TOXICOLOGICAL PROFILE FOR 1,4-DICHLOROBENZENE Prepared by: Life Systems, Inc. Under Subcontract to: Clement International Corporation Under Contract No. 205-88-0608 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry April 1993 pub! i 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. UPDATE STATEMENT A Toxicological Profile for 1,4-Dichlorobenzene was released in January 1989. 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 R A Division of Toxicology/Toxicology Information Branch [2472 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 P43 T49 129% PUBL FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987, on October 20, 1988, on October 26, 1989, on October 17, 1990, and on October 17, 1991. A revised list of 275 substances was published on October 28, 1992. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. Each profile must include the following: (A) The examination, summary, and interpretation of available toxicological information and epidemiological evaluations on a hazardous substance in order 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 which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This toxicological profile is prepared in accordance with guidelines developed by ATSDR and 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 is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties. Other pertinent literature is also presented but 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. Each toxicological profile begins with a public health statement, which describes in nontechnical language a substances 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 will be identified by ATSDR and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. vi Foreword 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. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists from ATSDR, the Centers for Disease Control and Prevenuon (CDC). and other federal agencies. It has also been reviewed by a panel of nongovemment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. Caen L William L. Roper, M.D., Administrator Agency for Toxic Substances and Disease Registry vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHOR(S): Malcolm Williams, D.V.M., Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Yvonne N. Hales, Ph.D. Life Systems, Inc., Washington, DC M. Janet Normandy, Ph.D. Life Systems, Inc., Washington, DC Joyce M. Donohue, Ph.D. Life Systems, Inc., Washington, DC THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. Green Border Review. Green Border review assures the consistency with ATSDR policy. 2. 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 endpoints. 3 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. 4. Quality Assurance Review. The Quality Assurance Branch assures that consistency across profiles is maintained, identifies any significant problems in format or content, and establishes that Guidance has been followed. CONTENTS FOREWORD .,cuvrvsmiav sma fshasidifasissnintian nen tm sams esswenssns v CONTRIBUTORS © ©. titi it ee ee te tet ee ee ee et ee ee eee es vii LIST OF FIGURES... csv ves saan tnt sa nats tat sed ua had SERRE HA TE Rs 2 FE BM AK 3a xiii LISTOF TABLES .ciusonnmsm as ans tt nisin insriessurssmrs expen t essen eye Xv 1. PUBLIC HEALTH STATEMENT . . .. iit tiie iii iin 1 1.1 WHAT IS 14-DICHLOROBENZENE? ......... 0.0 innnnnnnennn. 1 1.2 WHAT HAPPENS TO 1,4-DICHLOROBENZENE WHEN IT ENTERS THE ENVIRONMENT? «cio umsmsns mswmm sss vmanvsnsnamanasssssenmss umes 2 1.3 HOW MIGHT I BE EXPOSED TO 14-DICHLOROBENZENE? ................ 2 1.4 HOW CAN 1,4-DICHLOROBENZENE ENTER AND LEAVE MY BODY? ........ 3 1.5 HOW CAN 1,4-DICHLOROBENZENE AFFECT MY HEALTH? ................ 4 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO 1,4-DICHLOROBENZENE? .............tiiitiueniunnennn. 5 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? . us cvavn sn sr as mum ms atmos un pw amas ne 5 1.8 WHERE CAN I GET MORE INFORMATION? ............0iiiitininennn.. 6 2. HEALTH EFFECTS . . . «titi ttt ttt ett ett tt et ee eee ieee 7 21 INTRODUCTION io unv-nass tin sn tn satis sa sins enters pre su vu ne nen 7 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ............. 7 22.1 Inhalation EXpOSUre . . ....... cotinine 8 2211 Death Lo... 8 2212 Systemic Effects ....c viv vnvnwsvrnsmvnrsnsmrnvs ra sr ne ns 8 2213 Immunological Effects . ................ iii. 14 2.2.14 Neurological Effects ................ 14 22.1.5 Developmental Effects . ................ i... 15 2216 Reproductive BIfEelS « vo cv sir vm se ver em nemo mes nw mr sn on ma ms 15 2217 Genotoxde Effects « .« vo ss vn vnso san emsmsemin nn un mssnvs os 16 DALE CHDCEr «vv vv rr br br sd Ad Rd LF HERP RHE FER IRN RE DE NE REE 16 222 Oral EXpOSUIE . . «otitis 16 DAL DEUIR ov: wast om 8 vv 6% HE HE HE RYH EW AE EE EE PE eH HE 16 2222 Systemic Bffects .. .. cosvsusns issn ivnwmemsp nema mene wa 17 2223 Immunological Effects .... cv scssnisrsnsamsninnmvne nesses 29 2.22.4 Neurological Effects ................. iii... 29 2225 Developmental Effects . .................... a... 30 2226 Reproductive EIfects « «cu su vnwrarnrtnsmusxsonrsmnrnrmsns 30 2227 GenotoXiCEHfects . .. cco svi vinis sm rami na mun ns Ru uw new 30 DRAB CHOCEL ov + nrnr vn mt ss mk i pms id hm ek RGB RE wok ik hd 3 WER 31 223 Dermal Exposure . ......... iii ieee 32 223.1 Death ..... ee eee 32 2232 Systemic Bffects . cv cnvnsnvvavimsanimsmmi mswmm en nie sw ve we 32 2233 Immunological Effects . .................. .... . .. 32 2.23.4 Neurological Effects .............. iii... 32 3 4. 5 2235 Developmental Effects . « .. ccc vnvininsamsnrsnssnomsnsvins 32 223.6 Reproductive Effects . . .............. iii 32 2237 GenotoXic Bifects . . wv nuns snsnsssmsmrrnemsmrnvanrinamres 32 2238 Cancer . cu vv msm rama mi HIRI HI BIR RANI HP EE ME HERE ew 33 23 TOXICOKINETICS itt ttt tt eee ee ee eee eee eas 33 231 ADSOIPHON . vo .vvio nines mememmemamonsmemsmprans sumone nswsmons 33 2311 Inhalation BXposure . ....«civivivsntnsr ove nvmnnsssmsnamens 33 2312 Oral EXpOSUIe .. «sd sn ss mi Tin ins SARA RIX SB UB SL HE HEB 1H » 33 23.13 Dermal Exposure . .......... ii ee 34 232 Distribution . . .. oii 34 23.2.1 Inhalation Exposure ............ citi 34 2322 Om ESPOSUIE «sa su cro 18 18 45 48 AN KIRIN EN NU GIR E IH $5 50 3 34 2323 Dermal EXposure: «cv ois s am sd ma Sem sm mm 6 mi Hou boas ne 35 233 Metabolism . . oo... ee 35 2348 EXOrOtON. & so ve wits sum sid 5+ 51 R08 HE HE HE BEBE EU HEME NSH SW Bw wr 35 2341 Inhalation BXposure . .:c:issnsnsnansitmennmamrmessumn owns 35 2342 Oral Exposure . .:ccivinissnosninsminssusninsnsssnmmens 36 2343 Dermal EXposure . ........... citi ee 36 24 RELEVANCE TO PUBLIC HEALTH .............. 0 itiinnn.. 36 25 BIOMARKERS OF EXPOSURE AND EFFECT .. :: sc: vcr uravrnsmromunvimmn wos 49 2.5.1 Biomarkers Used to Identify or Quantify Exposure to 1,4-Dichlorobenzene . . . ... 50 2.52 Biomarkers Used to Characterize Effects Caused by 1,4-Dichlorobenzene . ...... 50 2.6 INTERACTIONS WITH OTHER CHEMICALS ............. citi... 50 27 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ................... 50 28 MITIGATION OF EFFECTS . . . tii ttt ite ie ieee eee 51 2.8.1 Reducing Peak Absorption Following Exposure . ........................ 51 2.82 Reducing Body Burden .............. 51 2.8.3 Interfering with the Mechanism of Action for Toxic Effects . ................ 51 29 ADEQUACY OF THE DATABASE . . .... iii ieee 52 29.1 Existing Information on Health Effects of 1,4-Dichlorobenzene . ............. 52 292 Identification of Data Needs . ........... coi iii int vnvrnssrns 54 203 Ong SUSIE iu vrnrnutsrnrnrnrsnrapsnsnsarnvamsmsnsnsd 58 CHEMICAL AND PHYSICAL INFORMATION .......... iii 59 31 CHEMICAL IDENTITY . . titi ttt ttt ete ee eee eee aes 59 3.2 PHYSICAL AND CHEMICAL PROPERTIES ................... 59 PRODUCTION, IMPORT, USE, AND DISPOSAL . . .. ou cn sss eminonsenrsusmensnns 63 AL PRODUCTION cs vv vs mom vim sm mss oman sn sn sos sis nim td bh BER sus 0S 5508 BE 63 42 IMPORT/EXPORT . . titi tt tee ee ee ee eee aa 63 43 USE © oii 63 AA DISPOSAL .. cv vinv someon ao ws smn simse es dose m oat siemens dowry wy 65 POTENTIAL FOR HUMAN EXPOSURE ........ iii 67 S51 OVERVIEW .vissaioso an au siesissontm nase sass ansontusssm sess ns 67 52 RELEASESTO THE ENVIRONMENT . .. i: i ivsnsnsnnnvovnmrnvnvmas vn 67 S21 AIL coven isnsmea bran na Bio nina hah i BER RIO Hs Re BW bE HE HE He HY 67 532 WAST « vc voor mrs rata atasasasnstsesensssnmemmensdsoiosd vase sin 70 523 S00 oi ivr r inv nestn tase mates a ts ay awn 70 53 ENVIRONMENTAL FATE ...cuininvnsussnsnsmsnimsiemensmen rn snnn an 70 531 Transportand Partitioning ............ cctv rsranrnrnsesenn 70 xi 53.2 Transformation and Degradation ...................... uu. u.... 71 53.2.1 BAC 2 5s 55 5 8 55 5 5.8 ok mv mdr mis ws mw yd aE EE EEE Ee Lk SE EE a 4 71 5322 Water . o.oo, nn 5323 Soil Lo. 72 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............ 2 J 72 542 Waler . «oo 72 543 Soil LLL 72 544 Other Environmental Media ................ 00... 74 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ............... 