4-dichlorobenzene. Enlargement of ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 35 2. HEALTH EFFECTS the spleen was reported in a woman who had been exposed to 1,4-chlorobenzene in her home for 3-4 months and in a man who used 1,4-dichlorobenzene to preserve raw furs (Cotter 1953). This, however, was most likely a secondary response to hematological disturbances rather than an immunoiogical effect. A slight decrease in relative spleen weight was observed in male guinea pigs exposed to 1,4-dichloro- benzene at an air concentration of 173 ppm, 7 hours a day, 5 days a week for 16 days (Hollingsworth et al. 1956); no effect was seen in rats under the same experimental conditions. In a chronic-duration inhalation study, groups of male and female Wistar rats exposed to 1,4-dichlorobenzene 5 hours a day, 5 days a week for 76 weeks exhibited no gross or hispathological alterations in the cervical, thoracic, and mesenteric lymph nodes; spleen; or thymus at air concentrations up to 500 ppm (Riley et al. 1980). No other immunological end points were evaluated. 2.2.1.4 Neurological Effects Information regarding neurological effects in humans exposed to 1,4-dichlorobenzene via inhalation is limited to several case reports. A 60-year-old man whose home had been saturated with 1,4-dichloro- benzene mothball vapor for 3 or 4 months complained of persistent headache, numbness, clumsiness, and a burning sensation in his legs (consistent with peripheral nerve damage); he also exhibited slurred speech (Cotter 1953). In a more recent case study, a 25-year-old woman was exposed to high concentrations of 1,4-dichlorobenzene from her bedroom, bedding, and clothing. She had used this compound liberally as an insect repellant for 6 years. The subject sought medical assistance because of severe ataxia, speech difficulties, and moderate weakness of her limbs. Brainstem auditory-evoked potentials (BAEPs) showed marked delays of specific brainwave patterns. Her symptoms gradually improved over the next 6 months after cessation of exposure and the BAEPs examined 8 months later had returned to normal. This study suggests that there may be measurable but reversible neurological effects associated with human inhalation exposure to 1,4-dichlorobenzene (Miyai et al. 1988). The level of 1.4-dichlorobenzene exposure was neither known nor estimated in either of the human case studies. In addition, there is no certainty that exposure to 1,4-dichlorobenzene was the only factor associated with the toxic effects reported. Neurological signs including marked tremors, weakness, and loss of consciousness were observed in rats, rabbits, and guinea pigs exposed to 798 ppm 1,4-dichlorobenzene 8 hours a day, 5 days a week ***DRAFT FOR PUBLIC COMMENT" 1,4-DICHLOROBENZENE 36 2. HEALTH EFFECTS (Hollingsworth et al. 1956). In a chronic-duration study in rats, exposure to up to 500 ppm 1,4-dichlorobenzene 5 hours a day, 5 days a week for 76 weeks did not cause gross or histological alterations in the brain, sciatic nerve, or spinal cord, but absolute brain weight was slightly decreased at the termination of the study (Riley et al. 1980). Adult rats exposed 6 hours per day for 10 weeks to 538 ppm 1.4-dichlorobenzene during a 2-generation study displayed symptoms associated with compound neurotoxicity, including tremors, ataxia, and hyperactivity (Tyl and Neeper-Bradley 1989). The animals also decreased their grooming behavior and developed an unkempt appearance. At sacrifice, the relative brain weights of the males, but not the females, were significantly increased compared to the controls. The highest NOAEL values and all reliable LOAEL values for neurological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.5 Reproductive Effects No studies were located regarding reproductive effects in humans after inhalation exposure to 1,4-dichlorobenzene. In an acute-duration study using pregnant Alderley-Park rats, whole-body exposure to 1,4-dichloro- benzene at air concentrations up to 508.4 ppm, 6 hours a day from Gd 6 to 15 did not adversely affect the number of implantations, resorptions, viable fetuses, corpora lutea, or sex ratios (Hodge et al. 1977). A similar study in inseminated New Zealand White rabbits exposed whole-body to I.4-dichlorobenzene at air concentrations of 100, 300, or 800 ppm, 6 hours a day on Gd 6-18 found no differences between treated and control groups in the mean number of corpora lutea per dam, the mean number of implantation sites per dam, the mean number of resorptions per litter, or the number of totally resorbed litters. At 300 ppm, there was a significant increase (p<0.05) in the percentage of resorbed implantations per litter and in the number of litters with resorptions; however, the results at 800 ppm were comparable to controls, and the percentage of litters with resorptions reported in the 300 ppm group was within the range reported for historical controls, suggesting this effect was not chemical- or dose-related (Hayes et al. 1985). Exposure of rats and guinea pigs to 1,4-dichlorobenzene at an air concentration of 173 ppm, 7 hours a day, 5 days a week for 2 weeks did not significantly alter relative testis weight. The same results ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 37 2. HEALTH EFFECTS ~ were obtained after intermittently exposing rats and guinea pigs to 1,4-dichlorobenzene at air concentrations up to 158 ppm for 5-7 months (Hollingsworth et al. 1956). There were no treatment- related effects on the reproductive organs of male or female Wistar rats exposed to 1,4-dichloro- benzene at concentrations up to 490-499 ppm, 5 hours a day, 5 days a week for 76 weeks (Riley et al. 1980). The evaluation of reproductive end points included organ weights and histopathology. The effects of 1,4-dichlorobenzene vapors on the reproductive performance of rats was assessed in a 2-generation study in which animals of both sexes were exposed before and during mating (Tyl and Neeper-Bradley 1989). The females were then exposed on Gd 0-19 and postnatal days 5-27. Effects on body weight, liver and kidney weight, and hepatocellular hypertrophy were found in the adult rats at exposure concentrations of 211 and 538 ppm and were indicative of toxicity to the breeding animals. These effects did not occur with the 66.3 ppm exposure concentration. Both generations of offspring exposed to the 538 ppm concentration had lower body weights than the controls at lactation day 4; average litter size and survival rates were decreased. When selected animals from the first filial generation were allowed to recover from the 1,4-dichlorobenzene exposure for a 5-week period, body weights of the 538 ppm exposure group remained lower than those for the controls. The study concluded that parental toxicity was the cause of the increased risk to offspring rather than inherent effects of 1,4-dichlorobenzene on reproductive processes. In addition, no reduction in reproductive performance (as measured by the percentage of males successfully impregnating females) was observed in an inhalation study in which male mice were exposed to 1,4-dichlorobenzene at 75-450 ppm for 6 hours per day for 5 days before being mated with virgin females (Anderson and Hodge 1976). These data are consistent with the data from the males used in the 2-generation study discussed above. The highest NOAEL values and all reliable LOAEL values for reproductive effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Developmental Effects No studies were located regarding developmental effects in humans after inhalation exposure to 1,4-dichlorobenzene. “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 38 2. HEALTH EFFECTS Exposure of pregnant Alderley-Park rats to 1,4-dichlorobenzene via inhalation at levels up to 508 ppm for 6 hours per day on Gd 6-15 did not result in developmental effects in the offspring (Hodge et al. 1977). End points examined included the number of viable fetuses, fetal weight, litter weight, sex ratio, external abnormalities, and skeletal and visceral abnormalities. In a 2-generation study of the effects of inhalation exposure to 1,4-dichlorobenzene in Sprague-Dawley rats, males and females who were exposed to 0, 66.3, 211, or 538 ppm 1,4-dichlorobenzene 6 hours daily for 10 weeks prior to mating were assessed. The females were also exposed during mating, and on Gd 0-19 and postnatal days 5-27; males were exposed throughout the study. F, and F, pup body weights in the 538 ppm group were significantly reduced from postnatal day 0 to 28. The number of F, and F, pups that died during the perinatal period was significantly elevated in the 538 ppm group (Tyl and Neeper-Bradley 1989). The developmental effects of 1,4-dichlorobenzene have been evaluated in New Zealand White rabbits (Hayes et al. 1985). Pregnant rabbits were exposed to 1,4-dichlorobenzene by inhalation at 800 ppm for 6 hours per day on Gd 6-18. At 300 ppm, there was a significant increase in the number of litters with resorptions and the percentages of resorbed implantations per litter; however, this effect was not seen at 800 ppm and was thus probably not treatment-related. An increased incidence of retroesophageal right subclavian artery present in the offspring was noted; it was not considered to constitute a teratogenic response to exposure to 1.4-dichlorobenzene, but was considered only a minor variation. Based on the NOAEL of 300 ppm, an acute-duration MRL of 0.8 ppm was calculated as described in the footnote to Table 2-1 and Appendix A (Hayes et al. 1985). The highest NOAEL values and a reliable LOAEL value for developmental effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans after inhalation exposure to 1,4-dichlorobenzene. Cytogenetic studies have been conducted using bone marrow cells of rats following inhalation exposure to 1.4-dichlorobenzene (Anderson and Richardson 1976). Three series of exposures were ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 39 2. HEALTH EFFECTS carried out: (1) one exposure at 299 or 682 ppm for 2 hours; (2) multiple exposures at 75 or 500 ppm, 5 hours per day for 5 days; and (3) multiple exposures to 75 or 500 ppm, 5 hours per day, 5 days per week for 3 months. Bone marrow cells from both femurs were examined for chromosome or chromatid gaps, chromatid breaks, fragments, or other complex abnormalities. In all three experiments, exposure to 1,4-dichlorobenzene failed to induce any effects indicative of chromosomal damage. Other genotoxicity studies are discussed in Section 2.5. 2.2.1.8 Cancer No studies were located regarding carcinogenic effects in humans after inhalation exposure to 1,4-dichlorobenzene. No evidence of carcinogenicity was observed in a long-term inhalation study in rats that were exposed to 1,4-dichlorobenzene at 75 or 500 ppm intermittently for 76 weeks (Riley et al. 1980). The reported lack of extensive organ toxicity in this study (compared with results seen in oral studies described in Section 2.2.2.2) strongly suggests that a maximum tolerated dose (MTD) was not achieved in this study. In addition, a less-than-lifetime dosing regimen was used. These study design limitations prevent a reliable evaluation of the potential carcinogenicity of 1,4-dichlorobenzene by inhalation. 2.2.2 Oral Exposure Most of the data described in this section were derived from laboratory studies in which 1,4-dichloro- benzene was administered to test animals via gavage. In addition, two human case studies of 1,4-dichlorobenzene consumption are described. Case studies are not generally scientifically equivalent to well conducted epidemiologic studies or laboratory experiments and should be viewed only as providing contributory evidence that 1,4-dichlorobenzene may have caused the reported effects. These case studies do not provide unequivocal proof that 1,4-dichlorobenzene is solely responsible for the reported toxicological end points. 2.2.2.1 Death No studies were located regarding death in humans after oral exposure to 1,4-dichlorobenzene. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 40 2. HEALTH EFFECTS Animal mortality data are available from acute-, intermediate-, and chronic-duration studies. In acute- duration animal studies, a single dose by gavage in olive oil of 1,000 mg/kg to rats and 1,600 mg/kg to guinea pigs resulted in no deaths, while a single dose of 4,000 mg/kg to rats and 2,800 mg/kg to guinea pigs resulted in 100% mortality (Hollingsworth et al. 1956). Similar results were seen in groups of adult male albino rats administered various doses of 1,4-dichlorobenzene in corn oil once daily for 14 days; administration of 1,4-dichlorobenzene at doses up to 600 mg/kg did not result in any deaths (Carlson and Tardiff 1976). Oral LDs (lethal dose, 50% kill) values for adult Sherman rats administered 1,4-dichlorobenzene in peanut oil were calculated to be 3,863 and 3,790 mg/kg for males and females, respectively (Gaines and Linder 1986). In one series of studies (NTP 1987), the lethality data for 1,4-dichlorobenzene, when administered for 14 days by gavage in corn oil to Fischer 344 rats and B6C3F, mice, were rather inconsistent. In one of these studies, no 1,4-dichlorobenzene-related deaths occurred in rats of either sex that received doses up to 1,000 mg/kg/day; however, in the second rat study, 4 of 5 females (80%) at 1,000 mg/kg/day died, and all rats dosed at >2,000 mg/kg/day died. In one 14-day study in mice, no 1,4-dichlorobenzene-related deaths occurred in either sex at levels up to 1,000 mg/kg/day; however, in a second 14-day mouse study, 70% of mice at 1,000 mg/kg/day died, and all mice that received 4,000 mg/kg/day died within 4 days. At 1,200 mg/kg/day, S of 10 males and 1 of 10 females rats died. No deaths occurred at 600 mg/kg/day. In 13-week gavage studies, 17 of 20 rats (8 of 10 males and 9 of 10 females) dosed with 1,4-dichloro- benzene in corn oil 5 days a week at 1,500 mg/kg/day died. When dosed in like manner with 1,200 mg/kg/day, 5 of 10 males and 1 of 10 females rats died. No deaths occurred at doses of 600 mg/kg/day or less (NTP 1987). Mortality rates in mice were somewhat lower; 8 of 20 (3 of 10 males and 5 of 10 females) animals dosed with 1,500 mg/kg/day 1,4-dichlorobenzene in corn oil 5 days a week died. No deaths occurred in males or females at doses up to 900 and 1,000 mg/kg/day, respectively (NTP 1987). High mortality was reported in male rats that received 1,4-dichlorobenzene 5 days a week by gavage in corn oil in a 2-year study (NTP 1987). At 300 mg/kg/day, 26 of 50 males (52%) died; however, survival of female rats at 600 mg/kg/day was comparable to controls. There was no excess mortality in mice of either sex that received 1,4-dichlorobenzene 5 days a week by gavage in corn oil for 2 years at levels up to 600 mg/kg/day (NTP 1987). The high rate of mortality in male rats was ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 41 2. HEALTH EFFECTS probably related, in part, to the severe nephrotoxic effects and renal tumors that were reported in these animals and are described in more detail in Sections 2.2.2.2 and 2.2.2.8. All reliable LOAEL values for lethality and LDs, values in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects The highest NOAEL values and all reliable LOAEL values for systemic effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Respiratory Effects. No studies were located regarding respiratory effects in humans after oral exposure to 1,4-dichlorobenzene. In a series of dose range-finding studies, groups of Fischer 344 rats were administered 1,4-dichloro- benzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). At sacrifice, animals were examined grossly and major tissues were examined histologically. No compound-related effects were observed in the lungs at any dose up to 900 mg/kg/day, while rats treated with 1,200 mg/kg/day or higher exhibited epithelial necrosis of the nasal turbinates (NTP 1987). In parallel studies, B6C3F, mice were administered 1,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks. No compound-related effects were observed in the lungs at any dose level (NTP 1987). In 2-year exposure studies in Fischer 344 rats, no respiratory effects were reported in males or females that received 1,4-dichlorobenzene by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively (NTP 1987). In similarly dosed B6C3F, mice, no respiratory effects were reported in either sex at doses up to 600 mg/kg/day (NTP 1987). Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after oral exposure to 1,4-dichlorobenzene. In a series of dose range-finding studies, groups of Fischer 344 rats were administered 1,4-dichloro- benzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week “**DRAFT FOR PUBLIC COMMENT*** «xLNIWNOD 0118Nd HO 14VHQA... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral Exposure/ LOAEL Ke to” } duration/ i y Species frequency NOAEL Less serious Serious ‘gure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Death 1 Rat once 3863 M (LDs=o) Gaines and Linder (Sherman) (GO) Rat once (NS) (GO) Rat 14d (Fischer- 344) 1 x/d (GO) Mouse 14d (B6C3F1) 1 x/d (GO) Gn Pig once (NS) (GO) Systemic Rat 3d (Wistar) 1 x/d (G) Rat 14d (albino) 1 x/d (GO) Rat 14 d (albino) 1 x/d (GO) 3790 F (LDso) 4000 (LD1oo) 2000 M (5/5 males died) 1000 F (4/5 females died) 4000 (10/10 deaths by day 4) 2800 (LD1oo) Hepatic 250F Bd Wt 250F Hepatic 300M 650M (6.5-fold increase in serum isocitrate dehydrogenase activity) Hepatic 650M (decreased hexobarbital sleeping time; increased isocitrate dehydrogenase) 1986 Hollingworth et al. 1956 NTP 1987 NTP 1987 Hollingsworth et al. 1956 Ariyoshi et al. 1975 Carlson and Tardiff 1976 Carlson and Tardiff 1976 S103443 HIV3H 2 3INIZN3IGOHOTHOIA vt [44 «+LNIJWWOD 01718Nd HOH 14vHQ... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ Key wo duration/ Species frequency NOAEL . Seri figure ; : Less serious 2TIOUS gure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) RélerBice 9 Rat 14 d Hepatic 10M 20M (increase in glucuronyl Carlson and (albino) 1 x/d transferase and EPN Tardiff 1976 (GO) detoxification activities) 10 Rat 7d Renal 120M (protein droplet formation) Charbonneau et (Fischer- 344) 1 x/d al. 1987 (GO) 11 Rat once Renal 500 F 500M (increase in protein Charbonneau et (Fischer- 344) (GO) droplet formation) al. 1987 12 Rat once Hepatic 600 F (increased liver weight) Eldridge et al. (Fischer- 344) (GO) 1992 Bd Wt 600 F 13 Rat once Hepatic 600 F (centrilobular hepatocyte Eldridge et al. (Fischer- 344) (GO) vacuolation) 1992 14 Rat 14d Bd Wt 500 M 1000M (7-12% decrease in final NTP 1987 (Fischer- 344) 1x/d 1000 F body weight) (GO) 15 Rat 14d Bd Wt 500 1000 (13.5% reduction in final NTP 1987 (Fischer- 344) 1x/d body weight in males, (GO) 16.7% in females) 16 Rat 5d Hepatic 770 M (porphyria; degeneration of Rimington and (albino) 1x/d hepatocytes; focal Ziegler 1963 (©) necrosis) Bd Wt 770M Other 770M (loss of appetite) 17 Rat 5d Hepatic 850 M (porphyria; degeneration of Rimington and (albino) 1 x/d hepatocytes; focal Ziegler 1963 (G) necrosis) S103443 H1v3H 2 INIZN3IgOHOTHOIA vt ey +~LNJWWOD 01N8Nd HOH L3VHA... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ LOAEL Key 0 duration/ Species frequency NOAEL : Serious figure (Strain) (Specifi t Svst Less serious (Specific route) ystem (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 18 Mouse once Hepatic 600 (increased liver weight) Eldridge et al. (B6C3F1) (GO) 1992 Bd Wt 600 19 Mouse once Hepatic 600 (centrilobular hepatocyte Eldridge et al. (B6C3F1) (GO) vacuolation) 1992 20 Mouse 14d Bd Wt 1000 NTP 1987 (B6C3F1) 1 x/d (GO) 21 Mouse 14d Bd Wt 250M (13.3% reduction in final NTP 1987 (B6C3F1) 1 x/d body weight) (GO) 22 Mouse 4d Hepatic 300 (increased liver weight Umemura et al. (B6C3F1) 1 x/d and hepatocyte 1992 (GO) proliferation) Renal 600 23 Mouse Once Hepatic 1000 M 1800M (increased ALT activity; Umemura et al. (B6C3F1) severe centrilobular 1996. hepatocyte swelling) 24 Mouse Once Hepatic 1800M (increased ALT activity; Umemura et al. (B6C3F1) increased BrdU labeling) 1996. Neurological 25 Rat 5d 770 M (clonic contractions; slight ~~ Rimington and (albino) 1 x/d tremors; hemiparesis) Ziegler 1963 ©) Reproductive 26 Rat 10d 1000 F Giavini et al. 1986 (CD) Gd 6-15 1 x/d (GO) S103443 HI1Vv3H ¢ 3IN3IZN3IgOHOTHOIA-¥' vy «+ INIJWWOD O118Nd HOH 14VHA..s Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ a duration/ LOARL Key Sie ee NOAEL Less serious Serious System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Developmental 27 Rat 10d 250 500 (extra rib in fetuses) Giavini et al. 1986 (CD) Gd 6-15 1 x/d (GO) INTERMEDIATE EXPOSURE Death 28 Rat 13 wk 1200 M (5/10 males died) NTP 1987 (Fischer- 344) 5 d/wk 1500 F (9/10 females died) (GO) 29 Mouse 13 wk 1500 (3/10 males and 5/10 NTP 1987 (B6C3F1) 5 d/wk females died) (GO) Systemic 30 Rat 13 wk Hepatic 600 (increased liver weight; Eldridge et al. (Fischer- 344) 5 d/wk hypertrophic centrilobular 1992 (GO) hepatocytes) Bd Wt 600 31 Rat 192d Hemato 188 F Hollingsworth et (NS) 5 d/wk al. 1956 (GO) Hepatic 18.8 188 F (slight increase in liver 376 F (slight cirrhosis, focal weight, but not necrosis) quantified) Renal 18.8 188 F (slight increase in kidney weight, but not quantified) Ocular 376 F S103d443 H1TV3H ¢ 3N3IZN3G0HOTHOIA-¥'} +» LNJWWOOD O1M8Nd HOH 14vHA... Exposure/ Key to? duration/ y Species frequency Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) LOAEL ; : NOAEL Less serious Serious figure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 32 Rat 13 wk Resp 600 NTP 1987 (Fischer- 344) 5 d/wk (GO) Cardio 600 Gastro 600 Musc/skel 600 Hepatic 600 Renal 300 M 600M (moderate tubular 600 F degeneration in 9/10) Endocr 600 Dermal 600 Ocular 600 Bd Wt 600 33 Rat 13 wk Resp 900 1200 (epithelial necrosis of NTP 1987 (Fischer- 344) 5 d/wk nasal turbinates) (GO) Cardio 1500 Gastro 900 1200 (epithelial necrosis of small intestine mucosa) Hemato 300M (slight decreases in red 300 F 600 F blood cell count, hematocrit, and hemoglobin concentration) Musc/skel 1500 Hepatic 300 M 600M (significant increase in 1200 (degeneration and necrosis 900 F serum cholesterol) of hepatocytes) Renal 1500 F 300 M (necrosis of renal cortical tubular epithelium) Endocr 1500 Dermal 1500 Ocular 900 M 1200 M (ocular discharge) 1200 F 1500 F Bd Wt 300M (11% decrease in final 1500 M (final body weight reduced 900 F 1200 F body weight) by 20-32%) S103443 HIV3H 2 INIZNISOHOTHOIa vt qv «»+LNIWWOD O118Nd HOH 14VHQ... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ LOAEL a duration/ Key 10 Species frequency NOAEL ] : : 2 Less serious Serious figure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 34 Mouse 13 wk Hepatic 300 600 (increased liver weight; Eldridge et al. (B6C3F1) 5 diwk hypertrophic centrilobular 1992 (GO) hepatocytes) Bd Wt 600 35 Mouse 13 wk Resp 1800 NTP 1987 (B6C3F1) 5 d/iwk (GO) Cardio 1800 Gastro 1800 Hemato 1800 F 600M (34% reduction in WBC count) Musc/skel 1800 Hepatic 600 (hepatocellular degeneration in 7/10 males and 9/10 females) Renal 1800 Endocr 1800 Dermal 1800 Ocular 1800 Bd Wt 600 (final body weight reduced 13.9% in males and 10.3% in females) S103443 H1VaH 2 3IN3ZN38OHOTHOIA-v't Ly «LNIFWWOD 2178Nd HOH 14VHQA... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ LOAEL Key 5 5 duration/ pecies frequency NOAEL L ; Serious figure (Strain) (Specific route) System (mg/kg/day) (ma/kglday) (mg/kg/day) Reference 36 Mouse 13 wk Resp 900 NTP 1987 (B6C3F1) 5 diwk (GO) Cardio 900 Gastro 900 Hemato 900 Musc/skel 900 Hepatic 338 675 (moderate hepatocytomegaly in 9/10 males and 10/10 females) Renal 900 Endocr 900 Dermal 900 Ocular 900 Bd Wt 900 Immunological/Lymphoreticular 37 Rat 13 wk 900 1200 (lymphoid depletion of NTP 1987 (Fischer- 344) 5 d/wk thymus and spleen) (GO) 38 Mouse 13 wk 1000 1500 (lymphoid necrosis in NTP 1987 (B6C3F1) 5 d/iwk thymus; lymphoid depletion (GO) in the spleen; hematopoietic hypoplasia in spleen and bone marrow) Neurological 39 Rat 13 wk 900 M 1200 M (tremors, poor motor NTP 1987 (Fischer- 344) 5 d/wk 1200 F 1500 F response) (GO) S103443 HITV3H 2 JN3IZNIGOHOTHOIA YL 1314 ~LNIFWWOD 2118Nd HOH 14VHA... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ LOAEL Key to duration/ o Species frequency NOAEL Less serous Serious igure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Reproductive 40 Rat 13 wk 1500 NTP 1987 (Fischer- 344) 5 d/wk (GO) 41 Mouse 13 wk 1000 F 1500 F (increase in relative NTP 1987 (B6C3F1) 5 d/wk 1800 M ovary weight) (GO) 42 CHRONIC EXPOSURE Death Rat 2yr (Fischer- 344) 5 d/wk (GO) 300 M (26/50 compound-related NTP 1987 deaths) S103443 H1V3H 2 3JN3IZN3g0HOTHOIA-t'L 6 «+LNIWWOO 0178Nd HOH 14VHA... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ S LOAEL Key to" Species sind NOAEL L i Serious : : €SS serious figure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Rolorencs Systemic 43 Rat 2yr Resp 300 M NTP 1987 (Fischer- 344) 5 d/wk 600 F (GO) Cardio 300M 600 F Gastro 300 M 600 F Hemato 300 M 600 F Musc/skel 300M 600 F Hepatic 300 M 600 F Renal 150M (moderate nephropathy) 300 (increased severity of the nephropathy) Endocr 600 F 150M (increased incidence of parathyroid hyperplasia) Dermal 300 M 600 F Ocular 300 M 600 F Bd Wt 150 M 300M (12.5% decrease in body 300 F 600 F weight gain) (12.4% decrease in body weight gain) S103443 HIVaH 2 3N3ZNIGOHOTHOIQ-¥'s 0S ~+LNIWWOD O118Nd HO4 14VHQ... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ LOAEL a duration/ oY 1° Species frequency NOAEL Less serious Serious figure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) mm 44 Mouse 2yr Resp 600 NTP 1987 (B6C3F1) 5 diwk (GO) Cardio 600 Gastro 600 Hemato 600 Musc/skel 600 Hepatic 300 (hepatocellular degeneration, hepatocyte swelling and vacuolation) Renal 300 (nephropathy, degeneration of cortical tubular epithelium) Endocr 600 F 300M (follicular cell hyperplasia in thyroid; adrenal medullary hyperplasia; focal hyperplasia of adrenal gland capsule) Dermal 600 Ocular 600 Bd Wt 600 Immunological/Lymphoreticular 45 Rat 2yr 600 NTP 1987 (Fischer- 344) 5 d/wk (GO) 46 Mouse 2yr 300 (increased incidence of NTP 1987 (B6C3F1) 5 diwk lymphoid hyperplasia of (GO) lymph nodes) S103443 HIV3H 2 3IN3ZN3IGOHOTHOIO-v't LS «LNIWWOD 21718Nd HOH 14VHAQ... Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ LOAEL Key to duration/ Species frequency NOAEL Less serious Serious igure (Strain) (Specific route) System (mg/kg/day) (mg/kg/day) (mg/kg/day) Baforancs Neurological 47 Rat 2yr 600 NTP 1987 (Fischer- 344) 5 d/wk (GO) 48 Mouse 2yr 600 NTP 1987 (B6C3F1) 5 diwk (GO) Reproductive 49 Rat 2yr 600 NTP 1987 (Fischer- 344) 5 d/wk (GO) 50 Mouse 2yr 600 NTP 1987 (B6C3F1) 5 diwk (GO) Cancer 51 Rat 2yr 300 M (CEL: increased incidence ~~ NTP 1987 (Fischer- 344) 5 d/wk of combined renal tubular (GO) cell adenocarcinoma and adenoma) S103443 HITVIH 2 3N3ZN38OHOTHDIA-¥'L cs ea INJNWNOU OI 1dl Id HOH L3V dU Table 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (continued) Exposure/ duration/ LOAEL a Key to Species frequency : NOAEL Less serious Serious gure (Strain) (Specific route) system (mggiday) (mg/kg/day) (mg/kg/day) Reference 52 Mouse 2yr 600 (CEL: increased incidence NTP 1987 (B6C3F1) 5 d/wk of hepatocellular (GO) carcinomas and adenomas) *The number corresponds to entries in Figure 2-2. ®Used to derive an intermediate oral minimal risk level (MRL) of 0.1 mg/kg/day; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). ALT = alanine aminotransferase; Bd Wt = body weight; BrdU = bromodeoxyuridine; Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Endocr = endocrine; EPN = O-ethyl-O-nitrophenul phenylphosphorothionate; F = female; (G) = gavage; Gastro = gastrointestinal; Gd = gestatinal day; (GO) = gavage in oil; Hemato = hematological; LDs, = lethal dose, 50% kill; LD4oo = lethal dose, 100% kill; LOAEL = lowest-observable-adverse-effect level; M = male; Musc/skel = musculoskeletal; NOAEL = no-observable-adverse-effect level; NS = not specified; wk = week(s); x = times; yr = year(s) S103443 H1TV3H ¢ INIZN3EOHOTHOIA-¥'I «~LNIWWOD O178Nd HOH 14vHQa... Figure 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral Acute (<14 days) Systemic go © 8 5 gE 5 £ o 5 g /kg/day) < & ~ F . £ 7 8 m £ mee 5 3 $ $ $d 55 § 10000 Q z @ & Ss £2 & 4 5g He; Oe ° 23m 24m 1000 Feo 7c 8 qa 160 im 19 9 0 a o> > 16r zr er 250 2 - 18m m 11r 22m 12r 27r «DO 009%05 0 23m oO «sO00°C0 21m 3 . o oO id a - O tar 15 18m oO 100 | 4 Se 0 27 or Qo 10 O 9r 1 Fk 0.1 Key 0.01 } ro rat ® | D,, (animals) 1 Minimal risk m mouse . . level for g guineapig ® LOAEL for serious effects (animals) I effects other 0001 L (» LOAEL for less serious effects (animals) than cancer O NOAEL (animals) The number next to . each point corresponds @ CEL: cancer effect level (animals) to entries in Table 2-2. 0.0001 } * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 0.00001 L S103443 HIIVIH 2 3IN3ZN3IBOHOTHOIA-v'} vs ~INIJWWOD 01M18Nd HO 14VHQA.. Figure 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (cont.) Intermediate (15-364 days) (mg/kg/day) 10000 1000 Ff 100 | 10 t+ 0.01 | 0.001 F 0.0001 0.00001 LE Systemic 0 x g 3 o < Ss 9 vet © 3 = 5S Q 5 > T $ & 3 & & 5 & Q x oO o I S IT 29m 33; 35M 33r 35m ay 30 33r 35m 28) O 36m O O 3m O 38m 36m O ©O 36m 33r ® 32r 3 oO 32r 0 32r of 0 35m 32r 0 30r ar @ 34m 36m O a O 0 33 O ® 300*0 0 0 31 ® Oo. oO 3m O oO Qo 33r 34m 36m 31r 1 I I 1 1 1 I 1 I i I 1 J Key ro rat B® | D,, (animals) 1 Minimal risk m mouse . . level for g guinea pig @® LOAEL for serious effects (animals) '. effects other Q LOAEL for less serious effects (animals) than cancer O NOAEL (animals) The number next to . each point corresponds @ CEL: cancer effect level (animals) to entries in Table 2-2. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 2 3N3ZN3I8OHOTHOIA vt SS «+LNJWWOD O178Nd HOH L4VHQ... Figure 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (cont.) Intermediate (15-364 days) Systemic = $8 ¥ 2 ¢ c 3 § § _ 5 5 5 S gs 5 3 (mofkalday) 2 g § 5 & £8 § § Oo o 10000 «& G 9 © 4 iE 2 35m 33r 35m 33r 35m 33 35m 33 38m 40r 41m O 36m O ©O mm O O 36m yO 36m ® Bm ® Oo 1000 | 32r fe) 32r O 32r 0 32r 3 0 30r 32r 34m 3m 8 8S Qo 33r Oo oO 3 Oo 33r oO oO 33r oO 0 37r 38m 39r 41m woe 0 o 100 } 10 | 1 0.1 } Key 0.01 k r rat n LD4, (animals) 1 Minimal risk m mouse . z level for g guinea pig @® LOAEL for serious effects (animals) I effects other 0.001 ( LOAEL for less serious effects (animals) than cancer O NOAEL (animals) The number next to . each point corresponds @ CEL: cancer effect level (animals) to entries in Table 2-2. 0.0001 * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 0.00001 I 3IN3IZN3GOHOTHOIA-v't S103443 H1TV3H 2 ~+LNIWWOD 2178Nd HOH L3VHA... Figure 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral (cont.) Chronic (>365 days) Systemic s & 3 33 ~ Cc [J] 5 = = = 0.0 -~ o > S 2 2 5 > 5 8 = 2 g g g 2 sg $8 > S x hg) 8 003 8 3 3 g @ 5 g & s §§ ¢ Ss & vee gs £8 gz ¢ gd § 5 § 3 & £5 5 §& 4 1000 Q @ oO O Ss 7 @ 3 Q Oo © £3 = @ oO a OO OO OO OO Oum 43 4am um O00 OC 40 Ow 00 OO sir @ @ 43r 44m 43r 44m 43r 44m 43r 44m 43r Qo ® ® “3 Qo 43r 44m 43r 44m Qo 44m 451 47r 48m 49r 50m $ 52m 100 | Qo 0 Oo 0 43r 43r 10 1} 01 | 0.01 10-4 Key Estimated 0.001 ror ® LD, (animals) 1 Minimal risk 10-5 4 Upper-Bound m mouse EL f . f imal I level for Human g guinea pig @® LOAEL for serious effects (animals) 1 effects other o mee C000 ® LOAEL for less serious effects (animals) ~~ than cancer _ poi 1s O NOAEL (animals) The number next to . each point corresponds @ CEL: cancer effect level (animals) to entries in Table 2-2. 0.00001 L *p oo 10-7 oses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 3NIZN38OHOTHIIA-v'L S103443 H1TV3H 2 Ls 1,4-DICHLOROBENZENE 58 2. HEALTH EFFECTS for 13 weeks (NTP 1987). At sacrifice, animals were examined grossly and major tissues were examined histologically. No compound-related cardiovascular effects were observed at any dose level. In parallel studies, B6C3F; mice were administered 1,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks. As with the rats, no compound-related cardiovascular effects were observed in mice at any of the doses used (NTP 1987). In 2-year exposure studies in Fischer 344 rats, no cardiovascular effects were reported in males or females that received 1,4-dichlorobenzene by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively (NTP 1987). In similarly dosed B6C3F, mice, no cardiovascular effects were reported in either sex at doses up to 600 mg/kg/day (NTP 1987). Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after oral exposure to 1,4-dichlorobenzene. In a series of dose range-finding studies, groups of Fischer 344 rats were administered 1,4-dichloro- benzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). At sacrifice, animals were examined grossly and major tissues were examined histologically. Gastrointestinal effects were observed at doses of 1,200 mg/kg/day or more and consisted of epithelial necrosis and villar bridging of the mucosa of the small intestines. No gastrointestinal effects were noted in rats treated with 1,4-dichlorobenzene at doses of 900 mg/kg/day or less (NTP 1987). In parallel studies with B6C3F, mice, no compound-related gastrointestinal effects were observed after administration of 1,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). In 2-year exposure studies in Fischer 344 rats, no gastrointestinal effects were reported in males or females that received 1,4-dichlorobenzene by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively (NTP 1987). In similarly dosed B6C3F, mice, no gastrointestinal effects were reported in either sex at doses up to 600 mg/kg/day (NTP 1987). Hematological Effects. A 21-year-old pregnant woman who had eaten 1-2 blocks of I.4-dichlorobenzene toilet air freshener per week throughout pregnancy developed severe microcytic, hypochromic anemia with excessive polychromasia and marginal nuclear hypersegmentation of the neutrophils. Heinz bodies were seen in a small number of the red cells. After she discontinued this ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 59 2. HEALTH EFFECTS practice (at about 38 weeks of gestation), her hemoglobin levels began to rise steadily. She gave birth to a normal infant with no hematological problems, and her own red blood cells were again normal at the final check 6 weeks after delivery (Campbell and Davidson 1970). Acute hemolytic anemia and methemoglobinuria were reported to have occurred in a 3-year-old boy who had been playing with 1,4-dichlorobenzene crystals (Hallowell 1959). It is not clear whether this child had actually ingested any of the 1,4-dichlorobenzene crystals. Hematological effects reported in animal studies have been mainly effects on red cells in rats and on white cells in mice. No adverse effects on hemoglobin levels or hematocrit were seen in adult male albino rats dosed with 1,4-dichlorobenzene by gavage in corn oil at levels up to 40 mg/kg/day for 90 days (Carlson and Tardiff 1976). In Fischer 344 rats administered 1,4-dichlorobenzene by gavage in corn oil, 7 days a week for 13 weeks at doses of 75-600 mg/kg/day, no compound-related hematological effects were noted (Bomhard et al. 1988). In a series of experiments performed by Hollingsworth et al. (1956), male rats were administered 1,4-dichlorobenzene by gavage in olive oil at doses of 10-500 mg/kg/day, 5 days a week for 4 weeks; female rats received 1,4-dichlorobenzene in like manner at doses of 18.8-376 mg/kg/day, S days a week for 192 days; and male and female rabbits received 500 mg/kg/day 1,4-dichlorobenzene, 5 days per week for 367 days. At all doses investigated, administration of 1,4-dichlorobenzene produced no hematological effects. In another 13-week study in Fischer 344 rats, male rats that received 1,4-dichlorobenzene at 300 mg/kg/day and above had decreased hematocrit levels, red blood cell counts, and hemoglobin concentrations (NTP 1987). None of these hematologic effects were consistently seen in female rats at the same dosage level; however, a decrease in mean corpuscular volume was noted in females at doses of 600 mg/kg/day or more. In a parallel study in male and female B6C3F, mice dosed with 84.4-900 mg/kg/day 1,4-dichlorobenzene for 13 weeks, no hematological effects were noted in male or female mice at doses up to 900 mg/kg/day (NTP 1987); however, in another study in B6C3F, mice dosed with 600-1,800 mg/kg/day 1,4-dichlorobenzene for 13 weeks, hematologic effects included 34-50% reductions in the white cell counts in all male dose groups; these decreases were accompanied by 26-33% decreases in lymphocytes and 69-82% decreases in neutrophils. No hematological effects were noted in female B6C3F, mice at doses up to 1,800 mg/kg/day (NTP 1987). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 60 2. HEALTH EFFECTS No hematologic effects were reported in 2-year studies in which male Fischer 344 rats received 1,4-dichlorobenzene at levels up to 300 mg/kg/day/day and female rats received levels up to 600 mg/kg/day (NTP 1987). Similar results were reported in B6C3F, mice of both sexes exposed to 600 mg/kg/day 1,4-dichlorobenzene for 2 years (NTP 1987). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after oral exposure to 1,4-dichlorobenzene. In a series of dose range-finding studies, groups of Fischer 344 rats were administered 1,4-dichloro- benzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks. At sacrifice, animals were examined grossly and major tissues were examined histologically. No musculoskeletal effects were noted in any of the 1,4-dichlorobenzene-treated rats. In parallel studies with B6C3F, mice, no compound-related musculoskeletal effects were observed after administration of 1,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). In 2-year exposure studies in Fischer 344 rats, no musculoskeletal effects were reported in males or females that received 1,4-dichlorobenzene by gavage in corn oil at levels up to 300 or 600 mg/kg/day, respectively. In similarly dosed B6C3F,; mice, no musculoskeletal effects were reported in either sex at doses up to 600 mg/kg/day (NTP 1987). Hepatic Effects. A single case study was located regarding hepatic effects in humans after oral exposure to 1,4-dichlorobenzene. In this case report, the author describes a 3-year-old boy who had been playing with crystals containing 1,4-dichlorobenzene for 4-5 days before being admitted to the hospital. On admission, the boy was jaundiced and his mucous membranes were pale. After a blood transfusion, the child gradually improved. It should be noted that it was unclear from this report whether the boy actually ingested any of the 1,4-dichlorobenzene (Hallowell 1959). In a series of experiments, Eldridge et al. (1992) studied the acute hepatotoxic effects of 1,4-dichloro- benzene and the role of cell proliferation in hepatotoxicity in B6C3F, mice and Fischer 344 rats. Mice and rats received a single dose of 1,4-dichlorobenzene by gavage in corn oil of 600, 900, or 1,200 mg/kg/day. At 1, 2, 4, and 8 days after 1,4-dichlorobenzene treatment, selected animals were injected intraperitoneally with 5-bromo-2’-deoxyuridine (BrdU) 2 hours prior to sacrifice to monitor ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 61 2. HEALTH EFFECTS cell proliferation. Other groups of mice and rats were sacrificed 24 or 48 hours after dosing, blood was collected for liver enzyme analysis, and liver sections were collected for histopathology. In mice dosed with 600 mg/kg/day 1,4-dichlorobenzene, liver weights were significantly increased 48 hours after dosing. Labeling index (LI), indicative of cell proliferation, peaked 24 hours after dosing in females and 48 hours in males. Activities of serum enzymes associated with liver damage (alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, sorbitol dehydrogenase) were not affected by 1,4-dichlorobenzene. Twenty-four and 48 hours after administration of 1,4-dichloro- benzene, the livers of males showed periportal hepatocytes with vacuolated cytoplasm and centrilobular hepatocytes with granulated basophilic cytoplasm; the severity of these changes was dose- related at 48 hours, but not at 24 hours. Similar but less pronounced effects were seen in females at 24 hours. In rats, liver weights were significantly increased at all time points after administration of 600 mg/kg/day 1,4-dichlorobenzene. The LI peaked 24 hours after dosing and was still elevated after 48 hours. Necrosis was not observed in the livers of mice or rats after treatment with 1,4-dichloro- benzene. In pregnant CD rats administered 1,4-dichlorobenzene in corn oil at doses of 250-1,000 mg/kg/day on Gd 6-15, no differences in maternal liver weight were noted (Giavini et al. 1986); however, hepatic effects have been reported in other oral studies in which 1,4-dichlorobenzene has been administered to test animals by gavage. These effects have ranged from temporary elevation of hepatic enzymes to hepatic degeneration and necrosis. In male B6C3F| mice, single doses of 600, 1,000 or 1,800 mg/kg/day 1,4-dichlorobenzene administered by gavage in corn oil resulted in significantly elevated BrdU labeling of hepatocytes at the 1,000 and 1,800 mg/kg/day doses. In addition, single doses of 1,800 mg/kg resulted in a 4.5-fold increase in serum alanine aminotransferase (ALT) activity and severe centrilobular hepatocyte swelling. In a companion time-course study, single doses of 1,800 mg/kg 1,4-dichlorobenzene administered by gavage in corn oil resulted in significantly elevated BrdU labeling in hepatic samples on days 2, 3, and 4, but not days 1 or 7. ALT activity was significantly elevated in 1,4-dichlorobenzene-treated mice on day 2 only. In all other aspects, hepatic toxicity was not evident in mice dosed with 1,800 mg/kg 1,4-dichlorobenzene (Umemura et al. 1996). 