74 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES .................. 74 5.7 ADEQUACY OF THE DATABASE . . ... iit, 75 5.71 Identification of Data Needs . ........... iii rumnenn 75 572 On-going Studies . ........... 77 6. ANALYTICAL METHODS . . . . tt ee eds 79 6.1 BIOLOGICAL MATERIALS . . ... ee esi, 79 6.2 ENVIRONMENTAL SAMPLES . . ee esi, 79 63 ADEQUACY OF THE DATABASE . . .... ieee ii, 83 6.3.1 Identification of Data Needs . ............ cium. 84 632 Ongoing SWAES ...cuvvvisrasssssisrasnemmunmennsrsnonssosss 84 7. REGULATIONS AND ADVISORIES . .... iit eee eee, 85 8. REFERENCES . . . ee dd 89 9. GLOSSARY ©... 109 APPENDICES A. USER'S GUIDE . . . .. A-1 B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS .............. iii... B-1 C. PEER REVIEW . iti it itis ttt sitet it iiennennn C-1 xiii LIST OF FIGURES 2-1 Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation ................... 2-2 Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral ....................... 2-3 Existing Information on Health Effects of 1,4-Dichlorobenzene ...................... 5-1 Frequency of the NPL Sites With 1,4-Dichlorobenzene Contamination ................. 2-1 2-2 2-3 4-1 5-1 5-2 6-2 7-1 Xv LIST OF TABLES Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation ................... 9 Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral ....................... 18 Genotoxicity of 1,4-Dichlorobenzene In Vitro ................................. 44 Genotoxicity of 1,4-Dichlorobenzene In Vivo . . ................................ 47 Chemical Identity of 1,4-Dichlorobenzene . ................................... 60 Physical and Chemical Properties of 1,4-Dichlorobenzene . . . ....................... 61 Facilities That Manufacture or Process 1,4-Dichlorobenzene . ....................... 64 Releases to the Environment from Facilities That Manufacture or Process 1,4-Dichlorobenzene . 69 Summary of 1,4-Dichlorobenzene Levels in Air... ............................. 73 Analytical Methods for Determining 1,4-Dichlorobenzene in Biological Materials . ......... 80 Analytical Methods for Determining 1,4-Dichlorobenzene in Environmental Samples ........ 81 Regulations and Guidelines Applicable to 1,4-Dichlorobenzene ...................... 86 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about 1,4-dichlorobenzene and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL). 1,4-Dichlorobenzene has been found in at least 244 of these sites. However, we do not know how many of the 1,300 NPL sites have been evaluated for 1,4-dichlorobenzene. As EPA evaluates more sites, the number of sites at which 1,4-dichlorobenzene is found may change. This information is important for you to know because 1,4-dichlorobenzene may cause harmful health effects and because these sites are potential or actual sources of human exposure to 1,4-dichlorobenzene. When a chemical 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 as a chemical emission. This emission, which is also called a release, does not always lead to exposure. You can be exposed to a chemical only when you come into contact with the chemical. You may be exposed to it in the environment by breathing, eating, or drinking substances containing the chemical or from skin contact with it. If you are exposed to a hazardous chemical such as 1,4-dichlorobenzene, several factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, sex, nutritional status, family traits, life style, 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 used to make mothballs. 1,4-Dichlorobenzene is used to make deodorant blocks used in restrooms, as well as to control odors in animal holding facilities. At room temperature, 1,4-dichlorobenzene is a white solid with a strong odor which you would probably recognize as the smell of mothballs. When 1,4-dichlorobenzene is exposed to the air, it slowly changes from its solid state into a vapor. 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 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 ppm and in water at a concentration of 0.011 ppm. 2 1. PUBLIC HEALTH STATEMENT 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 1,4-dichlorobenzene enters the environment as a result of its uses in moth repellant products and in toilet deodorizer blocks. Because it evaporates 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. 1,4-Dichlorobenzene that enters the air can be broken down into harmless products in about a month. 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. 14-Dichlorobenzene in soil is not usually easily broken down by soil organisms. Plants are thought to take up and retain 1,4-dichlorobenzene, and fish have also been shown to take up and retain this compound. More information of how 1,4-dichlorobenzene behaves in the environment may be found in Chapters 4 and S. 1.3 HOW MIGHT | BE EXPOSED TO 1,4-DICHLOROBENZENE? Human exposure to 1,4-dichlorobenzene results mainly from breathing vapors from 1,4-dichlorobenzene 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 of air (ppb). 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. 3 1. PUBLIC HEALTH STATEMENT 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 in 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, since it has been detected in human breast milk at 5 locations in the United States. These levels were 0.04-68 ppb. Average daily adult intake of this chemical is estimated to be about 35 micrograms (ug), which comes mainly from breathing in 1,4-dichlorobenzene that is released from products in the home. These levels would not be expected to result in harmful effects. Workers may be exposed to 1,4-dichlorobenzene in 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 parts per million parts of air (ppm) (1 ppm is 1,000 times more than 1 ppb). There are about 35,000 people in the United States who 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 1,4-dichlorobenzene products. When you breathe in this chemical for a few hours, about 20% of the 14-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 which 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. 4 1. PUBLIC HEALTH STATEMENT 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 period of time. In your body, most 14-dichlorobenzene is broken down to the chemical 2,5-dichlorophenol. It 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? 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 health effects such as dizziness, headaches, and liver problems as a result of 1,4-dichlorobenzene exposure in the home. However, these were generally cases of extremely high usage of 1,4-dichlorobenzene products, and the persons involved 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 of time (months to years) because of the 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 can cause cancer or birth defects or affect 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 no information on the effects of skin contact with 1,4-dichlorobenzene. In laboratory animals, breathing or eating 1,4-dichlorobenzene can cause harmful effects in the liver, kidney, and blood. Rats and mice that were given oral doses of 1,4-dichlorobenzene in life-long studies had increased rates of cancer when compared with animals that did not receive 1,4-dichlorobenzene. We do not know if 1,4-dichlorobenzene can play a role in the development of cancer. The Department of Health and Human Services (DHHS) has determined that 1,4-dichlorobenzene may reasonably be anticipated to be a carcinogen. 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. 5 1. PUBLIC HEALTH STATEMENT 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 tests include measuring 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 worker exposure. There is also a test that can measure levels of 1,4-dichlorobenzene in your blood, but it is less commonly used. Neither 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 has taken a number of steps to protect humans from excessive 1,4-dichlorobenzene exposure. The EPA has listed 1,4-dichlorobenzene as a hazardous waste and has subjected it to hazardous waste regulations. The EPA has set a maximum level of 75 pug of 14-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 used as a pesticide. The Occupational Safety and Health Administration (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. 6 1. PUBLIC HEALTH STATEMENT 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, E-29 Atlanta, Georgia 30333 This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. These clinics specialize in the recognition, evaluation, and treatment of illnesses resulting from exposure to hazardous substances. 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-dichlorobenzene and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for 1,4-dichlorobenzene based on toxicological studies and epidemiological investigations. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals 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, developmental, reproductive, 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 (LOAELS:) reflect the actual doses (levels of exposure) used in the studies. LOAELs have been classified into "less serious" or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine 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 tables and figures may differ depending on the user’s perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with “serious” effects. Public health officials and project managers 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 (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of interest to health professionals and citizens alike. Levels of exposure associated with the carcinogenic effects of 1,4-dichlorobenzene are indicated in Figure 2-2. Because cancer effects could occur at lower exposure levels, the figures 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 (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRLs include adjustments to reflect human variability and extrapolation of data from laboratory animals to humans. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1989a), 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 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. 8 2. HEALTH EFFECTS 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 contributing 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 of 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. This case study did not address whether these individuals were alcoholics or had previous medical problems. No studies were located regarding death in animals after inhalation exposure to 1,4-dichlorobenzene. 2.2.1.2 Systemic Effects No studies were located regarding cardiovascular, gastrointestinal, hematological, or musculoskeletal effects in humans or animals after inhalation exposure to 1,4-dichlorobenzene. Data on respiratory, hepatic, renal, and dermal/ocular effects are 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 occur 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. Mild histopathological changes of interstitial edema, congestion, and alveolar hemorrhage were observed in the lungs of male rats, female guinea pigs, and one 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 two rabbits exposed to 798 ppm for 12 weeks (Hollingsworth et al. 1956). These observations TABLE 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene - Inhalation Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure Species frequency System (ppm) (ppm) (ppm) Reference ACUTE EXPOSURE Developmental 1 Rat 10 d 500 Hodge et al. 6hr/d 1977 Gdé-15 2 Rabbit 13d 300 800 (retroesophageal Hayes et al. 6hr/d right subclavian 1985 Gd6-18 artery) INTERMEDIATE EXPOSURE Systemic 3 Rat 2-12 wk Resp 173 (slight Hollingsworth 5d/wk interstitial et al. 1956 7hr/d edema; alveolar hemorrhage) 4 Rat 70 d pm Hepatic 66.3 211 (increased liver 538 (hepatocellular Tyl and 21d m weight) hypertrophy) Neeper-Bradely Gd 0-19 Renal 66.3 (increased kidney 1989 ppd 5-27 weight and hyalin 6 hr/d droplets in 7 d/wk males) Other 66.3 211 (reduced weight gain, food intake; salivation; periocular, peroral and perinasal encrustation) 5 Rat 4.5-7 mo Hepatic 96° 158 (cloudy swelling, Hollingsworth Sd/wk granular et al. 1956 7hr/d degeneration) Renal 96 158 (increased kidney weight) S103443 H1TVaH °C TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species frequency System (ppm) (ppm) (ppm) Reference 6 Rabbit 2-12 wk Resp 173 (interstitial 798 (emphysema) Hollingsworth 5d/wk edema, et al. 1956 7hr/d congestion) 7 Gn Pig 4.5-7 mo Hepatic 96 158 (cloudy swelling) 341 (focal necrosis, Hollingsworth 5d/wk slight cirrhosis) et al. 1956 7hr/d 8 Gn Pig 2-4.5 wk Resp 173 (slight Hollingsworth 5d/wk interstitial et al. 1956 7hr/d edema, alveolar hemorrhage) Neurological ° Rat 70 d pm 211 538 (increased Tyl and 21d m relative brain Neeper-Bradely Gd 0-19 weight, ataxia, 1989 ppd 5-27 hyperactivity, 6 hr/d tremors) 7 d/wk Developmental 10 Rat 70 d pm 211 538 (reduced litter Tyl and 21dm size, increased Neeper-Bradely Gd 0-19 postnatal death) 1989 ppd 5-27 6 hr/d 7 d/wk Reproductive 1" Rat 70 d pm 211 538 (increased testes Tyl and 21d m weight) Neeper-Bradely Gd 0-19 1989 ppd 5-27 6 hr/d 7 d/wk S103443 H1TV3H C ot TABLE 2-1 (Continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure Species frequency System (ppm) (ppm) (ppm) Reference CHRONIC EXPOSURE Systemic 12 Human 5 yr Derm/oc 80 (eye and nose Hollingsworth average irritation) et al. 1956 (occup) 13 Rat 76 wk Hemato 500 Riley et al. 5d/wk Hepatic 75 500 (increased 1980 Shr/d liver weight) Renal 75 500 (increased kidney weight) Other 500 (no change in body weight, food or water intake) ‘The number corresponds to entries in Figure 2-1. ®Used to derive an intermediate-duration MRL; dose adjusted for less than continuous exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability), resulting in an MRL of 0.2 ppm. d = day(s); Derm/oc = dermal/ocular; Gd = gestation day; Gn pig = guinea pig; Hemato = hematological; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; m = mating; mo = month(s); NOAEL = no-observed-adverse-effect level; occup = occupational; pm = premating; Resp = respiratory; wk = week(s); yr = year(s) S103443 H1TV3H 2 Li FIGURE 2-1. Levels of Significant Exposure to 1,4-Dichlorobenzene — Inhalation ACUTE INTERMEDIATE CHRONIC (s14 Days) (2365 Days) Systemic Systemic & @ & & Ss & £5 © & & m & qt & & 5 RO ry & & > & + om of & ® & F&F gf FEE Ff 1,000 ~ on @®sh on ov 3x ow ow x Ox ox ox ou oor or 8% Ox Ob ox 100 | ox 1 , ox ox Ai 1 1 ' | 1 | | | | | | 10 : 4 Key : Bl Lc50 ! Minimal risk level ) h Rabbit @ LOAEL for serious effects (animals) | for effects other i g Guinea pig LOAEL for less serious effects (animals) 1 than cancer 1+ y NOAEL (animals) w | A LOAEL for less serious effects (humans) The number next to each point corresponds to entries in Table 2-1. J 0A S103443 HITV3H CT zl 13 2. HEALTH EFFECTS were derived from a large study with several inconsistent variables such as the exposed species, numbers, and sex of animals per species, and duration of exposure at each exposure level. (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 for 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.) Therefore, the reported observations provide qualitative evidence of respiratory effects as a result of intermediate-duration inhalation exposure to 1,4-dichlorobenzene. Hepatic Effects. Hepatic effects have been reported in humans following long-term exposure to 1,4-dichlorobenzene via inhalation. As described above, 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 probably more than 1 year. No estimates of the 1,4-dichlorobenzene exposure levels 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. Therefore, these case studies indicate that the liver is a target organ for 1,4-dichlorobenzene in humans, but they do not provide quantitative information. Liver effects have been reported in rats and guinea pigs in inhalation studies with 1,4-dichlorobenzene at various levels and durations of exposure (Hollingsworth et al. 1956). As mentioned previously, 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 inhaled 158-341 ppm 1,4-dichlorobenzene intermittently for 5-7 months, several hepatic effects were noted. Male and female rats displayed cloudy swelling and degeneration of the hepatic parenchymal cells from the central zone of the liver, and increased relative liver weights at a 158 ppm. These changes were not seen at a concentration of 96 ppm. Based on the NOAEL of 96 ppm, an intermediate MRL was calculated as described in the footnote for Figure 2-1. In the same study, guinea pigs that were exposed to 341 ppm for a comparable duration had focal necrosis and slight cirrhosis in some animals as well as hepatocyte swelling and degeneration. In a long-term inhalation study in rats, exposure to 1,4-dichlorobenzene at 500 ppm intermittently for 76 weeks resulted in increases in organ weights, including the liver (Riley et al. 1980). However, 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. Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to 1,4-dichlorobenzene. Inhalation of 1,4-dichlorobenzene at 158 or 341 ppm intermittently for 4.5-7 months by rats caused a slight increase in renal weight in males but not females (Hollingsworth et al. 1956). The limitations on the interpretation of these data have been discussed, but the findings in this study are consistent with those reported by Riley et al. (1980) in a 76-week study in rats, as described below. In a long-term inhalation study in rats, exposure to 1,4-dichlorobenzene at 500 ppm intermittently (5 hours per day, 5 days per week) for 76 weeks resulted in increases in organ weights, including the kidneys (Riley et al. 1980). It is interesting to note 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. 14 2. HEALTH EFFECTS Dermal/Ocular Effects. Dermal effects resulting from 1,4-dichlorobenzene exposure were reported to occur in a 69-year-old man who had been exposed for approximately 3 weeks to 1,4-dichlorobenzene used in his home, including on a chair on which he had been sitting. He gradually developed petechiac (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, as 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 report on 58 men who had worked for 8 months to 25 years (average: 4.75 years) in a plant using 1,4-dichlorobenzene, painful irritation of the nose and eyes were reported to occur at 1,4-dichlorobenzene levels ranging from 80 to 160 ppm. At levels greater than 160 ppm, the air was considered unbreathable by unacclimated persons. Neither cataracts nor any other lens changes were found upon occasional careful examination of their eyes (Hollingsworth et al. 1956). There is no clear, quantitative evidence of dermal or ocular effects resulting from inhalation exposure to 1,4-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-dichlorobenzene at 798 ppm for 12 weeks (Hollingsworth et al. 1956). However, these data are too limited to form the basis for concern for ocular effects resulting from 1,4-dichlorobenzene exposure. 2.2.1.3 Immunological 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. No studies were located regarding immunological effects in animals after inhalation exposure to 1,4-dichlorobenzene. 2.2.1.4 Neurological Effects Neurological effects have been reported in case studies of humans exposed to 1,4-dichlorobenzene via inhalation. Intense headaches were reported in a 36-year-old woman who used 1,4-dichlorobenzene as a moth killer in her home; headaches, nausea, and vomiting were reported in a 34-year-old woman who demonstrated products containing 1,4-dichlorobenzene in an enclosed booth in a department store; persistent headaches were among the symptoms reported in a 60-year-old man and his wife whose home had been saturated with 1,4-dichlorobenzene mothball vapor for 3 or 4 months (Cotter 1953). The man also complained of numbness, clumsiness, and a burning sensation in his legs, which is consistent with peripheral nerve damage. 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 (Miyai et al. 1988). Brainstem auditory evoked potentials (BAEPs) showed marked delays of certain brainwaves. Her symptoms gradually improved over the next 6 months after cessation of 15 2. HEALTH EFFECTS exposure and BAEPs examined 8 months later were normal. This study suggests that there may be measurable but reversible neurological effect associated with human inhalation exposure to 1,4-dichlorobenzene. The level of 1,4-dichlorobenzene exposure was neither known nor estimated in any 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. Adult rats exposed to 538 ppm 1,4-dichlorobenzene during a 2-generation study displayed symptoms associated with compound neurotoxicity, including tremors, ataxia, and hyperactivity. 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 as compared to the controls (Tyl and Neeper-Bradley 1989). 2.2.1.5 Developmental Effects No studies were located regarding developmental effects in humans after inhalation exposure to 1,4-dichlorobenzene. Exposure of pregnant rats to 1,4-dichlorobenzene via inhalation at levels up to 500 ppm for 6 hours per day on days 6-15 of pregnancy did not result in developmental effects in the offspring (Hodge et al. 1977). In another study, exposure of pregnant rabbits to 1,4-dichlorobenzene by inhalation at 800 ppm for 6 hours per day on days 6-18 of gestation resulted in a significant increase in the incidence of retroesophageal right subclavian artery (Hayes et al. 1985). Slight maternal toxicity was also observed at 800 ppm, as indicated by significantly decreased body weight gain during the first 3 days of exposure. 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. The authors concluded that the structural effect seen in this study was a minor variation in the circulatory system (seen in 2% of control litters in their laboratory) and did not constitute a teratogenic response. As an alternative view, this structural anomaly might suggest that 1,4-dichlorobenzene inhaled by the dams reached and elicited an effect on developing fetal tissue. The highest NOAEL values and a reliable LOAEL value for developmental effects in rats and rabbits in the acute duration category are recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Reproductive Effects No studies were located regarding reproductive effects in humans after inhalation exposure to 1,4-dichlorobenzene. 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. The females were then exposed on gestational days 0 through 19 and post natal days 5 through 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. Hyalin droplet nephropathy was also present in the kidneys of all the males (Tyl and Neeper-Bradley 1989). 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 16 2. HEALTH EFFECTS survival 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 authors concluded that parental toxicity was the cause of the increased risk to offspring rather than inherent effects of 1,4-dichlorobenzene on reproductive processes. 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 utilized in the 2-generation study discussed above. 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 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 2.4. 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 (as 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 via the inhalation route. 2.2.2 Oral Exposure Most of the data described in this section were derived from laboratory studies in which 1,4-dichlorobenzene was administered to test animals via gavage. In addition, two human case studies of 1,4-dichlorobenzene consumption are described. As mentioned previously, case studies in general are not scientifically equivalent to well-conducted epidemiologic studies or laboratory experiments and should be viewed only as providing contributory evidence that 1,4-dichlorobenzene may cause the reported effects. 2.2.2.1 Death No studies were located regarding death in humans after oral exposure to 1,4-dichlorobenzene. 17 2. HEALTH EFFECTS Animal mortality data are available from acute-, intermediate-, and chronic-duration studies. In acute- duration animal studies, a single gavage dose of 1,000 mg/kg to rats or 1,600 mg/kg to guinea pigs resulted in no deaths (Hollingsworth et al. 1956); whereas a dose of 4,000 mg/kg to rats or 2,800 mg/kg to guinea pigs resulted in 100% mortality (Hollingsworth et al. 1956). Oral LD, values for 1,4-dichlorobenzene in adult rats were reported as 3,900 and 3,800 mg/kg for males and females, respectively (Gaines and Linder 1986). The lethality data for 1,4-dichlorobenzene presented in four 14-day gavage studies (NTP 1987) have been somewhat 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. In another 14-day study, however, 4/5 females (80%) at 1,000 mg/kg/day died, and all rats dosed at 2,000 mg/kg/day and higher 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, whereas in another 14-day study, 70% of mice at 1,000 mg/kg/day died, and all mice that received 4,000 mg/kg/day died. In 13-week gavage studies, 17 of 20 rats (85%) dosed with 1,4-dichlorobenzene at 1,500 mg/kg/day died. Mortality rates in mice were somewhat lower; at 1,500 mg/kg/day, 8 of 20 (40%) died, and no deaths resulted from dosages up to 900 mg/kg/day (NTP 1987). High mortality was reported in male rats that received 1,4-dichlorobenzene in a 2-year study (NTP 1987). At 300 mg/kg/day, 26 out 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 at levels up to 600 mg/kg/day for 2 years (NTP 1987). The high rate of mortality in male rats was probably related, in part, to the severe nephrotoxic effects and renal tumors that were reported in these animals as described in Sections 2.2.2.2 and 2.2.2.8. All reliable LOAEL values for lethality and LD, 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 2-year studies in animals, no respiratory effects were reported in female rats or mice of either sex that received 1,4-dichlorobenzene by gavage at levels up to 600 mg/kg/day or in male rats that received 1,4-dichlorobenzene at levels up to 300 mg/kg/day (NTP 1987). Cardiovascular Effects. No studies were located regarding cardiovascular effects in humans after oral exposure to 1,4-dichlorobenzene. In 2-year studies in animals, no cardiovascular effects were reported in female rats or mice of either sex that received 1,4-dichlorobenzene by gavage at levels up to 600 mg/kg/day or in male rats that received 1,4-dichlorobenzene at levels up to 300 mg/kg/day (NTP 1987). TABLE 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene - Oral LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference ACUTE EXPOSURE Death 1 Rat (GO) 14d 2000 (LD100) NTP 1987 1x/d 2 Rat (Go) 1d 3800 (LD50) Gaines and 1x/d Linder 1986 3 Rat (Go) 1d 4000 (LD100) Hol lingsworth 1x/d et al. 1956 4 Gn pig (GO) 1d 2800 (LD100) Hollingsworth 1x/d et al. 1956 5 Mouse (Go) 14d 4000 (LD100) NTP 1987 1x/d Systemic 6 Rat (G) 5d Hepatic 770 (porphyria) Rimington and 1x/d Ziegler 1963 7 Rat (GO) 14d Hepatic 20 (increased activities Carlson and 1x/d of glucuronyl trans- Tardiff 1976 ferase benzopyrene hydroxylase and azoreductase 8 Rat (G) 3d Hepatic 250 (increased delta- Ariyoshi et al. 1x/d aminolevulinic 1975 acid synthetase and microsomal protein content) 9 Rat (GO) 14d Hepatic 300 650 (decreased hexo- Carlson and 1x/d