1,4-Dichlorobenzene has been shown to produce disturbances in porphyrin metabolism after high-level/ acute-duration exposure. Increased excretion of porphyrins, especially coproporphyrin and ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 62 2. HEALTH EFFECTS uroporphyrin, are considered to be indicators of liver damage. Administration of 1,4-dichlorobenzene in liquid paraffin to male rats at gradually increasing doses, until a dose level of 770 mg/kg/day was maintained for 5 days, resulted in high porphyrin excretion (Rimington and Ziegler 1963). Mean peak values of urinary coproporphyrin increased to about 10—15-fold above levels in controls. A 37-100-fold increase in urinary uroporphyrin levels occurred; porphobilinogen levels increased 200-530-fold; and a 10-fold increase in d-aminolevulinic acid (3-ALA) levels was observed. In the liver itself, coproporphyrin levels were similar to controls, uroporphyrin levels were increased 46-fold, and protoporphyrin levels were increased 6-fold. These dramatic increases, which suggest severe damage to the liver, were not observed when 1,4-dichlorobenzene was administered to rats at higher levels (850 mg/kg/day) in 1% cellofas (Rimington and Ziegler 1963) or at lower levels for a longer period of time in another study (Carlson 1977), as discussed below. Also, Trieff et al. (1991) have used animal data on porphyrogenicity from various chlorinated benzenes to perform a QSAR study allowing prediction of ambient water criteria. Changes in other markers of liver function including cytochrome Py, levels, and activities of some drug-metabolizing enzymes (aminopyrine N-demethylase and aniline hydroxylase) were investigated in rats treated with of 1,4-dichlorobenzene by gavage at 250 mg/kg/day for up to 3 days (Ariyoshi et al. 1975). Activity of 3-ALA synthetase, an enzyme used in synthesis of the heme moiety found in cytochromes, was increased 42% by treatment with 1,4-dichlorobenzene. However, the cytochrome P,so content did not change, although the microsomal protein content of liver preparations was increased. The toxicological significance of these findings is not clear since 6-ALA synthetase activity did not correlate with cytochrome Ps, concentration. Effects on hepatic enzyme activities were reported to have occurred in adult male rats that were given 1,4-dichlorobenzene by gavage for 14 days (Carlson and Tardiff 1976). Significant decreases in hexobarbital sleeping time and a 6.5-fold increase in serum isocitrate dehydrogenase activity were observed after a 14-day treatment regimen at 650 mg/kg/day. In addition, even at considerably lower levels (20 or 40 mg/kg/day) increases were observed in the activities of hepatic microsomal xenobiotic metabolic systems including levels of glucuronyl transferase, and benzpyrene hydroxylase and O-ethyl- O-nitrophenyl phenylphosphorothionate (EPN) detoxification to nitrophenol. In a 90-day study at the same dosage levels, significant increases were seen in EPN detoxification, benzpyrene hydroxylase, and azoreductase levels. The former 2 levels were still elevated at 30 days after the cessation of administration of the compound. Most increases were noted at 20 mg/kg/day and above as in the ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 63 2. HEALTH EFFECTS 14-day studies; however, azoreductase levels were elevated even at 10 mg/kg/day (Carlson and Tardiff 1976). These observations are important because they demonstrate that hepatic effects occur at levels of 1.4-dichlorobenzene that are far below those associated with severe histopathology. Histopathological effects in the liver, including cloudy swelling and centrilobular necrosis, were observed after gavage administration of 1,4-dichlorobenzene in rats (2 per group) at 500 mg/kg/day for 4 weeks: similar results (cloudy swelling, focal caseous necrosis) were obtained in rabbits (5 per group) given 92 doses of 1,000 mg/kg/day 1,4-dichlorobenzene in olive oil over a 219-day period (Hollingsworth et al. 1956). The interpretation of this study is limited by the size of the test groups and the fact that observations in controls were not presented. Histopathological changes were also reported in a 13-week study in which rats received 1,4-dichlorobenzene by gavage (NTP 1987). Doses of 1,200 or 1,500 mg/kg/day produced degeneration and necrosis of hepatocytes. Serum cholesterol levels were increased by doses of 600 mg/kg/day or more in male rats and by 900 mg/kg/day or more in female rats, while serum triglycerides and protein levels were reduced at doses of 300 mg/kg/day or more in male rats. Urinary porphyrins were increased in both sexes at 1,200 mg/kg/day or more. However, these increases were modest and considered by the authors to indicate mild porphyrinuria rather than hepatic porphyria. Liver porphyrins were not increased at any dose. In a second 13-week study in the same laboratory, hepatic effects were not observed in rats at dosage levels up to 600 mg/kg/day (NTP 1987). Similar hepatic effects were reported in two 13-week gavage studies in mice (NTP 1987). Hepato- cellular degeneration was observed in both sexes at all doses (600-1,800 mg/kg/day). Serum cholesterol levels were increased in male mice at doses of 900 mg/kg/day or more, and serum protein and triglycerides were increased at doses of 1,500 mg/kg/day or more. These changes were thought by the authors to reflect the hepatic effects of this compound. Hepatic porphyria was not found in mice at any dose level in this study. Because hepatic effects were seen in mice in all dose groups in the first 13-week study, a second 13-week study was conducted at lower dosage levels. Hepatocellular cytomegaly was observed in mice at doses of 675 mg/kg/day and above. The lowest level at which hepatic effects were observed in mice was 600 mg/kg/day (in the first study). Other intermediate-duration oral studies with 1,4-dichlorobenzene have reported liver toxicity. In female rats dosed with 1,4-dichlorobenzene by gavage for about 6 months, doses of 188 mg/kg/day and above resulted in increased liver weights. At 376 mg/kg/day, slight cirrhosis and focal necrosis of ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 64 2. HEALTH EFFECTS the liver were also observed (Hollingsworth et al. 1956). No effects on the liver were seen at a dose of 18.8 mg/kg/day. Based on a NOAEL (increased liver weight) of 18.8 mg/kg/day, an intermediate-duration MRL of 0.1 mg/kg/day was calculated as described in the footnote to Table 2-2 and Appendix A (Hollingsworth et al. 1956). The ability of 1,4-dichlorobenzene to induce porphyria was investigated in female rats that were administered 1,4-dichlorobenzene by gavage for up to 120 days (Carlson 1977). Slight but statistically significant increases in liver porphyrins were seen in all dosed rats (50-200 mg/kg/day) at 120 days. Urinary excretion of 8-ALA, porphobilinogen, or porphyrins was not increased over control levels. These results indicated that 1,4-dichlorobenzene had only a slight potential for causing porphyria at these doses in female rats compared with the far more pronounced porphyrinogenic effects reported earlier in male rats that received 770 mg/kg/day for 5 days in a study by Rimington and Ziegler (1963). However, sex-related differences in susceptibility to 1,4-dichlorobenzene's effects on these parameters cannot be ruled out in a comparison of these two studies. Female rats were used in the Carlson (1977) study because the author thought that females would be more susceptible to the porphyrinogenic effects of 1,4-dichlorobenzene and the other compounds tested in their study based on the results of other studies that had been previously conducted using hexachlorobenzene. The role of cell proliferation in liver toxicity induced by 1,4-dichlorobenzene was examined in groups of mice (5-7 per sex per dose level) administered 0 (vehicle only), 300, or 600 mg/kg 1,4-dichlorobenzene in corn oil by gavage 5 days a week for 13 weeks (Eldridge et al. 1992). The liver toxicity induced by 1,4-dichloro- benzene was also examined in groups of female rats (5-7 per dose level) administered 0 (vehicle only), or 600 mg/kg 1,4-dichlorobenzene in corn oil by gavage 5 days a week for 13 weeks. At various times during the study, mice were implanted with osmotic pumps to deliver BrdU. Liver weights were significantly increased in high-dose male and female mice and in female rats throughout the 13-week study. Treated male mice showed a centrilobular pattern of labeled hepatocytes, whereas females were labeled throughout the lobules. At the lower-dose level, liver weight was increased in male and female mice at weeks 6 and 13. In a group of mice in which treatment with 600 mg/kg/day ceased after 5 weeks and the animals were allowed to recover for 1 week, liver weight returned to control values. The authors concluded that 1,4-dichlorobenzene induced a mitogenic stimulation of cell proliferation in the liver rather than a regenerative response following cytotoxicity. This was evidenced by an increase in liver weight without increase in liver-associated plasma enzymes (Eldridge et al. 1992). “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 65 2. HEALTH EFFECTS Studies of the hepatic effects of chronic 1,4-dichlorobenzene exposure are sparse. The toxicity of 1 4-dichlorobenzene was evaluated in a group of 7 rabbits administered 1,4-dichlorobenzene in olive oil at a dose of 500 mg/kg/day a total of 263 times over a 367-day period. Slight changes in the liver (cloudy swelling and a few areas of focal caseous necrosis) were noted at sacrifice (Hollingsworth et al. 1956). In the only study of lifetime oral exposure to 1,4-dichlorobenzene in laboratory animals, groups of male and female Fischer 344 rats were administered 1,4-dichlorobenzene by gavage in corn oil 5 days a week for 103 weeks at doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females). Groups of male and female B6C3F; mice were administered 1,4-dichlorobenzene at doses of 300 or 600 mg/kg/day by gavage in corn oil, 5 days a week for 103 weeks. No hepatic effects were seen in rats: in mice, the incidence of hepatocellular degeneration was greatly increased in treated mice (in males: 0 of 50 control, 36 of 49 low-dose, 39 of 50 high-dose; in females 0 of 50 control, 8 of 48 low-dose, 36 of 50 high-dose). The primary degenerative change was cellular swelling with clearing or vacuolation of the cytoplasm. Individual hepatocytes had pyknotic or karyorrhectic nuclei and condensed eosinic cytoplasm. Some necrotic hepatocytes formed globular eosinophilic masses in the sinusoids (NTP 1987). Renal Effects. No studies were located regarding renal effects in humans after oral exposure to 1,4-dichlorobenzene. The role of cell proliferation in kidney toxicity induced by 1,4-dichlorobenzene was examined in groups of male and female B6C3F| mice and Fischer 344 rats (Umemura et al. 1992). Mice were administered 300 or 600 mg/kg 1,4-dichlorobenzene; in rats, males received 150 or 300 mg/kg 1.4-dichlorobenzene while females received 300 or 600 mg/kg 1,4-dichlorobenzene. All doses were administered by gavage in corn oil for 4 consecutive days. Cell proliferation was evaluated by means of immunohistochemical measurement of BrdU-labeled cells. In mice, kidney weights and cell proliferation in the kidney tubules were not altered by 1,4-dichlorobenzene treatment; in rats, kidney weight was significantly increased in male rats at both dose levels, but was not affected in females. Cell proliferation was greatly increased in the proximal convoluted tubule from high-dose males. A lesser increase was seen in the proximal straight tubule from high-dose males; no increase was observed in the distal tubule from males or in any kidney region from treated female rats. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 66 2. HEALTH EFFECTS In a study which examined the role of the protein ay, -globulin in 1,4-dichlorobenzene-induced nephrotoxicity in male rats, NCI-Black-Reiter (NBR) rats, known not to synthesize the hepatic form of the 0, -globulin, were administered 500 mg/kg/day 1,4-dichlorobenzene by gavage in corn oil for 4 consecutive days. Positive controls consisted of Fischer 344 male rats treated with lindane; the results were also compared with those obtained in a group of female Fischer 344 rats treated with lindane. End points examined consisted of kidney lesions and protein droplet evaluation. a, -Globulin was detected in kidney sections from male Fischer 344 rats, but not in male NBR or female Fischer 344 rats. No lesions or hyaline droplets were detected in treated or control male NBR and female Fischer 344 rats (Dietrich and Swenberg 1991). Renal tubular degeneration has been observed in male but not female Fischer 344 rats in two 13-week gavage studies (NTP 1987). These effects were severe in male rats receiving 300 mg/kg/day or more in the first study, but in the second study, only slight changes were seen at 300 mg/kg/day, while moderate tubular degeneration was present at 600 mg/kg/day. Renal effects reported in another intermediate-duration gavage study in rats included increased renal weights at doses of 188 mg/kg/day or more (Hollingsworth et al. 1956). Renal effects were not observed in mice in either of two 13-week gavage studies using dosage regimens of 600-1,800 mg/kg/day and 84.4-900 mg/kg/day (NTP 1987). In a study designed to investigate the mechanism of renal toxicity for 1,4-dichlorobenzene reported in the NTP (1987) studies, 1,4-dichlorobenzene administered by gavage to male Fischer 344 rats at 7 daily doses of 120 or 300 mg/kg/day significantly increased the level of protein droplet formation in the kidneys of males but not females (Charbonneau et al. 1987). Administration of a single dose of 14C-1,4-dichlorobenzene by gavage at S00 mg/kg gave similar results. An analysis of the renal tissue of animals administered radio-labeled 1,4-dichlorobenzene indicated that it was reversibly associated with the protein 0, -globulin. In a study designed to correspond to the experimental conditions of the 13-week NTP (1987) study in rats, 1,4-dichlorobenzene was administered to Fischer 344 rats by gavage at 75-600 mg/kg/day for 13 weeks; interim sacrifices were performed at 4 weeks (Bomhard et al. 1988). At 4 weeks, females had no structural damage to the kidneys, while males experienced damage at the corticomedullary junction at a doses of 150 mg/kg or more; damage consisted of dilated tubules with granular and crystalline structures, hyaline droplets, and desquamated epithelia. At all dose levels in the males, hyaline bodies were seen in the proximal tubule epithelial cells. At 13 weeks, males exhibited an increase urinary excretion of lactate dehydrogenase (LDH) and of "**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 67 2. HEALTH EFFECTS epithelial cells over the entire dose range tested. These changes did not always appear to be dose- related. No signs of structural damage were seen in the females’ kidneys. In males, a dose-dependent incidence of hyaline droplets in the cortical tubular epithelium was seen at 75 mg/kg/day and above. At 2150 mg/kg/day, single-cell necrosis was observed, and at 300 and 600 mg/kg/day, epithelial desquamation of longer parts of the tubules were occasionally seen. In the only available study of chronic-duration oral exposure to 1,4-dichlorobenzene, renal effects were observed to occur preferentially in males. Male Fischer 344 rats exposed to 1,4-dichlorobenzene at 150 and 300 mg/kg/day by gavage for 2 years exhibited the following effects with greater severity and in greater numbers: nephropathy, epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal medulla, and focal hyperplasia of renal tubular epithelium (NTP 1987). There was also increased incidence of nephropathy in female rats dosed with 1,4-dichlorobenzene at 300 and 600 mg/kg/day, but there was minimal hyperplasia of the renal pelvis or tubules. Two-year administration of 1,4-dichlorobenzene at 300 and 600 mg/kg/day also increased the incidence of nephropathy in male B6C3F; mice. Renal tubular degeneration was noted in female mice but these changes occurred at a lower frequency and were qualitatively different from those in male rats (NTP 1987). Endocrine Effects. No studies were located regarding endocrine effects in humans after oral exposure to 1,4-dichlorobenzene. In a series of dose range-finding studies, groups of Fischer 344 rats were administered 1,4-dichloro- benzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks. At sacrifice, animals were examined grossly and major tissues were examined histologically. No endocrine organs were affected in any of the 1,4-dichlorobenzene-treated rats. In parallel studies with B6C3F, mice, no compound-related endocrine effects were observed after administration of 1,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). In the only study of lifetime oral exposure to 1,4-dichlorobenzene in laboratory animals (NTP 1987), groups of male and female Fischer 344 rats were administered 1,4-dichlorobenzene by gavage in corn oil, 5 days a week for 103 weeks at doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females). Groups of male and female B6C3F; mice were administered 1,4-dichlorobenzene at doses “**DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 68 2. HEALTH EFFECTS of 300 or 600 mg/kg/day by gavage in corn oil, 5 days a week for 103 weeks. In the Fischer 344 rats, an increased incidence of parathyroid hyperplasia was observed in males (4 of 42 controls, 13 of 42 low-dose, 20 of 38 high-dose), while no effect was seen in females. In mice, the incidence of thyroid follicular cell hyperplasia increased with dose in males (1 of 47 control, 4 of 48 low-dose, 10 of 47 high-dose), but not in females. The incidence of adrenal medullary hyperplasia and focal hyperplasia of the adrenal gland capsule also increased with dose in males (controls, 11 of 47; low- dose, 21 of 48; high-dose, 28 of 49). Dermal Effects. A 19-year-old black woman who had been eating 4-5 moth pellets made of 1,4-dichlorobenzene daily for 2.5 years developed symmetrical, well demarcated areas of increased pigmentation in a bizarre configuration over various parts of her body. After she discontinued this practice, the skin discolorations gradually disappeared over the next 4 months (Frank and Cohen 1961). In laboratory animals, groups of Fischer 344 rats were administered 1,4-dichlorobenzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks. No dermal effects were noted in any of the 1,4-dichlorobenzene-treated rats. In parallel studies with B6C3F; mice, no compound-related dermal effects were observed after administration of I,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). In the only study of lifetime oral exposure to 1.4-dichlorobenzene in laboratory animals (NTP 1987), groups of male and female Fischer 344 rats were administered 1,4-dichlorobenzene by gavage in corn oil, 5 days a week for 103 weeks at doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females). Groups of male and female B6C3F, mice were administered 1,4-dichlorobenzene at doses of 300 or 600 mg/kg/day by gavage in corn oil, 5 days a week for 103 weeks. No dermal effects have been reported in rats or mice at any of the studied doses. Ocular Effects. No studies were located regarding the ocular effects in humans after oral exposure to 1,4-dichlorobenzene. In a series of intermediate-duration studies, groups of Fischer 344 rats were administered 1,4-dichloro- benzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil 5 days a week ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 69 2. HEALTH EFFECTS for 13 weeks. Ocular discharge was noted prior to death in males dosed with 1,200 mg/kg and in all rats exposed to 1,500 mg/kg. In parallel studies with B6C3F| mice, no compound-related ocular effects were observed after administration of 1,4-dichlorobenzene at concentrations ranging from 84.4 to 1,800 mg/kg/day by gavage in corn oil 5 days a week for 13 weeks (NTP 1987). The ocular effects of oral administration of 1,4-dichlorobenzene were examined in groups of white (strain no reported) female rats and male and female rabbits. Rats received 1,4-dichlorobenzene in olive oil at doses of 18.8-376 mg/kg/day, 5 days a week for 192 days; rabbits received 1,4-dichloro- benzene in olive oil at a dose of 1,000 mg/kg/day for 219 days. Under the study conditions, administration of 1,4-dichlorobenzene did not produce cataracts in either species (Hollingsworth et al. 1956). In chronic-duration toxicity studies in laboratory animals, Hollingsworth et al. (1956) found no evidence of cataract formation in rabbits administered a total of 263 doses of 500 mg/kg/day 1,4-dichlorobenzene in olive oil over a 367-day period. In two lifetime oral exposure studies (NTP 1987), groups of male and female Fischer 344 rats were administered 1,4-dichlorobenzene by gavage in corn oil, 5 days a week for 103 weeks at doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females); groups of male and female B6C3F, mice were administered 1,4-dichlorobenzene at doses of 300 or 600 mg/kg/day by gavage in corn oil, 5 days a week for 103 weeks. In both species, no ocular effects were noted at any of the studied doses. Body Weight Effects. No studies were located regarding body weight effects in humans after oral exposure to 1,4-dichlorobenzene. The effects of acute exposure to 1,4-dichlorobenzene on body weight were examined in female Wistar rats given 1,4-dichlorobenzene suspended in 2% tragacanth gum solution (a suspending agent obtained from the dried gummy exudation of Astragalus gummifer) at a dose of 250 mg/kg/day for 3 days. Under these conditions, no effects on body weight were seen (Ariyoshi et al. 1975). Male and female mice and female rats dosed once with 600 mg/kg/day 1,4-dichlorobenzene also showed no discernible changes in body weight (Eldridge et al. 1992). Male rats administered 770 mg/kg/day of 1.4-dichloro- benzene once a day for 5 days showed no changes in body weight (Rimington and Ziegler 1963). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 70 2. HEALTH EFFECTS Pregnant CD rats that were administered 250—1,000 mg/kg/day 1,4-dichlorobenzene in corn oil on Gd 6-15 experienced a reversible loss in maternal body weight (Giavini et al. 1986). Body weight changes were observed in two studies in rats and mice (NTP 1987). In the first, both sexes of mice and female rats dosed at concentrations up to 1,000 mg/kg/day for 14 days by gavage demonstrated no changes in body weight during the test period. Male rats dosed at 500 mg/kg/day also showed no changes in body weight; however, a 7-12% decrease in body weight was noted in the 1,000 mg/kg/day dose group. In the second study (same route and duration as the first), male mice experienced a 13.3% decrease in body weight at the 250 mg/kg/day dose and a 14.7% decrease in body weight at the 2,000 mg/kg/day dose; however, results of intermediate doses demonstrated that there was no observable dose-response relationship for body weight changes. Neither male nor female rats dosed with 500 mg/kg/day showed any effects on body weights; however, a dose of 1,000 mg/kg/day resulted in a 13.5% decrease in weight for males and a 16.7% decrease in females. In intermediate-duration studies, no compound-related effects on weight gain were noted in albino or Fischer 344 rats administered 1,4-dichlorobenzene by gavage in corn oil at doses up to 600 mg/kg/day, 7 days a week for 13 weeks (Bomhard et al. 1988; Carlson and Tardiff 1976). Male and female mice and female rats dosed with concentrations of 600 mg/kg/day 1,4-dichlorobenzene 5 days a week for I3 weeks also showed no discernible changes in body weight (Eldridge et al. 1992). In a series of dose range-finding studies, groups of Fischer 344 rats were administered 1,4-dichlorobenzene at concentrations ranging from 37.5 to 1,500 mg/kg/day by gavage in corn oil, 5 days a week for 13 weeks (NTP 1987). In the first of these studies, there were no treatment-related effects on body weight at doses up to 600 mg/kg/day. In the second study, final body weight was decreased by 11% in low-dose males (300 mg/kg/day) relative to controls; in high-dose males (1,500 mg/kg/day) the reduction was 32%. The effect was less marked in females (6% reduction at 900 mg/kg/day; 11% reduction at 1,200). In parallel studies with B6C3F, mice, no compound-related effects on body weight were observed after administration of 1,4-dichlorobenzene at concentrations up to 900 mg/kg/day; however, in the second study, final body weight was reduced in all males receiving I.4-dichlorobenzene (11.4% at 1,500 mg/kg/day to 13.9% at 600 mg/kg/day) and in females at 600 mg/kg/day (10.3%) (NTP 1987). In 2 lifetime oral exposure studies, groups of male and female Fischer 344 rats and BO6C3F,| mice were administered 1,4-dichlorobenzene by gavage in corn oil, 5 days a week for 103 weeks. Fischer 344 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 71 2. HEALTH EFFECTS rats were administered 1,4-dichlorobenzene at doses of 150 or 300 mg/kg/day (males) or 300 or 600 mg/kg/day (females); mice were administered 1,4-dichlorobenzene at doses of 300 or 600 mg/kg/day (NTP 1987). In mice, no effects on body weight attributable to treatment with I.4-dichlorobenzene were observed at doses up to 600 mg/kg/day. In rats, body weight gain was depressed by 12.5% in high-dose males (300 mg/kg/day) and by 12.4% in high-dose females (600 mg/kg/day) relative to vehicle controls. 2.2.2.3 Immunological and Lymphoreticular Effects No studies were located regarding immunological effects in humans after oral exposure to 1,4-dichlorobenzene. Symmetrical lesions with a bizarre pattern of skin pigmentation over most of her body were reported in the case study of a 19-year-old black woman who ingested 4-5 moth pellets of 1,4-dichlorobenzene per day for a 2.5-year period (Frank and Cohen 1961). The lesion disappeared 4 months after cessation. The described lesions may have been the result an immunological response to 1,4-dichlorobenzene. However, this possibility was not addressed by the authors. Groups of Fischer 344 rats were administered 1,4-dichlorobenzene at concentrations ranging from 300 to 1,500 mg/kg/day by gavage in corn oil, 5 days a week for 13 weeks (NTP 1987). Treatment- related immunological and lymphoreticular effects noted in the study included hypoplasia of the bone marrow and lymphoid depletion of the spleen and thymus in males and females at doses of 1,200 mg/kg/day and above. In parallel studies with B6C3F, mice administered 1,4-dichlorobenzene at concentrations ranging from 300 to 1,500 mg/kg/day, lymphoid necrosis in the thymus, lymphoid depletion in the spleen, and hematopoietic hypoplasia of the spleen and bone marrow were noted in both males and females at doses of 1,500 mg/kg/day and above (NTP 1987). Minimal lymphoreticular changes were noted in a chronic-duration study (NTP 1987). Male rats administered doses of 150 or 300 mg/kg/day and female rats given 300 or 600 mg/kg/day of 1,4-dichlorobenzene by gavage 5 days a week for 2 years showed no discernible changes in the lymphoreticular system; however, mice dosed in a similar fashion and at a dose of 600 mg/kg/day showed an increased incidence of lymph node hyperplasia. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 72 2. HEALTH EFFECTS 2.2.2.4 Neurological Effects Two case studies have reported neurological effects in humans exposed to 1,4-dichlorobenzene via ingestion have been reported in two case studies. A 21-year-old pregnant woman developed pica (a craving for unnatural substances) for 1,4-dichlorobenzene toilet bowl deodorizer blocks, which she consumed at the rate of 1-2 per week throughout pregnancy (Campbell and Davidson 1970). Reported neurological effects included fatigue, dizziness, and mild anorexia. These effects, however, are common general symptoms that occur in many women during normal pregnancy. A 19-year-old black woman who ingested 4-5 pellets of 1,4-dichlorobenzene daily for about 2.5 years developed tremors and unsteadiness after she stopped eating this chemical. However, in the opinion of the neurologist who evaluated the woman in this case report, the effects were considered to be psychological rather than the physiological effects of withdrawal from 1,4-dichlorobenzene (Frank and Cohen 1961). Two studies in laboratory animals indicate that oral exposure to 1,4-dichlorobenzene may result in adverse neurological effects. In a study performed by Rimington and Ziegler (1963), three male albino rats were administered daily doses of 1,4-dichlorobenzene in liquid paraffin at gradually increasing doses until a dose was reached (770 mg/kg/day) which resulted in high porphyrin excretion with very few fatalities; this dose was given for 5 days. Clinical symptoms associated with highly porphyric rats included extreme weakness, ataxia, clonic contractions, and slight tremors (a rarity). One rat receiving 1,4-dichlorobenzene developed left-sided hemiparesis. In Fischer 344 rats administered 1,4-dichlorobenzene by gavage in corn oil 5 days a week for 13 weeks, tremors and poor motor response were observed in males at 1,200 mg/kg/day and above, and in both sexes at 1,500 mg/kg/day. However, administration of 1,4-dichlorobenzene had no effect on brain weight or on the microscopical appearance of the brain, sciatic nerve, or spinal cord (NTP 1987). In a chronic-duration study (NTP 1987), no neurological effects were noted either in rats dosed with 300 mg/kg/day of 1,4-dichlorobenzene, 5 days a week for 2 years, or in mice dosed with 600 mg/kg/day, 5 days a week for 2 years. 2.2.2.5 Reproductive Effects Several studies were located which addressed the reproductive effects of oral exposure to 1,4-dichloro- benzene in laboratory animals. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 73 2. HEALTH EFFECTS In pregnant CD rats administered 1,4-dichlorobenzene by gavage in corn oil on Gd 6-15, doses up to 1,000 mg/kg/day had no adverse effect on the mean number of corpora lutea, mean number of implantations, mean percentage of pre- or post-implantation losses, or mean percentage of dams with resorptions (Giavini et al. 1986). In addition, male and female B6C3F; mice exposed to 1,4-dichloro- benzene by gavage in corn oil at doses of 600, 900, 1,000, 1,500, or 1,800 mg/kg/day, 5 days a week for 13 weeks showed no compound-related effects in regarding organ weight changes (organ/brain) of the testes or uteri; however, relative ovarian weights were significantly increased in the 1,500 mg/kg/day group. The gross and histological appearance of the mammary glands, testes, ovaries, and uteri were not affected by treatment with 1,4-dichlorobenzene (NTP 1987). In a chronic-duration study (NTP 1987), no effects were noted in the reproductive organs in either the rats dosed with 300 mg/kg/day of 1,4-dichlorobenzene, 5 days a week for 2 years, or in mice dosed with 600 mg/kg/day, 5 days a week for 2 years. 2.2.2.6 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to 1,4-dichloro- benzene. A dose-related increase in the incidence of an extra rib was observed in the fetuses of pregnant rats administered 1,4-dichlorobenzene by gavage on Gd 6-15 at doses of 500, 750, and 1,000 mg/kg/day (Giavini et al. 1986). A reduction in fetal weight was observed at 1,000 mg/kg/day. The reduction in fetal weight was not considered to be a fetotoxic effect since it was associated with a decrease in maternal weight gain at the same dosage level. The structural anomaly observed in these fetuses was dose-dependant but was not considered to be an true adverse effect by the authors. However, these results raise the question of whether 1,4-dichlorobenzene ingested by the dams reached developing fetal tissue and elicited a structural effect. The NOAEL and LOAEL for this study are recorded in Table 2-2 and plotted in Figure 2-2. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 74 2. HEALTH EFFECTS 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans after oral exposure to 1,4-dichloro- benzene. Gavage administration of 1,4-dichlorobenzene to B6C3F, mice and Fischer 344 rats at single doses of 300-1,000 mg/kg/day did not result in unscheduled deoxyribonucleic acid (DNA) synthesis in the mouse hepatocytes or in the renal tissue of the rats (Steinmetz and Spanggord 1987a, 1987b). However, 1.4-dichlorobenzene at the highest level did induce an increase in DNA replication (S-phase of cell division) in the renal tissue of the male rats and in the hepatocytes of the male mice. Based on a comparison with historical controls, the authors concluded that levels of DNA replication were also significantly elevated in the hepatocytes of female mice. No evidence of a clastogenic effect was found in mouse bone marrow erythroblasts after a single gavage administration of 1,4-dichlorobenzene at 2,500 mg/kg/day (Herbold 1986a). Similarly, no evidence of clastogenic effects were found in mouse bone erythroblasts after a single oral administration of 2,5-dichlorophenol (the major metabolite of 1,4-dichlorobenzene) at 1,500 mg/kg/day (Herbold 1986b). 2,5-Dichlorophenol with or without metabolic activation did not induce an increase in mutagenic response in the Chinese hamster ovary HGPRT forward mutation assay (Litton Bionetics 1986a). This compound was also inactive in the Balb/3T3 in vitro transformation assay (Litton Bionetics 1985). Cytogenetic effects were not found in bone marrow cells from mice treated with 1,4-dichlorobenzene by gavage at levels up to 1,800 mg/kg/day in a 13-week study (NTP 1987). No increase in micronucleated cells occurred even at levels that were extremely toxic to the test animals, resulting in liver toxicity and decreased survival rates. As noted by the authors of that study, the observed carcinogenic activity of 1,4-dichlorobenzene cannot be adequately predicted on the basis of the available genotoxicity data; all of the available information strongly suggests that 1,4-dichlorobenzene acts as a tumor promoter rather than as a mutagen. Other genotoxicity studies are discussed in Section 2.5. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 75 2. HEALTH EFFECTS 2.2.2.8 Cancer No studies were located regarding carcinogenic effects in humans after oral exposure to 1,4-dichloro- benzene. 1,4-Dichlorobenzene was found to have carcinogenic properties in B6C3F, mice and male (but not female) Fischer 344 rats exposed to 1,4-dichlorobenzene for 2 years in a carcinogenesis bioassay (NTP 1987). 1,4-Dichlorobenzene was administered by gavage to male rats at doses of 150 or 300 mg/kg/day and female rats at doses of 300 or 600 mg/kg/day. Significant dose-related increases in the incidence of renal tubular cell adenocarcinomas were reported in male rats (controls, 2%; low- dose, 6%; high-dose, 14%). Spontaneous tumors of this type are uncommon in male Fischer 344 rats; they have been diagnosed in only 4 of 1,098 (0.4%) of the corn oil-gavage controls in previous NTP studies. There were no tubular cell tumors in dosed or vehicle-control female rats. There also was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats which was only slightly higher than the incidence in historical controls from the same laboratory. The NTP study concluded that 1,4-dichlorobenzene was carcinogenic in male rats, but not in female rats. In a 2-year bioassay in B6C3F, mice that received 1,4-dichlorobenzene at 300 or 600 mg/kg/day (NTP 1987), increased incidences of hepatocellular carcinomas were observed in high-dose male mice (controls, 28%; low-dose, 22.5%; high-dose, 64%) and high-dose female mice (controls, 10%: low- dose, 10.4%; high-dose, 38%). Hepatocellular adenomas were increased in high- and low-dose male mice (controls, 10%; low-dose, 26.2%; high-dose, 32%) and in high-dose female mice (controls, 20%: low-dose, 12.5%: high-dose:, 42%). Female control mice in this bioassay had a substantially higher incidence of liver tumors than did historical controls. Hepatoblastomas (a rare form of hepatocellular carcinoma) were observed in four high-dose male mice along with other hepatocellular carcinomas. This tumor type had not been previously observed in 1,091 male vehicle-control mice in NTP studies. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice, and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice. The incidence of pheochromocytomas (tumors of chromaffin tissue of the adrenal medulla or sympathetic pregangliar, benign and malignant, combined) of the adrenal gland was 0 of 47 (control), 2 of 48 (low dose) and 3 of 49 (high dose), and the incidence of adrenal gland medullary hyperplasia and focal hyperplasia of the adrenal gland capsule were increased as well in dosed male mice. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 76 2. HEALTH EFFECTS The observation that kidney tumors are induced in male, but not female, rats in response to exposure to certain chemicals has been the subject of recent research. It has been hypothesized that the male rat kidney is susceptible to the induction of certain tumors because it contains the protein oy, globulin, which has not been found at significant levels in either female rats, or in mice and humans of either sex (Charbonneau et al. 1987, 1989a, 1989b). It was demonstrated that chemicals like 1,4-dichloro- benzene, which reversibly bind to this protein, cause the formation of hyalin droplets in the proximal convoluted tubules of male rats. The hyalin droplet-protein complex is resistant to degradation by lysosomal enzymes and accumulates in the tubule, leading to localized hyperplasia of the epithelium (Borghoff et al. 1991; EPA 1991). It is hypothesized that the resulting cellular damage and cell proliferation enhances tumor formation via a mechanism not yet elucidated. It has also been demonstrated that the same effects can be elicited in male rats administered other a,,-globulin-binding chemicals such as hexachloroethane, d-limonene [1-methyl-4(1-methylethenyl)cyclohexene], unleaded gasoline, and pentachloroethane (EPA 1991). Based on these data, EPA (1991) concluded that tumors associated with 0ty,-globulin and hyalin droplets are specific to species that produce this protein in large quantities, and that these tumors should be distinguished from other renal tumors. The finding of hepatocellular carcinomas and adenomas in mice in the NTP (1987) study has been the subject of scientific debate. There was a high incidence of these tumors in both male and female control animals, but this is fairly common in mice. However, in this case the tumor incidence in the female controls was substantially higher than the historical control value. In addition, 1,4-dichloro- benzene has not been demonstrated to be mutagenic in any of the microbial or mammalian systems tested (NTP 1987), suggesting that the liver tumors are not the result of genotoxicity. Hepatocellular degeneration with resultant initiation of tissue repair was present in both male and female treated mice. This led NTP (1987) to speculate that 1,4-dichlorobenzene acted as a tumor promotor rather than a tumor initiator during the formation of the liver tumors found in male and female mice. As shown in Table 2-2, 300 mg/kg/day is the cancer effect level (CEL) for renal tubular cell adenomas in male rats and 600 mg/kg/day is the CEL for hepatocellular carcinomas and hepatoblastomas in mice (NTP 1987). A q,;* (the upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure) of 6x10 has been calculated from the data on renal tumors in rats (Battelle and Crump 1986). The q,* for the mouse liver tumor data is 2.4x1072 (HEAST 1992). These values are currently under review by the EPA (HEAST 1990) and have not been included in the IRIS (1996) database. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 77 2. HEALTH EFFECTS 2.2.3 Dermal Exposure 2.2.3.1 Death No studies were located regarding death in humans after dermal exposure to 1,4-dichlorobenzene. The dermal LD, for 1,4-dichlorobenzene in Sherman rats was greater than 6,000 mg/kg/day (Gaines and Linder 1986). It is not clear how many rats died after dermal exposure to 1,4-dichlorobenzene in this study, and there are no toxicokinetic data that address the question of absorption of 14-dichloro- benzene by the dermal route. 2.2.3.2 Systemic Effects No studies were located regarding systemic effects in humans after dermal exposure to 1,4-dichloro- benzene. Solid 1,4-dichlorobenzene was noted to produce a burning sensation when held closely to the skin for an excessive period of time, but it does not produce irritation or systemic effects (Hollingsworth et al. 1956). One study was located regarding the systemic effects in rabbits after dermal exposure to 1,4-dichlorobenzene (Hollingsworth et al. 1956). However, there was considerable variability in this study regarding the number of animals exposed, and the total number of exposures. No studies were located regarding the following effects in humans or animals after dermal exposure to 1,4-dichlorobenzene: 2.2.3.3 Immunological and Lymphoreticular Effects 2.2.3.4 Neurological Effects 2.2.3.5 Reproductive Effects 2.2.3.6 Developmental Effects 2.2.3.7 Genotoxic Effects Other genotoxicity studies are discussed in Section 2.5. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 78 2. HEALTH EFFECTS 2.2.3.8 Cancer No studies were located regarding cancer effects in humans or animals after dermal exposure to 1,4-dichlorobenzene. 2.3 TOXICOKINETICS Quantitative absorption studies are not available for 1,4-dichlorobenzene in either humans or animals. This compound is structurally similar to benzene and the smaller chlorinated aliphatics, and is thus assumed to be 100% absorbed when administered orally. Available data on 1,4-dichlorobenzene itself shows that under specific conditions, about 20% was absorbed via inhalation during a 3-hour exposure period. The potential for dermal absorption has not been assessed. Animal studies have demonstrated that 1,4-dichlorobenzene, once absorbed, is highly concentrated in adipose tissue, with much lower levels in liver and kidney. Detectable levels have also been reported in blood, lung, heart, and brain. 2,5-Dichlorophenol has been demonstrated to be the major urinary metabolite of 1,4-dichlorobenzene in both humans and animals. This metabolite is eliminated principally as a conjugate of glucuronic or sulfuric acid. Some elimination in feces and expired air has been observed, and there is also evidence of reabsorption in the enterohepatic circulation and excretion in bile. 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No studies were located regarding the rate or amount of absorption of 1,4-dichlorobenzene by humans or animals after inhalation exposure to 1,4-dichlorobenzene. Based on a study of tissue concentrations of 14C-1,4-dichlorobenzene administered to CFY rats via inhalation, gavage (in oil), or subcutaneous injection, it has been estimated that tissue levels of 1,4-dichlorobenzene and/or its metabolites would be similar when these animals inhaled He. 1,4-dichlorobenzene at 1,000 ppm for 3 hours per day for 10 days or received 10 repeated oral or “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 79 2. HEALTH EFFECTS subcutaneous doses of 250 mg/kg/day (Hawkins et al. 1980). Based on a body weight of 200 g for rats in this study and a breathing rate of 0.34 m’/day (EPA 1985), these rats absorbed approximately 20% of the administered dose. Because a 3-hour per day exposure regimen was used in the inhalation studies, it is not possible to make comparisons with results observed in the more commonly used 6-8-hour per day exposure regimens in inhalation studies. 2.3.1.2 Oral Exposure No studies were located that specifically addressed the rate or amount of absorption of 1,4-dichloro- benzene by humans or animals after oral exposure to 1,4-dichlorobenzene. Based on the absorption rates of benzene and the smaller chlorinated aliphatics, EPA (1987a) has assumed that 100% of an oral dose of 1,4-dichlorobenzene is absorbed. This assumption is supported by data that demonstrate that tissue levels of '*C are similar in female rats that have received 14C-1,4-dichlorobenzene at 250 mg/kg/day for 10 days via gavage or by subcutaneous injection (Hawkins et al. 1980). 2.3.1.3 Dermal Exposure No studies were located that specifically addressed the rate or amount of absorption of 1,4-dichloro- benzene by humans or animals after dermal exposure to 1,4-dichlorobenzene. Solid 1,4-dichloro- benzene was noted to produce a burning sensation when held closely to the skin for an excessive period of time, but it does not produce irritation or systemic effects (Hollingsworth et al. 1956). This observation indicates that some of the chemical must penetrate the skin to produce an effect on nerve endings in the skin. In a study of the acute dermal toxicity of 1,4-dichlorobenzene in adult Sherman rats, the dermal LDs, was estimated to be greater than 6,000 mg/kg/day in both sexes (Gaines and Linder 1986). Assuming there were no incidental oral or inhalation exposures, these data do not conclusively indicate that 1,4-dichlorobenzene is absorbed to any extent after dermal exposure, and if dermal exposure does occur, it is associated with low systemic toxicity in both humans laboratory animals. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 80 2. HEALTH EFFECTS 2.3.2 Distribution 2.3.2.1 Inhalation Exposure No studies were located regarding the tissue distribution of 1,4-dichlorobenzene in humans after inhalation exposure to 1,4-dichlorobenzene. The compound has been found, however, in human blood, fatty tissue, and breast milk, presumably as a result of exposure via inhalation. In a study of Tokyo residents, detectable levels of 1,4-dichlorobenzene were found in all of 34 adipose tissue samples and all of 16 blood samples tested (Morita and Ohi 1975; Morita et al. 1975). In a national survey of various volatile organic compounds (VOC) found in composites of human adipose tissue, samples were collected from persons living in the nine geographic areas that comprise the United States (within this survey). The specimens (subcutaneous, perirenal, or mesenteric adipose tissue) were collected from October 1981 through September 1982 and were excised during surgery or as part of postmortem examinations. For each geographic location, three age groups were represented: 0-14 years, 15-44 years, and 45 or more years. Positive results were reported for 1,4-dichlorobenzene in these composites in every category of analysis, with levels ranging from 0.012 to 0.50 ug/g wet tissue (EPA 1986¢). In human milk samples collected from 42 lactating women in five locations in the eastern United States, measured values of 1,4-dichlorobenzene ranged from 0.04 to 68 pg/mL with an average of 9.15 pg/mL (EPA 1983b). In animal studies, the tissue distribution of 14C_1,4-dichlorobenzene in female CFY rats was found to be similar following inhalation, oral, and subcutaneous exposure (Hawkins et al. 1980). The inhalation exposure regimen was 10 consecutive days of exposure to 14C-1,4-dichlorobenzene at 1,000 ppm for 3 hours per day, and the highest concentrations of 14C were measured in fat (up to 557 pg/g via inhalation) and next highest levels in kidneys and liver. Concentrations in kidney and liver were about 5-10% of that found in adipose tissue, irrespective of the route of exposure. Distribution patterns for all routes were also similar to those observed by Kimura et al. (1979) using the oral route, as described below. 2.3.2.2 Oral Exposure No studies were located regarding the distribution of 1,4-dichlorobenzene in humans after oral exposure to 1,4-dichlorobenzene. “**DRAFT FOR PUBLIC COMMENT"*** 1,4-DICHLOROBENZENE 81 2. HEALTH EFFECTS Several studies in animals clearly demonstrate that adipose tissue is a major repository of ingested I.4-dichlorobenzene. In male rats that received a single gavage dose of 200 mg/kg/day, the highest concentration of 1,4-dichlorobenzene was found in adipose tissue, peaking at 800 ppm 12 hours after exposure, and was present in decreasing quantities at all sampling intervals up to 120 hours postexposure in the adipose tissue (Kimura et al. 1979). Kidney (30 ppm) and liver (23 ppm) contained the next highest levels of 1,4-dichlorobenzene. Low levels of 1,4-dichlorobenzene were also found in blood, lung, heart, and brain. Most of the 1,4-dichlorobenzene in all tissues except for adipose had disappeared within 48 hours after administration of the chemical. Low levels of 1,4-dichlorobenzene were still detected in the adipose tissue after 120 hours. Similar results were obtained in male rats administered a single 500 mg/kg/day dose of 14C-1,4-dichlorobenzene by gavage in corn oil and sacrificed 24 hours after dosing (Charbonneau et al. 1989). In another study in which male and female Fisher 344 rats were administered a single dose of 900 mg/kg/day 14C-1,4-dichlorobenzene by gavage in corn oil and sacrificed at 72 hours, the percentage of the dose found in tissues and excreta from males was: tissues (all organs pooled), 0.05%; fat, 0.1%; blood, 0.04%; feces, 3.6%: and urine, 41.3%. In females recovery of radioactivity was: tissue, 0.04%; fat, 0.1%; blood, 0.03%; feces, 2.5%; and urine, 37.8%. In the tissues examined, the radioactivity bound to protein was below the detection limit (Klos and Dekant 1994). Charbonneau et al. (1987) reported that 49.8% of 1,4-dichlorobenzene-equivalent was in the kidney cytosol of male Fischer 344 rats administered a single dose of 300 or 500 mg/kg/day 14C-1 4-dichloro- benzene by gavage in corn oil and sacrificed 24 hours after completion of dosing. However, fat samples were not analyzed for 1,4-dichlorobenzene content. In female rats that received gavage doses of 50-500 mg/kg/day for 10 days, distribution patterns were similar to those observed by Kimura et al. (1979) and Charbonneau et al. (1989), as described above, with the highest concentrations measured in fat and the next highest, but much lower, levels in kidney and liver (Hawkins et al. 1980). 2.3.2.3 Dermal Exposure No studies were located regarding the distribution of 1,4-dichlorobenzene in humans or animals after dermal exposure to 1,4-dichlorobenzene. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 82 2. HEALTH EFFECTS 2.3.3 Metabolism 2,5-Dichlorophenol appears to be the principal metabolic product of 1,4-dichlorobenzene in both humans and laboratory animals. The metabolism of 1,4-dichlorobenzene to 2,5-dichlorophenol appears to involve phase II metabolism pathways. Analysis of the urine specimens of a 3-year-old boy who had been playing with 1,4-dichlorobenzene yielded 2,5-dichlorophenol as well as 4 other unidentified phenols. These compounds were shown to be conjugated with glucuronic and sulfuric acids (Hallowell 1959). In adult female CFY rats exposed by inhalation (whole-body) to nominal concentrations of 1,000 ppm 14C-1,4-dichlorobenzene, 3 hours a day for 10 days, analysis of metabolites in urine indicated that more than 50% was a sulfate of 2,5-dichlorophenol, and much of the rest was a glucuronide conjugate of 2,5-dichlorophenol. A minor component was a dihydroxydichlorobenzene, assumed by the authors to be 2,5-dichloroquinol. Analysis of bile revealed the same metabolites, but with quantitative differences (Hawkins et al. 1980). Following oral administration to Chinchilla rabbits, 1,4-dichlorobenzene was also oxidized principally to 2.,5-dichlorophenol. A very high percentage of this metabolite was eliminated in the urine as conjugates of glucuronic or sulfuric acids (Azouz et al. 1955). Male Wistar rats given single oral doses of 10, 50, or 250 mg/kg of 14C-1,4-dichlorobenzene (vehicle not given) excreted the majority of 14¢C derived from 1,4-dichlorobenzene in the urine as either the sulfate conjugate (60%) or the glucuronide (30%). Bile contained 5 and 30% of the total radioactivity after the low and high doses, respectively. Only minor amounts of mercapturic acid were found (Hissink et al. 1996). The excretion of 1,4-dichlorobenzene and metabolites was examined in male rats administered a single dose of 200 mg/kg 1.4-dichlorobenzene given by gavage in corn and monitored up to 120 hours after dosing (Kimura et al. 1979). Within 12 hours after dosing, 2 sulfur-containing metabolites, 2,5-dichlorophenyl methyl sulfoxide, and 2,5-dichlorophenyl methyl sulfone (M2), were found in the blood, urine, fat, liver, and kidneys. These metabolites remained in the blood after most of the 1,4-dichlorobenzene had fallen below the detection limits of the assay. The maximum concentration ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 83 2. HEALTH EFFECTS of 2,5-dichlorophenyl methyl sulfoxide in blood was reached 15 hours after dosing and declined rapidly thereafter. For 2,5-dichlorophenyl methyl sulfone, 2 peaks were detected at 18 and 48 hours after dosing, which suggested to the authors that 2,5-dichlorophenyl methyl sulfone might undergo enterophepatic circulation. Changes in the levels of these metabolites in blood and tissues over a 120-hour period led the authors to suggest that 2,5-dichlorophenyl methyl sulfone might arise from 2,5-dichlorophenyl methyl sulfoxide. In a later study, male and female Fisher 344 rats were administered a single dose of 900 mg/kg/day 14C-1 4-dichlorobenzene by gavage in corn oil, the excretion of radioactivity in the urine reached a peak both in males and females between 24 and 36 hours after dosing. The major urinary metabolite was 2,5-dichlorophenol, mostly in the form of sulphate and glucuronide conjugates. 