barbital sleeping Tardiff 1976 time) 10 Rat (Go) 7d Renal 120 (protein droplet Charbonneau 1x/d formation) et al. 198% S103443 H1TV3H 2 81 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Developmental 1" Rat (Go) 10d 250 500 (extra rib in Giavini et al. 1x/d fetuses) 1986 Gdé-15 INTERMEDIATE EXPOSURE Death 12 Rat (GO) 13 wk 1500 (17/20 died; 85%) NTP 1987 5d/wk 13 Mouse (GO) 13 wk 1500 (8/20 died; 40%) NTP 1987 5d/wk Systemic 14 Rat (GO) 13 wk Renal 75 (hyaline droplet 150 (single cell Bomhard et al. 1x/d formation) necrosis) 1988 15 Rat (GO) 6 mo Hepatic 18.8° 188 (increased liver 376 (cirrhosis, focal Hollingsworth 5d/wk weight) necrosis) et al. 1956 Renal 18.8 376 (cloudy swelling in tubular epithelium) 16 Rat (GO) 13 wk Renal 600 (moderate tubular NTP 1987 5d/wk degeneration) Derm/oc 600 S103443 H1TV3H 2 61 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure’ Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference 17 Rat (GO) 30-120 d Hepatic 50 (porphyria) Carlson 1977 1x/d 18 Rat (Go) 13 wk Gastro 900 1200 (epithelial NTP 1987 5d/wk necrosis of small intestine) Hemato 300 (decreased hemato- crit, hemoglobin and red blood cell levels) Hepatic 600 (increased serum 1200 (necrosis of cholesterol) hepatocytes) Renal 300 (severe tubular degeneration) Derm/oc 900 1200 (necrosis of nasal epithelium) 19 Rat (GO) 90d Hemato 40 Carlson and 1x/d Hepatic 10 (increased Tardiff 1976 azoreductase levels) 20 Mouse (GO) 13 wk Hemato 600 (decreased white NTP 1987 5d/wk cell count) Hepatic 600 (hepatocellular degeneration) 21 Mouse (GO) 13 wk Hepatic 338 675 (mild hepatocyto- 900 (moderate hepato- NTP 1987 5d/wk megaly) cytomegaly) Other 900 (no change in body weight) S103443 H1TV3H 2 TABLE 2-2 (Continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference CHRONIC EXPOSURE Death 22 Rat (GO) 2 yr 300 (26/50 males died; NTP 1987 5d/wk 52%) Systemic 23 Rat (GO) 2 yr Resp 600 NTP 1987 5d/wk Cardio 600 Gastro 600 Hemato 600 Musc/skel 600 Hepatic 600 Renal 150 (moderate 300 (severe nephropathy in nephropathy in males) males) Derm/oc 600 24 Mouse (GO) 2 yr Resp 600 NTP 1987 5x/wk Cardio 600 Gastro 600 Hemato 300 (lymphoid hyper- plasia of lymph nodes) Musc/skel 600 Hepatic 300 (hepatocellular degeneration) Renal 300 (nephropathy, tubular degenera- tion) Derm/oc 600 Other 600 (no change in body weight) S103443 H1TV3H 2 12 TABLE 2-2 (Continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg/kg/day) (mg/kg/day) (mg/kg/day) Reference Cancer 25 Rat (GO) 2 yr 300 CEL (renal NTP 1987 5d/wk tubular cell adenocarcinomas in males) 26 Mouse (GO) 2 yr 600 CEL (hepato- NTP 1987 5x/wk cellular carcinomas, hepatoblastomas) ‘The number corresponds to entries in Figure 2-2. "Used to derive an intermediate-duration MRL; dose adjusted for less than continuous exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability), resulting in an MRL of 0.1 mg/kg/day. Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Derm/oc = dermal/ocular; (G) = gavage; Gastro = gastrointestinal; Gd = gestation day; Gn pig = guinea pig; (GO) = gavage oil; Hemato = hematological; LD50 = lethal dose, 50% kill; LD100 = lethal dose, 100% kill; LOAEL = lowest-observed-adverse-effect level; mo = month(s); Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s); x = time(s); yr = year(s) S103443 H1TV3H FIGURE 2-2. Levels of Significant Exposure to 1,4-Dichlorobenzene — Oral ACUTE (<14 Days) Systemic > EN; 3 & 8 ° (mg/kg/day) Ff Ne < Q 10,0001 osm Wer [ Xd ®4g or 1,000 6 or Q11r sr Q9r Or 100} @r0r 10} or 1+ 0.14 0.01} 0.001 Key r Rat Hl LDso ' Minimal risk level m Mouse @ LOAEL for serious effects (animals) , for effects other 0.0001} g Guinea pig (B LOAEL for less serious effects (animals) ~~. than cancer NOAEL (animals) CEL - Cancer Effect Level (animals) 0.00001} The number next to each point corresponds to entries in Table 2-2. * Doses represent the lowest dose tested that produced a tumerigenic _";I response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H ¢C €e FIGURE 2-2 (Continued) INTERMEDIATE (15-364 Days) Systemic N © & 3 2 OS F o* © ¥ N > & Ss & & & © © (mg/kg/day) Q o > Ns <& F o 10,000 | @13m @12 er 2 @18r 18r 1,000 oer 020 oxn zm O77 2 Qe or Oa Q@ er O21m @ 150 15 @® er 100} 15 gar Q14r Q19r Q17r Q 150 Q15r 10+ Q19r 1 1 | 1 ' | | 1 0.1} w 0.01} 0.001} Key r Rat HM L050 ' Minimal risk level m Mouse @ LOAEL for serious effects (animals) 1 for effects other 0.0001F g Guinea pig (D LOAEL for less serious effects (animals) J cancer O NOAEL (animals) CEL — Cancer Effect Level (animals) 0.00001F The number next to each point corresponds to entries in Table 2-2. * Doses represent the lowest dose tested that produced a tumerigenic 0.000001 response and do not imply the existence of a threshold for the cancer end point. S103443 H1TV3H 2 ve NN (mg/kg/day) oF 10,000 1,000 100 10 0.1 0.01 0.001 0.0001 0.00001 FIGURE 2-2 (Continued) 0.000001 CHRONIC (2365 Days) Systemic a 5 $ @ @ N oi © & of 5 © > & \ & o’ . & oF & N ¥ © > § eS & 2 5 $ $ 3 ¢ ¢ & ? oP QE & RX & 2 3 << o NN < Q Qo o 024m Q23r 024m Q23r 024m Q23r O23r 024m Q23r 020r 024m QO 293r 024m @ 26m @22 @24m @24m @24m @23r 250 @23r nN 7 | ip 2 m m m m 0 — » 10° | Estimated Upper- 10 Bound Human Cancer Risk 10 6 Levels Key 1077 r Rat HB Los0 ! Minimal risk level m Mouse @ LOAEL for serious effects (animals) , for effects other g Guinea pig (J LOAEL for less serious effects (animals) ~~! han cancer O NOAEL (animals) @ CEL - Cancer Effect Level (animals) The number next to each point corresponds to entries in Table 2-2. * Doses represent the lowest dose tested that produced a tumerigenic response and do not imply the existence of a threshold for the cancer end point. 26 2. HEALTH EFFECTS Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after oral exposure to 1,4-dichlorobenzene. In 13-week gavage studies in rats, evidence of gastrointestinal irritation included epithelial necrosis and villar bridging of the mucosa of the small intestines in rats that received 1,4-dichlorobenzene at doses of 1,200 mg/kg/day and above, but not at 900 mg/kg/day or lower doses (NTP 1987). In 2-year studies, no gastrointestinal effects were reported in female rats or mice of either sex that received 1,4-dichlorobenzene at doses up to 600 mg/kg/day or male mice that received doses up to 300 mg/kg/day (NTP 1987). Hematological Effects. 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 hypochromic, microcytic 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 rose 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 occur 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 rats dosed with 1,4-dichlorobenzene at levels up to 40 mg/kg/day for 90 days (Carlson and Tardiff 1976). In another 13-week study in rats, however, 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 was consistently seen in female rats at the same dosage level. Hematologic effects seen in a 13-week study in mice included 34-50% reductions in the white cell counts of all dosed male groups (600-1,800 mg/kg/day) (NTP 1987). These decreases were accompanied by 26-33% decreases in neutrophils. No hematologic effects were reported in 2-year studies in which male rats received 1,4-dichlorobenzene at levels up to 300 mg/kg/day and female rats received levels up to 600 mg/kg/day (NTP 1987). In mice of both sexes, 2-year administration of 300 or 600 mg/kg/day resulted in an increased incidence (22-24%) of lymphoid hyperplasia of the mandibular lymph node (NTP 1987). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after oral exposure to 1,4-dichlorobenzene. In 2-year studies in animals, no musculoskeletal effects were reported in female rats or mice of either sex that received 1,4-dichlorobenzene by gavage at levels up to 600 mg/kg/day or in male rats that received 1,4-dichlorobenzene at levels up to 300 mg/kg/day (NTP 1987). Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to 1,4-dichlorobenzene. Hepatic effects have been reported in several 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. 27 2. HEALTH EFFECTS 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 uroporphyrin, is considered to be an indication of liver damage. Administration of 1,4-dichlorobenzene 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- to 15-fold above levels in controls. A 37- to 100-fold increase in urinary uroporphyrin levels occurred; porphobilinogen levels increased 200- to 530-fold; and a 10-fold increase in &-aminolevulinic acid (8-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 lower levels for a longer period of time in another study (Carlson 1977), as discussed below. Changes in certain markers of liver function including cytochrome P-450 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 14-dichlorobenzene. However, the cytochrome P-450 content did not change; although the microsomal protein content of liver preparations was increased. The toxicological significance of these findings is not clear since 8-ALA synthetase activity did not correlate with cytochrome P-450 concentration. Effects on hepatic enzyme activities were reported to occur 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 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-p-nitrophenyl phenylphosphorothionate (EPN) detoxification to p-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 two 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 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 sensitive 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 (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). 28 2. HEALTH EFFECTS Similar hepatic effects were reported in two 13-week gavage studies in mice (NTP 1987). Hepatocellular 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 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 this NOAEL, an intermediate MRL was calculated as described in the footnote for Table 2-2. 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 §-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 as 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.) In the only study of lifetime oral exposure to 1,4-dichlorobenzene, hepatic effects were seen in mice, but not in rats (NTP 1987). In this 2-year bioassay, male rats were dosed with 1,4-dichlorobenzene by gavage at 150 or 300 mg/kg/day and females at 300 or 600 mg/kg/day. In mice dosed at 300 or 600 mg/kg/day, there were increased incidences of alterations in cell size (cytomegaly and karyomegaly), hepatocellular degeneration, and individual cell necrosis. Renal Effects. No studies were located regarding renal effects in humans after oral exposure to 1,4-dichlorobenzene. Renal tubular degeneration has been observed in male but not female 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 a dose of 188 mg/kg/day and cloudy swelling in the renal tubular epithelium at a dose of 376 mg/kg/day (Hollingsworth et al. 1956). Renal effects were not observed in mice in either of two 13-week gavage studies, using dosage regimens of 600-1,000 mg/kg/day and 80-900 mg/kg/day (NTP 1987). 29 2. HEALTH EFFECTS 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 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. 1989a). Administration of a single dose of '“C-1,4-dichlorobenzene by gavage at 500 mg/kg gave similar results. An analysis of the renal tissue of animals administered radio-labelled 1,4-dichlorobenzene indicated that it was reversibly associated with the protein a-2p-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 rats (also Fischer-344 rats, as in the NTP study) by gavage at 75-600 mg/kg/day for 13 weeks (Bomhard et al. 1988). By 4 weeks, pronounced cortico-medullary changes in the proximal convoluted tubules of the nephrons were evident in most males at dosage levels of 150 mg/kg/day and higher. Cortical tubules had hyaline droplets in the epithelia and large hyaline droplets and sporadic desquamated epithelia in the lumina. At 13 weeks, one male at 75 mg/kg/day and all males at 150 mg/kg/day and above were observed to have an increased incidence of these changes. The female rats showed no comparable changes. Renal effects have also been observed in male rats in the only available study of chronic oral exposure to 1,4-dichlorobenzene. Male rats exposed to 1,4-dichlorobenzene at 150 and 300 mg/kg/day by gavage for 2 years exhibited 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 mice. Renal tubular degeneration was noted in female mice but these changes were qualitatively different from those in male rats (NTP 1987). Dermal/Ocular Effects. A 19-year-old female 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 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). Necrosis of the nasal epithelium was observed in rats that received 1,4-dichlorobenzene by gavage at 1,200 mg/kg/day for 13 weeks. Neither dermal nor ocular effects have been reported to occur in 2-year studies in which female rats and mice of both sexes received 1,4-dichlorobenzene by gavage at doses of up to 600 mg/kg/day and male rats received doses of up to 300 mg/kg/day (NTP 1987). 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans or animals after oral exposure to 1,4-dichlorobenzene. Symetrical lesions with increased skin pigmentation were reported in the case study of the 19-year-old woman who ingested 4-5 moth pellets of 1,4-dichlorobenzene per day for a 2.5 year period (Frank and Cohen 1961). As described in Section 2.2.2.2, this may have been the result an immunological response to 1,4-dichlorobenzene. However, this possibility was not addressed by the authors. 2.2.2.4 Neurological Effects 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 30 2. HEALTH EFFECTS 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 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, these effects were considered to be psychological rather than the physiological effects of withdrawal from 1,4-dichlorobenzene (Frank and Cohen 1961). No studies were located regarding neurological effects in animals after oral exposure to 1,4-dichlorobenzene. 2.2.2.5 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to 1,4-dichlorobenzene. 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 days 6-15 of gestation at doses of 500 mg/kg/day and above (Giavini et al. 1986). A reduction in fetal weight was observed at 1,000 mg/kg/day, and maternal weight gain was retarded at levels of 500 mg/kg/day and above. 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 not considered to be an 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. 2.2.2.6 Reproductive Effects No studies were located regarding reproductive effects in humans or animals after oral exposure to 1,4-dichlorobenzene. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans after oral exposure to 1,4-dichlorobenzene. Gavage administration of 1,4-dichlorobenzene to mice and rats at single doses of 300-1,000 mg/kg did not result in unscheduled deoxyribonucleic acid (DNA) synthesis in the mouse hepatocytes or 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 (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 (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). 31 2. HEALTH EFFECTS 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. 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 2.4. 2.2.2.8 Cancer No studies were located regarding carcinogenic effects in humans after oral exposure to 1,4-dichlorobenzene. 1,4-Dichlorobenzene was carcinogenic in mice and male (but not female) 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 were reported in the incidence of renal tubular cell adenocarcinomas 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 4/1,098 (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 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 concluded that 1,4-dichlorobenzene was carcinogenic in male rats, but not in female rats. In a 2-year bioassay in 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 elevated in high-dose males and the incidence of adrenal gland medullary hyperplasia and focal hyperplasia of the adrenal gland capsule were increased in dosed male mice. 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. Toxicologists at the Chemical Industry Institute of Toxicology (CIIT) have hypothesized that the male rat kidney is susceptible to the induction of certain tumors because it contains the protein a-2u-globulin, which has not been found at significant levels in female rats or in mice or humans (Charbonneau et al. 1987, 1989a, 1989b). They have demonstrated that chemicals like 1,4-dichlorobenzene 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 32 2. HEALTH EFFECTS tumor formation via a mechanism that has not yct been clucidated. It has also been demonstrated that the same effects can be elicited in male rats administered other «-2p-globulin binding chemicals such as hexachlorocthane, d-limonene ~~ [1-methyl-4(1-methylethenyl)cyclohexcne], unleaded gasoline, and pentachlorocthane (EPA 1991). Based on these data, EPA (1991) concluded that tumors associated with a-2p-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 also 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-dichlorobenzene 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 the genotoxicity of the compound. 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,* 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 2.4x10% (HEAST 1992). These values are currently under review by the EPA (HEAST 1990) and have not been included in the IRIS database. 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 rats was greater than 6,000 mg/kg (Gaines and Linder 1986). However, it is not clear whether any 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 1,4-dichlorobenzene by the dermal route. No studies were located regarding the following effects in humans or animals after dermal exposure to 1,4-dichlorobenzene: 2.2.3.2 Systemic Effects 2.2.3.3 Immunological Effects 2.2.3.4 Neurological Effects 2.2.3.5 Developmental Effects 2.2.3.6 Reproductive Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 33 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 show that 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 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 '“C-labelled 1,4-dichlorobenzene administered to rats via inhalation, gavage, or subcutaneous injection, it has been estimated that tissue levels of 1,4-dichlorobenzene and/or its metabolites are similar when these animals inhaled 1,4-dichlorobenzene at 1,000 ppm for 3 hours per day for 10 days or received 10 repeated oral or 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/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/day exposure regimens in inhalation studies. 