2-(N-acetyl- cysteine-S-yl)-2,3-dihydro-3-hydroxy-1,3-hydroxy-1,4-dichlorobenzene and 2-(N-acetyl-cysteine-S-yl)- 1,4-dichlorobenzene were minor metabolites in the urine from both males and females. Minor amounts of 2,4-dichlorohydroquinone were excreted as an unidentified conjugate. A mercapturic acid of chlorophenol also appeared to be formed and excreted in the urine. The latter compound would result from the reaction of glutathione (GHS) with a 3,4-epoxide of 1,4-dichlorobenzene. Quantification of the metabolites in the urine 72 hours after a single 1,000 mg/kg/day oral dose of 1,4-dichlorobenzene showed about 17% of the dose as 2,5-dichlorophenol after acid hydrolysis; 1.1% in males and 1.4% in females as 2,5-dichlorohydroquinone, also after acid hydrolysis; and 0.4% in males and 1.4% in females as 2-(N-acetyl-cysteine-S-yl)-1,4-dichlorobenzene. The mercapturic acid of chlorophenol and 2-(N-acetyl-cysteine-S-yl)-2,3-dihydro-3-hydroxy-1,3-hydroxy-1,4-dichlorobenzene could not be quantified. Male rats excreted the conjugates of 2,5-dichlorophenol and 2,5-dichloro- hydroquinone in greater amounts than females. The opposite was true for 2-(N-acetyl-cysteine-S-yl)- 1,4-dichlorobenzene. However, these differences were minor (Klos and Dekant 1994). The mechanism of 1,4-dichlorobenzene oxidation to 2,5-dichlorophenol has not yet been thoroughly investigated. The metabolism of 1,4-dichlorobenzene could involve the formation of an arene oxide intermediate, as has been proposed to occur in the oxidative metabolism of many halogenated aromatic hydrocarbons (Jerina and Daly 1974). However, it has been demonstrated that the ring hydroxylation of 2,2,5,5-tetrachlorobiphenyl (a dimer of 1,4-dichlorobenzene) takes place without the formation of an arene oxide intermediate (Preston et al. 1983). 1,4-Dichlorobenzene has not been shown to be mutagenic in microbial or mammalian systems, a result that may be viewed as further suggestive evidence that an arene oxide intermediate is not involved in its metabolism. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 84 2. HEALTH EFFECTS Fischer et al. (1995) compared the metabolism and toxicity of the dichlorobenzene isomers in liver slices prepared from human donor tissues, and from male Sprague-Dawley and Fischer 344 rats. At 2 and 6 hours, the metabolism of 1,4-dichlorobenzene in human liver slices was similar to that seen in Sprague-Dawley and Fischer 344 rats. In human and Fischer 344 rat liver slices, the metabolism of 1,4-dichlorobenzene was intermediate to that of 1,3- and 1,2-dichlorobenzene at 2 hours; at 6 hours the metabolism of 1,4-dichlorobenzene was lower than that of 1,3- or 1,2-dichlorobenzene. In Sprague- Dawley rats, the hepatic metabolism of 1,4-dichlorobenzene was greater than that of 1,3- and 1,2-dichlorobenzene at 2 hours, while at 6 hours, the metabolism of 1,4-dichlorobenzene was intermediate to that of 1,3- or 1,2-dichlorobenzene. In all 3 species, the metabolism of 1,4-dichloro- benzene was not linear over time; the amount metabolized at 6 hours was only slightly higher than that metabolized after 2 hours. At both 2 and 6 hours, the amount of glucuronide and sulfate conjugates produced from 1,4-dichlorobenzene was similar across all species. 2.3.4 Elimination and Excretion 2.3.4.1 Inhalation Exposure No studies were located regarding excretion in humans after inhalation exposure to 1,4-dichloro- benzene. In an animal study, inhaled 1,4-dichlorobenzene was excreted mainly in the urine. When 14C-1 4-dichlorobenzene was administered to female rats for 10 days via inhalation at 1,000 ppm for 3 hours per day, 97.4% of the total excreted He activity was recovered in the urine. The amount of 14C-label excreted in the expired air during 48 hours after the tenth dose represented a small proportion of the total 14C excreted (Hawkins et al. 1980). This level was similar after inhalation (0.2%) and oral (1%) exposure. In rats with cannulated bile ducts, no 14C was detected in the feces up to 24 hours after inhalation exposure or after a single subcutaneous dose. Of the total lic recovered, 48.5% was eliminated in the bile and 51.5% in the urine. The lower level of '*C excretion in the urine of cannulated rats than of noncannulated rats indicated that in noncannulated rats, much of the label that was eliminated in the bile was reabsorbed and ultimately excreted in the urine. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 85 2. HEALTH EFFECTS 2.3.4.2 Oral Exposure No studies were located on excretion in humans after oral exposure to 1,4-dichlorobenzene. Based on a study in animals, orally administered 1,4-dichlorobenzene appears to be excreted mainly in the urine in metabolite form. Male Wistar rats given single oral doses of 10, 50, or 250 mg/kg of 14C-1 4-dichlorobenzene excreted the majority of 14C derived from 1,4-dichlorobenzene in the urine as either the sulfate conjugate (60%) or the glucuronide (30%). Bile contained 5 and 30% of the total radioactivity after the low and high doses, respectively. Only minor amounts of mercapturic acid were found (Hissink et al. 1996). The excretion of 1,4-dichlorobenzene and metabolites was examined in male Wistar rats administered a single dose of 200 mg/kg 1,4-dichlorobenzene by gavage in corn and monitored up to 120 hours after dosing (Kimura et al. 1979). Within 12 hours after dosing, 2 sulfur-containing metabolites, 2,5-dichlorophenyl methyl sulfoxide and 2,5-dichlorophenyl methyl sulfone, were found in the urine. Over a 96-hour period, 46% of the dose was excreted as 2,5-dichlorophenol, the major metabolite of 1,4-dichlorobenzene; only 0.031 and 0.122% of the dose was excreted in the urine as 2,5-dichloro- phenyl methyl sulfoxide and 2,5-dichlorophenyl methyl sulfone, respectively. The authors also mentioned that 2,5-dichlorophenyl methyl sulfoxide and 2,5-dichlorophenyl methyl sulfone were detected in the urine from rats dosed with 800 mg/kg 1,4-dichlorobenzene for 1 week, but no experimental details were provided. Chinchilla rabbits gavaged once with 500 mg/kg/day 1,4-dichlorobenzene in olive oil excreted 35% of the administered dose in the urine as 2,5-dichlorophenol. Another 6% of the administered dose was excreted in the urine as 2,5-dichloroquinol. At 6 days after dosing, urinary excretion of 1,4-dichloro- benzene metabolites was still in progress; however, fecal excretion could not be detected during the 6-day monitoring period (Azouz et al. 1955). In male and female Fischer 344 rats administered a single dose of 900 mg/kg/day 14C-1 4-dichloro- benzene by gavage in corn oil, the excretion of radioactivity in the urine reached a peak in both males and females between 24 and 36 hours after dosing. Seventy-two hours after dosing, 41.3 and 3.6% of the dose was found in the urine and feces, respectively, of males; corresponding values in the urine and feces of females were 41.3 and 3.6%, respectively (Klos and Dekant 1994). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 86 2. HEALTH EFFECTS When '#C-1,4-dichlorobenzene was administered by gavage to female rats for 10 days at 250 mg/kg/day, 97% of the recovered 14C was eliminated in the urine within 5 days post-treatment. Approximately 1% was recovered in expired air (Hawkins et al. 1980). In rats with cannulated bile ducts, only 9% of the recovered 14C was excreted in the feces during the 24 hours following the last dose and was presumed to be unabsorbed material. Another 63% was recovered in the bile and 28.1% in the urine. The lower level of '*C excretion in the urine of cannulated rats than in that of noncannulated rats indicated that in noncannulated rats, much of the label that was eliminated in the bile was reabsorbed or metabolized and ultimately excreted in the urine. 2.3.4.3 Dermal Exposure No studies were located on excretion in humans or animals after dermal exposure to 1,4-dichloro- benzene. 2.3.5 Physiologically Based Pharmacokinetic (PBPK)/Pharmacodynamic (PD) Models Physiologically based pharmacokinetic (PBPK) models use mathematical descriptions of the uptake and disposition of chemical substances to quantitatively describe the relationships among critical biological processes (Krishnan et al. 1994). PBPK models are also called biologically based tissue dosimetry models. PBPK models are increasingly used in risk assessments, primarily to predict the concentration of potentially toxic moieties of a chemical that will be delivered to any given target tissue following various combinations of route, dose level, and test species (Clewell and Andersen 1985). Physiologically based pharmacodynamic (PBPD) models use mathematical descriptions of the dose-response function to quantitatively describe the relationship between target tissue dose and toxic end points. PBPK/PD models refine our understanding of complex quantitative dose behaviors by helping to delineate and characterize the relationships between: (1) the external/exposure concentration and target tissue dose of the toxic moiety, and (2) the target tissue dose and observed responses (Andersen and Krishnan 1994; Andersen et al. 1987). These models are biologically and mechanistically based and can be used to extrapolate the pharmacokinetic behavior of chemical substances from high to low dose, from route to route, between species, and between subpopulations within a species. The ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 87 2. HEALTH EFFECTS biological basis of PBPK models results in more meaningful extrapolations than those generated with the more conventional use of uncertainty factors. The PBPK model for a chemical substance is developed in four interconnected steps: (1) model representation, (2) model parametrization, (3) model simulation, and (4) model validation (Krishnan and Andersen 1994). In the early 1990s, validated PBPK models were developed for a number of toxicologically important chemical substances, both volatile and nonvolatile (Krishnan and Andersen 1994; Leung 1993). PBPK models for a particular substance require estimates of the chemical substance-specific physicochemical parameters, and species-specific physiological and biological parameters. The numerical estimates of these model parameters are incorporated within a set of differential and algebraic equations that describe the pharmacokinetic processes. Solving these differential and algebraic equations provides the predictions of tissue dose. Computers then provide process simulations based on these solutions. The structure and mathematical expressions used in PBPK models significantly simplify the true complexities of biological systems. If the uptake and disposition of the chemical substance(s) is adequately described, however, this simplification is desirable because data are often unavailable for many biological processes. A simplified scheme reduces the magnitude of cumulative uncertainty. The adequacy of the model is, therefore, of great importance, and model validation is essential to the use of PBPK models in risk assessment. PBPK models improve the pharmacokinetic extrapolations used in risk assessments that identify the maximal (i.e., the safe) levels for human exposure to chemical substances (Andersen and Krishnan 1994). PBPK models provide a scientifically sound means to predict the target tissue dose of chemicals in humans who are exposed to environmental levels (for example, levels that might occur at hazardous waste sites) based on the results of studies where doses were higher or were administered in different species. Figure 2-3 shows a conceptualized representation of a PBPK model. If PBPK models for 1,4-dichlorobenzene exist, the overall results and individual models are discussed in this section in terms of their use in risk assessment, tissue dosimetry, and dose, route, and species extrapolations. No PBPK models were identified for 1,4-dichlorobenzene. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 88 2. HEALTH EFFECTS Figure 2-3. Conceptual Representation of a Physiologically Based Pharmacokinetic (PBPK) Model for a Hypothetical Chemical Substance Inhaled chemical — — — © —> Exhaled chemical | Y Ingestion Lungs — Ti I -< Liver < : V A v A E R N Vmax Km Gl [| T Oo Tract E u < Fat ” R S A Slowly L AG perfused “ B tissues L : 2 0 Richly B D * perfused L tissues 0 Oo D < Kidney -«— Urine rt Skin < x | L — — Chemicals in air contacting skin Source: adapted from Krishnan et al. 1994 Note: This is a conceptual representation of a physiologically based pharmacokinetic (PBPK) model for a hypothetical chemical substance. The chemical substance is shown to be absorbed via the skin, by inhalation, or by ingestion, metabolized in the liver, and excreted in the urine or by exhalation. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 89 2. HEALTH EFFECTS 2.4 MECHANISMS OF ACTION 2.4.1 Pharmacokinetic Mechanisms Absorption. Quantitative inhalation, oral, or dermal absorption studies in humans are not available for 1,4-dichlorobenzene. In the few studies available in laboratory animals, absorption was demonstrated to occur during a 3-hour inhalation exposure to 1,000 ppm of 1,4-dichlorobenzene (Hawkins et al. 1980) as evidenced by accumulation of 14C in liver, kidney, plasma, and adipose tissue. No studies were located that described the absorption characteristics of 1,4-dichlorobenzene after oral exposure; however, given the structural and physicochemical similarity to benzene, oral absorption is thought to be at or near 100% (EPA 1987a; Hawkins et al. 1980). Specific studies assessing dermal absorption have not been performed; however, one study did report a dermal LDs, of >6,000 mg/kg/day in rats (Gaines and Linder 1986). 1,4-Dichlorobenzene is a lipid-soluble chemical and has low solubility in water. Given the physicochemical properties, similarity to benzene, and lipid-soluble properties of 1,4-dichlorobenzene, absorption by the inhalation, oral, and dermal routes of exposure is most likely by simple diffusion across cellular lipid membranes. No information is available that describes site-specific absorption within the respiratory tract (nasal epithelial absorption as opposed to alveolar absorption) or in the gastrointestinal tract. Distribution. Quantitative inhalation, oral, or dermal distribution studies in humans are not available for 1,4-dichlorobenzene. 1,4-Dichlorobenzene has been detected in human blood, adipose tissue, and breast milk after an assumed inhalation exposure in Tokyo residents (Morita and Ohi 1975; Morita et al. 1975), as well as people in some parts of the United States (EPA 1983b, 1986b). The available data indicates that after inhalation, oral, and subcutaneous exposure, 1,4-dichlorobenzene preferentially distributes to the fat tissue and organ-specific sites within the body (Hawkins et al. 1980), following the order: adipose > kidney > liver > blood (Charbonneau et al. 1989; Hawkins et al. 1980). Adipose tissue deposition and retention seem to be likely consequences of exposure to 1,4-dichlorobenzene exposure, given its lipid-soluble properties (see Chapter 3). Independent of exposure route, most of the 1,4-dichlorobenzene will have fallen to near- or below-detectable assay limits in all tissues of the body except adipose tissues 48-72 hours after exposure, depending on the dose (Charbonneau et al. 1989; Kimura et al. 1979). 1,4-Dichlorobenzene could be detected in adipose tissue at 120 hours after exposure (Charbonneau et al. 1989). When absorbed by the kidney, 50% of the 1,4-dichlorobenzene appears to localize within the cytosol in male Fischer 344 rats ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 90 2. HEALTH EFFECTS (Charbonneau et al. 1987), which may be important in the formation of a, -globulin. 1,4-Dichloro- benzene also does not appear to bind to tissue proteins (Klos and Dekant 1994). Metabolism/Excretion. Quantitative inhalation, oral, or dermal metabolism and excretion studies in humans are not available for 1,4-dichlorobenzene. One case study involving a 3-year-old boy who may have ingested 1,4-dichlorobenzene reported the presence of 2,5-dichlorophenol in the urine (Hallowell 1959). A number of laboratory animal studies have indicated that 1,4-dichlorobenzene is metabolized by phase I metabolism to 2,5-dichlorophenol (probably by cytochrome P,s0), which then undergoes phase II metabolism/conjugation to the glucuronide or sulfate endproducts (Azouz et al. 1955; Hawkins et al. 1980; Hissink et al. 1996; Kimura et al. 1979; Klos and Dekant 1994). Metabolism occurs in the liver, with none of the detected metabolites having been reported to be associated with the toxic effects seen with 1,4-dichlorobenzene. Minor amounts of 2.4-dichloro- hydroquinone may also be present (Klos and Dekant 1994). Excretion of the metabolites is mostly through the urine (Azouz et al. 1955; Hissink et al. 1996; Kimura et al. 1979); however, some forms (mainly the glucuronide conjugate) may also be excreted through the bile and exit the body through the feces (Hissink et al. 1996). The role of enterohepatic circulation in the metabolism and excretion of metabolites is not completely known; however, it has been suggested that enterohepatic circulation may occur with some sulfated metabolites (Kimura et al. 1979). This phase I and II metabolic pathway mechanism seems plausible, in that other chemicals with similar physicochemical properties (halogenated- and lipid-soluble) undergo very similar metabolic routines to become more water-soluble in order to be excreted. The data suggest that metabolism and excretion are similar across species lines. Based on the limited human data available, it is likely that human metabolic pathways would be similar, if not identical, to the laboratory animal models. 2.4.2 Mechanisms of Toxicity The precise mechanism of 1.4-dichlorobenzene oxidation to 2,5-dichlorophenol has not thoroughly been investigated. However, some information can be gleaned from other chlorinated hydrocarbons with known metabolic pathways, which produce similar toxicological effects. For example, chloro- form is known to undergo metabolism by cytochrome P,s, and forms toxic intermediates that are responsible for the hepatic and renal effects observed in mice, rats, and other laboratory animals. Carbon tetrachloride and some chlorinated and brominated aliphatic and aromatic hydrocarbons are known to follow similar metabolic pathways, so it seems likely that 1,4-dichlorobenzene would follow ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 91 2. HEALTH EFFECTS suit (Den Besten et al. 1991, 1992). 1.4-Dichlorobenzene is known to be metabolized by cytochrome P50 (Azouz et al. 1955; Hawkins et al. 1980) in order to be presented to phase II metabolic pathways to increase its water solubility for excretion. A proposed metabolic pathway involving cytochrome P45, with intermediate formations of metabolites has been outlined for 1,4-dichlorobenzene (Den Besten et al. 1992). The hepatotoxicity and nephrotoxicity observed in laboratory animals are likely due to the formation of toxic intermediates formed while converting 1,4-dichlorobenzene to 2,5-dichlorophenol by cytochrome Ps, or by depletion of GSH at higher doses of 1,4-dichloro- benzene, or both. Some indirect evidence of this was provided by Mizutani et al. (1994). In mice pretreated with DL-buthionine sulfoximine (BSO), a glutathione synthesis inhibitor, a single dose of 300 mg/kg 1,4-dichlorobenzene caused significant elevations of ALT and liver calcium, both peaking between 24 and 32 hours after dosing and declining thereafter, indicative of hepatic damage. Necrotic changes were observed at those times as well as hemorrhage, fatty changes, and appearance of altered eosinophilic cells. A single 1,200 mg/kg dose of 1,4-dichlorobenzene did not significantly alter ALT or liver calcium, but doses of 100 mg/kg or higher in mice pretreated with BSO produced dose-related alterations in these parameters. Increasing cellular GSH with GSH monoethyl ester protected the liver from the combination of 1,4-dichlorobenzene and BSO. In addition, pretreatment with microsomal cytochrome P,5,-dependent monooxygenase inhibitors also protected the liver from the combined toxicity of 1,4-dichlorobenzene and BSO. Pretreatment with the Ps, inducer beta-naphthoflavone did not significantly alter the effect of 1,4-dichlorobenzene plus BSO. Pretreatment with phenobarbital partially blocked the effect of 1,4-dichlorobenzene plus BSO on ALT and completely prevented the increase in liver calcium. PCBs prevented the effect on both ALT and liver calcium. Treatment with BSO alone or in combination with 1,4-dichlorobenzene (300 mg/kg) greatly decreased hepatic GSH concentration, the effect being more pronounced with the combination. 1,4-Dichlorobenzene alone had no such effect. Depletion of GSH also has been reported to increase the toxicity of 1,4-dichloro- benzene in rats (Stine et al. 1991). The data provide a strong indication that the mechanism behind the hepatic (and probably renal) toxicity of 1,4-dichlorobenzene lies in the intermediate steps of metabolite formation and conjugation by cytochrome P,s,. Formation of 2,5-dichlorophenol from 1,4-dichlorobenzene via cytochrome Ps, metabolism likely produces some intracellular, intermediate metabolite(s) that are also hepatotoxic when sufficient amounts accumulate intracellularly. These yet unidentified metabolites are detoxified by GSH; but when GSH depletion occurs, which is likely to occur at higher oral doses (such as those used in the NTP 1987 studies), toxicity is enhanced. Hepatocytes respond to these insults by releasing intracellular enzymes (Carlson and Tardiff 1976; Umemura et al. 1996), degeneration, vacuolation (Eldridge et al. 1992; NTP 1987; Rimington & ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 92 2. HEALTH EFFECTS Ziegler 1963), necrosis, and increases in gross liver weight (Hollingsworth et al. 1956; Riley et al. 1980). However, these changes are not specific to 1,4-dichlorobenzene and likely occur in a dose- responsive manner. At lower doses, cellular proliferation in the liver in the absence of these toxic-type responses have been observed (Eldridge et al. 1992; Umemura et al. 1996); however, the mechanism behind this response needs to be more clearly defined. Exposure to 1,4-dichlorobenzene likely follows similar metabolic pathways in the kidneys and would be responsible for the toxicity (increased organ weight, tubular degeneration, nephropathy) observed in that organ, and may also be testosterone- dependent. The metabolism of 1,4-dichlorobenzene could involve the formation of an arene oxide intermediate, as has been proposed to occur in the oxidative metabolism of many halogenated aromatic hydrocarbons (Jerina and Daly 1974). However, it has been demonstrated that the ring hydroxylation of 2,2",5,5 -tetrachlorobiphenyl (a dimer of 1,4-dichlorobenzene) takes place without the formation of an arene oxide intermediate (Preston et al. 1983). 1,4-Dichlorobenzene has not been shown to be mutagenic in microbial or mammalian systems, a result that may be viewed as further suggestive evidence that an arene oxide intermediate is not involved in its metabolism. 1,4-Dichlorobenzene has also been reported to produce hematological effects associated with exposure in humans and laboratory animals. These findings have been limited to red and white blood cell anomalies (NTP 1987) in rats and mice, and may take place within the bone marrow at the time of red and white cell formation, although a precise and careful mechanism behind this finding has not been produced. Acute hemolytic anemia and methemoglobinuria reportedly occurred in a 3-year-old boy who had played with, and possibly ingested, 1,4-dichlorobenzene crystals (Hallowell 1959). A 21-year-old pregnant woman who had eaten 1-2 blocks of 1,4-dichlorobenzene toilet air freshener per week throughout pregnancy developed severe microcytic, hypochromic anemia with excessive polychromasia and marginal nuclear hypersegmentation of the neutrophils. Heinz bodies were seen in a small number of the red cells. After she discontinued this practice (at about 38 weeks of gestation), her hemoglobin levels began to rise steadily. The mechanism behind these findings in the human exposures are unknown, but it appears that 1,4-dichlorobenzene may have some local effect on the hemoglobin content of the red blood cell (hemolysis, methemoglobinemia, Heinz bodies). These are rare events in humans and only occur at very high exposure doses in laboratory animals. The clinical finding of Heinz-body formation in red blood cells and methemoglobinemia suggest that some form of oxidative stress is occurring to produce these findings, although the mechanisms behind these end ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 93 2. HEALTH EFFECTS points are not known. While there may not be any direct evidence, it is not unreasonable to suspect that oxidant metabolites of 1,4-dichlorobenzene may inhibit glucose-6-phosphate dehydrogenase (G6PD), as does metabolites of aniline, leading to Heinz body production, methemoglobinemia, and hemolysis (Trieff et al. 1993). The effect on the red and white blood cell production processes in the bone marrow (anemia, polychromasia) is quite likely an effect related to blood loss associated with bleeding from esophageal varices which form secondary to liver cirrhosis. 2.4.3 Animal-to-Human Extrapolations No studies were identified that specifically addressed the use of animal data applied to human exposure issues specifically related to 1,4-dichlorobenzene. No physiologically based pharmacokinetic models are available to estimate risk associated with human exposure to 1,4-dichlorobenzene. It is difficult to compare the toxicity of 1,4-dichlorobenzene in laboratory animals to the toxicity observed in humans, since little reliable human data are available for examination (see Section 2.2). From the little data available, it appears that humans do have the potential to exhibit the same toxicological features of 1,4-dichlorobenzene toxicosis as have the laboratory animal models studied. Although the mechanisms have not been outlined, human hematological responses (Campbell and Davis 1970) and liver responses (Hallowell 1959) to 1,4-dichlorobenzene have been similar to the responses of laboratory animals tested (Hollingsworth et al. 1956; NTP 1987). (However, the human hematological responses were vague and quite possibly unrelated.) Although the data are not sufficient to make direct comparisons, the possibility strongly exists that human responses may be similar to those of laboratory animals, and animal data should be taken into consideration until better human data become available. With the exception of the ay, -globulin observation in the male rat kidney (Bombhard et al. 1988), all of the detoxication pathways present in the laboratory animal models are present in humans. This means that humans are likely to detoxify 1,4-dichlorobenzene in a similar or identical manner to that of the laboratory animals, and suggests that humans are susceptible to the liver and possibly the renal lesions outlined for the laboratory animals studied (see Section 2.4.2). Due to the lack of acceptable dosing and exposure data in humans, it is not possible at present to definitively determine the magnitude of these human toxicological responses, the dose-response relationship, or whether humans are more or less susceptible to these effects on a mg/kg/day (oral and dermal) or ppm (inhalation) basis. It is also unknown whether the sex predilection found in male rats to 1,4-dichloro- benzene renal or endocrine toxicity occurs in the human male. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 94 2. HEALTH EFFECTS 2.5 RELEVANCE TO PUBLIC HEALTH Overview. As discussed in Section 2.2.1, most human exposure to 1,4-dichlorobenzene results from inhalation of vapors due to home use of mothballs and deodorizer blocks that contain this chemical. Exposure resulting from all other sources, including proximity to hazardous waste sites, is considered to be low. Based on a combination of available human case studies and experiments with laboratory animals, the major public health concerns associated with exposure to 1,4-dichlorobenzene are effects on the liver, kidneys, and blood. Some immunological, dermatological, and neurological effects have also been reported in exposed humans. There is information from animal studies which raises the question of whether 1,4-dichlorobenzene can cross the placenta and elicit structural effects on the developing fetus. Data from a study conducted in rats using the intraperitoneal route have demonstrated sperm abnormalities. Cancer of the liver as a result of lifetime exposure to 1,4-dichlorobenzene has been shown in mice, and renal cancer has been reported in male rats. However, recent studies related to the mechanism of renal carcinogenesis in rats suggest that these tumors may not be expected to occur in exposed humans. In addition, several studies in animals have demonstrated that increased mortality can result from acute-, intermediate-, or chronic-duration oral exposure to 1,4-dichlorobenzene. Because 1,4-dichloro- benzene mothballs are used in many homes, they are often readily accessible in closets and storage areas. Therefore, there is a potential concern for the lethal effects of 1,4-dichlorobenzene, especially if accidentally consumed by young children. Minimal Risk Levels for 1,4-Dichlorobenzene Inhalation MRLs. * An MRL of 0.8 ppm has been derived for acute-duration inhalation exposure (less than 14 days) to 1,4-dichlorobenzene. This MRL was calculated using a NOAEL of 300 ppm based on the absence of significant developmental effects in rabbits (Hayes et al. 1985). The NOAEL of 300 ppm was converted to ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 95 2. HEALTH EFFECTS 75 ppm after incorporating adjustments for intermittent exposure (6 hours a day). The NOAEL was further adjusted for Human Equivalent Concentration (NOAEL yg) using Equation 4-48a of EPA (1994k) and by applying an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). In this study, groups of inseminated New Zealand White rabbits were exposed whole body to 0 (filtered air), 100, 300, or 800 ppm p-DCB 6 hours a day on Gd 6-18. Vapors of p-DCB were generated by passing air through glass tubes packed with pieces of p-DCB. Sacrifices were conducted on Gd 29. End points examined included maternal body weight and liver and kidneys weights. Fetal observations included number and position of fetuses in utero, number of live or dead fetuses, number and position of resorption sites, number of corpora lutea, sex, body weight and crown-rump length of the fetuses, gross external alterations, and soft tissue and skeletal alterations. Dams in the 800 ppm exposure group gained less weight than did controls during the exposure period. However, after day 18, they rapidly recovered and the final body weight and weight gains were similar to those of controls. There were no effects on absolute or relative maternal liver or kidney weights. At 300 ppm, there was a significant increase (p<0.05) in the percentages of resorbed implantations and litters with resorptions. Results at 800 ppm, however, were comparable to controls. At 800 ppm, there were nonsignificant increases in the incidence of acephaly (headlessness), omphalocele (umbilical hernia), and forelimb flexure. Other deformities found only in the offspring of that exposure group were shortened long bones, an extra rib fused to the tenth rib, and a right subclavian artery originating off the pulmonary trunk. A statistically significant increase (p<0.05) in the incidence of retroesophageal right subclavian artery was noted in the offspring; however, this effect was considered by the authors not to be a major malformation and had been previously observed in 29% of the litters of control rabbits in that laboratory. The authors concluded that under the conditions of this study, p-DCB was not embryotoxic or teratogenic in rabbits at 300 ppm. More information on how this MRL was calculated is presented in Appendix A of this profile. « An MRL of 0.2 ppm has been derived for intermediate-duration inhalation exposure (15 to 364 days) to 1,4-dichlorobenzene. This MRL was calculated using a NOAEL of 96 ppm, based on the absence of liver effects in rats (Hollingsworth et al. 1956). The concentration of 96 ppm was converted to 20 ppm, incorporating adjustments for intermittent exposure (7 hours a day, 5 days a week). The NOAEL was further adjusted for Human Equivalent Concentration (NOAEL yg) using Equation 4-48a of EPA (1994k) and an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 96 2. HEALTH EFFECTS variability). Cloudy swelling and granular degeneration of the liver parenchymal cells from the central zone were reported at concentrations of 158 ppm or greater. More information on how this MRL was calculated is presented in Appendix A of this profile. The MRL was based on liver toxicity rather than kidney toxicity because the effects of 1,4-dichloro- benzene on the kidneys of male rats are associated with the occurrence of hyaline droplets from 0,,-globulin and are not applicable to humans (EPA 1991). * An MRL of 0.1 ppm has been derived for chronic-duration inhalation exposure (365 days or more) to 1,4-dichlorobenzene. This MRL was calculated using a NOAEL of 75 ppm, based on the absence of liver effects in rats (Riley et al. 1980). The NOAEL of 75 ppm was converted to 11 ppm after incorporating adjustments for intermittent exposure (5 hours per day, 5 days per week). The NOAEL was further adjusted for Human Equivalent Concentration (NOAEL gc) using Equation 4-48a of EPA (1994k) and by applying an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Groups of young rats (90-110 g body weight) were exposed whole-body to 0 (air control), 75, or 500 ppm p-DCB 5 hours a day, 5 days a week for 76 weeks. Interim sacrifices were conducted at weeks 26, 52, and 76. After exposure terminated, groups of rats were kept until natural death or week 112. End points examined include clinical or behavioral abnormalities, body and organ weights (liver, kidney, adrenal, spleen, gonads, heart, lung, brain, and pituitary), food and water consumption, histopathology (adrenal, aorta, bladder, brain, bone marrow, cecum, colon, cervix, duodenum, epididymis, esophagus, eyes, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph nodes, mammary gland, nasal sinuses ovaries, pancreas, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicle, spinal cord, spleen, stomach, testes, trachea, thymus, thyroid, uterus, voluntary muscle, Zymbal's gland and Harderian gland), blood chemistry, urinalysis and hematology. Exposure to p-DCB had no effect on survival rate, body weight, food intake, or water consumption. No significant toxicological effects were noted on the respiratory, cardiovascular, hepatic, or renal systems at 75 ppm. There was a slight increase in lung weight only at termination (week 122) at 500 ppm in males and females, but no histopathological effects in the nasal sinuses, trachea, or lungs. Both sexes showed a significantly increase in heart weight at termination, but no histopathological effects in the heart or aorta. No effects were observed in the gastrointestinal tract or in skeletal muscle. Although some changes in blood chemistry and hematology parameters were seen, there was no evidence of ""*DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 97 2. HEALTH EFFECTS dose-related patterns. Liver weights were increased at 500 ppm (except in females at week 76), but there were no histological changes or changes in enzyme activity that would indicate liver damage. There was also no increase in the activity of hepatic aminopyrine demethylase. Kidney weights were increased at 500 ppm in males, but there was no evidence of histologic changes. There were no treatment-related effects on the thyroid, pituitary, adrenals, or the eyes. More information on how this MRL was calculated is presented in Appendix A of this profile. Oral MRLs. An acute-duration MRL was not derived for oral exposure to 1,4-dichlorobenzene due to the lack of adequate data in humans or animals for identifying reliable NOAEL or LOAEL values. « An MRL of 0.1 mg/kg/day has been derived for intermediate-duration (15 to 364 days) exposure to 1,4-dichlorobenzene. This MRL was calculated using a NOAEL of 18.8 mg/kg/day, based on the presence of minimal liver effects (increased liver weights) in rats at the next highest dose (Hollingsworth et al. 1956). This dose was converted to 13.4 mg/kg/day, incorporating adjustments for exposure for 5 days a week and an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). In this study, increased liver weight was reported at doses of 188 mg/kg/day and greater, and hepatic necrosis and slight cirrhosis were seen at a dose levels of 376 mg/kg/day. More information on how this MRL was calculated is presented in Appendix A of this profile. A chronic-duration oral MRL was not derived for oral exposure to 1,4-dichlorobenzene because the data were not considered to be suitable. Hepatocellular degeneration was observed in mice at a LOAEL of 300 mg/kg/day and was accompanied by hepatocellular carcinomas and hepatoblastomas (NTP 1987). There was no NOAEL in this study. The lack of the NOAEL and the occurrence of tumors at the LOAEL concentration indicate that this study is not suitable for an MRL determination. Death. There are some data to suggest that lethality may be a public health concern for persons exposed for prolonged periods of time to high levels of 1,4-dichlorobenzene in confined areas (e.g., in homes). The only available information related to the death of humans exposed to 1,4-dichlorobenzene is a case study of a 60-year-old man and his wife who both died of liver ailments after the air ***DRAFT FOR PUBLIC COMMENT"*** 1,4-DICHLOROBENZENE 98 2. HEALTH EFFECTS in their home had been found to contain increased air concentrations of 1.4-dichlorobenzene (described as “saturated”) for 3-4 months (Cotter 1953). However, the exact air concentration of 1,4-dichloro- benzene was not measured or reported, nor was the existence or nature of other possible factors contributing to their deaths (e.g., pattern of alcohol consumption, exposure to other chemicals, or pre- existing medical conditions). By comparison, no mice died when exposed to 320 ppm for 5 days, while 2 of 6 died at 640 ppm (Anderson and Hodge 1976). Increased mortality was also noted in one intermediate-duration study when rats, guinea pigs, and rabbits were exposed to 798 ppm for 9-12 weeks (Hollingsworth et al. 1956). These data suggest that if humans are as sensitive to the effects of inhaled 1,4-dichlorobenzene as these laboratory animals, an increased probability of death may be expected at exposures of >500 ppm. There is insufficient data available, however, to determine if humans are more or less sensitive to the 1,4-dichlorobenzene than are laboratory animals. It is unlikely that levels of 1,4-dichlorobenzene in the air of the general environment or in the vicinity of hazardous waste sites would be high enough to cause mortality. There are several studies available on the lethality of 1,4-dichlorobenzene via the oral route in laboratory animals. Acute-duration oral studies indicate no deaths occurred in rats, guinea pigs, or mice at doses <1,000 mg/kg/day. Acute oral LD, (lethal dose, 100% kill) values in rats and guinea pigs have been reported as 4,000 and 2,800 mg/kg/day, respectively (Hollingsworth et al. 1956); 3,800 mg/kg/day has been reported as the acute oral LDs in rats (Gaines and Linder 1986). In 14-day studies, doses of 600 mg/kg/day failed to elicit death (Carlson and Tardiff 1976), while 4 of 5 female rats that received 1,4-dichlorobenzene at 1,000 mg/kg/day died (NTP 1987). High mortality was also seen.in male rats that received 1,4-dichlorobenzene at 300 mg/kg/day for 2 years (NTP 1987). Mice tested in the NTP (1987) study seemed far less susceptible than rats to the lethal effects of 1,4-dichlorobenzene. No reports of human death after ingesting 1,4-dichlorobenzene have been reported; however, there is some concern that ingestion of 1,4-dichlorobenzene could result in human mortality based on two factors. First, 1,4-dichlorobenzene is used in many homes in the form of consumer products such as mothballs and toilet bowl deodorant blocks. Because of its availability in the form of mothballs and its pleasant taste, 1,4-dichlorobenzene can be accidentally ingested by young children. Secondly, a 19-year-old woman ingested 4-5 pellets of 1,4-dichlorobenzene daily for about 2.5 years (Frank and Cohen 1961); in another case a 21-year-old woman consumed one or two 1,4-dichlorobenzene toilet bowl deodorizer blocks per week throughout her pregnancy (Campbell and Davidson 1970). Thus, "**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 99 2. HEALTH EFFECTS based on its availability and potential organoleptic appeal, it is possible that sufficient amounts of 1.,4-dichlorobenzene could be consumed to pose a threat to human life. However, no reports of death resulting from accidental or intentional ingestion of 1,4-dichlorobenzene have been located. Based on its minimal solubility in water, it is unlikely that levels of this chemical in drinking water at any location, even a hazardous waste site, would be high enough to cause lethality. Systemic Effects. Respiratory Effects. Respiratory effects associated with inhalation of 1,4-dichlorobenzene have been reported in two human case studies and three animal studies. In one human case study, a 53-year-old woman developed pulmonary granulomatosis as a result of inhaling 1,4-dichlorobenzene crystals in her home for 12-15 years (Weller and Crellin 1953). These crystals apparently lodged and accumulated in her lungs for some period of time, resulting in fibrosis, thickening of the alveolar and arterial walls, and infiltration by large numbers of lymphocytes and mononuclear phagocytes. These effects were apparently related to the physical characteristics of the 1,4-dichlorobenzene crystals that this pation had inhaled. Inhalation of large amounts of particulate matter of any composition is generally damaging to the lung and usually associated with fibrotic changes. Although this case study is most appropriately viewed as an unusual and isolated incident, it is important as a demonstration that chemical toxicity is not necessarily the only concern for a product that is available in crystalline or powdered form. In another study involving occupationally exposed men, 1.4-dichlorobenzene resulted in local irritant effects in the nose at concentrations of 80-160 ppm (Hollingsworth et al. 1956). An apparent tolerance threshold of >160 ppm was also established for this population of men. Respiratory effects have also been reported in animal studies using 1,4-dichlorobenzene vapor. After 16 days of exposure to 1,4-dichlorobenzene at 173 ppm, slight changes (interstitial edema and congestion and alveolar hemorrhage) were reported in the lungs of male rats, female guinea pigs, and a female rabbit. Congestion and emphysema were also reported in the lungs of rabbits exposed to 1,4-dichlorobenzene at 798 ppm for 12 weeks (Hollingsworth et al. 1956). In rats exposed chronically to 1.4-dichlorobenzene concentrations up to 499 ppm, small increases in lung weights were noted, with no histopathological changes noted in the lungs, trachea, or larynx. These findings suggest that respiratory effects are a possible concern for humans exposed to 1,4-dichlorobenzene via inhalation. However, relatively high concentrations of inhaled 1,4-dichlorobenzene are apparently needed to elicit ***DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 100 2. HEALTH EFFECTS any significant changes, and it is unlikely that levels of 1,4-dichlorobenzene in the air of the general environment or in the vicinity of hazardous sites would be high enough to cause respiratory effects. Respiratory effects after oral exposure to 1,4-dichlorobenzene in humans have not been reported. Rats exposed to 21,200 mg/kg/day 1,4-dichlorobenzene for 13 weeks exhibited necrosis of the nasal turbinates, yet no such effects were noted in mice exposed to similar oral concentrations (NTP 1987). The mechanism related to this effect is not readily apparent. No effect on the respiratory system was noted in one study of chronic duration in both rats and mice exposed to <600 mg/kg/day for 2 years (NTP 1987). Cardiovascular Effects. No reports of cardiovascular alterations after inhalation or oral exposure to 1,4-dichlorobenzene in humans have been reported. Acute exposures in rats (Hodge et al. 1977) up to 508 ppm for 10 days produced no cardiovascular effects. Other acute- or intermediate-duration exposures using lower doses confirmed a no-effect scenario on the cardiovascular system. One chronic-duration study in which rats were exposed to 490-499 ppm of 1,4-dichlorobenzene for 112 weeks, did produce a significant increase in absolute heart weight, yet no abnormal histopathology was noted. No such effect was observed in rats exposed to 72 ppm for similar durations of exposure. The significance of this increased heart weight is not known. Oral exposure of 1,4-dichlorobenzene in rats (1,500 mg/kg/day) and mice (1,800 mg/kg/day) by gavage for 13 weeks failed to produce any observable cardiovascular effects. Rats and mice exposed chronically to concentrations up to 600 mg/kg/day via gavage for 2 years also failed to produce any observable cardiovascular effects. It appears that the cardiovascular system is not a target organ for 1,4-dichlorobenzene after inhalation or oral exposures. Gastrointestinal Effects. Limited information is available for the gastrointestinal effects of I.4-dichlorobenzene in humans after inhalation exposure. Two reports provide rather vague and non- specific information on gastrointestinal disturbances, such as increased frequency of bowel movements and blood in the gastrointestinal tract, after inhalation exposure to unknown concentrations of I.4-dichlorobenzene (Cotter 1953). Blood in the gastrointestinal tract was reported in this study; however, the presence of blood was likely not due to a direct effect of 1,4-dichlorobenzene, but rather due to the presence of ruptured esophageal varices that formed in response to liver cirrhosis. The human data available are not sufficient to draw any conclusions about the