2.3.1.2 Oral Exposure No studies were located on the rate or amount of absorption of 1,4-dichlorobenzene 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 '‘C-1,4-dichlorobenzene at 250 mg/kg/day for 10 days via gavage or by subcutaneous injection (Hawkins et al. 1980). 34 2. HEALTH EFFECTS 2.3.1.3 Dermal Exposure No studies were located regarding the absorption of 1,4-dichlorobenzene by humans or animals after dermal exposure to 1,4-dichlorobenzene. 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 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 pg/g wet tissue (EPA 1986¢c). 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 1,4-dichlorobenzene in female 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 '“C-1,4-dichlorobenzene at 1,000 ppm for 3 hours per day, and highest concentrations of '*C were measured in fat (up to 598 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. Two studies in animals clearly demonstrate that adipose tissue is a major repository of ingested 1,4-dichlorobenzene. In male rats that received a single gavage dose of 200 mg/kg, the highest concentration of 1,4-dichlorobenzene was found in adipose tissue at all sampling intervals and up to 120 hours postexposure (Kimura et al. 1979). Kidney and liver contained the next highest levels of 1,4-dichlorobenzene, which were about 4% and 3%, respectively, of the concentrations found in adipose tissue. 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. 35 2. HEALTH EFFECTS 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), 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. 2.3.3 Metabolism 2,5-Dichlorophenol appears to be the principal metabolic product of 1,4-dichlorobenzene in humans and animals. Analysis of the urine specimens of a 3-year-old boy, who had been exposed to 1,4-dichlorobenzene yielded 2,5-dichlorophenol as well as four unidentified phenols. These compounds were shown to be conjugated with glucuronic and sulfuric acids (Hallowell 1959). Following oral administration to rabbits, 1,4-dichlorobenzene was also oxidized principally to 2,5-dichlorophenol (Azouz et al. 1955). A very high percentage of this metabolite was eliminated in the urine as conjugates of glucuronic or sulfuric acids. In addition to 2,5-dichlorophenol, two sulfur-containing metabolites of 1,4-dichlorobenzene, 2,5-dichlorophenyl methyl sulfoxide and 2,5-dichlorophenyl methyl sulfone, were identified in the tissues, blood, and urine of rats following a single gavage dose of 200 mg/kg or a series of 800 mg/kg/day doses over a week (Kimura et al. 1979). 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. 2.34 Excretion 2.3.4.1 Inhalation Exposure No studies were located regarding excretion in humans after inhalation exposure to 1,4-dichlorobenzene. In an animal study, inhaled 1,4-dichlorobenzene was excreted mainly in the urine. When C-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 “C was recovered in the urine. The amount of '*C-label excreted in the expired air during 48 hours after the tenth dose represented a small proportion of the total '*C excreted (Hawkins et al. 1980). This level was similar after inhalation (0.2%) and oral (1.0%) exposure. In rats with cannulated bile ducts, no '“C was detected in the feces up to 24 hours after a single dose. Of the total '*C 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. 36 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. When '‘C-1,4-dichlorobenzene was administered by gavage to female rats for 10 days at 250 mg/kg/day, 97% of the recovered '“C 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 '‘C was excreted in the feces during the 24 hours following the last dose and was presumed to be unabsorbed material. Another 63.0% was recovered in the bile and 28.1% 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. 2.3.4.3 Dermal Exposure No studies were located on excretion in humans or animals after dermal exposure to 1,4-dichlorobenzene. 2.4 RELEVANCE TO PUBLIC HEALTH As discussed in Section 5.0, 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 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 in rats, conducted 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-dichlorobenzene 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. Inhalation MRLs ® An MRL of 0.2 ppm has been derived for intermediate-duration inhalation exposure 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 coverted to 20 ppm, incorporating adjustments for intermittent exposure (7 hours/day, 5 days/week). Cloudy swelling and granular degeneration of the liver parenchymal cells from the central zone were reported at concentrations of 158 ppm or greater. 37 2. HEALTH EFFECTS The MRL was based on liver toxicity rather than kidney toxicity because the effects of 1,4-dichlorobenzene on the kidneys of male rats are associated with the occurrence of hyaline droplets from a2p-globulin and are not applicable to humans (EPA 1991). An MRL was not derived for acute-duration inhalation exposure to 1,4-dichlorobenzene due to the lack of sufficient data in humans or animals to identify reliable NOAEL or LOAEL values. An MRL was not derived for chronic exposure conditions because the data from studies in humans and animals were not considered suitable. Riley et al. (1990) observed increased liver weights in rats exposed to 500 ppm for 76 weeks. However, the histopathological effects observed by Hollingworth et al. (1956) were not seen by Riley et al. (1990). Lacking the histological support for the organ weight change, the NOAEL from this study could not be used for the derivation of an MRL. Oral MRLs ® An MRL of 0.1 mg/kg/day has been derived for intermediate-duration exposure to 1,4-dichlorobenzene. This MRL was calculated using a NOAEL of 18.8 mg/kg/day, based on the absence of liver effects in rats (Hollingsworth et al. 1956). This dose was converted to 13.4 mg/kg/day, incorporating adjustments for exposure for 5 days/week. Hepatic necrosis and slight cirrhosis were seen at dose levels of 376 mg/kg/day or greater and liver weights were also increased at doses of 188 mg/kg/day and greater. An acute 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. A chronic 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 (such as in homes). The only available information related to the death of humans exposed to 1,4-dichlorobenzene is a case study about a 60-year-old man and his wife who both died of liver ailments after their home had been saturated with 1,4-dichlorobenzene vapor for 3-4 months (Cotter 1953). However, nothing was known about their 1,4-dichlorobenzene exposure levels or 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); there are no mortality data from animals exposed to 1,4-dichlorobenzene via inhalation for comparison. 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 oral LD, values in rats and guinea pigs have been reported as 4,000 and 2,800 mg/kg, respectively, (Hollingsworth et al. 1956), and 3,800 mg/kg as the acute oral LD, in rats (Gaines and Linder 1986). In 14-day studies, 4 out 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 38 2. HEALTH EFFECTS for 2 years (NTP 1987). Mice tested in the NTP (1987) study were far less susceptible than rats to the lethal effects of 1,4-dichlorobenzene. There is also 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 the other case a 21-year-old woman consumed 1-2 1,4-dichlorobenzene toilet bowl deodorizer blocks per week throughout her pregnancy (Campbell and Davidson 1970). Thus, 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 a human case study and an animal study. In the 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 patient 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 single 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. 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). These findings suggest that respiratory effects are a possible concern for humans exposed to 1,4-dichlorobenzene via inhalation. However, 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. Hematological Effects. 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 occur 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 (blood is pale), microcytic anemia with excessive polychromasia, marginal nuclear hypersegmentation of the neutrophils, and the presence of Heinz 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 methemoglobinuria were 39 2. HEALTH EFFECTS reported to occur in a 3-year-old boy who had played with, and possibly eaten, some 1,4-dichlorobenzene moth crystals (Hallowell 1959). In rats, 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 mice, effects on white blood cells were seen in all males that received 1,4-dichlorobenzene at levels of 600-1,800 mg/kg/day. There were 34-50% reductions in white cell counts, accompanied by 26-33% decreases in neutrophils (NTP 1987). 