gastrointestinal toxicity of “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 101 2. HEALTH EFFECTS 1,4-dichlorobenzene either by inhalation or oral routes of exposure. No gastrointestinal effects were noted in rats exposed to 1,4-dichlorobenzene concentrations of 490-499 ppm for 76 weeks. It would appear more likely that gastrointestinal effects would be more frequently observed after oral exposure; however, only one laboratory animal study found gastrointestinal effects associated with oral exposure to 1,4-dichlorobenzene (NTP 1987). In that study, 1,200 mg/kg/day via gavage for 13 weeks resulted in epithelial necrosis and villar bridging of the small intestine mucosa. Lower-concentration exposures did not produce any effects on the gastrointestinal system in rats; oral exposures as high as 1,800 mg/kg/day for 13 weeks in mice also failed to produce any gastrointestinal effects. A 2-year chronic-duration study in both rats and mice exposed to <600 mg/kg/day by gavage also did not produce any discernible gastrointestinal effects (NTP 1987). The laboratory animal data suggest that the gastrointestinal tract is relatively resistant to any toxicological effects that may be produced by exposure to 1,4-dichlorobenzene. Rats appear to be somewhat more susceptible to oral toxicity of 1,4-dichlorobenzene than mice. Hematological Effects. Limited information is available for the hematological effects of 1,4-dichloro- benzene in humans after inhalation exposure. Two reports provide rather vague and non-specific information on hematological disturbances (anemia), with no exposure concentrations or information on other factors that could produce a similar finding (Cotter 1953), but the disturbances are likely related to the formation of and bleeding from esophageal varices that occur secondary to 1,4-dichloro- benzene-induced liver cirrhosis. However, no adverse hematological alterations were noted in an occupational study of men exposed to 10-550 ppm of 1,4-dichlorobenzene for 8 months to 25 years (Hollingsworth et al. 1956), indicating that in healthy men, 1,4-dichlorobenzene appears to have little toxicological effect. Overall, there are insufficient human data available to draw any conclusions about the hematological toxicity of 1,4-dichlorobenzene by the inhalation route of exposure. No hematological alterations were reported in rats exposed to 1,4-dichlorobenzene concentrations as high as 499 ppm for as long as 76 weeks (Riley et al. 1980). Hematological effects resulting from oral exposure to 1,4-dichlorobenzene have been reported in one human case study and in several studies in rodents. Severe anemia was reported to have occurred in a 21-year-old pregnant woman who had consumed 1-2 blocks of 1,4-dichlorobenzene air freshener per week throughout pregnancy. Her condition was described as hypochromic (pale blood due to reduced hemoglobin content), microcytic (smaller and rounder red blood cells) anemia with excessive polychromasia, marginal nuclear hypersegmentation of the neutrophils, and the presence of Heinz ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 102 2. HEALTH EFFECTS bodies in her red blood cells (Campbell and Davidson 1970). Her infant was born with no hematological abnormalities and the woman's own hematological condition gradually reversed itself after she discontinued consumption of 1,4-dichlorobenzene. Acute hemolytic anemia and methemo- globinuria were reported to have occurred in a 3-year-old boy who had played with, and possibly eaten, some 1,4-dichlorobenzene moth crystals (Hallowell 1959). The results of both investigations could be explained by the inhibition of G6PD in red blood cells by oxidant metabolites of 1,4-dichlorobenzene with subsequent Heinz body formation, methemaglobinemia, and hemolysis (Trieff et al. 1993). Rats administered 1,4-dichlorobenzene doses of 75-600 mg/kg/day by gavage in corn oil for 13 weeks did not experience any changes in hematologic parameters (Bomhard et al. 1988), neither did rats in a study by Hollingsworth et al. (1956) in which rats received 376-500 mg/kg/day for 28-192 days. In contrast, decreased hematocrit levels, red blood cell counts, and hemoglobin concentrations were measured in male rats that received 1,4-dichlorobenzene for 13 weeks at 300 mg/kg/day and above (NTP 1987). However, these effects were not seen in male rats that received 1,4-dichlorobenzene at 300 mg/kg/day for 2 years (NTP 1987). No hematologic effects were seen in female rats at any level of 1,4-dichlorobenzene tested (up to 600 mg/kg/day for 2 years) in the same set of studies. In the NTP (1987) study, mice dosed with concentrations up to 900 mg/kg/day for 13 weeks produced no hematological alterations, while in a second study by NTP (1987), mice dosed with 600-1,800 mg/kg/day for 13 weeks produced lymphopenia and neutropenia (no red blood cell anomalies). The human and laboratory animal data suggest that the hematological system is susceptible to the effects of 1,4-dichlorobenzene. It is not known, however, if this is a result of a direct action on the red and white blood cells, or an effect on the red and white cell precursor cells of the bone marrow (as is the case with benzene toxicosis in humans). It is assumed that 1,4-dichloro- benzene is the chemical responsible for this alteration; however, interaction with the primary metabolite on the hematopoietic system can not be ruled out from this set of data. The inhibition of GO6PD in red blood cells by oxidant metabolites of 1,4-dichlorobenzene with subsequent Heinz body formation, methemaglobinemia, and hemolysis could be responsible for this effect (Trieff et al. 1993). The effects of 1,4-dichlorobenzene ingestion on hematological parameters reported in both human and animal studies indicate that this is an area of potential concern for humans exposed to 1,4-dichloro- benzene. Possible effects in humans have been associated with red blood cells anomalies. Because of sex and species differences seen in animal studies (i.e., effects on red blood cells in rats and effects on ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 103 2. HEALTH EFFECTS white blood cells in mice), the total spectrum of concern for exposed humans is currently not clear. However, it is unlikely that levels of 1,4-dichlorobenzene in the drinking water of any location would be high enough to cause hematological effects. Musculoskeletal Effects. There were no reports of human exposure that resulted in musculoskeletal effects. The few reports that examined the musculoskeletal system after exposure to 1,4-dichloro- benzene in laboratory animals failed to elicit detectable changes in this system. Hepatic Effects. Liver effects reported in case studies in humans exposed to 1,4-dichlorobenzene via inhalation have included jaundice, cirrhosis, and atrophy (Cotter 1953). Estimates of exposure duration ranged from 1 to 18 months; however, quantitative data on 1,4-dichlorobenzene levels were not available. One report was located that described a 3-year-old boy who may have ingested 1,4-dichlorobenzene crystals. Jaundice was reported, indicating that liver function was in some way compromised, although no further details were reported. No dermal exposures to 1,4-dichlorobenzene in humans were reported. The lack of reliable information regarding human exposures to 1,4-dichloro- benzene by all three routes of exposure makes it difficult to draw any helpful conclusions about the toxicity of 1,4-dichlorobenzene in humans. Hepatic effects have been demonstrated in several animal studies conducted via inhalation and oral exposure with durations ranging from 3 days to 2 years. Observed effects have ranged from enzyme changes and porphyria to liver degeneration and necrosis. Hepatic effects reported in inhalation studies have not been consistent. Acute-duration studies in rats and rabbits exposed to concentrations as high as 500-800 ppm failed to produce detectable hepatic effects (Hayes et al. 1985; Hodge et al. 1977). In inhalation studies of 5-7 months duration, exposure of rats and guinea pigs to 158-341 ppm resulted in cloudy swelling, granular degeneration, slight cirrhosis, focal necrosis, and fatty degeneration of the liver (Hollingsworth et al. 1956). Relative liver weights were also increased in rats exposed to 173 ppm and above. In a more recent study, however, a 1.5-year exposure of rats to 1,4-dichlorobenzene at 500 ppm resulted in increased liver weight but no other liver pathology, including no increases in serum transaminase activity (Riley et al. 1980). In oral studies, severe cases of porphyria (an indication of liver damage as evidenced by increased urinary excretion of porphyrins and high hepatic levels of porphyrins) were induced in male rats that ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 104 2. HEALTH EFFECTS received 1,4-dichlorobenzene during a short-term, high-level dosage regimen (770 mg/kg/day for 5 days) (Rimington and Ziegler 1963). However, only slight increases in liver porphyrins (but not in urinary excretion of porphyrins) were seen in female rats that received 1,4-dichlorobenzene at 50 mg/kg/day and above for 120 days (Carlson 1977). It is not clear if the observed differences are due to the dosing regimens or to sex-related differences in sensitivity to 1,4-dichlorobenzene. Oral exposure to 1,4-dichlorobenzene has been shown to result in changes in the activities of certain hepatic enzymes in rats, including increases in the activity of -ALA synthetase at a 1,4-dichloro- benzene level of 250 mg/kg/day for up to 3 days (Ariyoshi et al. 1975); increases in the activities of glucuronyl transferase, benzpyrene hydroxylase, and the enzyme system involved in EPN detoxification to p-nitrophenol at 1,4-dichlorobenzene levels of 20 mg/kg/day and above for 14 days (Carlson and Tardiff 1976); increases in benzpyrene hydroxylase, and EPN detoxification activities at 1,4-dichlorobenzene levels of 20 mg/kg/day and above for 90 days, and increases in azoreductase levels at 10 mg/kg/day and above for 90 days (Carlson and Tardiff 1976). These findings are viewed as an important component of the hepatotoxic potential of 1,4-dichloro- benzene. Even though elevations in levels of hepatic enzymes are not in themselves always considered to be of major toxicological concern, the fact that these changes can occur even at 1,4-dichlorobenzene levels as low as 10 or 20 mg/kg/day in 14- and 90-day exposure regimens indicates that the liver is sensitive to 1,4-dichlorobenzene at exposure levels far below those that evoke severe histopathological damage. It is also important to note that a true NOAEL for hepatic effects has not been identified since effects on hepatic enzymes have been found at the lowest levels of 1,4-dichlorobenzene tested and the potential long-term consequences of these effects on enzyme activities and their relationship to overt hepatic lesions are not clearly understood. Histopathologic lesions of the liver have been demonstrated in several oral studies in rodents dosed at higher levels of 1,4-dichlorobenzene. Cloudy swelling and centrilobular necrosis were observed in the livers of rats that received 1,4-dichlorobenzene at 500 mg/kg/day for 4 weeks (Hollingsworth et al. 1956). Thirteen-week studies have resulted in degeneration and necrosis of hepatocytes in rats that received doses of 1,200 mg/kg/day and above; and in mice, hepatocellular degeneration was observed at 600 mg/kg/day and above and hepatocellular cytomegaly at 675 mg/kg/day and above (NTP 1987). Focal necrosis and slight cirrhosis were reported in the livers of rats dosed at 376 mg/kg/day for about 6 months (Hollingsworth et al. 1956). In 2-year studies, mice that received 1,4-dichlorobenzene at “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 105 2. HEALTH EFFECTS 300 mg/kg/day and above, had increased incidences of cytomegaly, karyomegaly, hepatocellular degeneration, and single-cell necrosis (NTP 1987). No hepatic effects, however, were found in a 2-year study in rats (males received up to 300 mg/kg/day; females received up to 600 mg/kg/day) (NTP 1987). The results of the available studies generally indicate that mice are somewhat more sensitive than rats to the more severe histopathological effects of 1,4-dichlorobenzene on the liver. However, the liver is clearly a target organ in both species. Oral exposure to 1,4-dichlorobenzene in rats and mice has been demonstrated to elicit a cellular proliferation response in the livers of these animals. 1,4-Dichlorobenzene is not known to be reactive with DNA (i.e., not genotoxic as determined by standard assays); however, it has been reported to induce liver tumors in mice (NTP 1987). Studies by Eldridge et al. (1992) demonstrated sharp increases in cell proliferation in mouse livers beginning 24 hours after a single dose of 600 mg/kg/day of 1,4-dichlorobenzene in oil. There was also an increase in liver weight without increase in liver- associated plasma enzymes, indicating a lack of cytotoxicity to the hepatocytes. From these data, it was demonstrated that 1,4-dichlorobenzene induced a mitogenic stimulation of cell proliferation in the liver rather than a regenerative response following cytotoxicity. A similar study was performed in mice (Umemura et al. 1996). From the sum of these data it is hypothesized that this early mitogenic stimulation of cell proliferation after oral exposure to 1,4-dichlorobenzene may be, at least in part, the mechanism behind the tumor formations found in mice in the NTP (1987) study. This increased cellular proliferation response may provide a selective growth advantage for neoplastic cell in the mouse liver after long-term treatments, which ultimately results in hepatic neoplasms. The implications for human cancer health risks are unknown at this point; however, it is unlikely that levels of 1,4-dichlorobenzene in the drinking water would be high enough to cause proliferative and mitogenic hepatic effects observed in rats and mice, based on the potential human exposure data presented in Chapter 5 of this profile. Based on the results of studies in humans and animals, humans exposed to 1,4-dichlorobenzene could experience a variety of hepatic effects ranging from increased hepatic enzyme activity at low levels of exposure to severe histopathological effects resulting from high levels of exposure. It is unlikely, based on the NOAELs and LOAELs demonstrated in laboratory animal studies and human case reports, that the reported levels of 1,4-dichlorobenzene in the air of the general environment, or in the “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 106 2. HEALTH EFFECTS vicinity of hazardous waste sites, or in the drinking water of any location (measured at concentrations as low as parts per billion) would be high enough to cause hepatic or other toxicological effects in humans. More information on the amounts and presence of 1,4-dichlorobenzene in the environment can be found in Chapter 5 of this profile. Endocrine Effects. No studies were identified that described endocrine organ effects in humans after inhalation or oral exposure to 1,4-dichlorobenzene. No endocrine organ effects were noted in rats exposed to 490-499 ppm 1,4-dichlorobenzene for 76 weeks (Riley et al. 1980). No endocrine effects were noted in rats dosed with 1,500 mg/kg/day of 1,4-dichlorobenzene in oil for 13 weeks (NTP 1987). However, rats dosed with 150 or 300 mg/kg/day (males) or 300-600 mg/kg/day (females) 1,4-dichlorobenzene in oil for 103 weeks produced an increased incidence of parathyroid hyperplasia in males only; females, given higher doses than the males, were unaffected. The dosing of male and female mice with 300 and 600 mg/kg/day in oil for 103 weeks produced thyroid follicular cell hyperplasia in males only; females were unaffected. Adrenal medullary hyperplasia and focal hyperplasia of the adrenal gland capsule were also observed in these male mice (NTP 1987). Clearly, there is a sex-related difference in toxicity relating to endocrine organ toxicity, and it appears to be related to the production of testosterone in male rats and mice. Chemical disruption of endocrine function has been described for a number of other chemicals; however, the significance to human exposure to these chemicals (including 1,4-dichlorobenzene) is not known. Renal Effects. Renal effects have not been reported in humans exposed to 1,4-dichlorobenzene by any route, but renal effects have been reported in inhalation and oral studies in animals. Several studies have identified no-effect levels after inhalation exposure in laboratory animals (Hayes et al. 1985; Hodge et al. 1977). In inhalation studies, renal effects have been limited to increased kidney weights in male, but not female, rats exposed to 158 or 341 ppm for 5-7 months (Hollingsworth et al. 1956). Severe renal changes have been reported in oral studies using rats; some of these effects have been seen only in male Fischer 344 rats as opposed to female rats or mice of either sex. In 13-week studies in rats, histologic changes, including tubular degeneration, were seen in the kidneys of all males dosed ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 107 2. HEALTH EFFECTS with 1,4-dichlorobenzene at 300-1,500 mg/kg/day (NTP 1987). In a follow-up 13-week study at lower doses, however, only slight to moderate changes in the tubules were seen in males at 300-600 mg/kg/day. Studies by Eldridge et al. (1992) demonstrated that B6C3F,; mice dosed with 300 or 600 mg/kg/day of 1,4-dichlorobenzene for 4 days had no altered kidney weights or cell proliferation rates as measured by BrdU-labeling of the cells. Male rats dosed with 150 or 300 mg/kg/day for 4 days showed marked increases in both kidney weight and cell proliferation, while female rats dosed with 300 or 600 mg/kg/day mimicked the results found in both male and female mice. Cell proliferation in the kidneys of male rats was mainly limited to the proximal tubules, and to a lesser extent the proximal straight tubules. These data suggest that male rats are more sensitive to the renal effects of 1,4-dichlorobenzene and that cell proliferation in these male rats may play a role in the development of tubular cell adenocarcinomas of the kidneys (see the discussion on cell proliferation and carcinogenesis in Hepatic Effects, above) found in a chronic-duration study (NTP 1987). Administration of 1,4-dichlorobenzene by gavage to certain strains of rats under a wide variety of acute- and intermediate-duration dosage regimens has resulted in an increase in renal hyaline droplet formation in males, but not females (Bomhard et al. 1988; Charbonneau et al. 1987, 1989a, 1989b). Renal cell proliferation was also increased as indicated by 3H-thymidine incorporation into renal DNA. The C from radiolabeled 14-dichlorobenzene was reversibly bound to the renal protein 0y,-globulin in the hyalin droplets. This protein is produced in large amounts by male rats, accounting for 26% of their total urinary protein, but not in human males where it was found to be present at 1% of the amount measured in male rats (Olson et al. 1990). This protein is only produced in minimal quantities by females of any species or the males of other laboratory species, including mice (EPA 1991). Observations have led t6 suggestions that humans are probably not at risk for the type of nephropathy induced by 1,4-dichlorobenzene in male rats. Renal effects have been observed in both male and female rats in a chronic-duration oral study. Male Fischer 344 rats exposed to 1,4-dichlorobenzene at 150 and 300 mg/kg/day for 2 years exhibited nephropathy, epithelial hyperplasia of the renal pelvis, mineralization of the collecting tubules in the renal medulla, and focal hyperplasia of the tubular epithelium. Each of these effects was associated with hyalin droplet formation. There were also increased incidences of nephropathy in female Fischer 344 rats dosed with 1,4-dichlorobenzene at 300 and 600 mg/kg/day. Histopathologically, the nephropathy was characterized by degeneration and regeneration of the tubular epithelium, tubular ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 108 2. HEALTH EFFECTS dilatation with attenuation and atrophy of the epithelium, granular casts in the tubules of the outer stripe of the medulla, thickening of the basement membranes, and minimal accumulation of interstitial collagen (NTP 1987). In mice dosed at 300 and 600 mg/kg/day, there was also an increased incidence of nephropathy (consisting primarily of degeneration of the cortical tubular epithelium with thickening of the tubular and glomerular basement membranes and increased interstitial collagen in male mice, and renal tubular regeneration in female mice). These observations of renal effects in female rats and in mice of both sexes are important because they provide evidence that renal lesions in response to 1,4-dichlorobenzene exposure are not limited to male rats and do not require the presence of high levels of the renal protein of oy, -globulin. Therefore, although humans may not be at risk for certain 1,4-dichlorobenzene-induced renal lesions (renal hyaline droplet nephropathy), they are possibly at risk for others. However, it is unlikely that levels of 1,4-dichlorobenzene in the air of the general environment, or in the vicinity of hazardous waste sites, or in the drinking water of any location would be high enough to cause renal effects. Dermal Effects. Dermal effects have been reported in humans exposed to 1,4-dichlorobenzene via inhalation or ingestion. In a study of 58 men who had been occupationally exposed to 1,4-dichloro- benzene for 8 months to 25 years, painful irritation of the nose and eyes was reported to have occurred at 1,4-dichlorobenzene levels of 80-160 ppm, yet no cutaneous effects were noted. Above 160 ppm, the air was considered unbreathable by unacclimatized persons (Hollingsworth et al. 1956). Petechiae, purpura, and swelling of the hands and feet were reported to have occurred in a 69-year-old man who had been exposed to 1,4-dichlorobenzene for about 3 weeks in his home (Nalbandian and Pearce 1965). Well demarcated areas of increased pigmentation developed in a 19-year-old black woman who had eaten four to five 1,4-dichlorobenzene moth pellets daily for the previous 2.5 years (Frank and Cohen 1961). Hollingsworth et al. (1956) reported a burning sensation occurring in men that placed solid 1,4-dichlorobenzene in close contact with the skin. Although there is no clear pattern to these observations, both irritation and sensitization reactions may potentially result from human inhalation or oral exposure to 1,4-dichlorobenzene. There is little laboratory animal data available that describe the dermal affects related to inhalation, oral, or dermal exposure to 1,4-dichlorobenzene. Fischer 344 rats and B6C3F,; mice exposed to concentrations up to 1,500 mg/kg/day and 1,800 mg/kg/day, respectively, for 13 weeks produced no dermal effects (NTP 1987). In rats exposed to 1,4-dichlorobenzene at 150-600 mg/kg/day and in mice exposed to 300 and 600 mg/kg/day in oil for 2 years no dermatological effects were produced. There ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 109 2. HEALTH EFFECTS are no data related to dermal effects resulting specifically from dermal exposure to 1,4-dichloro- benzene in humans Ocular Effects. No ocular effects have been reported in humans exposed to 1,4-dichlorobenzene by any route, including in the 58 men who had been occupationally exposed for 8 months to 25 years and occasionally examined for ocular effects (Hollingsworth et al. 1956). Ocular effects described as reversible, nonspecific eye ground changes (changes in the fundus or back of the eye) were seen in rabbits exposed to 1,4-dichlorobenzene at 798 ppm for 12 weeks (Hollingsworth et al. 1956). In the same study, no changes in lens morphology and opacity were observed in rats and guinea pigs exposed to 1,4-dichlorobenzene. Rats exposed to 1,4-dichlorobenzene at doses up to 499 ppm for 76 weeks also failed to produce an adverse ocular response. These few findings do not support a clear concern for potential ocular effects in humans exposed to 1,4-dichlorobenzene in any environment. However, no studies were located that directly dosed 1,4-dichlorobenzene onto the surface of the eye in either humans or animals. Organic compounds with similar physicochemical properties and structure have been identified as ocular irritants when dosed in this fashion. It would, therefore, be premature to assume that 1,4-dichlorobenzene is not an ocular irritant when placed on the eye in the absence of the appropriate toxicological studies. Body Weight Effects. Unknown amounts of inhaled 1,4-dichlorobenzene have been reported to cause decreases in body weight in humans (Cotter 1953). Little more significant information was reported in these individual case studies, indicating that other factors may have resulted in the loss of body weight. The human database is insufficient to draw any substantial conclusion about 1,4-dichloro- benzene’s ability to cause decreases in body weight. Changes in body weight were not reported for the majority of laboratory animals exposed to I,4-dichlorobenzene by inhalation, even at relatively high concentrations of 798 ppm for 5-7 months. No studies were identified that described changes in body weight in humans after oral exposure to 1,4-dichlorobenzene. A few laboratory animal studies examined changes in body weight. Acute exposure in rats to 600 mg/kg/day once (Eldridge et al. 1992), 250 mg/kg/day for 3 days (Ariyoshi et al. 1975), and 770 mg/kg/day for 5 days (Eldridge et al. 1992) revealed no changes in body weight. Intermediate- ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 110 2. HEALTH EFFECTS duration studies using similar doses have also proved to have little if any effect on body weight in rats and mice (NTP 1987). Other studies (NTP 1987) of intermediate- and chronic-durations in rats and mice showed mixed results as to whether 1,4-dichlorobenzene actually produces discernible changes in body weight in laboratory animals. Immunological and Lymphoreticular Effects. Little information was located on immunological effects in humans or animals exposed to 1,4-dichlorobenzene via inhalation, oral, or dermal routes. An enlarged spleen was noted in two people exposed to 1,4-dichlorobenzene (dose not reported); data on alterations in spleen weights have varied in laboratory animals exposed for different durations (Hollingsworth et al. 1956; Riley et al. 1980). Observations of blotchy skin pigmentations in a black 19-year-old woman who had eaten 4-5 pellets of 1,4-dichlorobenzene daily for 2.5 years (Frank and Cohen 1961), and the observations of purpura, petechiae, and swelling of the hands and feet of the 69-year-old man who had been exposed to 1,4-dichlorobenzene for about 3 weeks via inhalation (Nalbandian and Pearce 1965) suggest that immunological mechanisms were involved and that this is an area of potential concern for humans exposed to 1,4-dichlorobenzene. Bone marrow hypoplasia and lymphoid depletions of the spleen were reported in one study using both rats and mice dosed with 1,200-1,500 mg/kg/day of 1,4-dichlorobenzene for 13 weeks (NTP 1987); however, at 600 mg/kg/day for 2 years, no changes to the lymphoreticular system were noted in rats (NTP 1987). Mice still showed an increased incidence of lymph node hyperplasia. Together, these data suggest that there may be an immunological component involved in 1,4-dichlorobenzene toxicity; however, the threshold for these effects and their mechanisms is not known. Neurological Effects. Neurological effects have been reported in humans exposed to 1,4-dichloro- benzene via inhalation. Symptoms have included dizziness, weakness, headaches, nausea, vomiting, numbness, clumsiness, a burning sensation, and speech difficulties (Cotter 1953; Miyai et al. 1988). In the recent case study of a 25-year-old woman who had been exposed to high concentrations of | .4-dichlorobenzene in her bedroom, bedding, and clothes for 6 years, there were marked delays of certain brainwaves, as indicated by electronic testing of BAEPs, in addition to severe ataxia, speech difficulties, and weakness in her limbs (Miyai et al. 1988). Non-specific clinical neurological alterations (tremors, weakness, unconsciousness, ataxia, hyperactivity, etc.) have been reported in rats, rabbits, and guinea pigs (Hollingsworth et al. 1956; Riley et al. 1980; Rimington and Ziegler 1963; Tyl and Neeper-Bradley 1989); however, these type of effects have been reported with other volatile organic chemicals (carbon tetrachloride, chloroform, benzene) as well, indicating some neurological ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 111 2. HEALTH EFFECTS component to its toxicity. While there is no clear evidence of neurological effects in humans who ingested 1,4-dichlorobenzene and no information on neurological effects in animals exposed by any route, the available information on humans and laboratory animals exposed to 1,4-dichlorobenzene via inhalation strongly suggests that this is an area of potential concern. However, it is not probable that the levels of 1,4-dichlorobenzene in the air of the general environment or in the vicinity of hazardous waste sites would be high enough to cause neurological effects. Reproductive Effects. No information was located regarding the reproductive effects in humans exposed to 1,4-dichlorobenzene by any route. From the available data on 1,4-dichlorobenzene, exposure by inhalation and oral routes appears to have little to no effect on the reproductive systems of either male or female laboratory animals. In a 2-generation study of reproductive performance using exposure concentrations of 66.3-538 ppm 1,4-dichlorobenzene, toxic effects on the liver, kidney, and body weight were noted in breeding rats (males and females) (Tyl and Neeper-Bradley 1989). The effects of exposure on litter size, weight, and survival appeared to result from the maternal toxicity of the compound rather than direct effects on reproductive processes. However, offspring were not examined for developmental or teratogenic effects. In addition, no decrease in reproductive performance (ability to impregnate females) was found in an inhalation study in which male mice were exposed to 1,4-dichlorobenzene for 5 days at levels up to 450 ppm (Anderson and Hodge 1976). No effect on testicular weight was noted in rats and guinea pigs exposed to 173 ppm 1,4-dichlorobenzene for 2 weeks (Hollingsworth et al. 1956), and no changes were noted in the reproductive organs of male and female rats exposed up to 499 ppm for 76 weeks (Riley et al. 1980). In another study, statistically significant increases in the incidences of abnormal sperm heads and tails were seen in male rats that had received a single intraperitoneal injection of 1,4-dichlorobenzene at 800 mg/kg/day (Murthy et al. 1987). The potential effects of these abnormalities (e.g., banana- and wedge-shaped heads, twisted and curly tails) on reproductive capacity is not known, but paternal effects were not noted in the 2-generation study discussed above. However, the nonbiological route of administration complicates the interpretation of these results. It is not likely, based on the potential for human exposure data presented in Chapter 5, coupled with the NOAELs and LOAELs gathered from human case reports and laboratory animal studies, that the levels of 1,4-dichlorobenzene in the air of ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 112 2. HEALTH EFFECTS the general environment, or in the vicinity of hazardous waste sites, or in drinking water in any location would cause reproductive effects. Developmental Effects. There is little reported evidence of developmental effects in the offspring of humans exposed to 1,4-dichlorobenzene via any route. Only one human case report mentioned the potential developmental effects of ingesting 1,4-dichlorobenzene at 38 weeks of gestation. The mother developed hematological effects due to 1,4-dichlorobenzene consumption, but she did deliver a normal 4.3-kg female infant (Campbell and Davidson 1970). Effects reported in animal studies have been an increased incidence of retroesophageal right subclavian artery in fetuses of rabbits exposed to 1,4-dichlorobenzene via inhalation at 800 ppm on Gd 6-18 (Hayes et al. 1985), and an increased incidence in the presence of an extra rib in the fetuses of rats that received 1,4-dichlorobenzene by gavage at doses of 500 mg/kg/day and above (Giavini et al. 1986). Although neither effect was viewed as constituting a true teratogenic response by the authors, the results of these two studies suggest that 1,4-dichlorobenzene inhaled or ingested by pregnant animals can reach the developing fetus and affect its development. However, it is not likely that the levels of 1,4-dichlorobenzene in the air of the general environment, or in the vicinity of hazardous waste sites, or in drinking water in any location would be high enough to pose a risk for developmental effects in humans. Genotoxic Effects. No studies were located regarding genotoxic effects in humans after inhalation, oral, or dermal exposure to 1,4-dichlorobenzene. Cytogenetic studies conducted using rats exposed to 1,4-dichlorobenzene via inhalation using various dosage regimens have been negative (Anderson and Richardson 1976). Similarly, no cytogenetic effects were observed in studies using mice treated with 1,4-dichlorobenzene via gavage at levels that resulted in liver toxicity and decreased survival in the test animals (NTP 1987). However, gavage administration of a single 1,000 mg/kg/day dose of 1,4-dichlorobenzene to mice and rats resulted in an increase in DNA replication in the renal tissue of the male rats and in the hepatocytes of mice of both sexes (Steinmetz and Spanggord 1987a, 1987b). Increased 3H-thymidine incorporation into renal DNA has also been demonstrated in rats dosed with 1,4-dichlorobenzene by gavage at 120 mg/kg/day for 7 days (Charbonneau et al. 1989b). These observations suggest that “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 113 2. HEALTH EFFECTS 1,4-dichlorobenzene promotes cell division, a finding that may help to elucidate the mechanism of carcinogenic action of 1,4-dichlorobenzene in male rat kidneys and mouse liver in the NTP (1987) bioassay. However, it is important to note that in these studies, only kidney tissue was tested in the rat for increased DNA replication, and in the mouse, only liver tissue was tested. Therefore, it is not clear whether increased cell replication also occurs in other tissue in each species or is limited to the tissues in which the carcinogenic effects occurred. Summaries of the in vivo and in vitro studies related to the genotoxicity of 1,4-dichlorobenzene are presented in Tables 2-3 and 2-4, respectively. 1,4-Dichlorobenzene is generally nonmutagenic except in plant systems (see Table 2-4) (Prasad 1970; Sarbhoy 1980; Sharma and Battacharya 1956; Srivastava 1966). The results of in vivo systems, as discussed above, were positive only for increased DNA replication in the livers of orally exposed mice (Steinmetz and Spanggord 1987a) and in the kidneys of orally exposed rats (Charbonneau et al. 1989b; Steinmetz and Spanggord 1987b). Cancer. No studies were located regarding cancer in humans after inhalation, oral, or dermal exposure to 1,4-dichlorobenzene. In studies conducted using animals, evidence of carcinogenicity from 1,4-dichlorobenzene exposure is based on 2-year oral studies in mice and rats. 1,4-Dichlorobenzene was administered by gavage to male rats at doses of 150 mg/kg/day and 300 mg/kg/day, and to female rats and mice of both sexes at doses of 300 mg/kg/day and 600 mg/kg/day. There was a dose-related increase in the incidence of tubular cell adenocarcinomas of the kidneys of male rats. There were no tubular cell tumors in dosed or vehicle-control female rats. There was a marginal increase in the incidence of mononuclear cell leukemia in dosed male rats compared with either vehicle controls or historical controls (NTP 1987). Based on the finding of renal tumors this study, 1,4-dichlorobenzene was found to be carcinogenic in male rats. 1,4-Dichlorobenzene also increased the incidences of hepatocellular carcinomas in high-dose male mice and of hepatocellular adenomas in both high- and low-dose male and in high-dose female mice. The combined increase in adenomas plus carcinomas was statistically significant at the high dose but not at the low dose. Female control mice in this bioassay had a substantially higher incidence of liver tumors than did historical controls. Hepatoblastomas (a rare form of hepatocellular carcinoma) were observed in four high-dose male mice along with other hepatocellular carcinomas, but not in vehicle ***DRAFT FOR PUBLIC COMMENT*** «LNIJWWNOD O1N8Nd HOS L4vHd... Table 2-3. Genotoxicity of 1,4-Dichlorobenzene /n Vivo Species (test system) End point Results Reference Mammalian cells: Rat? bone marrow Chromosomal aberrations - Anderson and Richardson 1976 Mouse bone marrow Micronuclei formation - Shelby and Witt 1995 Mouse? erythrocytes Micronucleated erythrocytes - NTP 1987 Rat® kidney cells Unscheduled DNA synthesis - Steinmetz and Spanggord 1987b Increased DNA replication + Mouse® hepatocytes Unscheduled DNA synthesis - Steinmetz and Spanggord 1987a Rat kidney cells Increased DNA replication + Charbonneau et al. 1989 Mouse® erythrocytes of femoral bone marrow Induction of micronuclei Mohtashamipur et al. 1987 5 days/week, 5 hours/day at 75 or 500 ppm oOo oO 96 hours before sacrifice for DNA replication experiment «QQ —™ 0 Qa the second injection. Males only were tested. + = positive result; - = negative result; DNA = deoxyribonucleic acid Exposed to 1,4 dichlorobenzene via gavage for 13 weeks, 5 days/week at 600-1800 mg/kg/day Exposed to 1,4 dichlorobenzene via gavage in corn oil at 300, 600, or 1000 mg/kg at 16 hrs before sacrifice for UDS experiment or at Results were positive for male rats only in which a significant S-phase response was induced Exposed to 1,4 dichlorobenzene via gavage in corn oil at 300, 600, or 1000 mg/kg at 16 or 48 hours before sacrifice Exposed to 1,4 dichlorobenzene via gavage in corn oil at 120 or 300 mg/kg/day for 7 days and sacrificed 24 hours after the last dose Exposed to 1,4 dichlorobenzene via two intraperitoneal injections of 355, 710, 1065, 1420 mg/kg (24 hours apart) and sacrificed 6 hours after Exposed to 1,4 dichlorobenzene via inhalation for 2 hours at 299 or 682 ppm; for 5 days, 5 hours/day at 75 or 500 ppm; or for 3 months, S103443 H1IV3H ¢ INIZNIGOHOTHIIA-¥'+ vil «xLNIFWWOD O1M8Nd HOH 14VHQ.xx Table 2-4. Genotoxicity of 1,4-Dichlorobenzene /n Vitro Results With Without Species (test system) End point activation activation Reference Mammalian systems: Hela cells Unscheduled DNA synthesis - - Instituto di Ricerche Biomediche 1986a Human lymphocytes Unscheduled DNA synthesis - - Perocco et al. 1983 Human lymphocytes Unscheduled DNA synthesis - - Instituto di Ricerche Biomediche 1987 Chinese hamster ovary cells Chromosomal aberrations - = NTP 1987 Sister chromatid exchanges - - Chinese hamster lung cells Gene mutation - = Instituto di Ricerche Biomediche 1986b L5178Y/TK © mouse lymphoma Gene mutation (+) - NTP 1987 cells Plant systems: Root tips (16 species of Chromosomal aberrations NS + Sharma and Battachary 1956 dicotyledons and monocotyledons) Lens esculenta (L.) Moench Mitotic abnormalities NS Sarbhoy 1980 Aspergillus nidulans Back mutation frequency NS Prasad 1970 Tribe viceae Chromosomal aberrations NS Srivastava 1966 Microbial systems: Salmonella typhimurium Gene mutation Anderson 1976 TA98® - - TA100% - - TA15352 - _ TA1538% - - TA9g® i, i; TA100° . - TA1535° + - TA1538° S103443 H1TV3H ¢ INIZNIEOHOTHOIA-¥'} SLi «x LNTFWWOO O1M8Nd HOH 14VYHuxs Table 2-4. Genotoxicity of 1,4-Dichlorobenzene In Vitro (continued) Results With Without Species (test system) End point activation activation Reference Mammalian systems: Hela cells Unscheduled DNA synthesis - = Instituto di Ricerche Biomediche 1986a Salmonella typhimurium Gene mutation Shimizu et al. 1983 TAS8 - - TA100 - _ TA1535 - - TA1537 _ _ TA1538 - - TA98 Gene mutation - - Haworth et al. 1983 TA100 = _ TA1535 - _ TA1537 - _ a Exposed to 1,4-dichlorobenzene gas b Exposed to 1,4-dichlorobenzene in DMSO © Positive result was not reproducible in other experiments in this series NS = not studied; - = negative results; + = positive results; (+) = weakly positive result; DNA = deoxyribonucleic acid S103443 H1TV3H ¢ INIZNIGOHOTHOIA-V'} gli 1,4-DICHLOROBENZENE 117 2. HEALTH EFFECTS controls. An increase in thyroid gland follicular cell hyperplasia was observed in dosed male mice, and there was a marginal positive trend in the incidence of follicular cell adenomas of the thyroid gland in female mice. Pheochromocytomas of the adrenal gland (benign and malignant, combined) occurred with a positive trend in dosed male mice, and the incidence in the high-dose group was significantly greater than in vehicle controls. The incidences of adrenal gland medullary hyperplasia and focal hyperplasia of the adrenal gland capsule were also elevated in dosed male mice (NTP 1987). Further analysis of the results of the NTP (1987) bioassay has raised certain questions as to the relevance of the observed renal tumors in male rats and hepatic tumors in mice to the potential carcinogenicity of 1,4-dichlorobenzene in humans. The observation that kidney tumors are induced in male but not female rats in response to exposure to chemicals in addition to 1,4-dichlorobenzene has been the focus of recent research. Toxicologists at CIIT have hypothesized that the male rat kidney is susceptible to the induction of certain tumors because it contains the protein ay, -globulin, which has not been found at significant levels in female rats, or mice, or humans (Charbonneau et al. 1987, 1989a, 1989b; Olson et al. 1990). They have demonstrated that a, -globulin in combination with compounds that bind reversibly with this protein enhances the formation of hyalin droplets in the proximal convoluted tubules of male rats. The resulting cellular damage and cell proliferation are hypothesized to result in enhanced tumor formation. Based on these considerations, EPA (1991) and the Consumer Product Safety Commission have concluded that renal tumors in male rats associated with a, -globulin should not be used in assessing the potential carcinogenicity of 1,4-dichlorobenzene in humans. There has also been much discussion of the interpretation of the finding of hepatocellular carcinomas and adenomas in mice in the NTP (1987) study. There was a higher than usual rate of these tumors in control female mice. Because 1,4-dichlorobenzene has not been demonstrated to be mutagenic in any of the microbial or mammalian systems tested, NTP (1987) has suggested that it may act as a tumor promoter by inducing DNA replication for tissue repair processes. As discussed previously, oral administration of 1,4-dichlorobenzene has been shown to increase DNA replication in the hepatocytes of mice (Steinmetz and Spanggord 1987a) and in the renal tissue of male rats (Charbonneau et al. 1989b; Steinmetz and Spanggord 1987b). These findings are consistent with the role of a promoter and suggest that 1,4-dichlorobenzene may not be a direct-acting carcinogen. Studies by Eldridge et al. (1992) and Umemura et al. (1996) suggest that cell proliferation may also play a role in the carcinogenic mechanisms of 1,4-dichlorobenzene. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 118 2. HEALTH EFFECTS The EPA Office of Drinking Water (EPA 1987a) has placed 1,4-dichlorobenzene into Category C (possible human carcinogen). This category is for substances with evidence of oncogenic potential in animal studies without supporting human data. In an analysis of the NTP (1987) carcinogenicity data, EPA (1992) used the liver tumors in male mice and the linearized multistage model to calculate a q;* of 2.4x1072 (mg/kg/day)! Using the male rat kidney tumor data in the NTP (1987) study with 1,4-dichlorobenzene, Battelle and Crump (1986) report a q;* of 6x10 by the linearized multistage model, as well as by the multistage-Weibull and Crump's multistage models, taking time to death into account. Although the q;* for the male rat kidney tumors is lower than that for the mouse liver tumors, EPA (1992) has decided to base estimates of risk on the mouse liver tumor data because the rat renal tumors are associated with oy, globulin and hyalin droplet formation. Humans do not secrete 0.,-globulin in their urine and are, accordingly, not susceptible to renal tumorigenesis by way of the hyalin droplet mechanism. Based on the q;* of 2.4x1072 (mg/kg/day)! for liver tumors, oral doses associated with upper-bound risks of 104,107, 10°, and 107 would be 0.0042, 0.00042, 0.000042, and 0.0000042 mg/kg/day, respectively. These values are currently under review by EPA and have not been included in the IRIS (1996) database. It is not likely, based on the potential for human exposure data presented in Chapter 5, coupled with the NOAELs and LOAELSs gathered from human case reports and laboratory animal studies, that levels of 1,4-dichlorobenzene in the drinking water in any location would be high enough to cause a concern for cancer in humans. 2.6 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators of signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). Due to a nascent understanding of the use and interpretation of biomarkers, implementation of biomarkers as tools of exposure in the general population is very limited. A biomarker of exposure is a xenobiotic substance or its metabolite(s), or the product of an interaction between a xenobiotic agent and some target molecule(s) or cell(s) that is measured within a compartment of an organism (NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 119 2. HEALTH EFFECTS metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to 1,4-dichlorobenzene are discussed in Section 2.6.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are not often substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by 1,4-dichlorobenzene are discussed in Section 2.6.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism's ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.8, Populations That Are Unusually Susceptible. 2.6.1 Biomarkers Used to Identify or Quantify Exposure to 1,4-Dichlorobenzene 1.4-Dichlorobenzene can be measured in blood (Bristol et al. 1982; Langhorst and Nestrick 1979; Pellizzari et al. 1985) or adipose tissue (Jan 1983; Pellizzari et al. 1985), and its metabolite, 2,5-dichlorophenol, and/or its conjugates can be measured in urine (Langhorst and Nestrick 1979; Pagnotto and Walkley 1965) in order to confirm recent or prior exposure. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 120 2. HEALTH EFFECTS As discussed in Section 2.3, 1,4-dichlorobenzene may be present in blood for a limited time after exposure (Kimura et al. 1979). Therefore, measurement of 2,5-dichlorophenol in urine may provide a more reliable indication of 1,4-dichlorobenzene exposure since it can be excreted for several days (Hallowell 1959). Since 1,4-dichlorobenzene accumulates in fat, measurements of adipose concentrations of 1,4-dichlorobenzene provide information on long-term exposure (Morita et al. 1975). Several chlorophenols, including 2,5-dichlorphenol, have been identified in laboratory animals exposed to lindane. This indicates that the presence of 2,5-dichlorphenol is fairly specific, but not completely specific, for 1,4-dichlorobenzene exposure. Information on the analytical methods commonly used to detect and quantify 1,4-dichlorobenzene in biological samples is presented in Chapter 6, Section 6.1. There are currently no data available to assess a potential correlation between the values obtained with these measurements and the toxic effects observed in humans or laboratory animal species. 2.6.2 Biomarkers Used to Characterize Effects Caused by 1,4-Dichlorobenzene There are no known specific biomarkers of effects for 1,4-dichlorobenzene since none of the health effects identified in humans or animals appears to be uniquely associated with exposure to 1,4-dichlorobenzene. In oral studies using rats, characteristic effects have included increased enzyme activities at lower levels of exposure and porphyria at higher levels of exposure; in the kidneys of male rats, hyaline droplet formation accompanied by tubular degeneration has been seen at moderate- to-high levels of exposure. However, each of these effects can be seen as a consequence of exposure to a wide variety of chemicals. Saito et al. (1996) studied the effect of oral treatment with 1,4-dichlorobenzene on the urinary excretion of kidney-type 0.,,-globulin (aG-K) in male Sprague-Dawley rats. Groups of 3 rats received placebo or 1,4-dichlorobenzene (1.5 mmol/kg/day; 220 mg/kg/day) by gavage in corn oil for 7 days. Concentrations of aG-K in the urine of 1,4-dichlorobenzene-treated rats ranged from 0.04 to 0.18 mg/mL; urine concentrations increased steadily throughout the study. In contrast, aG-K concentrations were undetectable in the urine of controls at all time points. The mean concentration of aG-K in the kidneys of rats treated with 1,4-dichlorobenzene was 1.15 mg/mg of soluble protein, compared to 0.35 mg/mg protein in the control group. The authors concluded that measurement of urinary aG-K would be a good indicator of 1,4-dichlorobenzene exposure; however, this response is neither unique to 1,4-dichlorobenzene nor applicable to human exposure cases. As discussed earlier in ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 121 2. HEALTH EFFECTS Section 2.5, this particular protein is produced in large amounts by male rats, accounting for 26% of their total urinary protein, but not in human males, where it was found to be present at 1% of the amount measured in male rats (Olson et al. 1990). This protein is also not produced in anything other than minimal quantities by females of any species or the males of other laboratory species including mice (EPA 1991). This combination of observations has led to suggestions that humans are probably not at risk for the type of nephropathy induced by 1,4-dichlorobenzene in male rats, and that the oy, ~globulin biomarker would be inappropriate to use in humans. For more information on biomarkers for renal and hepatic effects of chemicals see ATSDR/CDC Subcommittee Report on Biological Indicators of Organ Damage (1990) and for information on biomarkers for neurological effects see OTA (1990). 2.7 INTERACTIONS WITH OTHER CHEMICALS No specific studies were located regarding the interactions of 1,4-dichlorobenzene with other chemicals. It is evident that because 1,4-dichlorobenzene is a liver toxin, it would likely interact with other chemicals which exert adverse liver effects. These toxicants are many, and include such chemicals as ethanol, halogenated hydrocarbons (chloroform, carbon tetrachloride, etc.), benzene, and other haloalkanes and haloalkenes. In addition, 1,4-dichlorobenzene toxicity may also be exacerbated by concurrent exposure with acetaminophen, heavy metals (copper, iron, arsenic), aflatoxins, pyrrolizidine alkaloids (from some types of plants), high levels of vitamin A, and hepatitis viruses. Such interactions could either be additive or synergistic effects. Regarding its effect on hemolysis and formation of Heinz bodies, methemaglobinemia, and hemolytic anemia, it is likely that either additive or synergistic interaction would occur with other oxidants, such as aniline and acrolein, which are known to inhibit G6PD. 2.8 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to 1,4-dichlorobenzene than will most persons exposed to the same level of 1,4-dichlorobenzene in the environment. Reasons may include genetic makeup, age, health and nutritional status, and exposure to other toxic substances (e.g., cigarette smoke). These parameters may result in reduced detoxification or excretion of 1,4-dichloro- ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 122 2. HEALTH EFFECTS benzene, or compromised function of target organs affected by 1,4-dichlorobenzene. Populations who are at greater risk due to their unusually high exposure to 1,4-dichlorobenzene are discussed in Section 5.6, Populations With Potentially High Exposure. No population has been identified as exhibiting an unusual susceptibility to the effects of exposure to 1,4-dichlorobenzene. However, based on data from studies in humans and animals, individuals with compromised liver function, infants and children with immature liver function (Hallowell 1959), and elderly people (Cotter 1953; Nalbandian and Pearce 1965) may be more at risk than the general population. Individuals having a genetic susceptibility to methemoglobin formation (such as those individuals with a deficiency of G6PD in their red blood cells) may also be at increased risk from inhalation or oral exposure to 1,4-dichlorobenzene. 2.9 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to 1,4-dichlorobenzene. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to 1,4-dichlorobenzene. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. The following texts provide specific information about treatment following exposures to 1,4-dichlorobenzene: Ellenhorn, MJ and Barceloux, DG, (eds.) (1988). Medical Toxicology: Diagnosis and Treatment of Human Poisoning. Elsevier Publishing, New York, NY. Dreisback, RH, (ed.) (1987). Handbook of Poisoning. Appleton and Lange, Norwalk, CT. Haddad, LM and Winchester, JF, (eds.) (1990). Clinical Management of Poisoning and Drug Overdose. 2nd edition, WB Saunders, Philadelphia, PA. Grossel, TA and Bricker JD (1994). Principles of Clinical Toxicology. 3rd edition, Raven Press, New York, NY. Aaron, CK and Howland, MA (eds.) (1994). Goldfrank's Toxicologic Emergencies. Appleton and Lange, Norwalk, CT. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 123 2. HEALTH EFFECTS 2.9.1 Reducing Peak Absorption Following Exposure Human exposure to 1,4-dichlorobenzene can occur by inhalation, ingestion, or dermal contact. General recommendations for reducing absorption of 1,4-dichlorobenzene following acute-duration inhalation exposure have included moving the patient to fresh air and administration of 100% humidified supplemental oxygen with assisted ventilation (HSDB 1996). General recommendations for reducing absorption following acute ingestion exposure have included inducing emesis (unless the patient is or could rapidly become obtunded, comatose, or convulsing, and considering the risk of aspiration of vomitus), gastric lavage, or administration of a charcoal slurry (HSDB 1996). Intake of fatty foods which would promote absorption should be avoided. In the case of eye exposure, irrigation with copious amounts of water has been recommended (HSDB 1996). For dermal exposure, and to minimize dermal absorption, the removal of contaminated clothing and a thorough washing of any exposed areas with soap and water has been recommended (HSDB 1996). 2.9.2 Reducing Body Burden 1,4-Dichlorobenzene does distribute to fatty tissues and is probably retained there at low concentrations (EPA 1986d; Hawkins et al. 1980; Morita and Ohi 1975; Morita et al. 1975). However, most of an absorbed dose is excreted within 5 days of exposure (Hawkins et al. 1980), and there is no evidence suggesting that the low levels of 1,4-dichlorobenzene that are likely to remain in fatty tissues would cause adverse effects. For these reasons, methods for enhancing elimination of 1,4-dichlorobenzene shortly after high-dose exposure could reduce toxic effects; however, no such methods have been identified. There have been no reports of methods that would enhance the elimination of 1,4-dichlorobenzene after high- or low-dose exposure in humans or laboratory animals. While it might be possible to develop methods to alter metabolism of 1,4-dichlorobenzene to promote formation of metabolites that are more easily excreted, this could be difficult because the current lack of knowledge of the specific metabolic pathways of 1,4-dichlorobenzene precludes speculation concerning which pathways it might be most beneficial to stimulate or inhibit. One pathway for which stimulation may be contraindicated is sulfate conjugate formation (Kimura et al. 1979). Methylation of 1,4-dichlorobenzene sulfate conjugates can occur, and these methylated conjugates are excreted less rapidly than nonmethylated conjugates (Kimura et al. 1979). Since little is known concerning the ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 124 2. HEALTH EFFECTS toxicity of these conjugates, it is presently not possible to determine the consequences of promoting formation of these metabolites. 2.9.3 Interfering with the Mechanism of Action for Toxic Effects The mechanism of action for liver effects of 1,4-dichlorobenzene has not been clearly delineated; however, based on in vitro experiments, induction of P,5, metabolism by pretreatment with phenobarbital may enhance hepatotoxicity (Fisher et al. 1991). This suggests that one mechanism of hepatotoxicity may be the production of reactive intermediates through phase I P,5,-mediated oxidation, although it should be noted that the Ps, inhibitors metyrapone and SKF 525-A did not block hepatotoxicity of 1,4-dichlorobenzene in human liver tissue in vitro (Fisher et al. 1991). Lattanzi et al. (1989) provide evidence indicating that the microsomal mixed-function oxidase system and microsomal glutathione transferases and, to a lesser degree cytosolic glutathione transferases, can be involved in the bioactivation of 1,4-dichlorobenzene. More information concerning the mechanism of action for hepatic effects is needed before methods for blocking that mechanism and reducing toxic effects can be developed. The mechanisms of action for nephrotoxic (with the exception of a.,,-globulin-mediated nephropathy specific to male rats) or hematotoxic effects have not been clearly delineated, and with the available information, it is difficult to speculate how 1,4-dichlorobenzene might cause such effects. More information concerning the mechanisms of action for blood and kidney effects are needed before methods for blocking those mechanism and reducing toxic effects can be developed. 2.10 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of 1,4-dichlorobenzene is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,4-dichlorobenzene. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 125 2. HEALTH EFFECTS The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.10.1 Existing Information on Health Effects of 1,4-Dichlorobenzene The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to 1,4-dichlorobenzene are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information concerning the health effects of 1,4-dichlorobenzene. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not necessarily imply anything about the quality of the study or studies, nor should missing information in this figure be interpreted as a "data need." A data need, as defined in ATSDR's Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature. Some limited information (i.e., anecdotal, single acute-duration exposure, and workplace exposure) is available on the health effects of human exposure to 1,4-dichlorobenzene via inhalation and the oral route. For persons exposed via inhalation, there is information on death, systemic effects, neurologic effects, or the role of lifestyle factors resulting from intermediate- and chronic-duration exposure. There is also information on systemic effects in humans resulting from acute-, intermediate-, and chronic-duration oral exposure. It is important to note that most of this information was obtained from case studies in which levels and durations of exposure to 1,4-dichlorobenzene were often unknown or uncertain. The data available on 1,4-dichlorobenzene's health effects in animal studies are more extensive. Information is available on the developmental, reproductive, genotoxic, and carcinogenic effects of inhalation exposure to 1,4-dichlorobenzene, as well as on the systemic effects resulting from intermediate-duration exposure. In studies using oral exposure, information is available on death; systemic effects resulting from acute-, intermediate-, and chronic-duration exposure; and ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 126 2. PUBLIC HEALTH Figure 2-4. Existing Information on Health Effects of 1,4-Dichlorobenzene . @ Systemic © Q & \ 2 oO 2 Q® 2 S i NN < » \O S > <& “OO e/g C/N SS RSet Sk L/S L/S CS OSS Se PS FS ESS ESS BS ES EA A Q v S/O LN <& Q O O Inhalation | ® | ° Oral (0 !» Dermal Human ne ) & Systemic © K 5 \ » o 8 yo > 7 SN @ No \O © aS & no So SOS Rt XS / L/S SOS OSS XS © Bf TA oA AS ES BS BS ol ES QL SLL) Inhalation . | 9%)» Oral ° ° ° ® ° ° ° ° Dermal . Animal e Existing Studies “**DRAFT FOR PUBLIC COMMENT *** 1,4-DICHLOROBENZENE 127 2. HEALTH EFFECTS developmental, genotoxic, and carcinogenic effects. Only data on the lack of a lethal effect are available in studies using the dermal route. 2.10.2 Identification of Data Needs Acute-Duration Exposure. The only information available for humans exposed to 1,4-dichloro- benzene for acute-duration exposure period is a case study of a 3-year-old boy who developed acute hemolytic anemia and methemoglobinuria after playing with and possibly ingesting 1,4-dichloro- benzene crystals (Hallowell 1959). Thus, he may have been exposed via the inhalation, oral, and dermal routes. The finding of methemoglobinemia in this child suggests that this may be an important end point for investigation in future animal studies with 1,4-dichlorobenzene via any route and for any duration of exposure. No general toxicity studies of animals exposed to 1,4-dichlorobenzene via inhalation for this duration period were located. Several studies were conducted via the oral route including single-dose lethality studies in rats and guinea pigs (Hollingsworth et al. 1956): a 3-day study in rats that showed effects on the activities of some hepatic drug-metabolizing enzymes, a 5-day study in rats that resulted in porphyria (Rimington and Ziegler 1963), a 14-day study in rats that resulted in porphyria, a 14-day study in rats that resulted in increased activities of some microsomal xenobiotic metabolism systems (Carlson and Tardiff 1976), and two 14-day pilot studies in rats and two 14-day pilot studies in mice (NTP 1987). However, because a NOAEL for effects on hepatic enzymes was never identified and their relationship to overt hepatic lesions or deleterious health effects is not clearly understood, and because of uncertainty about the histopathological effects in mice and rats at the nonlethal exposure levels in the 14-day pilot studies, the data are not considered sufficient to derive an acute-duration MRL for oral exposure, based on a hepatotoxicity end point. The data were sufficient to derive an acute-duration inhalation MRL of 0.8 ppm, based on a NOAEL of 300 ppm for lack of developmental effects in rabbits. Further studies of acute-duration are needed to establish the NOAEL and LOAEL for hepatic effects. The only available study using the dermal route is a lethality study that attempted to determine a dermal LDy level in rats (Gaines and Linder 1986). There are no available toxicokinetic data that have examined absorption of 1,4-dichlorobenzene via the dermal route. If dermal absorption and systemic distribution of 1,4-dichlorobenzene could be demonstrated, acute-duration studies using this route would be useful since humans are commonly exposed to it by handling various consumer products in the home and being exposed to the vapor form. Data on the effects of acute-duration ***DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 128 2. HEALTH EFFECTS exposure to I.4-dichlorobenzene via inhalation would be extremely useful because inhalation of I.4-dichlorobenzene by persons using consumer products containing it in the home and other indoor environments is the major route of exposure to this substance. In any further studies using the oral route, a broader range of dosage levels, including dosages lower than those used in currently available studies, would prove useful in order to determine a NOAEL. Any further studies conducted by any route should investigate hepatic, renal, central nervous system, and hematological (methemo- globinemia) effects as potential toxic end points. In addition, a recent study in which rats were given a single intraperitoneal injection of 1,4-dichlorobenzene resulted in abnormalities in sperm morphology; therefore, any further acute-duration studies should assess this parameter. Further information on neurological effects resulting from acute-duration exposure would also be useful since these effects have been reported in several human case studies. Intermediate-Duration Exposure. Case studies are available on humans exposed to 1,4-dichloro- benzene via inhalation and the oral route for intermediate-duration exposure. These include the report of a 69-year-old man who developed skin discolorations and swelling of his hands and feet after about 3 weeks of exposure to 1,4-dichlorobenzene in his home (Nalbandian and Pearce 1965), the cases of a 60-year-old man and his wife who both died of liver atrophy after their home had been saturated with mothball vapor for 3-4 months (Cotter 1953), and the case of a 21-year-old woman who developed hypochromic, microcytic anemia as a result of ingesting 1,4-dichlorobenzene toilet air freshener blocks throughout pregnancy (Campbell and Davidson 1970). All of these case studies lack critical dosing amounts and durations, which makes it difficult to establish a dose-response curve for the toxicological effects in humans exposed to 1,4-dichlorobenzene. It would be helpful if future reports of accidental or intentional exposure would include more dose information (measured or estimated) so that dose- response relationships could be established (or at least reasonably estimated) for effects in humans. A considerable amount of data are available on the renal and hepatic effects of intermediate-duration inhalation exposure on a variety of laboratory animals (i.e., rats, mice, rabbits, guinea pigs, and monkeys) (Hollingsworth et al. 1956). These data were derived from a single large study with several inconsistent variables (discussed in Section 2.2.1.2). The data from the exposure of rats to concentrations of 1, 96, and 158 ppm showed enlargement and degeneration of hepatic parenchymal cells which were used as the basis of an inhalation MRL of 0.2 ppm (Hollingsworth et al. 1956). However, additional studies that follow current standards of good laboratory practice would be valuable for confirming these observations. "*DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 129 2. HEALTH EFFECTS Several animal studies were located using the oral route for intermediate-duration and based on a combination of these studies, adverse effects have been reported in many organ systems. Hepatic, renal, and hematologic (Bomhard et al. 1988; Carlson 1977; Hollingsworth et al. 1956; NTP 1987) effects have been the most consistent observations. The MRL was based on a minimal LOAEL of 188 mg/kg/day based on increased liver weights in rats. Since kidney effects involve hyaline droplet nephropathy, the renal effects were not considered to be a suitable basis for the MRL. Effects on hepatic enzyme systems have been reported at 1,4-dichlorobenzene levels far below those levels at which histopathologic effects were seen in other oral studies and a NOAEL for these enzyme effects has not yet been identified. In any further studies using the oral route, it would be useful to investigate potential histopathological effects at the low-dosage levels associated with effects on hepatic enzyme activities in order to identify NOAEL or LOAEL values. Some work has been done in this area pertaining to cell proliferation and a possible mechanism for hepatic neoplastic lesions observed in mice exposed to 1,4-dichlorobenzene (Eldridge et al. 1992; NTP 1987; Umemura et al. 1992). Further studies are needed to determine the relationship between cell proliferation and the cellular events that produce neoplasia in these animals and to determine more clearly the cancer risks to human health after exposure to 1,4-dichlorobenzene. Studies using the dermal route for intermediate-duration exposure would be useful if absorption and systemic distribution of 1,4-dichlorobenzene by this route could first be demonstrated in toxicokinetic studies. In any further studies conducted for this duration period, methemoglobinemia, neurological effects, and effects on sperm morphology would be valuable. Chronic-Duration Exposure and Cancer. Several case studies of chronic human exposure to 1,4-dichlorobenzene have been located. Reported effects resulting primarily from chronic inhalation exposure have included pulmonary granulomatosis in a 53-year-old woman who had been inhaling 1 4-dichlorobenzene crystals in her home for 12-15 years (Weller and Crellin 1953); atrophy and cirrhosis of the liver in a 34-year-old woman who was exposed to 1,4-dichlorobenzene-containing products in a small enclosed booth in a department store for one or more years (Cotter 1953); jaundice and liver atrophy in a 52-year-old man after 2 years of exposure to 1,4-dichlorobenzene in the fur storage plant where he worked (Cotter 1953); and ataxia, speech difficulties, limb weakness, and altered brainwave activity in a 25-year-old woman who had been exposed to high concentrations of 1,4-dichlorobenzene in her bedroom, bedding, and clothes for about 6 years (Miyai et al. 1988). A ***DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 130 2. HEALTH EFFECTS limited occupational health survey has also been located in which nasal and ocular irritation, but no major systemic health effects, were reported to be the only 1,4-dichlorobenzene-related complaints (Hollingsworth et al. 1956). Further occupational health data on individuals exposed chronically to I, 4-dichlorobenzene would be useful for both cancer and non-cancer health effect end points already mentioned. The only data located relating to chronic oral human exposure to 1,4-dichlorobenzene come from a case study of a 19-year-old black woman who developed an increase in skin pigmentation as a result of eating 1,4-dichlorobenzene moth pellets daily for about 2.5 years (Frank and Cohen 1961). All of these case studies lacked critical dosing amounts and durations, which makes it difficult to establish a dose-response curve for the toxicological effects in humans exposed to 1,4-dichlorobenzene. No studies of chronic dermal exposure to 1,4-dichlorobenzene were located, although it seems likely that chronic inhalation and oral exposure scenarios, both in the home and in the workplace, have also involved dermal contact with 1,4-dichlorobenzene. Available data on chronic exposure to 1,4-dichlorobenzene in animal studies include a 76-week inhalation study in rats that resulted in increased liver and kidney weights (Riley et al. 1980); a 2-year oral study in mice that resulted in liver effects (NTP 1987), such as hepatocellular degeneration, and cell necrosis and renal effects such as nephropathy and renal tubular degeneration; and a 2-year oral study in rats that resulted in a high rate of mortality and renal effects including nephropathy and degeneration of the renal tubules (NTP 1987). No animal studies of chronic dermal contact with 1,4-dichlorobenzene have been located. The data were considered sufficient to derive a chronic-duration inhalation MRL of 0.1 ppm based on a NOAEL of 75 ppm for lack of hepatic effects (Riley et al. 1980). The database for oral exposure contains two lifetime studies, one in rats and one in mice (NTP 1987). However, derivation of an MRL for chronic oral exposure does not appear to be justified because neither study identifies a clear NOAEL for all adverse effects. Hepatic effects were seen at the lowest dose tested in mice and renal effects at the lowest dose tested in rats. Further data on the effects of chronic inhalation exposure to 1,4-dichlorobenzene would be useful, especially because chronic exposures to 1,4-dichlorobenzene in the air, in the home, and the workplace are the main sources of human exposure to this chemical. Any further testing of the effects of chronic exposure to 1,4-dichlorobenzene via the oral route should probably be done at lower levels of 1.4-dichlorobenzene than those that have already been used in the NTP (1987) bioassay, and should ""*DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 131 2. HEALTH EFFECTS focus on dose-response relationships involving the hepatic, renal, hematopoietic, central nervous system, and metabolic pathways. Data on the effects of chronic dermal exposure to 1,4-dichloro- benzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated from toxicokinetic studies, since chronic dermal exposure to 1,4-dichlorobenzene occurs as a result of bathing and showering in drinking water that contains low levels of this chemical in many U.S. communities. Any further testing by any route for duration should investigate the potential for methemoglobinemia, neurological effects, and effects on sperm morphology as possible end points. No data have been located related to carcinogenicity in humans exposed to 1,4-dichlorobenzene via inhalation, orally, or dermally. Epidemiological studies which used occupational exposure data would be useful to elicit such information on human exposure and potential cancer risks to 1,4-dichloro- benzene. Animal data include a 76-week inhalation study in rats that did not result in cancer (Riley et al. 1980), a 2-year oral study in rats that resulted in renal cancer in males (NTP 1987), and a 2-year study in mice that resulted in liver cancer (NTP 1987). No data using the dermal route were located. Additional data via the inhalation route would be useful since chronic inhalation exposures to 1,4-dichlorobenzene in the air of the home and the workplace are the main sources of human exposure to this compound. No further studies via the oral route appear to be necessary. Chronic-duration cancer studies via the dermal route may be useful since chronic dermal contact with 1,4-dichloro- benzene at low levels in drinking water occurs in several U.S. communities. Genotoxicity. No studies were located regarding the potential genotoxic effects of 1,4-dichloro- benzene in humans exposed via inhalation, orally, or by the dermal route. Several in vivo studies in animals and in vitro studies are available that indicate that 1,4-dichlorobenzene is non-reactive with DNA and that the mechanism of carcinogenesis is that it acts as a tumor promoter rather than as a mutagen (Charbonneau et al. 1989b; Steinmetz and Spanggord 1987a, 1987b). There is no apparent need for further data in this area. Reproductive Toxicity. No information was located on potential reproductive effects in humans exposed to 1,4-dichlorobenzene via inhalation, orally, or by the dermal route. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 132 2. HEALTH EFFECTS Inhalation exposure to 1,4-dichlorobenzene did not appear to affect reproductive processes in rats except through its systemic toxicity in the dams (Tyl and Neeper-Bradley 1989). Although there were decreases in litter size, weight, and survival, these were considered to be the results of maternal toxicity. An inhalation study using male mice exposed to 1,4-dichlorobenzene for 5 days did not report an adverse impact on their ability to impregnate females (Anderson and Hodge 1976). In one study where male rats were intraperitoneally injected with 1,4-dichlorobenzene, there were increased incidences of morphologically abnormal sperm (Murthy et al. 1987); however, paternal effects were not noted in the 2-generation study (Tyl and Neeper-Bradley 1989). Further data assessing the impact of I.4-dichlorobenzene exposure on reproductive end points in both males and females exposed via the oral route would be useful. Studies using the dermal route would also be useful if absorption and systemic distribution by this route could first be demonstrated by toxicokinetic studies. Developmental Toxicity. No studies have been located that reported developmental effects on the offspring of humans exposed to 1,4-dichlorobenzene via the inhalation, oral, or dermal routes. Only one human case report mentioned the potential developmental effects of ingesting 1,4-dichlorobenzene at 38 weeks of gestation. The mother developed hematological effects due to 1,4-dichlorobenzene consumption, but she did deliver a normal 4.3-kg female infant. Based on this one report, there appears to be little developmental toxicity of 1,4-dichlorobenzene in humans (Campbell and Davidson 1970); however, more information is clearly needed to confirm this observation in humans. Animal data include an inhalation study in rabbits that resulted in an increased incidence of retroesophageal right subclavian artery in the fetuses (Hayes et al. 1985), and an oral study in rats that resulted in an increased incidence of an extra rib (Giavini et al. 1986). The data were considered sufficient to derive an acute-duration inhalation MRL of 0.8 ppm, based on a NOAEL of 300 ppm for lack of developmental effects in rabbits. It would be useful to have additional information on the developmental effects of 1,4-dichlorobenzene by inhalation and oral exposure in relation to maternal toxicity. There are currently no data available for the dermal route. Information on the developmental effects of dermal exposures would be useful if dermal absorption and systemic distribution of I.4-dichlorobenzene could be demonstrated in toxicokinetic studies. Immunotoxicity. No studies were located that directly assess the potential immunotoxic effects of I.4-dichlorobenzene in humans or animals exposed by inhalation, orally, or dermally. However, case reports of skin reactions in a 69-year-old man who was exposed via inhalation (Nalbandian and Pearce ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 133 2. HEALTH EFFECTS 1965) and a 19-year-old woman who ingested moth pellets (Frank and Cohen 1961) suggest that the immune system may be a target for 1,4-dichlorobenzene. Splenomegaly was noted in two people exposed to unknown amounts of 1,4-dichlorobenzene; however, it is unclear if the effect was chemical-related or due to another cause. The small amount of available data suggest that immunological effects may be produced from exposure to 1,4-dichlorobenzene. In any future intermediate- or chronic-duration animal studies by any route of exposure, it would be useful to specifically assess the potential immunotoxic effects of 1,4-dichlorobenzene in both humans and laboratory animal models. Neurotoxicity. Neurological effects including dizziness, weakness, headaches, nausea, vomiting, numbness, clumsiness, speech difficulties, and altered patterns of certain brainwaves have been reported to have occurred in case studies of persons exposed to 1,4-dichlorobenzene via inhalation (Cotter 1953; Miyai et al. 1988), as well as with other halogenated hydrocarbons. There are no data on neurological effects in humans exposed to 1,4-dichlorobenzene through the oral or dermal routes. Neurotoxic effects of 1,4-dichlorobenzene in animals were only seen with inhalation exposures of adult rats to high doses (Tyl and Neeper-Bradley 1989). Additional data on the neurological effects of 1 4-dichlorobenzene in animals exposed via inhalation and orally would be useful in confirming the effects reported in human case studies and in quantifying dose-response relationships. Studies using the dermal route would be useful if dermal absorption and systemic distribution were first demonstrated by toxicokinetic studies. Epidemiological and Human Dosimetry Studies. There are no available case studies or epidemiological data that suggest that levels of 1,4-dichlorobenzene found in the environment are associated with significant human exposure. The available data suggest that levels of 1,4-dichloro- benzene in outside air are relatively insignificant, although the compound is widespread (IARC 1982; Scuderi 1986; Wallace et al. 1986). Levels in groundwater and surface water are also relatively low (Coniglio et al. 1980; Dressman et al. 1977; IJC 1989; Oliver and Nicol 1982a; Page 1981; Staples et al. 1985). These observations indicate that the most likely population to exhibit the effects of 1,4-dichlorobenzene exposures would be occupationally exposed groups. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 134 2. HEALTH EFFECTS Biomarkers of Exposure and Effect. Exposure. It is possible to measure 1,4-dichlorobenzene and its metabolite, 2,5-dichlorophenol, in blood, adipose tissue, and urine (Bristol et al. 1982; Jan 1983; Kimura et al. 1979: Langhorst and Nestrick 1979; Pagnotto and Walkley 1965; Pellizzari et al. 1985). Additional data with which to correlate these measurements to exposure levels, particularly by the inhalation route, and the potential health effects, would be useful. Effect. There are no health effects that are uniquely associated with exposure to 1,4-dichlorobenzene. As a result, studies to identify a biomarker of effect for 1,4-dichlorobenzene would be useful. Absorption, Distribution, Metabolism, and Excretion. There are no data on the toxicokinetics of 1,4-dichlorobenzene available from human studies. In the available case reports of human ingestion or inhalation of 1,4-dichlorobenzene, quantification of the doses is not possible. Experiments with laboratory animals show that 1,4-dichlorobenzene is absorbed via oral or inhalation exposure and is distributed mainly to adipose tissue, with some distribution to the liver and kidney, and minor amounts to other organs (Hawkins et al. 1980; Kimura et al. 1979). Absorbed 1,4-dichlorobenzene is principally metabolized to 2,5-dichlorophenol by oxidation and is rapidly eliminated, primarily in urine (Azouz et al. 1955; Hawkins et al. 1980), but also to some extent in the bile. There is extensive enterohepatic cycling. The available data indicate that the route of exposure has little effect on the subsequent metabolism and excretion of 1,4-dichlorobenzene. However, there are no data available on absorption and systemic distribution resulting from exposure via the dermal route. This information would be useful because it could provide the basis for decisions about the probability of toxic effects resulting from dermal exposure and the need to conduct various toxicity studies via the dermal route. Additional toxicokinetic data would be useful to quantitate route-specific absorption rates. A physiologically based pharmacokinetic model would also be useful. Comparative Toxicokinetics. There are no available studies that compare the toxicokinetics of I.4-dichlorobenzene across species. This has been an important area of concern in interpreting the results of animal studies with 1,4-dichlorobenzene with respect to their relevance to humans, most notably in the observations of renal toxicity and carcinogenicity in male rats. Although this specific issue has been largely resolved, it would be useful to have further data comparing the toxicokinetics of 1.4-dichlorobenzene across species in order to understand better which animal model is likely to "**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 135 2. HEALTH EFFECTS compare most directly with humans with regard to other toxic effects in response to 1,4-dichloro- benzene exposure. Methods for Reducing Toxic Effects. Based on the chemical and physical properties of 1,4-dichlorobenzene, its absorption is most likely to occur by passive diffusion. However, this has not been investigated. Studies which investigate the mechanism by which 1,4-dichlorobenzene is absorbed may be useful in developing methods for reducing its absorption. Standard methods exist for reducing the absorption of 1,4-dichlorobenzene across the skin, lungs, and gastrointestinal tract (HSDB 1996) and are described in more detail in Chapter 6 of this profile; however, none of these are specific for exposures to 1,4-dichlorobenzene. 1,4-Dichlorobenzene can be retained in fatty tissues at low levels (EPA 1986d; Hawkins et al. 1980; Morita and Ohi 1975; Morita et al. 1975). Additional studies which characterize the metabolic pathways which enhance excretion may be useful in developing a method for reducing body burden. However, since most of the absorbed dose is eliminated within 5 days (Hawkins et al. 1980), it seems unlikely that methods for reducing body burden would be of much benefit. There is limited evidence that 1,4-dichlorobenzene is metabolically activated to hepatotoxic intermediates (Fisher et al. 1991; Lattanzi et al. 1989). Additional studies which further characterize the metabolic activation of 1,4-dichlorobenzene may be useful to understand how metabolites interact and to develop methods for interfering with the mechanism of action. 2.10.3 Ongoing Studies No known ongoing studies related to the toxicity or toxicokinetics of 1,4-dichlorobenzene were identified. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 137 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY 1.4-Dichlorobenzene is a chlorinated aromatic compound. It is used as a deodorant for restrooms (Howard 1990), for moth control (Merck 1989), and as an insecticide (Farm Chemicals 1983). Information regarding the chemical identity of 1,4-dichlorobenzene is located in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES 1,4-Dichlorobenzene is a volatile crystalline material with a distinctive aromatic odor. Information regarding the physical and chemical properties of 1,4-dichlorobenzene is located in Table 3-2. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 3. CHEMICAL AND PHYSICAL INFORMATION 138 Table 3-1. Chemical Identity of 1,4-Dichlorobenzene Characteristic Value Reference Chemical name 1,4-Dichlorobenzene Lide 1994 Synonyms p-Dichlorobenzene; p-chlorophenyl chloride; PDB; HSDB 1996 Trade names Chemical formula Chemical structure Identification numbers: CAS Registry NIOSH RTECS EPA Hazardous Waste OHM/TADS DOT/UN/NA/IMCO Shipping HSDB NCI p-dichlorobenzol Paracide; Paradow; Santochlor Paramoth CeH 4Cly Cl G Cl 106-46-7 CZ4550000 uo72 No data UN 1592; IMO 6.1 5523 C54955 Farm Chemicals 1983 Merck 1989 Howard 1990 Merck 1989 HSDB 1996 HSDB 1996 HSDB 1996 HSDB 1996 HSDB 1996 CAS = Chemical Abstracts Service; NIOSH = National Institute for Occupational Safety and Health; RTECS = Registry of Toxic Effects of Chemical Substances; EPA = Environmental Protection Agency, OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 3. CHEMICAL AND PHYSICAL INFORMATION 139 Table 3-2. Physical and Chemical Properties of 1,4-Dichlorobenzene Property Value Reference Molecular weight Color Physical state Melting point Boiling point Density at 20 °C Odor Odor threshold: Water Air Solubility: Water Organic solvents Partition coefficients: Log octanol/water Log K. Vapor pressure at 20 °C Henry's law constant Autoignition temperature Flashpoint Flammability limits Conversion factors Explosion limits 147.00 Colorless or white Solid 53.1 °C 174.55 °C 1.2475 g/mL Aromatic 0.011 mg/L 0.18 ppm (1.1 mg/m°) Practically insoluble 79 mg/L at 25 °C Soluble in alcohol, ether, acetone, benzene 3.52 2.44 0.6 mm Hg 0.0015 atm-m%mol No data 66 ‘C No data 1 ppm = 6.01 mg/m> 1 mg/m> = 0.166 ppm No data Lide 1994 Verschueren 1983 Verschueren 1983 Lide 1994 Lide 1994 Lide 1994 Verschueren 1983 Amoore and Hautala 1983 Amoore and Hautala 1983 Merck 1989 Verschueren 1983 Lide 1994 Howard 1990 Chiou et al. 1983 Verschueren 1983 Howard 1990 NFPA 1994 Verschueren 1983 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 141 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.1 PRODUCTION 1,4-Dichlorobenzene is produced by the chlorination of benzene or chlorobenzene in the presence of a catalyst (typically ferric oxide) followed by either fractional distillation or crystallization of the resulting mixture of chlorinated benzenes to yield 1,4-dichlorobenzene (HSDB 1996; IRPTC 1985). The volume of 1,4-dichlorobenzene produced in the United States in 1972, 1975, 1977, and 1981 was estimated to be 35 million kg (77.2 million pounds), 20.8 million kg (45.9 million pounds), 16-116 million pounds (7.25-52.6 million kg), and 15 million pounds (6.8 million kg), respectively (HSDB 1996). The production of 1,4-dichlorobenzene steadily increased from 1980 to 1989 at a rate of about 2% per year (Chemical Marketing Reporter 1990). The production volume of 1,4-dichloro- benzene increased from 1984 to 1994 at a rate of 4% annually. The production volume was 4.264 (1984), 4.779 (1985), 5.035 (1986), 5.155 (1987), 5.601 (1938), 5.344 (1989), 5.200 (1990), 5.350 (1991), 5.656 (1992), 5.791 (1993), and 6.227 billion pounds (1994) (C&EN 1995a). 1,4-Dichlorobenzene is currently produced by 3 U.S. companies at 3 different locations: Monsanto Company, in Sauget, Illinois; PPG Industries, Inc., in Natrium, West Virginia; and Standard Chlorine of Delaware, Inc., in Delaware City, Delaware (SRI 1996). Current annual production capacity for the Monsanto Company, PPG Industries, Inc., and Standard Chlorine Chemical Company is 33, 30, and 75 million pounds, respectively (SRI 1996). Total annual production capacity has fluctuated during the last decade. The annual production capacity was 132, 127, 371, and 138 million pounds in 1988, 1994, 1995, and 1996, respectively (SRI 1988, 1994, 1995, 1996). Table 4-1 lists the facilities in each state that manufacture or process 1,4-dichlorobenzene, the intended use, and the range of maximum amounts of 1,4-dichlorobenzene that are stored on site. The data listed in Table 4-1 are derived from the Toxics Release Inventory (TRI94 1996). Only certain types of facilities were required to report (EPA 1995). Therefore, this is not an exhaustive list. ***DRAFT FOR PUBLIC COMMENT*** +x LNFWWOO O178Nd HOH 14VHQuxs Table 4-1. Facilities That Manufacture or Process 1,4-Dichlorobenzene Facility Location? Range of maximum amounts on site in pounds Activities and uses Trans Resources Inc. Standard Chlorine Chemical Co. Crest Prods. Inc. Natl. Service Ind. NA Bay States/Sterling Inc. NA NA NA NA NA Hoechst Celanese Corp. - Agent NA NA Willert Home Prods. Inc. Phillips Petroleum Co. NA West Helena, AR Delaware City, DE Oldsmar, FL Atlanta, GA Atlanta, GA North Manchester, IN Westlake, LA Amelia, LA Easthampton, MA Westborough, MA Saint Louis, MO Wilmington, NC Paterson, NJ NJ NJ Bartlesville, OK New Eagle, PA 1,000-9,999 No data 10,000-99,999 1,000-9,999 10,000-99,999 1,000-9,999 1,000-9,999 1,000-9,999 100,000-99,9999 1,000-9,999 100,000-99,9999 100,000-99,9999 10,000-99,999 100,000-99,9999 10,000-99,999 10,000-99,999 10,000-99,999 Produce; As an impurity; As a reactant Produce; For on-site use/processing; For sale/distribution; As a reactant As a formulation component As a formulation component As a product component; In repackaging only As a manufacturing aid Produce; As a by-product As a reactant As a formulation component As a manufacturing aid As a product component As a reactant For sale/distribution; In repackaging only For sale/distribution; In repackaging only As a product component As a reactant In repackaging only FHNSOdX3 NVWNH HOH TVILN3LOd 'S 3INIZNIEOHOTHOIa-t' + vl «LNFWWOO O118Nd HOH L4VHO.ux Table 4-1. Facilities That Manufacture or Process 1,4-Dichlorbenzene (continued) Range of maximum amounts Facility Location? on site in pounds Activities and uses BTP PLC Elgin, SC 10,000-99,999 As a reactant Rhone-Poulenc Inc. TX 10,000-99,999 Ancillary uses Phillips Petroleum Co. Borger, TX 100,000-99,9999 Import; For on-site use/processing; As a PPG Inc. Inc. New Martinsville, WV 1,000,000-9,999,9999 reactant Produce; For sale/distribution Source: TRI94 1996 JPost office state abbreviations used NA = not available FHNSOdX3 NVIWNH HOH TVILNILOd 'S INIZNIGOHOTHOIA-v evi 1,4-DICHLOROBENZENE 144 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.2 IMPORT/EXPORT In 1978, about 1.09x10’ grams (24,030 pounds) of 1,4-dichlorobenzene were imported into the United States (HSDB 1996; NTP 1989). Recent import volumes increased almost 3-fold during 1993 and 1994 compared to the period from 1990 to 1992 (NTDB 1996). Import volumes of 1,4-dichloro- benzene were 867,441 kg (1.9 million pounds), 1,113,676 kg (2.5 million pounds), 996,649 kg (2.2 million pounds), 3,283,759 kg (7.2 million pounds), and 3,019,233 kg (6.7 million pounds) for 1990, 1991, 1992, 1993, and 1994, respectively. In 1972, U.S. exports of 1,4-dichlorobenzene were reported to be 4.5x10° grams (9.9 million pounds) (HSDB 1996). Exports of 1,4-dichlorobenzene have expanded through the 1980s at about 1-2% per year due to the growth in production of polyphenylene sulfide (PPS) resin overseas (HSDB 1996; NTP 1989). In 1990, the United States exported about 25% (about 33 million pounds) of its 1,4-dichloro- benzene production volume (Chemical Marketing Reporter 1990). Recent export volumes from 1990 to 1995 have remained relatively constant (NTDB 1996). Export volumes of 1,4-dichlorobenzene were 11,925,179 kg (24.1 million pounds), 11,185,034 kg (24.7 million pounds), 10,651,337 kg (23.5 million pounds), 13,390,545 kg (29.5 million pounds), and 11,078,150 kg (24.4 million pounds) for 1990, 1991, 1992, 1993, and 1994, respectively. 4.3 USE For the past 20 years, 1,4-dichlorobenzene has been used principally (35-55% of all uses) as a space deodorant for toilets and refuse containers, and as a fumigant for control of moths, molds, and mildews. A significant amount of 1,4-dichlorobenzene is exported (34%), with lesser amounts used in the production of polyphenylene sulfide (PPS) resin (approximately 27% of its total use), and as an intermediate in the production of other chemicals such as 1,2,4-trichlorobenzene (approximately 10%). Minor uses of 1,4-dichlorobenzene also include its use in the control of certain tree-boring insects and ants, and in the control of blue mold in tobacco seed beds (Chemical Marketing Reporter 1990; HSDB 1996). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 145 4. PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL 4.4 DISPOSAL Wastes containing 1,4-dichlorobenzene are considered hazardous if they meet certain criteria specified by law. Hazardous wastes are subject to the handling, transport, treatment, storage, and disposal regulations as promulgated under the Resource Conservation and Recovery Act (HSDB 1996; IRPTC 1985). Regulations governing the treatment and disposal of wastes containing 1,4-dichlorobenzene are detailed in Chapter 7. Incineration by appropriate means is the recommended method for the disposal of waste 1,4-dichloro- benzene (HSDB 1996). 1,4-Dichlorobenzene may be disposed of by making packages of the chemical in paper or other disposable material and burning in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device or by dissolving the chemical in a flammable solvent (such as alcohol) and atomizing in a suitable combustion chamber equipped with an appropriate effluent gas cleaning device (IRPTC 1985). Halogenated compounds may be disposed of by incineration provided they are blended with other compatible wastes or fuels so that the composite contains less than 30% halogens. Liquid injection, rotary kiln, and fluidized bed incinerators are typically used to destroy liquid halogenated wastes. Temperatures of at least 2,000-2,200 °F and residence times of seconds for liquids and gases, and hours for solids (HSDB 1996). No data were located regarding past disposal trends or the amounts of 1,4-dichlorobenzene disposed of by different means. According to the Toxics Release Inventory (TRI94 1996) 228,750 pounds of 1,4-dichlorobenzene wastes were transferred off-site (presumably for incineration) and only 3 pounds were sent to POTWSs in 1994. ***DRAFT FOR PUBLIC COMMENT"*** 1,4-DICHLOROBENZENE 147 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW 1,4-Dichlorobenzene is a widely used chemical that enters the environment primarily as a result of releases to air during its use as a space deodorant, toilet deodorizer, and moth repellant. The compound is not known to occur naturally in the environment and is solely produced by anthropogenic sources. 1,4-Dichlorobenzene is degraded in the atmosphere by reaction with hydroxyl radicals, with an atmospheric lifetime (theoretically calculated) of about I month (Atkinson et al. 1985; Singh et al. 1981). 1,4-Dichlorobenzene will exist predominantly in the vapor-phase in the atmosphere, and its detection in rainwater suggests that atmospheric removal via washout is possible. The compound is expected to be moderately mobile in soil and to volatilize from surface water and soil surfaces to the atmosphere. Volatilization, sorption, biodegradation, and bioaccumulation are likely to be competing processes, with the dominant fate being determined by local environmental conditions. The principal route of human exposure to 1,4-dichlorobenzene is via inhalation, with an average daily intake from ambient air estimated at about 35 pug (EPA 1985). Recent data suggest that exposure from indoor air may be an order of magnitude higher than exposures from ambient air. Consumer contact with 1,4-dichlorobenzene associated with its use in moth repellant crystals and deodorizers is the most frequent means of exposure in the home. The general population may also be exposed to the compound via consumption of contaminated foods, especially fish from contaminated waters. Occupational exposure is primarily associated with inhalation exposure or dermal contact with 1,4-dichlorobenzene, with the highest exposure resulting from production or processing of 1,4-dichlorobenzene. 1,4-Dichlorobenzene has been identified in at least 281 of 1,445 hazardous wastes sites that have been proposed for inclusion on the EPA National Priorities List (NPL) (HazDat 1996). However, the number of sites evaluated for 1,4-dichlorobenzene is not known. The frequency of these sites within the United States can be seen in Figure 5-1. Of these sites, 281 are located in the United States. ***DRAFT FOR PUBLIC COMMENT*** «x INIFWWOO O1789Nd HOH 14VHQux Figure 5-1. Derived from HazDat 1996 Frequency of NPL Sites with 1,4-Dichlorobenzene Contamination > EE 11-34 3HNSOdX3 NYWNH HOH TVILNILOd 'S INIZNIFOHOTHOIA-¥'} svi 1,4-DICHLOROBENZENE 149 5. POTENTIAL FOR HUMAN EXPOSURE 5.2 RELEASES TO THE ENVIRONMENT According to the Toxics Release Inventory (TRI), in 1994, a total of 177,783 pounds (80,642 kg) of 1,4-dichlorobenzene was released to the environment from 21 large processing facilities (TRI9%4 1996). Table 5-1 lists amounts released from these facilities. In addition, an estimated 3 pounds (1.4 kg) were released by manufacturing and processing facilities to publicly owned-treatment works (POTWs) and an estimated 228,750 pounds (103,760 kg) were transferred offsite (TRI94 1996). The TRI data should be used with caution because only certain types of facilities are required to report (EPA 1995). This is not an exhaustive list. 1,4-Dichlorobenzene has been identified in a variety of environmental media (air, soil gas, surface water, groundwater, leachate, soil, and sediment) collected at 281 of the 1,445 NPL hazardous waste sites (HazDat 1996). The frequency of these sites within the United States can be seen in Figure 5-1. Industrial releases contribute only a small fraction of the total environmental loading of 1,4-dichloro- benzene. Use of consumer products containing 1,4-dichlorobenzene is the major source of environmental releases (Anderson 1983b; EPA 1981). Quantitative information on releases of 1,4-dichlorobenzene to specific environmental media are discussed below. 5.2.1 Air Because 1,4-dichlorobenzene is a volatile substance and sublimes at room temperature, most environmental releases are to the atmosphere. It has been estimated that about 40% of the domestic use of 1,4-dichlorobenzene in recent years is for space deodorants and 16% is for moth repellents (ICF 1987). Assuming that 90% of the space deodorants and all of the moth repellents are released to the atmosphere (EPA 1981), and using current production data (6.227 billion pounds) (C&EN 1995a), about 3.238 billion pounds of 1,4-dichlorobenzene was released to the air in 1994 from these sources. 1,4-Dichlorobenzene may also be emitted to air from other sources, such as hazardous waste sites (EPA 1981), during its use as a fumigant (EPA 1981), or from emissions from waste incinerator facilities (Jay 1995). These emissions are likely to be a minor contribution to the total atmospheric loading of 1,4-dichlorobenzene, but may be locally important. There are no known natural sources of this compound (IARC 1982). ***DRAFT FOR PUBLIC COMMENT*** «xLNIWWNOD O1M8Nd HOH 14VHA... Table 5-1. Releases to the Environment from Facilities That Manufacture or Process 1,4-Dichlorobenzene Reported amounts released in pounds per year Off-site Underground Total POTW waste State® City Facility Air Water Land injection environment? transfer transfer AR West Helena Trans Resources Inc. 10 10 581 DE Delaware City Sandard Chlorine Chemical 51129 253 51382 59068 0. FL Oldsmar Crest Prods. Inc. GA Atlanta Natl. Service Inc. 226 26 3 750 GA Atlanta NA 750 750 IN North Bay State/Sterling Inc. 25820 25820 Manchester LA Amelia NA LA Westlake NA 6538 MA Easthampton NA 255 255 920 MA Westborough ~~ NA 15383 15383 MO Saint Louis NA 2653 2653 1900 NC Wilmington Hoechst Celanese Corp. - 7844 13 7857 149140 Agent NJ NA NA 250 250 NJ NA Willert Home Prods. Inc. 172 172 NJ Paterson NA 250 250 OK Bartlesville Phillips Petroleum Co. 1148 1148 JHNSOdX3 NYWNH "Od TVILNILOd 'S INIZNIGOHOTHOIA-v + 0St +x INIFWWNOD O118Nd HOS 14VH.ux Table 5-1. Releases to the Environment from Facilities That Manufacture or Process 1,4-Dichlorobenzene (continued) Reported amounts released in pounds per year Off-site Underground ~~ Total POTW waste State? City Facility Air Water Land injection environment® transfer transfer PA New Eagle NA SC Elgin BTP PLC 306 306 TX Borger Phillips Petroleum Co. 40000 1100 2000 43100 TX NA Rhone-Poulenc Inc. 5 5 WV New PPG Ind. Inc. 27,087 1,329 28,416 9.853 Martinsville TOTALS Source: TRI94 1996 8post office state abbreviations used bThe sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility. NA = not available; POTW = publicly owned treatment works 3JHNSOdX3 NVIWNH HOH TVILNILOd 'S 3INIZNIGOHOTHOIA-v' + 1S 1,4-DICHLOROBENZENE 152 5. POTENTIAL FOR HUMAN EXPOSURE According to the Toxics Release Inventory, in 1994, the estimated releases of 1,4-dichlorobenzene of 173,088 pounds (78,512 kg) to the air from 21 large processing facilities accounted for about 97.4% of total environmental releases (TRI94 1996). Table 5-1 lists amounts released from these facilities. The TRI data should be used with caution because only certain types of facilities are required to report (EPA 1996). Therefore, this is not an exhaustive list. 1,4-Dichlorobenzene has been identified in air and soil gas samples collected at 6 and 4 of the 281 NPL hazardous waste sites, respectively, where it has been detected in some environmental media (HazDat 1996). 5.2.2 Water Less than 1% of environmental releases of 1,4-dichlorobenzene are to surface water (EPA 1981). Its level of water solubility is considered low (49-79 mg/L at 22-25 °C) (Verschueren 1983). 1,4-Dichlorobenzene has been identified in industrial and municipal waste waters from several sources, at concentrations ranging from less than 10 ppb to more than 900 ppb (Oliver and Nichol 1982a; Perry et al. 1979; Young et al. 1983). In 1988, environmental releases to surface water and publicly owned treatment works (POTWs) reported by industry were 6,153 and 37,997 pounds, respectively (TRI88 1990). 1,4-Dichlorobenzene was monitored for, but not detected, in 86 samples of urban stormwater runoff in the National Urban Runoff Program (Cole et al. 1984). Dichlorobenzene (unspecified isomers) has been reported in the leachate from industrial and municipal landfills at concentrations from 0.007 to 0.52 ppm (Brown and Donnelly 1988). 1,4-Dichlorobenzene has also been monitored in wetland-treated leachate water at a municipal solid waste landfill in central Florida (Chen and Zoltech 1995). Groundwater samples contained concentrations of 0.08-10.71 ppb. Hallbourg et al. (1992) detected dichlorobenzene (unspecified isomers) in groundwater at several landfill sites in Orange County, Florida. These authors reported mean concentrations of dichloro- benzenes of 0.37-21.2 pg/L, 6-46.4 pg/L, and <1-7.4 pg/L (ppb) at the Orange County Landfill, Alachua County Southwest Landfill, and the Alachua County Northeast Landfill, respectively. In their study, dichlorobenzene was one of the 10 most frequently detected volatile organic compounds (VOCs). Plumb (1991) also reported 1,4-dichlorobenzene in groundwater samples collected at 34 of 479 (14%) hazardous waste sites. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 153 5. POTENTIAL FOR HUMAN EXPOSURE According to the Toxics Release Inventory, in 1994, the estimated releases of 1,4-dichlorobenzene of 1,595 pounds (723 kg) to water from 21 large processing facilities accounted for 0.9% of the total environmental releases (TRI94 1996). An additional 3 pounds (1.36 kg) were released indirectly to POTWs and some of this volume may have been released to surface water. Table 5-1 lists amounts released from these facilities. The TRI data should be used with caution because only certain types of facilities are required to report (EPA 1995). Therefore, this is not a exhaustive list. 1.4-Dichlorobenzene has been identified in surface water, groundwater, and leachate samples collected at 29, 182, and 32 of the 281 NPL hazardous waste sites, respectively, where it was detected in some environmental media (HazDat 1996). 5.2.3 Soil The principal sources of 1,4-dichlorobenzene release to land are disposal of industrial waste in landfills, application of sewage sludge containing 1,4-dichlorobenzene to agricultural land, and atmospheric deposition (Wang and Jones 1994; Wang et al. 1995). Industrial releases of 1,4-dichloro- benzene to land reported for 1988 and 1994 total 1,050 pounds (TRI88 1990) and 1,100 pounds, respectively (TRI94 1996). Municipal wastes may include unused space deodorants and moth repellents containing 1,4-dichlorobenzene, but these releases are not expected to be significant (EPA 1981). A survey of 215 sewage sludges conducted in the United States, reported a concentration range of 0.04-633 mg/kg (ppm) for 1,4-dichlorobenzene (Jacobs and Zabik 1983 as cited in Rogers 1996). 1,4-Dichlorobenzene from this source may be released to soils during land applications of sludge to agricultural soils. A similar survey of sewage sludges in England found 1.4-dichlorobenzene ranging from 561 to 2,320 pg/kg (0.561-2.32 ppm) (dry weight) in 100% of the samples tested (Wang and Jones 1994). Wang et al. (1995) reported, however, that 1,4-dichlorobenzene concentrations increased during the 1960s in both plots receiving sewage sludge applications and in control soil plots. The authors concluded that atmospheric deposition during the 1960s in particular, which corresponded to a period of increased production of many organochlorine compounds, was a likely source. According to the Toxics Release Inventory, in 1994, releases of 1,4-dichlorobenzene of 1,100 pounds (500 kg) to the soil from 21 large processing facilities accounted for 0.6% of total environmental releases (TRI94 1996). In addition, an estimated 2,000 pounds (907 kg) or 1.1% of total environmental releases were released via underground injection. Table 5-1 lists amounts released from ***DRAFT FOR PUBLIC COMMENT" 1,4-DICHLOROBENZENE 154 5. POTENTIAL FOR HUMAN EXPOSURE these facilities. The TRI data should be used with caution because only certain types of facilities are required to report (EPA 1995). Therefore, this is not a exhaustive list. 1,4- Dichlorobenzene has been identified in soil and sediment samples collected at 98 and 48 of the 281 NPL hazardous waste sites, respectively, where it was detected in some environmental media (HazDat 1996). 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning 1,4-Dichlorobenzene is a solid which sublimes readily at room temperature. Sublimation rates of 1,4-dichlorobenzene from consumer products were measured at 1.6x107 to 4.6x107> g/min at temperatures ranging from 21 to 24 °C during a 19-day test period (Scuderi 1986). Therefore, 1,4-dichlorobenzene tends to volatilize to the atmosphere from soil and water at a relatively rapid rate. The estimated volatilization half-life in a model river was 4.3 hours (Howard 1990), and reported volatilization half-lives in coastal seawater ranged from 10 to 18 days (Wakeham et al. 1983). 1,4-Dichlorobenzene (300 ppm) volatilized completely from nonaerated distilled water in less than 3 days and from aerated distilled water in less than 4 hours (Garrison and Hill 1972). Volatilization from surface soil may be an important transport mechanism for 1,4-dichlorobenzene, but adsorption to soil particulates may inhibit volatilization by an order of magnitude compared to volatilization from water (Wilson et al. 1981). Since 1,4-dichlorobenzene is slightly soluble in water (79 ppm at 25 °C) (Verschueren 1983), partitioning to clouds, rain, or surface water may occur. The Henry's law constant value (H), 1.5107 atm-m*/mol at 20 °C (Howard 1989), indicates that partitioning from air to water is likely to be minor relative to the reverse process of volatilization of the compound from water to air. However, this compound has been detected in 6 of 7 rainwater samples collected in Portland, Oregon, at concentrations ranging from 3 to 7 ppt (Ligocki et al. 1985). Based on measured soil organic carbon partition coefficient (K,.) values, which range from 275 to 1,833 in different soils (Bahnick and Doucette 1988; Newsom 1985; Schwarzenbach and Westall 1981: ’ Wilson et al. 1981), 1,4-dichlorobenzene is expected to sorb moderately to soils and sediments. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 155 5. POTENTIAL FOR HUMAN EXPOSURE Sorption is primarily to the soil organic phase (Chiou et al. 1983) and, therefore, depends on the organic content of the soil. However, sorption is likely to be reversible; therefore, 1,4-dichlorobenzene may leach from hazardous waste sites and be transported to groundwater, or may migrate from surface water through the soil to groundwater (Newsom 1985; Schwarzenbach and Westall 1981). In a sandy soil with low organic matter, 26-49% of 1,4-dichlorobenzene percolated through the soil to a depth of 140 cm (Wilson et al. 1981). 1,4-Dichlorobenzene is expected to bioconcentrate in aquatic organisms. The high octanol-water partition coefficient (K_,) value of 2,455 (Leo et al. 1971) also suggests that 1,4-dichlorobenzene has a high potential for bioaccumulation. A calculated bioconcentration factor (BCF) of 267 was reported for the fathead minnow (Pimephales promelas) (ASTER 1995). Measured mean BCF values of 370 and 720 were experimentally determined for rainbow trout exposed to water concentrations of 28 ng/L (ppb) and 670 ng/L (ppb), respectively, of 1,4-dichlorobenzene for up to 119 days in laboratory aquaria (Oliver and Niimi 1983). A study of chlorobenzenes in sediments, water, and selected fish from the Great Lakes indicated that chlorobenzenes, including 1,4-dichlorobenzene, are bioconcentrated by fish, but to a smaller extent than compounds such as DDT and PCB’s. For example, 1,4-dichlorobenzene concentrations of 2 ppb and 4 ppb were found in trout age 4+ and 6+ years, respectively, from Lake Ontario; the mean concentration of 1,4-dichlorobenzene found in water from Lake Ontario was 45 ppt (0.045 ppb). A BCF value of 1,800 (lipid basis) was measured for guppies exposed during a 19-day constant flow test (Chiou 1985). 1,4-Dichlorobenzene can enter soil-plant systems through many routes including atmospheric deposition, sewage sludge application to agricultural land, and through industrial activities (Wang and Jones 1994). Overcash et al. (1986) as cited in Wang et al. (1996), reported that monochlorobenzenes and 1,4-dichlorobenzene were the only organic compounds that had bioaccumulation factors greater than 1 from municipal sludge amended soil to plants. Wang et al. (1996) found that 1,4-dichloro- benzene (40 pg in 40 mL of medium [1 ppm]) was taken up by carrots (Daucus carota, 49%), soybeans (Glycine max, 50%), and red goosefoot (Chenopodium rubrum, 62%), but not by tomatoes (Lycopersicon esculentum). Only the soybean cell cultures provided evidence of the existence of metabolites of this compound, probably conjugates of chlorophenol. The authors further observed that the uptake, metabolism, and toxicity of 1,4-dichlorobenzene differed among the species tested. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 156 5. POTENTIAL FOR HUMAN EXPOSURE Data on biomagnification of 1,4-dichlorobenzene through aquatic or terrestrial food chains were not located. 5.3.2 Transformation and Degradation 5.3.2.1 Air The main degradation pathway for 1,4-dichlorobenzene in air is reaction with photochemically generated hydroxyl radicals (Cuppitt 1980; EPA 1985). Reactions with ozone or other common atmospheric species are not expected to be significant (Atkinson et al. 1985; Cuppitt 1980). Therefore, the atmospheric lifetime of 1,4-dichlorobenzene may be predicted from an assumed hydroxyl radical concentration in air and the rate of reaction. The reported rate for reaction of hydroxyl radicals with 1,4-dichlorobenzene is 3x10" cm?/mol-sec (Atkinson et al. 1985; Singh et al. 1981), and the estimated atmospheric residence time for 1,4-dichlorobenzene is about 39 days (Singh et al. 1981). Since this degradation process is relatively slow, 1,4-dichlorobenzene may become widely dispersed, but is not likely to accumulate in the atmosphere. The degradation pathways for 1,4-dichlorobenzene in the atmosphere are shown in Figure 5-2. 5.3.2.2 Water Biodegradation may be an important transformation process for 1,4-dichlorobenzene in water under aerobic, but not anaerobic, conditions (Bouwer and McCarty 1982, 1983, 1984; Spain and Nishino 1987; Tabak et al. 1981). Although volatilization of 1,4-dichlorobenzene may interfere with biodegradation studies, 14¢ studies indicate that significant biodegradation of 1,4-dichlorobenzene does occur (Spain and Nishino 1987). Using acetate as the primary carbon source under aerobic conditions and after an acclimation period of 10 days, rapid bacterial degradation of 98% of a 1,4-dichloro- benzene sample was reported (Bouwer and McCarty 1982). The compound was completely mineralized to inorganic end products. Longer acclimation periods are required when 1,4-dichloro- benzene is the sole carbon source (Spain and Nishino 1987). No degradation of 1,4-dichlorobenzene was reported under denitrification or methanogenic conditions (Bouwer and McCarty 1983, 1984). The degradation pathways for 1,4-dichlorobenzene in water are shown in Figure 5-3. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 157 5. POTENTIAL FOR HUMAN EXPOSURE Figure 5-2. The Decomposition of 1,4-Dichlorobenzene in Air Cl smog chamber Dichloronitrophenol en Dichloronitrobenzene tests Dichlorophenol Cl 1,4-Dichlorobenzene Source: Howard 1989 “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 158 5. POTENTIAL FOR HUMAN EXPOSURE 5.3.2.3 Sediment and Soil Based on its tendency to sublime, volatilization is the most likely fate process for 1,4-dichlorobenzene from surface soil. Biodegradation by soil organisms and leaching to groundwater from subsurface soils may also occur (EPA 1985). However, no quantitative data on rate or extent of volatilization were located. Pure cultures of Pseudomonas sp. isolated by selective enrichment from activated sludge were reported to degrade 1,4-dichlorobenzene (Spain and Nishino 1987). These authors reported that the 1,4-dichlorobenzene was initially converted by a dioxygenase to 3,6-dichloro-cis-1,2-dihydroxy- cyclohexa-3,5-diene, which was converted to 3,6-dichlorocatechol by an NAD+ dependent dehydrogenase. Ring cleavage of 3,6-dichlorocatechol was by a 1,2-oxygenase to form 2,5-dichloro- cis,cis-muconate. Pure cultures of Alcaligenes sp. were also reported to degrade 1,4-dichlorobenzene (Oltmans et al. 1988). Most recently, Spiess and Gorisch (1995) reported that the bacterium Xanthobacter flavus was isolated from river sediment by selective enrichment with 1,4-dichlorobenzene as the sole source of carbon and energy. This bacterium did not use other aromatic or chloroaromatic compounds as growth substrates. During growth on 1,4-dichlorobenzene, stoichiometric amounts of chloride ions were released. The degradation products of 1,4-dichlorobenzene were identified as 3,6-dichloro-cis-1,2-dihydroxycyclo- hexa-3,5-diene and 3,6-dichlorocatechol. 2,5-Dichloromuconic acid and 2-chloromalylacetic acid as well as decarboxylation product 2-chloroacetoacrylic acid were identified after enzymatic conversion of 3,6-dichlorocatechol by cell extract. The results demonstrate that 1,4-dichlorobenzene degradation is initiated by dioxygenation and that ring opening proceeds via ortho cleavage. The degradation pathways for 1,4-dichlorobenzene in soil and sediment are shown in Figure 5-3. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT Reliable evaluation of the potential for human exposure to 1,4-dichlorobenzene depends in part on the reliability of supporting analytical data from environmental samples and biological specimens. In reviewing data on 1,4-dichlorobenzene levels monitored or estimated in the environment, it should also be noted that the amount of chemical identified analytically is not necessarily equivalent to the amount ***DRAFT FOR PUBLIC COMMENT*** «ex INGWWOO 01N8Nd HO L4VHQuus Figure 5-3. The Decomposition of 1,4-Dichlorobenzene in Soil and Water 2,5-Dichloro-cis, cis-muconic acid Cl Cl OH 0, 0, — Rl OH Cl Cl 1,4-Dichlorophenzene 1,4-Dichlorobenzene dihydrodiol cl S NN COOH 7° decarboxylation ~~ "COOH © — COOH OCHj4 0 Cl 2-Chloroaceto- acrylic acid 2-Chloromaleyl- acetic acid Source: Spain and Nishino 1987; Schraa et al. 1986; Spiess et al. 1995 Cl ZZ e=0 o” x. COOH Cl proposed 2-Chloro-4-carboxy- methylene-but-2-en-4-olide 3IYNSOdX3 NYWNH HOH TVILNILOd 'S 3INIZNIEOHOTHOIA-V' | 6S 1,4-DICHLOROBENZENE 160 5. POTENTIAL FOR HUMAN EXPOSURE that is bioavailable. The analytical methods available for monitoring 1,4-dichlorobenzene in various environmental media are detailed in Chapter 6. 5.4.1 Air 1,4-Dichlorobenzene has been detected in indoor air, ambient outdoor air, and in occupational settings. A summary of levels of 1,4-dichlorobenzene detected in indoor air is shown in Table 5-2. An update of the 1980 national ambient VOCs database prepared for the EPA summarized concentrations of 1.4-dichlorobenzene by site type (Shah and Heyerdahl 1988). Median values were reported because they were considered to be less biased by a few high or low concentrations, and thus would better represent the data than would average values. The median indoor air concentration of 1,4-dichloro- benzene detected at 2,121 sites was 0.283 ppb (ppb) (mean 3.988 ppb), and the median concentration detected from personal air monitoring of 1,650 individuals was 0.416 ppb (Shah and Heyerdahl 1988). These values are a result of the use of 1,4-dichlorobenzene in air fresheners and to control moths that could damage woolen clothing. Because of its indoor uses, reports of indoor air monitoring show higher concentrations of 1,4-dichlorobenzene than those observed in ambient outdoor air. This was also observed during the Total Exposure Assessment Methodology (TEAM) Study conducted by EPA between 1979 and 1985 in an effort to measure exposures to 20 VOCs in personal air, outdoor air, and drinking water. Data from the TEAM study were presented for the sum of 1,3- and 1,4-dichlorobenzene (Wallace et al. 1986). Because 1,4-dichlorobenzene is produced and used in much greater volume than 1,3-dichloro- benzene, the authors assumed that the concentrations found were almost all 1,4-dichlorobenzene. The major cause for the higher personal air concentrations was felt to be the use of 1.4- dichlorobenzene sources such as moth crystals and room deodorizers in the home (Wallace et al. 1986). Wallace et al. (1989) reported that the median 1,4-dichlorobenzene concentration in outdoor air sampled at 4 test houses was <1 pg/m’ (maximum concentration of 17 pg/m’). The median indoor air concentration sampled from the same 4 study houses ranged from 2.2 to 240 ng/m’ (maximum ranged from 7.2 to 740 ng/m?). Furthermore, the mean personal exposure of 7 individuals living in the houses was 81 ng/m’), while the outdoor mean air concentration was 1 ng/m’. The personal air to outdoor air ratio of 81 was 4 times higher than the ratio calculated for other VOCs. Two individuals living in the same house had a mean personal exposure of 240 pg/m’; the median levels of ""*DRAFT FOR PUBLIC COMMENT*** +x LNTFWWOOD 2118Nd HOH 14VHAuus Table 5-2. Levels of 1,4-Dichlorobenzne in Indoor Air Concentration (ppm) Conditions Range Mean Median Maximum Reference Bathroom with 1 deodorizer block ~~ 7.80x102-1.26x10™" Scuderi 1986 Bathroom with 1 toilet deodorizer 1.16x10"'-2.20x10"" in 1 urinal and 1 toilet Inside closet with moth flakes in 2.19x107'-5.45x10™ closed garment bag Outside closet with moth flakes in 1.30x102-7.10x102 closed garment bag 2121 Indoor sites 4x10 2.83x10™ Shah and 1650 Personal air monitors 416x107 Heyerdahl 1983 Inside four test houses 365x107%-4x10° 1.2x10° Wallace et al. 1989 8_1.22x10" With solid deodorizer 5.64x102 With spray deodorizer 6.14x103 With liquid deodorizer 415x103 With no deodorizer 432x103 26 Normal houses 1.08x10% 1.33x10” 1.5x10 Kostiainen 1995 Nationwide Study of Canadian Homes Fellin and Otson Winter 5.93x10™3 to Spring 2.5x107 Summer 1.75x107 Fall 25x10 0°C 3.92x10°® 0-15 °C 3.66x10°° 215 °C 2.0x10° 34NSOdX3 NYIWNH HOH TVILNILOd 'S 3INIZN3GOHOTHIIa-v'} [8] 1,4-DICHLOROBENZENE 162 5. POTENTIAL FOR HUMAN EXPOSURE 1,4-dichlorobenzene in their breath were 40 and 47 pg/m’, which was far higher than the median breath level of 1.5 pg/m’ in an individual receiving a personal exposure of 5.7 pg/m’. Wallace et al. (1989) further studied the activities associated with increased personal exposure to, or increased indoor air concentrations of, 1,4-dichlorobenzene. The activities that increased both personal exposure and indoor air concentrations of 1,4-dichlorobenzene were the use of solid toilet deodorizers, followed by spray deodorizers and liquid deodorizers, compared to the use of no deodorizers at all. The median personal exposure concentrations to 1,4-dichlorobenzene were 330 pg/m’ (maximum, 500 pg/m’), 33 pg/m’ (maximum, 84 pg/m’), 12 pg/m’ (maximum, 28 ng/m?), and 2.4 pg/m’ (maximum, 6.6 pg/m’) for the solid, spray, liquid, and no deodorizer use, respectively. While median indoor air concentrations were 340 pg/m’ (maximum, 630 pg/m>), 37 ug/m> (maximum, 59 ug/m?), 25 g/m’ (maximum, 30 ng/m>), and 2.6 pg/m’ (maximum, 5.2 pg/m?) for solid, spray, liquid, and no deodorizer use, respectively. Most recently, Kostiainen (1995) identified over 200 VOCs in the indoor air of 26 normal houses. 1,4-Dichlorobenzene was detected at an average concentration of 0.65 g/m?’ (median 0.08 pg/m?, minimum 0 ng/m’, and maximum 8.94 pg/m’) in 100% of the houses studied. In a study of normal and sick houses, the median concentration of 1,4-dichlorobenzene (0.88 pg/m’) in the normal houses was exceeded by 5-10% in 6% of the normal houses and by 10-50% in 16% of the normal houses, while in the sick houses, the median concentration was exceeded by 5-10% in 7.9% of the sick houses, by 10-50% in 2.6% of the sick houses, and by 50-200% in 5.3% of the sick houses. A nationwide study of indoor air concentrations of 26 VOC compounds was conducted in Canada in 1991 (Fellin and Otson 1994). These authors reported that mean 1,4-dichlorobenzene concentrations were 35.75 g/m’ (winter), 15 pg/m’ (spring), 10.54 pg/m> (summer), and 15 pg/m’ (fall), and that the concentrations declined with an increase in ambient air temperature. At <0 °C, 0-15 °C, and >15 °C, the 1,4-dichlorobenzene mean concentrations were 23.64, 22.02, and 11.83 pg/m?>, respectively. A factors analysis revealed that 1,4-dichlorobenzene concentrations were associated with use of household products and moth repellant crystals. These authors concluded that indoor sources of 1.4-dichlorobenzene (household products and moth repellant crystal) are likely to have a more significant influence on indoor air concentrations than climatic variables. Summer conditions and outdoor temperatures >15.1 °C gave the lowest indoor air concentrations of 1,4-dichlorobenzene. Moth repellant crystals are also deployed in a manner that gives reasonably constant emissions over several weeks. This compound produced a trend consistent with expected ventilation results. The ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 163 5. POTENTIAL FOR HUMAN EXPOSURE highest average concentrations were observed during the winter or when temperatures were <0 °C, when ventilation is expected to be lowest. Intermediate values were measured during the fall and spring, while the lowest values were measured during the summer, when ventilation of homes is expected to be highest. 1,4-Dichlorobenzene has been detected in ambient air samples in several monitoring studies, as shown in Table 5-3. Kelly et al. (1994) reported that the median concentration of 1,4-dichlorobenzene was below detection limits based on 1,447 samples collected from 57 different locations. Concentrations were not quantifiable in rural air (Shah and Heyerdahl 1988), but increasingly higher concentrations were detected in suburban and urban air. Mean concentrations of 1,4-dichlorobenzene in air, and in the vicinity of hazardous waste sites and sanitary landfill sites, generally average less than 4.2x1073 ppm, but indoor air concentrations of 1,4-dichlorobenzene may be 1-3 orders of magnitude higher where 1,4-dichlorobenzene is used as a space deodorizer or moth repellant (IARC 1982; Scuderi 1986; Wallace et al. 1986) (see Table 5-2). Concentrations of 1,4-dichlorobenzene in workplace air were, not unexpectedly, the highest concentrations measured (IARC 1982), as shown in Table 5-4; concentrations ranged from 33-52 mg/m’ (5.48-8.62 ppm) detected in air sampled at a monochlorobenzene manufacturing facility to 4,350 mg/m’ (722 ppm) detected in air sampled at a plant manufacturing monochlorobenzene and dichlorobenzene. | 4-Dichlorobenzene has been identified in air and soil gas samples collected at 6 and 4 of the 281 NPL hazardous waste sites, respectively, where it has been detected in some environmental media (HazDat 1996). 5.4.2 Water 1,4-Dichlorobenzene has generally been detected at low concentrations in finished drinking water, surface water, and groundwater in the United States. Finished drinking water samples from 20 of the 113 cities monitored in the National Organics Monitoring Survey (NOMS) had levels of 1,4-dichloro- benzene ranging from 0.01 to 1.54 ppb, with a median value of 0.03 ppb (Dressman et al. 1977), and the compound was detected in about 13% of finished drinking water supplies using surface water sources (Coniglio et al. 1980). 1,4-Dichlorobenzene was reported in drinking water samples from ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 164 5. POTENTIAL FOR HUMAN EXPOSURE Table 5-3. Levels of 1,4-Dichlorobenzene in Outdoor Air Concentration (ppm) Location Mean Median Maximum Range Reference Rural 0.002 Shah and Heyerdahl 1988 Suburban 4.8x10°° Shah and Heyerdahl 1988 Suburban 2.8x10°3 <1.66x10% —2.8x10° Wallace et al. 1989 Urban 5x10°° Shah and Heyerdahl 1988 Urban (NJ) Harkov et al. Summer ~~ 4x107°-7x10°°P 1984 Winter 2xipsh Urban (NJ) 6x10 P 4.3x104-2x102 d Bozzelli and 5x107°-6.6x10 © Kebbekeus 1979 Hazardous 3x10 -5.4x1074°¢ 4.2x10°8 Harkov et al. waste sites 1984 (7 sites) Hazardous 4x107° —5.1x10™¢ 3.8x1073-4.2x10’ La Regina et waste sites 2x10 -2.2x107 © al. 1986 and sanitary landfill sites 2 level not quantifiable 0 geometric mean c d e range in arithmetic mean concentrations range in maximum concentrations detected range in geometric mean concentrations ""*DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 165 5. POTENTIAL FOR HUMAN EXPOSURE 3 cities on Lake Ontario at concentrations ranging from 8 to 20 ppt (Oliver and Nicol 1982a). Dichlorobenzene isomers were detected in 0-3% of drinking water samples from selected locations in New Jersey, North Carolina, and North Dakota locations (Wallace et al. 1986). The compound was detected in 3% of 8,576 surface water samples recorded in the STORET database at a median concentration of less than 0.1 ppb (<100 ppt) (Staples et al. 1985) and in 100% of 91 surface water samples from the Great Lakes at mean concentrations ranging from 0.28 ppt in Lake Huron to 1.5 ppt in Lake Ontario (IJC 1989). Oliver and Nicol (1982a) also reported concentrations of 1,4-dichlorobenzene in water samples collected from the Great Lakes region. These authors reported mean concentrations of 45 ppt (range, 33-64 ppt), 4 ppt (range, 3-6 ppt), and 10 ppt (range, ND [not detectable]-42 ppt) for surface water samples collected from Lake Ontario, Lake Huron, and the Grand River, respectively. Concentrations of 1,4-dichlorobenzene from the Niagara River sampled in 1980 ranged from 1 to 94 ppt with the highest concentration occurring just below a chemical manufacturing plant’s effluent discharge (Oliver and Nicol 1982a). 1,4-Dichlorobenzene was also reported in waste water effluent samples collected from 4 plants on the Great Lakes at a mean concentration of 660 ppt (range, 484-920 ppt) (Oliver and Nicol 1982a). In a New Jersey survey, 1,4-dichlorobenzene was detected in 6% of 463 surface water samples at a maximum concentration of 31 ppb (31,000 ppt) (Page 1981). 1,4-Dichlorobenzene has been reported in surface waters in the vicinity of hazardous waste sites at unspecified concentrations (Elder et al. 1981) and at a concentration of 52 ppt (Oliver and Nicol 1982a). 1,4-Dichlorobenzene was monitored in wetland-treated leachate water at a municipal solid waste landfill site in central Florida from 1989 to 1990 and from 1992 to 1993 (Chen and Zoltek 1995). During the first sampling period, 1,4-dichlorobenzene was detected in surface water samples ranging from 0.04 to 0.13 ppb, and in groundwater samples ranging from 0.08 to 10.71 ppb. During the second sampling period (1992-1993), the chemical was not detected in surface water samples and in 2 of the 4 groundwater samples; it was detected in 2 of the groundwater samples at concentrations of 0.45 and 3.74 ppb. No detection limits were given. Dichlorobenzene (isomers unspecified) was detected in a study of three landfills in central Florida (Hallbourg et al. 1992). These authors reported the concentrations of dichlorobenzene in groundwater ranging from 0.37 to 21.2, 646.4, and <1-7.4 pg/L (ppb) at 3 different landfill sites. In a New Jersey survey, 1,4-dichlorobenzene was detected in 3% of 685 groundwater samples with a maximum concentration of 995 ppb (Page 1981). Most recently, Plumb (1991) reported that 1,4-dichlorobenzene was detected in groundwater collected ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 166 5. POTENTIAL FOR HUMAN EXPOSURE at 34 of 479 (14%) hazardous waste sites. This author reported that the chemical was detected in 191 samples collected from 34 sites in 9 of the 10 EPA regions. 1.4-Dichlorobenzene has been identified in surface water, groundwater, and leachate samples collected at 29, 182, and 32 of the 281 NPL hazardous waste sites, respectively, where it was detected in some environmental media (HazDat 1996). 5.4.3 Sediment and Soil Little information on soil concentrations of 1,4-dichlorobenzene was located for the United States. One study conducted in England, however, reported 1,4-dichlorobenzene concentrations in agricultural soils increased during the 1960s, corresponding to a period of increased production of chlorobenzene compounds (Wang et al. 1995). The mean soil concentration reported for agricultural land was 2.17 ppb in 1942, 0.75 ppb in 1951, 1.73 ppb in 1960, 9.82 ppb in 1967, 3.9 ppb in 1972, 3.06 ppb in 1980, 1.4 ppb in 1984, and 0.4 ppb in 1991. It should be noted that 1,4-dichlorobenzene has been reported to occur in soils as a result of lindane degradation (IARC 1982), so the detection of 1,4-dichlorobenzene may not be indicative of 1,4-dichlorobenzene disposal per se. 1,4-Dichlorobenzene was detected in 2% of 357 sediment samples recorded on the STORET database (Staples et al. 1985), and in sediments near hazardous waste sites (Elder et al. 1981: Hauser and Bromberg 1982). Oliver and Nicol (1982a) reported 1,4-dichlorobenzene concentrations in surficial sediments from 13 sites in Lake Superior, 42 sites in Lake Huron, 5 sites in Lake Erie, and 11 sites in Lake Ontario. The mean concentrations detected were 5 ppb (range, ND-9 ppb), 16 ppb (range, 2-100 ppb), 9 ppb (range, 3-20 ppb), and 94 ppb (range, 22-210 ppb) for lakes Superior, Huron, Erie, and Ontario, respectively. These authors also reported detecting 1,4-dichlorobenzene concentrations in deep sediment layers in Lake Ontario from core samples from the Niagara Basin. Concentrations of 1,4-dichlorobenzene in various depths of the sediment cores were as follows: 110 ppb (0-1 cm), 120 ppb (1-2 cm), 88 ppb (2-3 cm), 230 ppb (3-4 cm), 88 ppb (4-5 cm), 29 ppb (506 cm), and 17 ppb (6-7 cm), but were not detected in the 7-8 cm sediment core. The highest concentration was detected in the 3—4 cm core sample, which corresponded to the period of 1958-65 which was one of the periods of greatest chlorobenzene production in the United States. Chapman et al. (1996) also reported detecting 1,4-dichlorobenzene in sediments collected around the diffuser of a large marine municipal sewage discharge outfall at Macaulay Point in Victoria, Canada. Sediment quality "**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE } 167 5. POTENTIAL FOR HUMAN EXPOSURE guidelines are set by the government to protect indigenous sediment-dwelling organisms. 1.4-Dichlorobenzene was detected at concentrations exceeding sediment quality guidelines (110 pg/kg [ppb] dry weight) and showed a distinctive concentration gradient which peaked at the outfall at concentrations up to 1,710 pg/kg ( ppb) dry weight and decreased with increasing distance from the outfall. The authors attributed the source of the 1,4-dichlorobenzene in the relatively untreated municipal sewage effluent to the extensive use of toilet block deodorizers. In a recent study conducted in England, Wang and Jones (1994) analyzed the chlorobenzene content of contemporary sewage sludge collected from 12 waste water treatment plants. Most of the plants surveyed received waste water from urban and industrial effluent and all of the sewage-treatment plants used primary treatment. Concentrations of 1,4-dichlorobenzene were detected in 100% of the samples tested and ranged from 561 to 2,320 pg/kg (ppb) dry weight (21.9108 ug/L [ppb] wet weight). For 1,4-dichlorobenzene, the mean and median concentrations for the 12 plants were 1,310 and 1,250 pg/kg (ppb) (dry weight), respectively. The authors also reported that 1,4-dichloro- benzene was the most abundant compound detected (exclusive of the monochlorobenzenes) and was detected at higher concentrations in the urban sludges compared to the sludges dominated by industrial sources. The authors believe this was a result of the extensive use of the compound in moth repellent crystals, insecticides, germicides, and space deodorants. Since 1,4-dichlorobenzene also has industrial uses, the absolute content of this compound was not lower in the industrial sludges as compared to the urban sludges. The authors also found that the 1,4-dichlorobenzene content and that of other chloro- benzene compounds in sewage sludges from the same treatment plant were consistent over time. Wang et al. (1995) further reported that at a site in Woburn, England, sewage sludge applied to agricultural land from 1942 to 1961 contained 1,4-dichlorobenzene concentrations of 7.76-71.8 ppb (mean, 29.8 ppb; median, 25.5 ppb). These authors found that the concentrations of 1,4-dichloro- benzene in both the sludge-amended and control soils increased during the 1960s after the sludge applications were halted in 1961. The authors concluded that the 1.4-dichlorobenzene could have increased in both soil plots as a result of pesticide applications since 1,4-dichlorobenzene was often found as an impurity in many organochlorine pesticides or via atmospheric deposition of airborne emissions from industrial facilities or municipal waste incinerators. 1,4-Dichlorobenzene has been identified in soil and sediment samples collected at 98 and 48 of the 281 NPL hazardous waste sites, respectively, where it was detected in some environmental media (HazDat 1996). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 168 5. POTENTIAL FOR HUMAN EXPOSURE 5.4.4 Other Environmental Media Although 1,4-dichlorobenzene has not generally been reported in food in the United States, fish and other types of foodstuffs may be contaminated with this compound. Pork and eggs reportedly had an unpleasant odor and taste resulting from exposure of pigs and hens to 1,4-dichlorobenzene (IARC 1982). 1,4-Dichlorobenzene was detected in lake and rainbow trout from the Great Lakes at concentrations ranging from 1 to 4 ppb (Oliver and Nicol 1982a) and concentrations of 1,4-dichloro- benzene reported in mackerel, mussels, and other fish species from around the world ranged up to 0.4 ppm (400 ppb) (IARC 1982). Most recently, Page and Lacroix (1995) analyzed a variety of beverage and food samples for 32 different volatile contaminants, including 1,4-dichlorobenzene. Soft drink and milk samples contained 0.1 pg/kg (ppb), while butter, margarine, peanut butter, flour, and pastry mix contained concentrations of 1.3-2.7 pg/kg, 12.2-14.5 pg/kg, 1.2-8.8 pg/kg, 7.3 pg/kg, and 22 pg/kg (ppb), respectively. 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE Inhalation is the predominant route of exposure to 1,4-dichlorobenzene for the general population. According to data from the TEAM study, 1,4-dichlorobenzene was found in 44-100% of air and breath samples from several U.S. locations, and indoor air levels were up to 25 times higher than ambient outdoor levels for dichlorobenzene (1,3- and 1,4-dichlorobenzene) (Wallace et al. 1986). The EPA has estimated that adult exposure to 1,4-dichlorobenzene is about 35 pg/day, based on a mean ambient air concentration of 1.6 pg/m?’ (EPA 1985). Inhalation exposure may be considerably higher indoors where 1,4-dichlorobenzene space deodorants or moth repellents are used. Because water and food concentrations of 1,4-dichlorobenzene are generally quite low, exposure from sources other than air is unlikely to be important. For example, drinking water containing 0.1 ppb 1,4-dichlorobenzene would provide an additional intake of only 0.2 ug per day for an adult drinking 2 L of water per day. In the past, concentrations of 1,4-dichlorobenzene also have been detected in some freshwater fish from the Great Lakes region (Oliver and Nichol 1982a) and from marine fishes, especially in areas near effluent discharges (Young et al. 1980); however, more recent information on concentrations in edible fish and shellfish tissues is lacking. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 169 5. POTENTIAL FOR HUMAN EXPOSURE Results of the National Human Adipose Tissue Survey (NHATS) conducted in 1982, which estimated the general population exposure to toxic organic chemicals, found that 1,4-dichlorobenzene was detected in 100% of 46 composite human adipose tissue specimens analyzed at levels ranging from 12-500 ppb (EPA 1989d; Stanley 1986). These measurements indicate widespread exposure of the general population to 1,4-dichlorobenzene. Ashley et al. (1994) reported a mean blood level of 1,4-dichlorobenzene of 1.9 ppb (median 0.33 ppb) in 1,037 samples collected from a reference group of non-occupationally exposed individuals. Concentrations of VOCs in blood samples from a group of 126 nonsmokers and 42 smokers were also studied (Ashley et al. 1995). These authors found that mean blood levels were 3.2 ng/L (ppb) (median, 0.45 ng/L; range ND-96 ng/L) for nonsmokers and 2.2 ng/mL (ppb) (median, 0.47 ng/L; range, ND-17 ng/L) for smokers. Blood levels of 1,4-dichlorobenzene were not dependent on whether the subject was from the smoking or control group. Hill et al. (1995) analyzed both blood and urine samples of 1,000 adults in the United States. These authors reported that 96% of the individuals in the study had detectable concentrations of 1,4-dichlorobenzene in their blood and 98% had detectable concentrations of 2,5-dichlorophenol (the metabolite of 1,4-dichlorobenzene) in their urine. 1,4-Dichlorobenzene levels in the blood ranged up to 49 pg/L (ppb), with median and mean concentrations of 0.33 pg/L and 2.1 pg/L, respectively. Urinary 2,5-dichlorophenol concentrations ranged up to 8,700 ug/L (ppb), with median and mean concentrations of 30 ug/L (ppb)and 2,000 pg/L (ppb), respectively. There was a highly significant correlation (p <0.0001) between 2,5-dichlorophenol in the urine and 1,4-dichlorobenzene in the blood. The authors concluded that 1,4-dichlorobenzene is a common, worldwide environmental contaminant. Dichlorobenzene (all isomers) was identified in 100% of 42 samples of human breast milk collected in 5 urban areas of the United States at concentrations of 0.04-68 ppb (Erickson et al. 1980). Dichloro- benzene (all isomers) was identified in human breast milk in 8 of 12 women who were residents of Bayonne, New Jersey (6 women), Jersey City, New Jersey (2 women), Bridgeville, Pennsylvania (2 women), and Baton Rouge, Louisiana (2 women); however, concentrations were not specified (Pellizzari et al. 1982). Occupational exposure to 1,4-dichlorobenzene may be important in several industries associated with the production of various chlorobenzene compounds. Workers may be exposed to 1,4-dichlorobenzene during production, processing, and industrial use of the compound, including the production and ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 170 5. POTENTIAL FOR HUMAN EXPOSURE packaging of space deodorants and moth repellents (IARC 1982). Workplace air levels of 1,4-dichlorobenzene ranging up to 4,350 mg/m’ (725 ppm) were measured at facilities producing or using the compound (IARC 1982). A summary of the levels of 1,4-dichlorobenzene detected in various occupational settings is presented in Table 5-4. NIOSH estimated that about 34,000 workers were potentially exposed to 1,4-dichlorobenzene in the early 1980s (NIOSH 1990). Currently, workers in the industries identified in Table 5-4 are likely to have the highest potential for exposure to 1,4-dichlorobenzene. The current OSHA Permissible Exposure Limit (PEL) for 1,4-dichlorobenzene for an 8-hour work-day is 75 ppm (450 mg/m’) (OSHA 1989). The American Conference of Governmental Industrial Hygienists (ACGIH) also recommends a Threshold Limit Value (TLV-TWA) of 75 ppm (450 mg/m?) (ACGIH 1996). Current control technologies should limit workplace concentrations to this level. 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES In addition to individuals who are occupationally exposed to 1,4-dichlorobenzene (see Section 5.5), there are several groups within the general population that have potentially higher exposures (higher than background levels) to 1,4-dichlorobenzene than the general population. These populations include individuals living near sites where 1,4-dichlorobenzene is produced or used in manufacturing and sites where 1,4-dichlorobenzene is disposed, including the 281 NPL hazardous waste sites where 1,4-dichlorobenzene has been detected in some environmental media (HazDat 1996). Those individuals living or working near industrial facilities or hazardous waste sites with higher than average levels of 1,4-dichlorobenzene in the air would have the potential for above-average exposures. In addition, individuals using space deodorants (air fresheners), toilet block deodorants, or moth repellents (moth balls or crystal) containing 1,4-dichlorobenzene in their homes have the potential for high exposure to this compound (Scuderi 1986). Indoor air concentrations resulting from the use of these products in bathrooms and closets have been measured at levels up to 1.3 mg/m’ (0.22 ppm) (Scuderi 1986). Individuals living in proximity to hazardous waste sites may also be exposed to 1,4-dichlorobenzene via contaminated groundwater. If residential wells are the primary source of drinking water, this may pose a risk to human health via consumption of contaminated water and by increased inhalation of and ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 171 5. POTENTIAL FOR HUMAN EXPOSURE Table 5-4. Levels of 1,4-Dichlorobenzene Detected in Workplace Air Concentration (ppm) Occupation Maximum Range Monochlorobenzene manufacturing 8.63 5.48-8.63 plant Abrasive-wheel plant 16.43 7.97-16.43 Mothball manufacturing plant 24.90 8.96-24.90 Chlorobenzene manufacturing plant 33.86 23.90-33.86 1,4-Dichlorobenzene manufacturing 548 11.95-548 plant Monochlorobenzene and 722 — dichlorobenzene manufacturing plant Source: IARC 1982 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 172 5. POTENTIAL FOR HUMAN EXPOSURE dermal contact with 1,4-dichlorobenzene during showering and bathing. 1,4-Dichlorobenzene has been detected in groundwater at 182 of the 281 NPL hazardous waste sites where it was detected in some environmental media (HazDat 1996). 5.7 ADEQUACY OF THE DATABASE Section 104(1)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of 1,4-dichlorobenzene is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,4-dichlorobenzene. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Identification of Data Needs Physical and Chemical Properties. The physical and chemical properties of 1,4-dichlorobenzene are sufficiently well characterized to allow estimation of its environmental fate (Bahnick and Doucette 1988: Howard 1990; Newsom 1985; Sax and Lewis 1987; Schwarzenbach and Westall 1981; Verschueren 1983; Wilson et al.1981). On this basis, it does not appear that further research in this area is required. Production, Import/Export, Use, Release, and Disposal. Data on the production and uses of 1,4-dichlorobenzene in the United States are available (C&EN 1995a; Chemical Marketing Reporter 1990; HSDB 1996; IRPTC 1985; SRI 1996; TRI94 1996). Production has increased over the past decade and is projected to increase for the next several years due to an increased demand for 1,4-dichlorobenzene to be used in the production of polyphenylene sulfide (PPS) resins. Incineration is the recommended disposal method for 1,4-dichlorobenzene (HSDB 1996; IRPTC 1985). Disposal “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 173 5. POTENTIAL FOR HUMAN EXPOSURE of this compound is controlled by federal regulations (HSDB 1996; IRPTC 1985). Available information appears to be sufficient for assessing the potential for release of, and exposure to, 1,4-dichlorobenzene. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1994, became available in May of 1996. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Environmental Fate. The environmental fate of 1,4-dichlorobenzene has been well characterized. Its volatilization into air from other media, reaction with hydroxyl radicals in the atmosphere, transport through soil, and biodegradation by water and soil microorganisms seem to be well understood (Atkinson et al. 1985; Bouwer and McCarty 1982, 1983, 1984; Chiou et al. 1983; Cuppitt 1980; Garrison and Hill 1972; Howard 1990; Ligocki et al. 1985; Newsom 1985; Schwarzenbach and Westall 1981; Singh et al. 1981; Scuderi 1986; Spain and Nishino 1987; Tabak et al. 1981; Wakeham et al. 1983; Wilson et al. 1981). Volatilization, sorption, biodegradation, and bioaccumulation appear to be competing processes for 1,4-dichlorobenzene removal from water (Spain and Nishino 1987). Additional data on the rates of these reactions under various environmental conditions would be useful, but do not appear to be essential to understand the behavior of 1,4-dichlorobenzene in the environment. Bioavailability from Environmental Media. 1.4-Dichlorobenzene has been shown to be well absorbed by laboratory animals via inhalation and oral exposure (Hawkins et al. 1980; Kimura et al. 1979). No information has been located regarding absorption via the dermal route. Although no information has been located on the absorption of this substance from breathing contaminated air or ingesting 1,4-dichlorobenzene that is contained in soil or plant material, it is expected to be well absorbed from these media. It would be useful to have information on whether, and to what extent, absorption of 1,4-dichlorobenzene can occur as a result of dermal contact with soil or from swimming in surface water or bathing or showering in groundwater that contains 1,4-dichlorobenzene. Food Chain Bioaccumulation. Bioconcentration of 1,4-dichlorobenzene has been documented for several aquatic species (ASTER 1995; Chiou 1985; Oliver and Nicol 1982a; Oliver and Niimi 1983). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 174 5. POTENTIAL FOR HUMAN EXPOSURE Based on the relatively high K__, it appears that bioaccumulation does occur (Leo et al. 1971). Oliver ow? and Nichol (1982) measured concentrations of chlorobenzenes in sediments, water, and selected fish from the Great Lakes. Their limited fish analyses indicate that chlorobenzenes, including 1,4- dichlorobenzene, are bioconcentrated by fish, but to a much smaller extent than compounds such as DDT or PCB’s. 1,4-Dichlorobenzene has also been shown to be accumulated by terrestrial plants (Overcash et al. 1986 as cited in Wang et al. 1996; Wang et al. 1996). No data were located on biomagnification of 1,4-dichlorobenzene through terrestrial or aquatic food chains. Additional information on bioconcentration of 1,4-dichlorobenzene by commercially important fish, shellfish, and plant species and biomagnification would be helpful in evaluating the potential importance of food chain bioaccumulation to human exposure. Exposure Levels in Environmental Media. Several studies are available documenting levels of 1.4-dichlorobenzene in indoor and ambient outdoor air, water, and soil and sediments in rural, suburban, and urban areas and in the environs of hazardous waste sites (Bozzelli and Kebbekus 1979; Coniglio et al. 1980; Dressman et al. 1977; Elder et al. 1981; Fellin and Otson 1994; Harkov et al. 1984, 1985; Hauser and Bromberg 1982; IARC 1982; IJC 1989; Kediainen 1995; La Regina et al. 1986; Oliver and Nicol 1982a; Page 1981; Scuder 1986; Shah and Heyerdahl 1988; Staples et al. 1985; Wallace et al. 1986, 1989). However, since production and use of 1,4-dichlorobenzene have increased in recent years and are projected to continue increasing, it would be valuable to have more recent monitoring data to better estimate the potential for current human exposure levels from these media, especially in the vicinity of hazardous waste sites. Although there is little information on 1,4-dichlorobenzene levels in food (IARC 1982; Oliver and Niimi 1983; Page and Lacroix 1995), it does not appear that this is an important source of human exposure. However, additional data on 1,4-dichlorobenzene levels in foodstuffs, especially commercially important fish, shellfish, and plants, would be useful to confirm this assumption. Reliable monitoring data for the levels of 1,4-dichlorobenzene in contaminated media at hazardous waste sites are needed so that the information obtained on levels of 1,4-dichlorobenzene in the environment can be used in combination with the known body burdens of 1,4-dichlorobenzene to assess the potential risk of adverse health effects in populations living in the vicinity of hazardous waste sites. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 175 5. POTENTIAL FOR HUMAN EXPOSURE Exposure Levels in Humans. Detection of 1,4-dichlorobenzene in breath, adipose tissue, breast milk, and blood, can be used as indicators of human exposure (Ashley et al. 1994, 1995; EPA 1989d; Erickson et al. 1980; Hill et al. 1995; Pellizzari et al. 1982; Stanley 1986; Wallace et al. 1986). Levels of 1,4-dichlorobenzene in breath appear to provide rough estimates of recent preceding exposure (Wallace et al. 1986), while levels in adipose tissue may be useful to indicate less recent past exposure (EPA 1989d; Stanley 1986). The level of 2,5-dichlorophenol (a metabolite of 1,4-dichloro- benzene) has also been reported in urine of 1,000 individuals (Hill et al. 1995), and is highly correlated to 1,4-dichlorobenzene in blood. Additional data correlating levels in environmental media with human tissue levels, particularly for populations living in the vicinity of hazardous waste sites that contain 1,4-dichlorobenzene, would be helpful in establishing levels of the chemical to which humans have been exposed. This information is necessary for assessing the need to conduct health studies on these populations. Exposure Registries. No exposure registries for 1,4-dichlorobenzene were located. This substance is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The substance will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to exposure to this substance. 5.7.2 Ongoing Studies As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for Disease Control and Prevention, will be analyzing human blood samples for 1,4-dichloro- benzene and other volatile organic compounds. These data will give an indication of the frequency of occurrence and background levels of these compounds in the general population. No additional information was obtained from a search of Federal Research in Progress (FEDRIP 1996) that would have addressed any of the data needs identified in Section 5.7.1 for this chemical. “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 177 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting, and/or measuring, and/or monitoring 1,4-dichlorobenzene, its metabolites, and other biomarkers of exposure and effect to 1,4-dichlorobenzene. The intent is not to provide an exhaustive list of analytical methods. Rather, the intention is to identify well established methods that are used as the standard methods of analysis. Many of the analytical methods used for environmental samples are the methods approved by federal agencies and organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that modify previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL SAMPLES Methods are available for determination of 1,4-dichlorobenzene in blood, urine, tissue, and breath. Representative methods are summarized in Table 6-1. Sample preparation techniques are usually required to separate the compound of interest from the complex biological sample medium. Gas purge and solvent extraction are used most frequently to separate 1,4-dichlorobenzene from blood, urine, and tissues. The breath matrix is relatively simple and does not require preparation steps; however, special techniques such as use of a spirometer are require to provide pure air for inhalation and a mechanism for collection of exhaled air. Gas chromatography (GC) is used most frequently to detect 1,4-dichloro- benzene in biological materials. Detectors used to identify 1,4-dichlorobenzene in biological materials include the electron capture detector (ECD) (Bristol et al. 1982; Jan 1983), the photoionization detector (PID) (Langhorst and Nestrick 1979), and mass spectrometry (MS) (Ashley et al. 1992; Michael et al. 1980). ECD and PID provide some selectivity, but confirmation using a different GC column or detector is often recommended. MS provides identification as well as quantitation of analytes. Separation of 1,4-dichlorobenzene from biological samples may be accomplished by extraction with hexane (Bristol et al. 1982; Jan 1983), or carbon tetrachloride (Langhorst and Nestrick 1979), or by purging with an inert gas and trapping on a sorbent material. Solvent extraction permits concentration, thereby increasing sensitivity, but the extraction solvents can interfere with the analysis, and “**DRAFT FOR PUBLIC COMMENT*** «x LNIFWNOD O1MaNd HOH 14VHQuxx Table 6-1. Analytical Methods for Determining 1,4-Dichlorobenzene in Biological Materials Analytical Sample Percent Sample matrix Sample preparation method detection limit ~~ Recovery Reference Blood Headspace purge; thermal desorption cap. GC/MS ~3 ng/mL 86.32 IARC Method 25; Pellizzari et al. 1985 Blood Headspace purge; thermal desorption cap. GC/MS Low-ppb level 86-120 (model Michael et al. compounds) 1980 Blood Solvent extraction; silica gel column clean- GC/PID 3 ppb 89 Langhorst and up Nestrick 1979 Blood Solvent extraction GC/ECD 2 ppb 81.6 Bristol et al. 1982 Blood Purge and trap cap. GC/MS 0.04 ppb 93-98 Ashley et al. 1992 Blood, urine purge-and-trap, thermal desorption cap GC/MS No data No data Barkley et al. \ 1980 Urine Solvent extraction; silica gen column GCPID 0.75 ppb 81 Langhorst and clean-up Nestrick 1979 Urine Headspace purge; thermal desorption cap. GC/MS Low-ppb level 48-110 (model Michael et al. compounds) 1980 Adipose Tissue Maceration; headspace purge; thermal cap. GC/MS Low-ppb level 13-80 (model Michael et al. desorption compounds 1980 Human milk Headspace purge; thermal desorption GC/MS 0.6 62.9° Erickson et al. 1980 Human milk Solvent extraction; cleanup with sulfuric GC/ECD 5 ppb >80 Jan 1983 acid, Florisil Adipose tissue Solvent extraction; cleanup with sulfuric GC/ECD 146 >80 Jan 1983 acid, Florisil Tissue Maceration; headspace purge; cap. GC/MS 6 ng/g No data IARC Method thermal desorption 25; Pellizzari et al. 1985 SAOHL3W TVOILATYNY “9 INIZNIFOHOTHOIA-¥ + 8LI «=«LNIFWWOD O118Nd HOH 14VH.ux Table 6-1. Analytical Methods for Determining 1,4-Dichlorobenzene in Biological Materials (continued) Analytical Sample Percent Sample matrix Sample preparation method detection limit ~~ Recovery Reference Breath Collection using a spirometer; adsorption GC/MS No data No data Barkley et al. on Tenax traps; thermal desorption cap 1980 Breath Collection into canisters using spirometer; cap. GC/MS-SIM low-pg/m® 49-80 Thomas et al. cryofocussing; thermal desorption levels 1991 a Value is for m-dichlorobenzene b Value is for chlorobenzene cap. = capillary; ECD = electron capture device; GC = gas chromatography; MS = mass spectrometry; SIM = selected ion monitoring SAOHL3IW TVOILATVNY 9 INIZNIGOHOTHOIA-v + 6L1 1,4-DICHLOROBENZENE 180 6. ANALYTICAL METHODS evaporative losses can result in low recovery. Gas purge techniques may be static (headspace) or dynamic (purge-and-trap). The static headspace technique is relatively simple, but may be less sensitive than the purge-and-trap method. The purge-and-trap method, while providing increased sensitivity, requires more complex instrumentation and may result in artifact formation (Seto 1994). Although a variety of methods are available for determination of 1,4-dichlorobenzene, few are well characterized and validated. A method has been developed which utilizes headspace purge followed by thermal desorption of the trapped, purged analytes. 1,4-Dichlorobenzene is determined by capillary GC/MS (Michael et al. 1980; Pellizzari et al. 1985). Recovery is very good (>85%) and detection limits are in the low-ppb range for model compounds (Michael et al. 1980; Pellizzari et al. 1985). Performance data are not available for 1,4-dichlorobenzene. A sensitive and reliable method for identification and quantitation of 1,4-dichlorobenzene in samples of whole blood has been developed by Ashley and coworkers at the Centers for Disease Control (CDC) (Ashley et al. 1992). The method involves purge-and-trap of a 10 mL blood sample with analysis by capillary GC/high resolution MS. Anti-foam procedures are utilized as well as special efforts to remove background levels of volatile organic compounds (VOCs) from reagents and equipment. The method is sensitive enough (ppt levels) to determine background levels of VOCs in the population and provides adequate accuracy (93-98% recovery) and precision (21% RSD) for monitoring 1,4-dichlorobenzene in the general population. Methods are available for monitoring 1,4-dichlorobenzene in urine and tissues, particularly adipose tissue and mother's milk. Solvent extraction, silica gel column clean-up, and GC/ECD or GC/PID analysis has been used for urine (Langhorst and Nestrick 1979), mother's milk (Jan 1983), and adipose tissue (Jan 1983). Recovery is good (>80% recovery) and detection limits are in the low-ppb range (Jan 1983; Langhorst and Nestrick 1979). Headspace purge, followed by capillarity GC/MS analysis has been utilized for urine (Michael et al. 1980), mother's milk (Erickson et al. 1980), and tissue (Pellizzari 1985). Recovery, where reported, is adequate (>60%) (Erickson et al. 1980), and detection limits are in the low-ppb range (Erickson et al. 1980). Breath samples are usually collected on a sorbent cartridge (Barkley et al. 1980) or into passivated canisters (Thomas et al. 1991). Analytes are concentrated cryogenically directly from the canister or after thermal desorption from the sorbent, then analyzed by GC/MS. Recovery using Tenax cartridges is 87-101%, precision for side-by-side samples is <30% RSD, and the detection limit is =1 g/m’ ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 181 6. ANALYTICAL METHODS (Wallace 1987). The method is sufficiently sensitive and reliable for monitoring exposure to 1,4-dichlorobenzene. Recovery for collection in canisters is 49-80%, precision is <20% and the detection limits are in the low-pg/m’ range (Thomas et al. 1991). The spirometer system utilizing canisters is compact, and may be useful as a field screening method (Thomas et al. 1991). 6.2 ENVIRONMENTAL SAMPLES Methods are available for determining 1,4-dichlorobenzene in a variety of environmental matrices. A summary of representative methods is shown in Table 6-2. Validated methods, approved by agencies and organizations such as EPA, ASTM, APHA, and NIOSH, are available for air, water, and solid waste matrices. These methods for analysis of drinking water, waste water, and soil/sediment samples are included in Table 6-2.. Many of the APHA methods (1995) and ASTM methods (1994) for water are equivalent to the EPA methods. GC is the most widely used analytical technique for quantifying concentrations of 1,4-dichlorobenzene in environmental matrices. Various detection devices used for GC include the flame ionization detector (FID), ECD, Hall electroconductivity detector (HECD), and PID. Confirmation using a second column is usually recommended. MS provides identification as well quantitation for GC analysis. Because of the complexity of the sample matrix and the usually low concentrations of VOCs in environmental media, sample concentration is generally required prior to GC analysis. Methods suitable for determining trace amounts of 1,4-dichlorobenzene in aqueous and other environmental media include three basic approaches to the pretreatment of the sample: gas purge-and-trap technique, headspace-gas extraction, and extraction with solvent. Charcoal adsorbent is used for collection of 1,4-dichlorobenzene in occupational air. The compounds are desorbed with carbon disulfide and analyzed by GC/FID. The method is sufficiently sensitive and reliable for determining occupational exposure to 1,4-dichlorobenzene (NIOSH 1994). Ambient air samples are collected on adsorbents such as Tenax (Wallace 1987), or multisorbent (Heavner et al. 1992; Oliver et al. 1996), or in passivated canisters (EPA 1988a). Tenax traps are thermally desorbed, concentrated cryogenically, and analyzed by capillary GC/MS (Wallace et al. 1987). Recovery is good (81-110%), precision for side-by-side samples is acceptable (9-45% RSD), and the detection limit is =1 pg/m’ (Wallace 1987). Multisorbent traps are solvent desorbed and ***DRAFT FOR PUBLIC COMMENT*** «x INIFWWOO O118Nd HOH 14VYHA..« Table 6-2. Analytical Methods for Determining 1,4-Dichlorobenzene in Environmental Samples Analytical Sample Sample matrix Sample preparation method detection Accuracy Reference Occupational Air Collection on charcoal tubes; GC/FID 0.01 mg/ +125 Method 1003 desorption with CS, sample? NIOSH 1994 Ambient air Collection in canisters; cap. GC with No data No data Method TO-14 cryofocussing; thermal desorption FID, ECD or MS EPA 1988a Air—emissions MM5 sampling train (condensate, cap. GC/MS No data Bias -13 to -16 Method 0010 sources filter, adsorbent); condensate, for selected EPA 1994f impinger and rinses, solvent compounds extraction, evaporation; XAD-2 adsorbent and filters, Soxhlet extraction, concentration Air—emission VOST sampling train (sorbent GC/MS No data No data Method 0030 sources traps); thermal desorption EPA 19949 Drinking water Purge and trap GC/HECD; conf. <0.01 pg/L for 90 Method 502.1 on second col. most VOCs EPA 1991a or GC/MS Drinking water Purge and trap GC/PID-HECD; 0.01-0.03 ug/L 97-103 (PID); Method 502.2 Drinking water Drinking water Purge and trap Purge and trap conf. by GC/MS GC/PID; conf. on second col. or GC/MS cap. GC/MS (PID); 0.01-0.04 pg/L (HECD) 0.006 pg/L 0.03-0.04 pg/L 97-98 (HECD) 91-107 93-103 EPA 1991b Method 503.1 EPA 1991c Method 524.2 EPA 1992a SAOHL3NW TVOILATIVNY 9 INIZNIEOHOTHOIA-¥'} [4:1 «LNINWOD O1M8Nd HOH 14VHQ.xx Table 6-2. Analytical Methods for Determining 1,4-Dichlorobenzene in Environmental Samples (continued) Analytical Sample Sample matrix Sample preparation method detection Accuracy Reference Waste water Purge and trap GC/HECD; conf. 0.24 pg/L 97.5 Method 601 on second col. EPA 1984a or GC/MS Waste water Purge and trap GC/PID; conf. 0.3 pg/L 120 Method 602 on second col. EPA 1984b or GC/MS Waste water Solvent extraction; optional Florisil GC/ECD 1.34 pg/L 89 Method 612 column clean-up EPA 1984c Waste water Purge and trap GC/MS No data No data Method 624 EPA 1984d Waste water Purge and trap GC/MS Not reported Not reported Method 6210 B APHA 1995a Waste water Purge and trap GC/MS 0.1-0.5 pg/L 105 Method 6210 C (all VOCs) APHA 1995b Waste water Purge and trap cap. GC/MS 0.02-0.2 ug/L 103-106 Method 6210 D (all VOCs) APHA 1995¢ Waste water Purge and trap GC/PID; conf. 0.3 pg/L Method 6220 B on second col. APHA 1995d Waste water Purge and trap GC/PID 0.01-0.05 pg/L 91-107 Method 6220 C Waste water Purge and trap GC/HECD; conf. on second col. (all VOCs) 0.24 pg/L APHA 1995e Method 6230 B APHA 1995f SAOHL3IW TVOILATYNY 9 INIZNIGOHOTHOIa-¥'} £81 «INIWWOD O1M18Nd HOS L4VH..x Table 6-2. Analytical Methods for Determining 1,4-Dichlorobenzene in Environmental Samples (continued) Analytical Sample Sample matrix Sample preparation method detection Accuracy Reference Drinking water Purge and trap GC/HECD 0.01-0.05 pg/L 90 Method 6230 C (optional PID); APHA 1995¢g conf. on second col. Drinking water Purge and trap cap. GC/PID, Not reported 103 (PID); 98 Method 6230 D HECD (HECD) APHA 1995h Drinking water Purge and trap GC low pg/L 99 (all VOCs) Method D 3871 ASTM 1994 Solid waste Purge and trap or direct injection GC/HECD; conf. Not reported =90 Method 5030A on second col. EPA 19943; Method 8010B EPA 1994b Solid waste Purge and trap or direct injection GC/PID; conf. 3-250 ppb =90 Method 8020A on second col. (purge and EPA 1994c trap) Solid waste Purge and trap or direct injection cap. GC/HECD, 0.1-5 pg/L 91 (HECD); 108 Method 8021A PID (HECD); (PID) EPA 1994d 0.07-3.5 (PID) Solid Waste Various injection options GC/ECD 13.4-900 pg/L Not reported Method 8120A EPA 1994e Solid waste Purge and trap cap. GC/MS 1-15 pg/L 103-106 Method 8260A EPA 1994f SAOHL3W TVOILATYNY ‘9 INIZNIGOHOTHOIa-v't cap. = capillary; conf. = confirmation; col. = column; ECD = electron capture detector; FID = flame ionization detector; GC = gas chromatography; HECD = Hall electrolytic conductivity detector; MS = mass spectrometry; PED= photoionization detector; VOC = volatile organic compound v8 1,4-DICHLOROBENZENE 185 6. ANALYTICAL METHODS analyzed by capillary GC/MS. Recovery and precision are good and detection limits as low as 0.019 ppb have been reported (Oliver et al. 1996). Collection of air samples in passivated stainless steel canisters is also widely utilized (EPA 1988a), but performance data are unavailable. Passive sampling devices are also widely used, due in part to their ease of use and small size (Lewis et al. 1985). For water, soil, or sediment samples, 1,4-dichlorobenzene is purged from the sample with an inert gas such as helium or nitrogen, and then passed through the sorbent (EPA 1984a, 1984b, 1991a, 1991b, 1991c, 1992a, 1994a, 1994f). The analytes are thermally desorbed and analyzed by GC/HECD, GC/PID, GC/ECD, or GC/MS techniques. Detection limits for waste waters and solid wastes are in the low-ppb range, which is probably well below levels of health concern. Detection limits for drinking water samples are in the ppt range (0.006-0.04 pg/L) (EPA 1991a, 1991b, 1991c, 1992a). Several physical parameters may interfere with analytical accuracy. High sampling flow rates and high temperature and humidity may cause decreased adsorption of 1,4-dichlorobenzene vapor on the solid sorbent (APHA 1995a). Interference by other VOCs with similar retention times may be resolved by using different GC column materials and temperatures. The use of capillary columns rather than packed column GC has improved resolution and sensitivity and shortened the analysis time (Washall and Wampler 1988). However, more stringent sample clean- up procedures are required for capillary column GC (Oliver and Nicol 1982b). The development of methods using whole column cryotrapping (Pankow and Rosen 1988; Pankow et al. 1988) and cryogenic refocusing (Washall and Wampler 1988) provide even greater sensitivity and resolution. 6.3 ADEQUACY OF THE DATABASE Section 104(1)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of 1,4-dichlorobenzene is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of 1,4-dichlorobenzene. ***DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 186 6. ANALYTICAL METHODS The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Exposure to 1,4-dichloro- benzene may be evaluated by measuring the levels of this compound in blood, breath, milk, and adipose tissue, and by measuring the level of 2,5-dichlorophenol, a metabolite of 1,4-dichlorobenzene, in urine (Bristol et al. 1982; Erickson et al. 1980; Jan 1983; Langhorst and Nestrick 1979; Pellizzari et al. 1985). Sensitive analytical methods are available for measurements in blood. Additional performance data would be helpful. Development of methods with improved specificity and sensitivity for other tissues and breath would be valuable in identifying individuals with low-level exposure. Development of standardized procedures would permit comparison of data and facilitate the study of correlations between exposure and measured levels biological samples. There are no known health effects such as elevated liver enzymes that are uniquely associated with exposure to 1,4-dichlorobenzene. Therefore, the identification of specific health effects and the development of analytical methods to determine biomarkers of effect for 1,4-dichlorobenzene would be useful. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Air is the environmental medium of most concern for human exposure to 1,4-dichloro- benzene. Exposure from drinking water may also be of concern in some areas, such as near hazardous waste sites. Existing analytical methods can measure 1,4-dichlorobenzene in these and other environmental media at background levels (EPA 1988a, 1984a, 1984b, 1991a, 1991b, 1991c, 1992a, 1994a, 1994f; NIOSH 1994). The accuracy and precision of the methods are well documented and MS provides adequate specificity. Development of techniques to improve the accuracy and ease of sample preparation, and transfer for these methods would be helpful. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 187 6. ANALYTICAL METHODS 6.3.2 Ongoing Studies The Environmental Health Laboratory Sciences Division of the National Center for Environmental Health, Centers for Disease Control and Prevention, is developing methods for the analysis of 1,4-dichlorobenzene and other volatile organic compounds in blood. These methods use purge and trap methodology, high resolution gas chromatography, and magnetic sector mass spectrometry which gives detection limits in the low parts per trillion (ppt) range. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 189 7. REGULATIONS AND ADVISORIES The national and state regulations and guidelines pertaining to 1,4-dichlorobenzene in air, water, and other media are summarized in Table 7-1. ATSDR has derived an acute inhalation MRL of 0.8 ppm for 1,4-dichlorobenzene based on a NOAEL of 300 ppm based on the absence of significant developmental effects in rabbits (Hayes et al. 1985). ATSDR has derived an intermediate-duration (15 to 364 days) inhalation MRL of 0.2 ppm for 1,4-dichloro- benzene based on a NOAEL for the absence of liver effects in rats (Hollingsworth et al. 1956). ATSDR has derived a chronic-duration (365 days or more) inhalation MRL of 0.1 ppm for 1,4-dichloro- benzene based on based on the absence of liver effects in rats (Riley et al. 1980). ATSDR has derived an intermediate duration (15 to 364 days) oral MRL of 0.1 mg/kg/day for 1,4-dichlorobenzene based on a NOAEL for the absence of liver effects in rats (Hollingsworth et al. 1956). The EPA inhalation reference concentration (RfC) for 1,4-dichlorobenzene is 0.8 mg/m? (IRIS 1996). EPA’s Office of Water notes a reference dose concentration of 0.1 mg/kg/day in its health advisory for 1,4-dichloro- benzene (EPA 1996). The health advisory from EPA’s Office of Water also classifies 1,4-dichlorobenzene as C (possibly carcinogenic to humans) (EPA 1996). The International Agency for Research on Cancer (IARC) has classified 1,4-dichlorobenzene as a Group 2B carcinogen; possibly carcinogenic to humans (IARC 1987). The American Conference of Governmental Industrial Hygienists (ACGIH) classifies 1,4-dichlorobenzene as A3 which indicates that the chemical is carcinogenic in experimental animals when administered at a relatively high dose (ACGIH 1996). Studies conducted by the National Toxicology Program showed clear evidence of carcinogenicity in male rats and both male and female mice (NTP 1995). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 190 7. REGULATIONS AND ADVISORIES 1,4-Dichlorobenzene is on the list of chemicals subject to the requirements of “The Emergency Planning and Community Right-to-Know Act of 1986 [EPCRA] (EPA 1988c). Section 313 of Title III of EPCRA, requires owners and operators of certain facilities that manufacture, import, process, or otherwise use the chemicals on this list to report annually their release of those chemicals to any environmental media (U.S. Congress 1986). OSHA requires employers of workers who are occupationally exposed to 1,4-dichlorobenzene to institute engineering controls and work practices to reduce and maintain employee exposure at or below the permissible exposure limit (PEL). The employer must use controls and practice, if feasible, to reduce exposure to or below an 8-hour time-weighted average (TWA) of 75 ppm (OSHA 1974). The 8-hour TWA is applicable to any 8-hour shift of a 40-hour work week. OSHA has not established a ceiling value; an exposure limit which must not be exceeded at any time for 1,4- dichlorobenzene. The EPA regulates 1,4-dichlorobenzene under the Clean Air Act (CAA) and has designated 1,4-dichlorobenzene as a hazardous air pollutant (HAP) (U.S. Congress 1990, EPA 19941). The major source category for which 1,4-dichlorobenzene emissions are controlled is the synthetic organic chemicals manufacturing industry (SOCMI)—equipment leaks (EPA 1983a) and process vents, storage vessels, transfer operations, and waste water (EPA 1994). 1,4-Dichlorobenzene is regulated by the Clean Water Effluent Guidelines in Subchapter N of Title 40 of the Code of Federal Regulations. Electroplating is the points source category for which 1,4-dichlorobenzene is controlled as a total toxic organic (EPA 1981b). The point source categories for which 1,4-dichlorobenzene has a specific regulatory limitation include steam electric power generation (EPA 1982d), metal finishing (EPA 1983d), and organic chemicals, plastics, and synthetic fibers (EPA 1987c through EPA 1987k). The World Health Organization (WHO) has not established a recommended drinking-water guideline value for chlorobenzenes. WHO guideline values are indicators of tolerable concentrations for drinking water, but are not to be interpreted as defining target levels for water quality. Where aesthetic properties are concerned, the WHO recommends a threshold odor concentration of 1 pg/L for 1,4-dichlorobenzene (WHO 1984). The Resource Conservation and Recovery Act (RCRA) identifies 1,4-dichlorobenzene as the hazardous constituent in various hazardous wastes. 1,4-Dichlorobenzene is the basis for listing waste assigned ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 191 7. REGULATIONS AND ADVISORIES the hazardous waste codes F024 and F025 (EPA 1981c). It is also the regulated constituent in hazardous wastes assigned the waste codes F039 and U072 (EPA 1988b). The treatment standard for waste water containing 1,4-dichlorobenzene is 0.090 mg/L. For nonwaste water the treatment standard for 1,4-dichlorobenzene is 6.0 mg/kg (EPA 1997) Under the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) owners of vessels or facilities are required to immediately report release of 1,4-dichlorobenzene equal to or greater than the reportable quantity of 100 pounds (45.4 kg) (EPA 1985b). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 7. REGULATIONS AND ADVISORIES 192 Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene Agency Description Information References INTERNATIONAL Guidelines: Carcinogenic classification Group 2B? IARC 1987 IARC WHO Drinking-water guideline values None WHO 1984 for health-related organics Aesthetic quality threshold odor 1 pg/L concentration NATIONAL Regulations: a. Air: OSHA Air contaminants Permissible exposure limit 75 ppm (450 mg/m3) 29 CFR 1910.1000 (PEL) 8-hr. Time weighted OSHA 1974° average (TWA) Vacated 1989 OSHA Short- 110 ppm (675 mg/m®) NIOSH 1994 term exposure limit (STEL) EPA OAR Hazardous Air Pollutants Yes Clean Air Act Amendment Standards of Performance for New Stationary Sources- Subpart VV: Equipment leaks Yes of VOCs in the Synthetic Organic Chemicals Manufacturing Industry (SOCMI)--chemicals produced by affected facilities National Emission Standards for Hazardous Air Pollutants for Source Categories Subpart F: National Emission Yes Standards for Organic Hazardous Air Pollution from the Synthetic Organic Chemical Manufacturing Industry Subpart G: National Emission Yes Standards for Organic Hazardous Air Pollutants from the SOCMI for Process Vents, Storage Vessels, Transfer Operations, and Wastewater ***DRAFT FOR PUBLIC COMMENT*** Title Ill, Section 112 (b) U.S. Congress 1990 40 CFR 60.489 EPA 1983a 40 CFR 63.106 EPA 1994i 40 CFR 63.110, Appendix, Table 9 EPA 1994 1,4-DICHLOROBENZENE 193 7. REGULATIONS AND ADVISORIES Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) b. Water EPA ODW National Primary Drinking Water Regulations Subpart D: Reporting, Public notification and Recordkeeping Enforceable drinking water 40 CFR 141.32 standard 0.075 ppm EPA 1987b Subpart G: National Revised Primary Drinking Water regulations Maximum contaminant levels for organic chemicals ~~ 0.075 mg/L 40 CFR 141.61 EPA 1991j BAT for organic contaminants listed in 40 GAC 40 CFR 141.61 CFR 141.61 (a) and (9) PTA EPA 1991j National Primary Drinking Water Regulations Implementation Subpart G: Identification of best technology, treatment techniques or other means generally available Variances and exemptions Yes 40 CFR 142.62 from the maximum EPA 1991k contaminant levels for organic and inorganic chemicals EPA OW Designation of Hazardous Substances List of hazardous substances Yes 40 CFR 116.4 EPA 1978 Determination of Reportable Quantities for Hazardous Substances RQ of hazardous substances 100 pounds 40 CFR 117.3 designated pursuant to (45.4 kg) EPA 1985b Section 311 of the CWA (dichlorobenzene) EPA Administered Permit Programs: The NPDES- Organic toxic pollutants in Yes 40 CFR 122, App. D each of four fractions in EPA 1983c analysis by GC/MS Criteria and Standards for the NPDES- ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 7. REGULATIONS AND ADVISORIES 194 Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) Instructions for Form 2C, Yes 40 CFR 125 application for permit to EPA 1984a discharge wastewater-- hazardous substances (dichlorobenzenes) Methods for organic chemical Yes 40 CFR 136, App. A analysis of municipal and EPA 1984b industrial wastewater (Methods 601, 602, 612, 624, and 1625) Designated as a toxic pollutant Yes 40 CFR 401.15 under Section 307 (a)(1) of the EPA 1979 Federal Water Pollution Control Act General pretreatment regulations for existing and new sources of pollution- 40 CFR 403, App. B List of toxic pollutants Yes EPA 1986d Electroplating Point Source Category- General definition Yes 40 CFR 413.02 EPA 1981b Organic Chemicals, Plastics, and Synthetic fibers Subpart B-Rayon Fibers-PSES Maximum for any one day 380 pg/L 40 CFR 414.25 Maximum for monthly 142 pg/L EPA 1987c average Subpart C-Other Fibers-PSES Maximum for any one day 380 pg/L 40 CFR 414.35 Maximum for monthly 142 pg/L EPA 1987 d average Subpart D-Thermoplastic Resins-PSES Maximum for any one day 380 pg/L 40 CFR 414.45 Maximum for monthly 142 pg/L EPA 1987e average Subpart E-Thermosetting Resins 380 pg/L 40 CFR 414.55 Maximum for any one day 142 pg/L EPA 1987f Maximum for monthly average Subpart F-Commodity Organic Chemicals Maximum for any one day 380 pg/L 40 CFR 414.65 Maximum for monthly 142 pg/L EPA 1987g average ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 195 7. REGULATIONS AND ADVISORIES Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) Subpart G-Bulk Organic Chemicals-PSES Maximum for any one day 380 pg/L 40 CFR 414.75 Maximum for monthly 142 pg/L EPA 1987h average Subpart H-Speciality Organic Chemicals--PSES Maximum for any one day 380 pg/L 40 CFR 414.85 Maximum for monthly 142 pg/L EPA 1987i average Subpart I-Direct Discharge Point Sources that Use End- of-Pipe Biological Treatment- effluent limitations: BAT and NSPS Maximum for any one day 28 pg/L 40 CFR 414.91 Maximum for monthly 15 pg/L EPA 1987] average Subpart J-Direct Discharge Point Source That Do Not Use End-of Pipe Biological Treatment-effluent limitations: BAT and NSPS Maximum for any one day 380 pg/L 40 CFR 414.101 Maximum for monthly 142 pg/L EPA 1987k average Steam Electric Power Generating Point Source Category Pretreatment standards for new sources (PSNS) Maximum for any time 0 mg/L 40 CFR 423.17 EPA 1982d List of 126 priority pollutants Yes 40 CFR 423, App. A EPA 1982d Metal Finishing Point Source Category Metal finishing subcategory- Yes 40 CFR 433.11 Definition of total toxic EPA 1983d organics (TTO) Pesticide Chemicals Subpart D-Test Methods for Pesticide Pollutants BAT and NSPS effluent limitations for priority pollutants for direct discharge point sources that use end-of-pipe biological treatment Daily maximum 28 pg/L 40 CFR 455.50, Monthly average 15 pg/L Table 4 EPA 1993 ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 7. REGULATIONS AND ADVISORIES 196 Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) BAT and NSPS effluent limitations for priority pollutants for direct discharge point sources that do not use end-of-pipe biological treatment Daily maximum 380 pg/L 40 CFR 455.50, Monthly average 142 pg/L Table 5 EPA 1993 PSES and PSNS for priority pollutants Daily maximum 380 pg/L 40 CFR 455.50, Monthly average 142 pg/L Table 6 EPA 1993 Ambient Water Quality Criteria For the Protection of Human Health: 0.04 pg/L IRIS 1996 c. Other: DOT EPA-OERR EPA-OSW Ingestion of water and aquatic organisms Ingestion of fish only Hazardous Materials Table Hazardous Substances Other Than Radionuclides: RQ List of Marine Pollutants List of Hazardous Substances and Reportable Quantities Toxic Chemical Release Reporting: Community Right-to- know Specific toxic Chemical Listings Criteria for Classification of Solid Waste Disposal Facilities and Practices Maximum contaminant levels promulgated under the Safe Drinking Water Act 2.0x10*2 pg/L UN 1592 100 pounds (45.4 kg) Yes 100 pounds (45.4 kg) (statutory) 100 pounds (45.4 kg) (final RQ) Yes 0.075 mg/L "**DRAFT FOR PUBLIC COMMENT*** 49 CFR 172.101 DOT 1990a 49 CFR 172.101, App. A DOT 1990b 49 CFR 172.101, App. B DOT 1990c 40 CFR 302.4 EPA 1985¢c 40 CFR 372.65 EPA 1988c 40 CFR 257, App. | EPA 1991] 1,4-DICHLOROBENZENE 197 7. REGULATIONS AND ADVISORIES Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) Criteria for Municipal Solid Waste Landfills Constituents for detection Yes 40 CFR 258, App. | monitoring EPA 1991d List of hazardous inorganic Yes 40 CFR 258, App. Il and organic constituents EPA 1991e Identification and Listing of Hazardous Wastes Subpart B: Criteria for Identifying the Characteristics of Hazardous Waste and for Listing Hazardous Waste Maximum concentrations of 7.5 mg/L (regulatory level) ~~ 40 CFR 261.24 contaminants for the toxicity EPA 1990a characteristic Subpart D: Lists of Hazardous Wastes Discarded commercial Yes 40 CFR 261.33 products, off-specification EPA 1980b species, container residues, and spill residues Chemical Analysis Test Yes 40 CFR 261, App. lll Methods EPA 1983e Basis for Listing Hazardous F024, F025 40 CFR 261, App. VII Waste EPA 1981c Hazardous Constituents uo72 40 CFR 261, App. Vill EPA 1988b Standards for Owners and Operators of Hazardous Waste Treatment, Storage, and Disposal Facilities 40 CFR 264, App. IX Ground-water monitoring list Yes EPA 19871 Standards for the Management of Specific Hazardous Wastes and Specific Types of Hazardous Waste Management Facilities Reference air concentrations 10 mg/m® 40 CFR 266, App. IV EPA 1991f Health-based limits for 7.5x10 2 40 CFR 266, App. VII exclusion of waste-derived EPA 1991g residues Land Disposal Restrictions- ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 7. REGULATIONS AND ADVISORIES 198 Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) Subpart B: Schedule for land Yes 40 CFR 268.12 disposal prohibition and EPA 1986e establishment of treatment standards Subpart C: Prohibitions on Yes 40 CFR 268.35 land disposal EPA 1990b Subpart D: Treatment Wastewater 62 FR 7502 standards for hazardous waste 0.090 mg/L EPA 1997 (regulated constituent FO39 __Nonwastewater and U072 wastes)--Technical 6.0 mg/kg amendment to final rule: 40 CFR 268.40 Universal treatment standards- Wastewater 62 FR 7502 -Technical amendment to final 0.090 mg/L EPA 1997 rule: 40 CFR 268.40 Nonwastewater 6.0 mg/kg List of halogenated organic Yes 40 CFR 268, App. lll compounds regulated under EPA 1987m 268,32 Organometallic lab packs Yes 40 CFR 268, App IV EPA 1991h EPA OPPTS Chemical Information Rules Chemical lists and reporting Yes 40 CFR 712.30 periods EPA 1982b Health and Safety Data Reporting Affected substances and Yes 40 CFR 716.120 mixtures EPA 1988d Guidelines: a: Air: ACGIH Permissible Exposure Limit 10 ppm ACGIH 1996 (PEL)-Time-weighted Average (60 mg/m?) (TWA) NIOSH Recommended Exposure Limit for 1.7 ppm LOQ NIOSH 1992 Occupation Exposure b. Water: EPA OW 1-d Health Advisory (child)-draft 10 mg/L EPA 1996 10-d Health Advisory (child)-draft 10 mg/L Lifetime Health Advisory (adult)- 0.075 mg/L Longer-term Health Advisory-draft ~~ 10 mg/L (child) RD Maximum contaminant level (MCL) 40 mg/L (adult) 0.1 mg/kg/day 0.075 mg/L ""*DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 7. REGULATIONS AND ADVISORIES 199 Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References NATIONAL (cont.) Maximum contaminant level goals ~~ 0.075 mg/L (MCLGs) for organic contaminants Ambient Water Quality Criteria for IRIS 1996 Human Health water and fish 0.4 mg/L fish only 2.6 mg/L d. Other: ACGIH Chemical Substance and other Yes ACGIH 1996 Issues Under Study Cancer classification A3°¢ EPA Cancer classification &3 EPA 1996 STATE Regulations and Guidelines: a. Air: Average Acceptable Ambient Air NATICH 1992 Concentrations AZ 1 hour 2.5x10*2 pg/m® 24 hours 6.6x10*" pg/m® Annual 1.8x107" pg/m?3 CT 8 hours 9.00x10*2 pg/m3 FL-Pinella 8 hours 4.5x10*° pg/m® 24 hours 1.08x10*3 pg/m® Annual 7.00x10™" pg/m?® IN 8 hours 2.25x10*3 pg/m® LA 8 hours 1.07x10%* pg/m3 MA 24 hours 1.25x10"2 pg/m® Annual 1.8x107" pg/m?3 NC 15 minutes 6.6x10*" mg/m? NC-Forsyth County 15 minutes 6.6 mg/m ND 1 hour 6.61 mg/m° 8 hours 4.51 mg/m? NV 8 hours 1.07x10*" mg/m? OK 24 hours 9.0x10*3 pg/m® sc 24 hours 4.50x10*% pg/m?® TX 30 minutes 1.08x10*3 g/m Annual 4.50x10%2 pg/m?® VA 24 hours 7.50x10*3 g/m? ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 200 7. REGULATIONS AND ADVISORIES Table 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene (continued) Agency Description Information References STATE (cont) WA-SWEST 24 hours 1.50x10*3 pg/m?3 b. Water Water Quality Criteria: Human Health AL Drinking water (standard) 75 pg/L FSTRAC 1995 AZ Drinking water (guideline) 75 pg/L CA Drinking water (standard) 5 pg/L CT Drinking water (guideline) 75 pg/L MA Drinking water (guideline) 5 pg/L ME Drinking water (guideline) 27 pg/L MN Drinking water (guideline) 10 pg/L WI Drinking water (standard) 75 pg/L Group 2B defines the agent as possibly carcinogenic to humans. The category is generally used for agents for which there is limited evidence in humans in the absence of sufficient evidence in experimental animals. A U.S. Court of Appeals rescinded the 1989 PELs promulgated by OSHA. Only PELs in place prior to the 1989 rule are currently allowed (58 FR 335338). Cancer classification A3 indicates that the agent is carcinogenic in experimental animals at a relatively high dose. Chemicals in cancer category C are considered possible human carcinogens. There is limited evidence from animal studies and inadequate or no data in humans ACGIH = American Conference of Governmental Industrial Hygienists; BAT = Best Available Technology Economically Achievable; CFR = Code of Federal Regulations; CWA = Clean Water Act; DOT = Department of transportation; EPA = Environmental Protection Agency; FSTRAC = Federal State Toxicology and Regulatory Alliance committee; IARC = International Agency for Research on Cancer; LOQ = Limit of Quantitation; MCL = Maximum contaminant Level; MCLG = Maximum Contaminant Level Goal; NATICH = National Air Toxics Information Clearinghouse; NIOSH = National Institute of Occupational Safety and Health; NPDES = National Pollution Discharge Elimination System; NSPS = New Source Performance Standards; OAR = Office of Air and Radiation; ODW = Office of Drinking Water; OERR = Office of Emergency and Remedial Response; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Wastes; OPPTS = Office of Prevention, Pesticides, and Toxic Substances; OW = Office of Water; PTA = Packed Tower Aeration; PEL = Permissible Exposure Limit; PSES = Pretreatment Standards for Existing Sources; PSNS = Pretreatment Standards for New Sources; RfD = Reference Dose; RQ = Reportable Quantities; SOCMI = Synthetic Organic Chemicals Manufacturing Industry; STEL = Short-term exposure Limit; TTO = Total Toxic Organic; TWA = Time-weighted Average; VOC = Volatile Organic Compound; WHO = World Health Organization “**DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 201 8. 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Mutat Res 116:217-238. Shiraishi H, Pilkington NH, Otsuki A, et al. 1985. Occurrance of chlorinated polynuclear aromatic hydrocarbons in tap water. Environ Sci Technol 19:585-590. Simmon VF, Riccio ES, Peirce MV. 1979. In vitro microbiological genotoxicity tests of chlorobenzene, m-dichlorobenzene, o-dichlorobenzene, and p-dichlorobenzene. Final Report. Report to U.S. Environmental Protection Agency by SRI International, Menlo Park, CA. U.S. EPA contract no. 68-02-2947. Singh HB, Salas LJ, Smith A, et al. 1980. Atmospheric measurements of selected hazardous organic chemicals. Report to U.S. Environmental Protection Agency, Environmental Sciences Research Laboratory, Research Triangle Park, NC, by SRI International, Menlo Park, CA. *Singh HB, Salas LJ, Smith AJ et al. 1981. Measurements of some potentially hazardous organic chemicals in urban atmospheres. Atmos Environ 15:601-612. *Sittig M. 1985. Handbook of toxic and hazardous chemicals and carcinogens. 2nd ed. Park Ridge, NJ: Noyes Publications, 313-316. *Spain JC, Nishino SF. 1987. Degradation of 1,4-dichlorobenzene by a Pseudomonas sp. Appl Environ Microbiol 53:1010-1019. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 225 8. REFERENCES Spicer CW, Riggin RM, Holdren MW, et al. 1985. Atmospheric reaction products from hazardous air pollutant degradation. Report to U.S. Environmental Protection Agency, Office of Research and Development, Research Triangle Park, NC, by Battelle Columbus Laboratories, Columbus, OH. EPA/600/3-85/028. NTIS no. PB85-185841. SRI. 1987. Directory of chemical producers: United States of America. Menlo Park, CA: SRI International, 568-569. SRI. 1988. Directory of chemical producers: United States of America. Menlo Park, CA: SRI International, 559. SRI. 1989. Directory of chemical producers: United States of America. Menlo Park, CA: SRI International, 558. *SRI. 1990. Directory of chemical producers: United States of America. Menlo Park, CA: SRI International, 561. *Srivastava LM. 1966. Induction of mitotic abnormalities in certain genera of tribe Vicieae by paradichlorobenzene. Cytologia 31:166-171. *Stanley JS. 1986. Broad scan analysis of the FY 82 National Human Adipose Tissue Survey specimens. Vol. I - Executive Summary. Report to U.S. Environmental Protection Agency, Office of Toxic Substances, Washington, DC, by Midwest Research Institute, Kansas City, MO. EPA-560/5-86-035. *Staples CA, Werner AF, Hoogheen TJ. 1985. Assessment of priority pollutant concentrations in the United States using STORET database. Environ Toxicol Chem 4:131-142. *Steinmetz KL, Spanggord RJ. 1987a. Examination of the potential of p-dichlorobenzene to induce unscheduled DNA synthesis or DNA replication in the in vivo - in vitro mouse hepatocyte DNA repair assay. *Steinmetz KL, Spanggord RJ. 1987b. Evaluation of the potential of p-dichlorobenzene to induce unscheduled DNA synthesis or DNA replication in the in vivo - in vitro rat kidney DNA repair assay. *Stine ER, Gunawardhana L, Sipes IG. 1991. The acute hepatotoxicity of the isomers of dichlorobenzene in Fischer 344 and Sprague-Dawley rats: Isomer specific and strain specific differential toxicity. Toxicol Appl Pharmacol 109:472-481. Symons JM, Bellar TA, Carswell JK, et al. 1975. National organics reconnaissance survey for halogenated organics. J Am Water Works Assoc (November):634-648. *Tabak HH, Quave SA, Mashni CI, et al. 1981. Biodegradability studies with organic priority pollutant compounds. J Water Pollut Contr Fed 53:1503-1518. *Thomas KW, Pellizzari ED, Cooper SD. 1991. A canister based method for collection and GC/MS analysis of volatile organic compounds in human breath. J Anal Toxicol 15:54-59. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 226 8. REFERENCES *TRI8S. 1990. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. *TRI94. 1996. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. *Trieff NM, Ficklen D, Gan J. 1993. In vitro inactivation of glucose-6-phosphate dehydrogenase from human red blood cells by acrolein: A possible biomarker of exposure. Toxicol Letters 69:121-127. *Trieff NM, Ramanujam VMS, Stara JF, et al. 1991. Water quality criteria assessment for chlorinated benzenes using the quantitative structure activity relation approach and porphyrogenic endpoint in rats. Int J Environ Health Res 1:215-230. *Tyl RW, Neeper-Bradley TL. 1989. Paradichlorobenzene: Two generation reproductive study of inhaled paradichlorobenzene in Sprague-Dawley (CD) rats. Laboratory Project 86-81-90605. Washington, DC: Chemical Manufacturers Association, Chlorobenzene Producers Association. *U.S. Congress. 1986. Superfund amendments and reauthorization act of 1986. Title III-Emergency Planning and Community Right-to-Know. Ninety-ninth Congress of the United States of America. *U.S. Congress. 1990. Clean Air Amendments. Title III, Hazardous Air Pollutants, Section 112(b), Hazardous Air Pollutants as Amended, October 26, 1990. One Hundred and First Congress of the United States of America, 2nd Session Report 101-952. *Umemura T, Saito M, Takagi A, et al. 1996. Isomer-specific acute toxicity and cell proliferation in livers of B6C3F1 mice exposed to dichlorobenzene. Toxicol Appl Pharmacol 137:268-274. *Umemura T, Tokumo K, Williams GM. 1992. Cell proliferation induced in the kidneys and livers of rats and mice by short term exposure to the carcinogen p-dichlorobenzene. Archives of Toxicology 66(7):503-507. USITC. 1987. Synthetic organic chemicals: United States production and sales, 1987. Washington, DC: U.S. International Trade Commission. USITC publication 2118, 3-2, 3-7. *Verschueren K. 1983. Handbook of environmental data on organic chemicals. 2nd ed. New York, NY: Van Nostrand Reinhold Company, 477-478. View Database. 1989. Agency for Toxic Substances and Disease Registry (ATSDR), Office of External Affairs, Exposure and Disease Registry Branch, Atlanta, GA. November 8, 1989. *Wakeham SG, Davis AC, Karas JL. 1983. Mesocosm experiments to determine the fate and persistence of volatile organic compounds in coastal seawater. Environ Sci Technol 17:611-617. *Wallace L, Pellizzari E, Sheldon L, et al. 1986a. The Total Exposure Assessment Methodology (TEAM) study: Direct measurement of personal exposures through air and water for 600 residents of several U.S. cities. In: Cohen Y, ed. Pollutants in a multimedia environment. New York, NY: Plenum Publishers Corporation, 289-315. ***DRAFT FOR PUBLIC COMMENT"*** 1,4-DICHLOROBENZENE 207 8. REFERENCES *Wallace LA. 1987. The total exposure assessment methodology (team) study: summary and analysis: volume I. Office of Research and Development U. S. Environmental Protection Agency 600/6-87/002a. *Wallace LA, Pellizzari ED, Hartwell TD, et al. 1986b. Total exposure assessment methodology (TEAM) Study: Personal exposures, indoor-outdoor relationships, and breath levels of volatile organic compounds in New Jersey. Environ Int 12:369-387. *Wang M-J, Bokern M, Boehmen C, et al. 1996. Phytotoxicity uptake and metabolism of 1,4-Dichlorobenzene by plant cells. Environ Toxicol Chem 15(7):1109-1114. *Wang M-J, McGrath SP, Jones KC. 1995. Chlorobenzenes in field soil with a history of multiple sewage sludge applications. Environ Sci Technol 29(2):356-362. *Wang MJ, Jones KC. 1994. The chlorobenzene content of contemporary U.K. sewage sludges. Chemosphere 28(6):1201-1210. Ware SA, Weast WL. 1977. Investigation of selected potential environmental contaminants: Halogenated benzenes. Washington, DC: U.S. Environmental Protection Agency, Office of Toxic Substances. EPA 560/2-77-004. *Washall JW, Wampler TP. 1988. Purge and trap analysis of aqueous samples with cryofocusing. Am Lab (July):70-74. Weast RC, ed. 1985. CRC handbook of chemistry and physics. 66th ed. Boca Raton, FL: CRC Press, Inc. “Weller RW, Crellin AJ. 1953. Pulmonary granulomatosis following extensive use of paradichlorobenzene. Arch Intern Med 91:408-413. *WHO 1984. Guidelines for Drinking-water Quality. Volume 1: Recommendations. World Health Organization. *WHO. 1984a. Guidelines for drinking-water quality. Vol. 1. Recommendations. Geneva, Switzerland: World Health Organization, 85-86. WHO. 1984b. Guidelines for drinking-water quality. Vol. 2. Health criteria and other supporting information. Geneva, Switzerland: World Health Organization, 224-228. Williams RT. 1959. The metabolism of halogenated aromatic hydrocarbons. In: Detoxication mechanisms. 2nd ed. New York, NY: John Wiley and Sons, 237-258. *Wilson JT, Enfield CG, Dunlap WIJ, et al. 1981. Transport and fate of selected organic pollutants in a sandy soil. J Environ Qual 10:501-506. *Young DR, Gossett RW, Baird RB, et al. 1981. Wastewater inputs and marine bioaccumulation of priority pollutant organics off Southern California. In: Jolley RW, Brungs WA, Cotruvo JA, et al., eds. Water chlorination environmental impact and health effects, Vol. 4, Book 2. Ann Arbor, MI: Ann Arbor Science 871-884. ***DRAFT FOR PUBLIC COMMENT"** 1,4-DICHLOROBENZENE 229 9. GLOSSARY Acute Exposure—Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K .)—The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd)—The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. ) Bioconcentration Factor (BCF)—The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL)—The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen—A chemical capable of inducing cancer. Ceiling Value—A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure—Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity—The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity—Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations. altered growth, and in utero death. EPA Health Advisory—An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH)—The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure—Exposure to a chemical for a duration of 15-364 days, as specified in the Toxicological Profiles. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 230 9. GLOSSARY Immunologic Toxicity—The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro—Isolated from the living organism and artificially maintained, as in a test tube. In Vivo—Occurring within the living organism. Lethal Concentration y (LC o)—The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentrations, (LCs9)—A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dose; (LDy o)—The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dose sy) (LDgy)—The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time sq, (LT59)—A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL)—The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations—Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level—An estimate of daily human exposure to a dose of a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. Mutagen—A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity—The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL)—The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (K,)—The equilibrium ratio of the concentrations of a chemical in n-octanol and water, in dilute solution. Permissible Exposure Limit (PEL)—An allowable exposure level in workplace air averaged over an 8-hour shift. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE 231 9. GLOSSARY q;*—The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q,* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m’ for air). Reference Dose (RfD)—An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ)—The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity—The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL)—The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity—This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen—A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV)—A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA)—An allowable exposure concentration averaged over a normal 8- hour workday or 40-hour workweek. Toxic Dose (TDg,)—A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. Uncertainty Factor (UF)—A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-1 APPENDIX A ATSDR MINIMAL RISK LEVEL The Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA) [42 U.S.C. 9601 et seq.], as amended by the Superfund Amendments and Reauthorization Act (SARA) [Pub. L. 99-499], requires that the Agency for Toxic Substances and Disease Registry (ATSDR) develop jointly with the U.S. Environmental Protection Agency (EPA), in order of priority, a list of hazardous substances most commonly found at facilities on the CERCLA National Priorities List (NPL); prepare toxicological profiles for each substance included on the priority list of hazardous substances; and assure the initiation of a research program to fill identified data needs associated with the substances. The toxicological profiles include an examination, summary, and interpretation of available toxicological information and epidemiologic evaluations of a hazardous substance. During the development of toxicological profiles, Minimal Risk Levels (MRLs) are derived when reliable and sufficient data exist to identify the target organ(s) of effect or the most sensitive health effect(s) for a specific duration for a given route of exposure. An MRL is an estimate of the daily human exposure to a hazardous substance that is likely to be without appreciable risk of adverse noncancer health effects over a specified duration of exposure. MRLs are based on noncancer health effects only and are not based on a consideration of cancer effects. These substance-specific estimates, which are intended to serve as screening levels, are used by ATSDR health assessors to identify contaminants and potential health effects that may be of concern at hazardous waste sites. It is important to note that MRLs are not intended to define clean-up or action levels. MRLs are derived for hazardous substances using the no-observed-adverse-effect level/uncertainty factor approach. They are below levels that might cause adverse health effects in the people most sensitive to such chemical-induced effects. MRLs are derived for acute (1-14 days), intermediate (15-364 days), and chronic (365 days and longer) durations and for the oral and inhalation routes of exposure. Currently, MRLs for the dermal route of exposure are not derived because ATSDR has not yet identified a method suitable for this route of exposure. MRLs are generally based on the most sensitive chemical-induced end point considered to be of relevance to humans. Serious health effects (such as irreparable damage to the liver or kidneys, or birth defects) are not used as a basis for ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-2 APPENDIX A establishing MRLs. Exposure to a level above the MRL does not mean that adverse health effects will occur. MRLs are intended only to serve as a screening tool to help public health professionals decide where to look more closely. They may also be viewed as a mechanism to identify those hazardous waste sites that are not expected to cause adverse health effects. Most MRLs contain a degree of uncertainty because of the lack of precise toxicological information on the people who might be most sensitive (e.g., infants, elderly, nutritionally or immunologically compromised) to the effects of hazardous substances. ATSDR uses a conservative (i.e., protective) approach to address this uncertainty consistent with the public health principle of prevention. Although human data are preferred, MRLs often must be based on animal studies because relevant human studies are lacking. In the absence of evidence to the contrary, ATSDR assumes that humans are more sensitive to the effects of hazardous substance than animals and that certain persons may be particularly sensitive. Thus, the resulting MRL may be as much as a hundredfold below levels that have been shown to be nontoxic in laboratory animals. Proposed MRLs undergo a rigorous review process: Health Effectss MRL Workgroup reviews within the Division of Toxicology, expert panel peer reviews, and agencywide MRL Workgroup reviews, with participation from other federal agencies and comments from the public. They are subject to change as new information becomes available concomitant with updating the toxicological profiles. Thus, MRLs in the most recent toxicological profiles supersede previously published levels. For additional information regarding MRLs, please contact the Division of Toxicology, Agency for Toxic Substances and Disease Registry, 1600 Clifton Road, Mailstop E-29, Atlanta, Georgia 30333. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-3 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical name(s): 1,4-Dichlorobenzene CAS number(s): 106-46-7 Date: August 1997 Profile status: Draft 4 For Public Comment Route: [X] Inhalation [ ] Oral Duration: [X] Acute [ ] Intermediate [ ] Chronic Key to figure: 8 Species: Rabbit MRL: 0.8 [ ] mg/kg/day [X] ppm [] mg/m’ Reference: Hayes WC, Hanley TR, Gushow TS, Johnson KA, and John JA (1985). Teratogenic potential of inhaled dichlorobenzenes in rats and rabbits. Fund Appl Toxicol. 5: 190-202. Experimental design: Groups of inseminated New Zealand White rabbits were exposed whole body to 0 (filtered air), 100, 300, or 800 ppm p-DCB 6 hours/day on days 6-18 of gestation. Vapors of p-DCB were generated by passing air through glass tubes packed with pieces of p-DCB. Sacrifices were conducted on gestation day 29. End points examined included maternal body weight and liver and kidneys weights. Fetal observations included number and position of fetuses in utero, number of live or dead fetuses, number and position of resorption sites, number of corpora lutea, sex, body weight and crown-rump length of the fetuses, gross external alterations, and soft tissue and skeletal alterations. Effects noted in study and corresponding doses: Dams in the 800 ppm exposure group gained less weight than did controls during the exposure period. However, after day 18, they rapidly recovered and the final body weight and weight gains were similar to those of controls. There were no effects on absolute or relative maternal liver or kidney weights. At 300 ppm, there was a significant increase (p<0.05) in the percentages of resorbed implantations and litters with resorptions. Results at 800 ppm, however, were comparable to controls. Because the authors did not include resorptions that were detected only after sodium sulfide staining in their calculations, it is difficult to interpret these findings. At 800 ppm, there were nonsignificant increases in the incidence of acephaly (headlessness), omphalocele (umbilical hernia), and forelimb flexure. Other deformities found only in the offspring of that exposure group were shortened long bones, an extra rib fused to the tenth rib, and a right subclavian artery originating off the pulmonary trunk. A statistically significant increase (p<0.05) in the incidence of retroesophageal right subclavian artery was noted in the offspring; however, this effect was considered by the authors not to be a major malformation and had been previously observed in 2% of the litters of control rabbits in that laboratory. The authors concluded that under the conditions of this study, p-DCB was not embryotoxic or teratogenic in rabbits at 300 ppm. Dose and end point used for MRL derivation: [X] NOAEL [ ] LOAEL: 300 ppm The NOAEL was adjusted for intermittent exposure: NOAEL ,; = 300 ppm x 6 hr/24 hrs NOAEL py = 75 ppm ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-4 APPENDIX A Uncertainty factors used in MRL derivation: 100 [X]1 [13 []10 (for use of a LOAEL) [11 [13 [X] 10 (for extrapolation from animals to humans) [11 [13 [X] 10 (for human variability) Was a conversion factor used from ppm in food or water to a mg/body weight dose? If so, explain: Not applicable If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Equation 4-48a of EPA (1994k) was used to calculate the human equivalent concentration. 1,4-Dichlorobenzene is a category 2 gas; however, the formula in the EPA (1994) document for extrarespiratory effects of category 2 gases is presently under review. Therefore, the equation used to derive this MRL is for category 3 gases. 1,4-Dichlorobenzene produces extrarespiratory effects (liver and kidney) and is expected not to obtain periodicity. A default value of 1 was used because the (Hypo) a / (Hyon values are not known. NOAEL gc = NOAEL py; x [(Hb/g), + (Hb/g)y] NOAELygc = 75 ppm x 1 NOAELygc = 75 ppm where: NOAELyg = Human Equivalent Concentrations of the NOAEL. (Hy/o)a / (Hy/o)y = the ratio of the blood:gas (air) partition coefficient of the chemical for the laboratory animal species to the human value. The MRL calculation is: MRL = NOAEL yg / UF MRL = 75 ppm / 100 MRL = 0.8 ppm Was a conversion used from intermittent to continuous exposure? If so, explain: Yes. The NOAEL of 300 ppm was normalized to 75 ppm by adjusting for the 6 hours a day exposure pattern: NOAEL py = 300 ppm x 6 hrs / 24 hrs Other additional studies or pertinent information that lend support to this MRL: Agency Contact (Chemical Manager): Malcolm Williams ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-5 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical name(s): 1,4-Dichlorobenzene CAS number(s): 106-46-7 Date: August 1997 Profile status: Draft 3 For Public Comment Route: [X] Inhalation [ ] Oral Duration: [ 1 Acute [X] Intermediate [ ] Chronic Key to figure: 13 Species: Rat MRL: 0.2 [ ] mg/kg/day [X] ppm [] mg/m’ Reference: Hollingsworth RL, Rowe VK, Oyen F, et al. (1956). Toxicity of paradichlorobenzene. Arch Ind Health 14: 138-147. Experimental design: Rats (7-13 male and 10-13 female) were exposed to 1,4-dichlorobenzene vapors for 7 hours a day, 5 days a week at concentrations of 0, 96, or 158 ppm for a total of 126-139 exposures. At the end of the exposure period, the animals were sacrificed, body and organ weights determined, and tissues examined microscopically. Hematology (parameters not specified), analysis of urine (blood, glucose, albumin, and sediment) and measurement of blood urea nitrogen were conducted for females exposed to the lowest concentration of 1,4-dichlorobenzene. Effects noted in study and corresponding doses: A statistically significant (p=0.001-0.005) increase in relative liver weight was observed in males and females with the 158 ppm exposure concentration. In addition, liver parenchymal cells from the central zone displayed cloudy swelling or granular degeneration. Neither of these histopathological findings were noted in the 96 ppm exposure concentration. Hematological parameters, blood urea nitrogen, and urinalysis results in females were not significantly different from controls at the low-dose exposure concentration, but these were the only animals evaluated for these parameters. Dose and end point used for MRL derivation: [X] NOAEL [ ] LOAEL: 96 ppm The NOAEL was adjusted for exposure patterns: NOAEL ,p; = 96 ppm x 7 hr/24 hrs x 5 days/7 days Uncertainty factors used in MRL derivation: 100 [X]1 [13 []10 (for use of a LOAEL) [11 [13 [X] 10 (for extrapolation from animals to humans) [131 [11 X] 10 (for human variability) Was a conversion factor used from ppm in food or water to a mg/body weight dose? If so, explain: Not applicable ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-6 APPENDIX A If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Equation 4-48a of EPA (1994k) was used to calculate the human equivalent concentration. 1,4-Dichlorobenzene is a category 2 gas; however, the formula in the EPA (1994) document for extrarespiratory effects of category 2 gases is presently under review. Therefore, the equation used to derive this MRL is for category 3 gases. 1,4-Dichlorobenzene produces extrarespiratory effects (liver and kidney) and is expected not to obtain periodicity. A default value of 1 was used because the (Hy/g)a / (Hy/o)y values are not known. NOAELygc = NOAEL, py; x ([(Hyyg) a / (Hyg) NOAEL gc = 20 ppm x 1 NOAEL gc = 20 ppm where: NOAELygc = Human Equivalent Concentrations of the NOAEL. (Hp) / (Hy/y = the ratio of the blood:gas (air) partition coefficient of the chemical for the laboratory animal species to the human value. The MRL calculation is: MRL = NOAEL gc / UF MRL = 20 ppm / 100 MRL = 0.2 ppm Was a conversion used from intermittent to continuous exposure? If so, explain: Yes. The NOAEL of 96 ppm was normalized to 20 ppm by adjusting for the 7 hours a day, 5 days a week exposure pattern: NOAEL py = 96 ppm x 7 hrs / 24 hrs x 5 days / 7 days NOAEL,; = 20 ppm Other additional studies or pertinent information that lend support to this MRL: A study by Tyl and Neeper-Bradley (1989) examined the effects of 1,4-dichlorobenzene during a 2-generation reproductive study. Male rats (n=28) were exposed to concentrations of 0, 66.3, 211, or 538 ppm 1,4-dichloro- benzene for 15 weeks. Female rats (n=28) were exposed to the same concentrations for 17 weeks. The animals were monitored throughout the exposure period for body weight, food intake, and clinical signs. Liver and kidney weights were determined at sacrifice, and these organs were examined microscopically. Absolute and relative liver weights were significantly increased (p<0.01) in males from the mid- and high-dose group and in females from the high-dose group. Relative liver weights were significantly increased (p<0.05) in the females from the mid-dose group. The increase in liver weights was dose- related. At the highest dose, hepatocellular hypertrophy in the centrilobular area was noted in both males and females. No effects on the liver were seen with the 66.3 ppm exposure concentration. These results are consistent with the results from Hollingsworth et al. (1956) study and support the use of the Hollingsworth et al. (1956) data for derivation of this MRL. Hyaline droplets and increased kidney weights were seen in males at the highest dose tested ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE APPENDIX A (66.3 ppm). Since hyaline droplet nephropathy is unique to the male rat, the LOAEL for this effect was not applicable to humans and was not selected as a basis for this MRL. Agency Contact (Chemical Manager): Malcolm Williams ***DRAFT FOR PUBLIC COMMENT"*** A-7 1,4-DICHLOROBENZENE A-8 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical name(s): 1,4-Dichlorobenzene CAS number(s): 106-46-7 Date: August 1997 Profile status: Draft 3 For Public Comment Route: [X] Inhalation [ ] Oral Duration: [ 1 Acute [ ] Intermediate [X] Chronic Key to figure: 31 Species: Rat MRL: 0.1 [ ] mg/kg/day [X] ppm [ ] mg/m’ Reference: Riley RA, Chart IS, Doss A, Gore CW, Patton D, and Weight, TM (1980). Para- dichlorobenzene: Long term inhalation study in the rat. Imperial Chemical Industries Limited Central Toxicology Laboratory, Alderley Park, Macclesfied, Cheshire, UK, Report # CTL/P/447. Experimental design: Groups of young rats (90-110 g bw) were exposed whole body to 0 (air control), 75, or 500 ppm p-DCB 5 hours a day, 5 days a week for 76 weeks. Interim sacrifices were conducted at weeks 26, 52, and 76. After exposure terminated, groups of rats were kept until natural death or week 112. End points examined include clinical or behavioral abnormalities, body and organ weights (liver, kidney, adrenal, spleen, gonads, heart, lung, brain, and pituitary), food and water consumption, histopathology (adrenal, aorta, bladder, brain, bone marrow, cecum, colon, cervix, duodenum, epidiymus, esophagus, eyes, heart, ileum, jejunum, kidneys, larynx, liver, lungs, lymph nodes, mammary gland, nasal sinuses ovaries, pancreas, pituitary, prostate, salivary glands, sciatic nerve, seminal vesicle, spinal cord, spleen, stomach, testes, trachea, thymus, thyroid, uterus, voluntary muscle, Zymbal's gland, and Harderian gland), blood chemistry, urinalysis, and hematology. Effects noted in study and corresponding doses: Exposure to p-DCB had no effect on survival rate, body weight, food intake, or water consumption. There was a slight increase in lung weight only at termination (week 122) at 500 ppm in males and females but no histopathological effects in the nasal sinuses, trachea, or lungs. Both sexes showed a significantly increase in heart weight at termination but no histopathological effects in the heart or aorta. No effects were observed in the gastrointestinal tract or in skeletal muscle. Although some changes in blood chemistry and hematology parameters were seen, there was no evidence of dose-related patterns. Liver weights were increased at S00 ppm (except in females at week 76), but there were no histological changes or changes in enzyme activity that would indicate liver damage. There was also no increase in the activity of hepatic aminopyrine demethylase. Kidney weights were increased at S00 ppm in males but there was no evidence of histologic changes. There were no treatment-related effects on the thyroid, pituitary, adrenals, or the eyes. Dose and end point used for MRL derivation: [X] NOAEL [ ] LOAEL: 75 ppm The NOAEL was adjusted for exposure patterns: NOAEL pp; = 75 ppm x 5 hr/24 hrs x § days/7 days ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-9 APPENDIX A Uncertainty factors used in MRL derivation: 100 [X]1 [13 []10 (for use of a LOAEL) [11 [13 [X] 10 (for extrapolation from animals to humans) [11 [13 [X] 10 (for human variability) Was a conversion factor used from ppm in food or water to a mg/body weight dose? If so, explain: Not applicable If an inhalation study in animals, list conversion factors used in determining human equivalent dose: Equation 4-48a of EPA (1994k) was used to calculate the human equivalent concentration. 1,4-Dichlorobenzene is a category 2 gas; however, the formula in the EPA (1994) document for extra- respiratory effects of category 2 gases is presently under review. Therefore, the equation used to derive this MRL is for category 3 gases. 1,4-Dichlorobenzene produces extrarespiratory effects (liver and kidney) and is expected not to obtain periodicity. A default value of 1 was used because the (Hyg) NU (Hyon values are not known. NOAELygc = NOAEL py; x ([(Hyye) al (Hp/g)nl NOAELygc = 11 ppm x 1 NOAELygc = 11 ppm where: NOAEL gc = Human Equivalent Concentrations of the NOAEL. (Hye) NU (Hy/o)y = the ratio of the blood:gas (air) partition coefficient of the chemical for the laboratory animal species to the human value. The MRL calculation is: MRL = NOAELygc / UF MRL = 11 ppm / 100 MRL = 0.1 ppm Was a conversion used from intermittent to continuous exposure? If so, explain: Yes. The NOAEL of 75 ppm was normalized to 11 ppm by adjusting for the 5 hours a day, 5 days a week exposure pattern: NOAEL pp; = 75 ppm x 5 hrs / 24 hrs x 5 days / 7 days NOAEL py = 11 ppm Other additional studies or pertinent information that lend support to this MRL: Agency Contact (Chemical Manager): Malcolm Williams ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-10 APPENDIX A MINIMAL RISK LEVEL (MRL) WORKSHEET Chemical name(s): 1,4-Dichlorobenzene CAS number(s): 106-46-7 Date: September 1997 Profile status: Draft 3 For Public Comment Route: [ ] Inhalation [X] Oral Duration: [ ] Acute [X] Intermediate [ ] Chronic Key to figure: 32 Species: Rat MRL: 0.1 [X] mg/kg/day [] ppm [] mg/m? Reference: Hollingsworth RL, Rowe VK, Oyen F, et al. (1956). Toxicity of paradichlorobenzene. Arch Ind Health 14: 138-147 Experimental design: Ten female rats were administered 1,4-dichlorobenzene at doses of 0, 18.8, 188, or 376 mg/kg/day by gavage in olive oil, 5 days a week for about 7 months. At the end of the exposure period, the animals were sacrificed. Clinical signs, growth, mortality, hematology (parameters not identified), organ weights, and histopathology were monitored. Effects noted in study and corresponding doses: There was a dose-related increase in liver weights for the two highest dose groups that was accompanied by necrosis and slight cirrhosis of the tissues in the highest dose group. Kidney weights were also increased slightly in both dose groups. There were no adverse effects noted at the lowest dose. Dose and end point used for MRL derivation: The minimal LOAEL of 188 mg/kg/day was used to derive the MRL. This concentration was normalized to 134 mg/kg/day by adjusting for a 5 days a week exposure pattern. NOAEL,, = 18.8 mg/kg/day x 5 days / 7 days NOAEL,, = 13.4 mg/kg/day [X ] NOAEL [] LOAEL: 134 mg/kg/day Uncertainty factors used in MRL derivation: 300 [11 [13 []10 (for use of a minimal LOAEL) [11 [13 [X] 10 (for extrapolation from animals to humans) [11 [13 [X] 10 (for human variability) The intermediate oral MRL is derived as follows: MRL = NOAEL,,,, / UF MRL = 13.4 mg/kg/day / 300 MRL = 0.1 mg/kg/day Ww versi m in f r water i ? If so, explain: Not applicable “**DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE A-11 APPENDIX A applicable Was a conversion used from intermittent to continuous exposure? If so, explain: This concentration was normalized to 13.4 mg/kg/day by adjusting for a 5 days a week exposure pattern. NOAEL,,, = 18.8 mg/kg/day x 5 days / 7 days NOAEL,,, = 13.4 mg/kg/day cr additiona dic C d Nn tha J | NL 10-13 female) were exposed to 1,4-dichlorobenzene vapors for 7 hours a day, 5 days a week at concentrations of 0, 96, or 158 ppm for a total of 126-139 exposures in the same study by Hollingsworth et al. (1956). At the end of the exposure period, the animals were sacrificed, body and organ weights determined, and tissues examined microscopically. Hematology (parameters not specified), analysis of urine (blood, glucose, albumin, and sediment), and measurement of blood urea nitrogen were conducted for females exposed to the lowest concentration of 1,4-dichlorobenzene. A statistically significant (p=0.001-0.005) increase in relative liver weight was observed in males and females with the 158 ppm exposure concentration. In addition, liver parenchymal cells from the central zone displayed cloudy swelling or granular degeneration. These indicators of chemical toxicity are similar to those noted with the oral-exposure route. Hematological parameters were not significantly different from controls with the low-dose exposure concentration; this is also in agreement with the oral exposure data. Agency Contact (Chemical Manager): Malcolm Williams ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE B-1 APPENDIX B USER'S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in non-technical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or chemical release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the chemical. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects and illustrate graphically levels of exposure associated with those effects. These levels cover health effects observed at increasing dose concentrations and durations, differences in response by species, minimal risk levels (MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper- bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. Use the LSE tables and figures for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse- Effect Levels (NOAELSs), Lowest-Observed-Adverse-Effect Levels (LOAELs), or Cancer Effect Levels (CELs). The legends presented below demonstrate the application of these tables and figures. Representative examples of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1) Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exists, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. Not all substances will have data on each route of exposure and will not therefore have all five of the tables and figures. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE B-2 (2 3) 4) (3) (6) (7 (8) ©) APPENDIX B Exposure Period Three exposure periods - acute (less than 15 days), intermediate (15-364 days), and chronic (365 days or more) are presented within each relevant route of exposure. In this example, an inhalation study of intermediate exposure duration is reported. For quick reference to health effects occurring from a known length of exposure, locate the applicable exposure period within the LSE table and figure. Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELSs and LOAELS can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table (see key number 18). Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to derive a NOAEL and a Less Serious LOAEL (also see the 2 "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Section 2.5, "Relevance to Public Health," covers the relevance of animal data to human toxicity and Section 2.3, "Toxicokinetics," contains any available information on comparative toxicokinetics. Although NOAELs and LOAELS are species specific, the levels are extrapolated to equivalent human doses to derive an MRL. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to 1,1,2,2-tetrachloroethane via inhalation for 6 hours per day, 5 days per week, for 3 weeks. For a more complete review of the dosing regimen refer to the appropriate sections of the text or the original reference paper, i.e., Nitschke et al. 1981. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, 1 systemic effect (respiratory) was investigated. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure, inhalation MRL of 0.005 ppm (see footnote "b"). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest dose used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific endpoint used to quantify the adverse effect accompanies the LOAEL. The respiratory effect reported in key number 18 (hyperplasia) is a Less serious LOAEL of 10 ppm. MRLs are not derived from Serious LOAELSs. (10) Reference The complete reference citation is given in chapter 8 of the profile. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE B-3 APPENDIX B (11) CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiologic studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report doses not causing measurable cancer increases. (12) Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. LEGEND See Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure concentrations for particular exposure periods. (13) Exposure Period The same exposure periods appear as in the LSE table. In this example, health effects observed within the intermediate and chronic exposure periods are illustrated. (14) Health Effect These are the categories of health effects for which reliable quantitative data exists. The same health effects appear in the LSE table. (15) Levels of Exposure concentrations or doses for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure concentration or dose is measured on the log scale "y" axis. Inhalation exposure is reported in mg/m’ or ppm and oral exposure is reported in mg/kg/day. (16) NOAEL In this example, 18r NOAEL is the critical endpoint for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates to a NOAEL for the test species-rat. The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). (17) CEL Key number 38r is 1 of 3 studies for which Cancer Effect Levels were derived. The diamond symbol refers to a Cancer Effect Level for the test species-mouse. The number 38 corresponds to the entry in the LSE table. (18) Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from the EPA's Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q;*). (19) Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. ***DRAFT FOR PUBLIC COMMENT*** «+INJWNOD O178Nd HOS 14VH.xs SAMPLE 12 1 TABLE 2-1. Levels of Significant Exposure to [Chemical x] — Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL - figure? Species duration System (ppm) Less serious (ppm) Reference 2 » INTERMEDIATE EXPOSURE Ls] Le] [2] [] [oe] [5] ~ Systemic l l ! | I l 4 18 Rat 13 wk Resp 3 ® 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE Cancer i 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 5d/wk organs) 7hr/d 39 Rat 89-104 wk 10 (CEL, lung tumors, NTP 1982 5d/wk nasal tumors) 6hr/d 40 Mouse 79-103 wk 10 (CEL, lung tumors, NTP 1982 5d/wk hemangiosarcomas) 6hr/d @ The number corresponds to entries in Figure 2-1. b an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). 8 XION3ddv INIZNIGOHOTHOIA-v'L v-9 «x LNTFWWOD O178Nd HOH L4VHuux — > Figure 2-1. Levels of Significant Exposure to [Chemical X] — Inhalation Acute Intermediate (<14 days) (15-364 days) Systemic Systemic N N > > < XY oN iS & o> & ° , > ¢ &@ xO © 3 © Jd & NN Q 2 IN Q & 2 £ o e? & & ¢ & & & XR > Q <= Q <& x NS x Oo 1000 0 & 37m o ® O oO @ 30 100 160 177 2 ad ao 20m @ BD 20m 31r d d 35m 2 dD ! 918rig, ~~ 22g21r O 28m® oor 27r 40m gg 10 > 3ar 22m el Q gr | 1 | | 10% — | 0.1 | 10-5 | Estimated <— v Upper Bound 0.01 6 Human Cancer Key 10 Risk Levels 0.001 r Rat @ LOAEL for serious effects (animals) I Minimal risk level for effects 1 07 | m Mouse (P LOAEL for less serious effects (animals) | other than cancer 0.0001 h Rabbit (OO NOAEL (animals) g Guinea Pig $ CEL - Cancer Effect Level The number next to each point 0.00001 k Monkey corresponds to entries in the accompanying table. 0.000001 * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 0.0000001 dg XIAN3ddV INIZNIGOHOTHOIA-¥'} S-9 1,4-DICHLOROBENZENE B-6 APPENDIX B Chapter 2 (Section 2.5) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicologic, epidemiologic, and toxicokinetic information. This summary is designed to present interpretive, weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3. What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section covers end points in the same order they appear within the Discussion of Health Effects by Route of Exposure section, by route (inhalation, oral, dermal) and within route by effect. Human data are presented first, then animal data. Both are organized by duration (acute, intermediate, chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. Minimal risk levels (MRLs) for noncancer end points (if derived) and the end points from which they were derived are indicated and discussed. Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information is available, we have derived minimal risk levels (MRLs) for inhalation and oral routes of entry at each duration of exposure (acute, intermediate, and chronic). These MRLs are not meant to support regulatory action; but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a chemical emission, given the concentration of a contaminant in air or the estimated daily dose in water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicologic information on which the number is based. Chapter 2.5, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.7, "Interactions with Other Substances,” and 2.8, "Populations that are Unusually Susceptible" provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology the Environmental Protection Agency (EPA) provides (Barnes and Dourson 1988) to determine reference doses for lifetime exposure (RfDs). ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE B-7 APPENDIX B To derive an MRL, ATSDR generally selects the most sensitive endpoint which, in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential systemic, neurological, and developmental effects. If this information and reliable quantitative data on the chosen endpoint are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. When a NOAEL is not available, a lowest-observed- adverse-effect level (LOAEL) can be used to derive an MRL, and an uncertainty factor (UF) of 10 must be employed. Additional uncertainty factors of 10 must be used both for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE C-1 ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLp cm CNS d DHEW DHHS DOL ECG EEG EPA EKG F F, FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO in Kd kg kkg oC ow APPENDIX C ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE L LC LCLO LCso LDLO LDs, LOAEL LSE m mg min ml mm mmHg mmol mo mppcf MRL MS NIEHS NIOSH NIOSHTIC ng nm NHANES nmol NOAEL NOES NOHS NPL NRC NTIS NTP OSHA PEL pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE SIC SMR APPENDIX C liter liquid chromatography lethal concentration, low lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH's Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio ***DRAFT FOR PUBLIC COMMENT*** 1,4-DICHLOROBENZENE STEL STORET TLV TSCA TRI TWA U.S. UF yr WHO wk <= om QIAN A LIV V = £ = 3 APPENDIX C short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micrometer microgram ***DRAFT FOR PUBLIC COMMENT*** C-3 # U. S. GOVERNMENT PRINTING OFFICE: 1997-538-074 U. C. BERKELEY LIBRARIES C047291885