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-dichlorobenzene. Effects in humans have been associated with red blood cells. Because of sex and species differences seen in animal studies (i.e., effects on red blood cells in rats and effects on 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. 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 range from 1 to 18 months; however, quantitative data on 1,4-dichlorobenzene levels are not available. No data on hepatic effects were available on humans exposed via the oral or dermal routes. 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. 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). 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 (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 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 38-ALA synthetase at a 1,4-dichlorobenzene 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 40 2. HEALTH EFFECTS 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-dichlorobenzene. 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 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. Based on the results of studies in humans and animals, humans exposed to 14-dichlorobenzene may 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. However, it is not likely 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 hepatic effects. Renal Effects. Renal effects have not been reported in humans exposed to 1,4-dichlorobenzene by any route, but have been reported in various inhalation and oral studies in animals. 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 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 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. 41 2. HEALTH EFFECTS Administration of 1,4-dichlorobenzene by gavage to 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 °H-thymidine incorporation into renal DNA. The '“C from radiolabelled 1,4-dichlorobenzene was reversibly bound to the renal protein a-2p-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 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. Renal effects have been observed in both male and female rats in a chronic oral study. Male 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 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 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 the presence of high levels of the renal protein of a-2p-globulin. Therefore, although humans may not be at risk for certain 1,4-dichlorobenzene-induced renal lesions, 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/Ocular 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-dichlorobenzene for 8 months to 25 years, painful irritation of the nose and eyes was reported to occur at 1,4-dichlorobenzene levels of 80-160 ppm. 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 occur 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 skin discoloration developed in a 19-year-old woman who had eaten 4-5 1,4-dichlorobenzene moth pellets daily for the previous 2.5 years (Frank and Cohen 1961). 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 are no data related to dermal effects resulting specifically from dermal exposure to 1,4-dichlorobenzene by humans and no data have been located relating to dermal effects in animals exposed to 1,4-dichlorobenzene via any route. No ocular effects have been reported in humans exposed to 1,4-dichlorobenzene by any route, including the 58 men who had been occupationally exposed for 8 months to 25 years and were occasionally examined for ocular effects (Hollingsworth et al. 1956). Ocular effects described as reversible, nonspecific eye ground 42 2. HEALTH EFFECTS changes (changes in the fundus or back of the eye) were seen in the eyes of rabbits exposed to 1,4-dichlorobenzene at 798 ppm for 12 weeks (Hollingsworth et al. 1956). However, these findings do not support a clear concern for potential ocular effects in humans exposed to 1,4-dichlorobenzene in any environment. Immunological Effects. No information has been located on immunological effects in humans or animals exposed to 1,4-dichlorobenzene via inhalation, oral, or dermal exposure. However, the observation of blotchy skin discolorations in the 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. Neurological Effects. Neurological effects have been reported in humans exposed to 1,4-dichlorobenzene 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 1,4-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). 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 exposed to 1,4-dichlorobenzene via inhalation, however, 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. Developmental Effects. There is no evidence of developmental effects in the offspring of humans exposed to 1,4-dichlorobenzene via any route. 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 days 6-18 of gestation (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. Reproductive Effects. No information has been located regarding reproductive effects in humans exposed to 1,4-dichlorobenzene by any route. 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. 43 2. HEALTH EFFECTS In addition, no decrement 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). 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 (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 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 cause reproductive effects. 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 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 °H-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 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 vitro and in vivo studies related to the genotoxicity of 1,4-dichlorobenzene are presented in Tables 2-3 and 2-4. As shown in Table 2-3, 1,4-dichlorobenzene is generally nonmutagenic except in plant systems (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 TABLE 2-3. Genotoxicity of 1,4-Dichlorobenzene In Vitro Species (test system) Results With Without End point activation activation Reference Microbial systems: Salmonella typhimurium TA98® TA100° TA1535° TA1538° TA98° TA100° TA1535° TA1538° S. typhimurium TA98 TA100 TA1535 TA1537 TA1538 TA98 TA100 TA1535 TA1537 Gene mutation Gene mutation Gene mutation — —_— Anderson 1976 Shimizu et al. 1983 Haworth et al. 1983 S103443 H1TV3H C vv TABLE 2-3 (Continued) Results With Without Species (test system) End point activation activation Reference Mammalian systems: Hela cells Human lymphocytes Human lymphocytes Chinese hamster ovary cells Chinese hamster lung cells L5178Y/TK*/ mouse lymphoma cells Plant systems: Root tips (16 species of dicotyledons and monocotyledons) Unscheduled DNA synthesis Unscheduled DNA synthesis Unscheduled DNA synthesis Chromosomal aberrations Sister chromatid exchanges Gene mutation Gene mutation Chromosomal aberrations (+) NS Instituto di Ricerche Biomediche 1986a Perocco et al. 1983 Instituto di Ricerche Biomediche 1987 NTP 1987 Instituto di Ricerche Biomediche 1986b NTP 1987 Sharma and Battacharya 1956 S103443 HITV3H 2 St TABLE 2-3 (Continued) Results With Without Species (test system) End point activation activation Reference Lens esculenta (L.) Moench Mitotic abnormalities NS + Sarbhoy 1980 Aspergillus nidulans Back mutation frequency NS + Prasad 1970 Tribe viceae Chromosomal aberrations NS + Srivastava 1966 *Exposed to 1,4-dichlorobenzene gas "Exposed to 1,4-dichlorobenzene exposed in DMSO “Positive result was not reproducible in other experiments in this series. — = negative result; + = positive result; (+) = weakly positive result; DNA = deoxyribonucleic acid; NS = not studied. S103443 H1TV3H 2 TABLE 2-4. Genotoxicity of 1,4-Dichlorobenzene In Vivo Species (test system) End point Results Reference Mammalian cells: Rat® bone marrow Chromosomal aberrations - Anderson and Richardson 1976 Mouse” erythrocytes Micronucleated erythrocytes = NTP 1987 Rat* kidney cells Unscheduled DNA synthesis ~ Steinmetz and Spanggord 1987b Increased DNA replication +9 » I Mouse ® hepatocytes Unscheduled DNA synthesis — Steinmetz and e Spanggord 1987a 7 m Rat’ kidney cells Increased DNA replication + Charbonneau et al. 1989 a oO 3 Mouse? erythrocytes of femoral Induction of micronuclei — Mohtashamipur @ bone marrow et al. 1987 *Exposed to 1,4-dichlorobenzene via inhalation for 2 hours at 299 or 682 ppm; for S days, 5 hours/day at 75 or 500 ppm; or for 3 months, 5 days/week, 5 hours/day at 75 or 500 ppm. "Exposed to 1,4-dichlorobenzene via gavage for 13 weeks, 5 days/week at 600-1,800 mg/kg/day. “Exposed to 1,4-dichlorobenzene via gavage in corn oil at 300, 600, or 1,000 mg/kg at 16 hours before sacrifice for UDS experiment or at 96 hours before sacrifice for DNA replication experiment. “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 1,000 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 killed 24 hours after the last dose. %Exposed to 1,4-dichlorobenzene via two intraperitoneal injections of 355, 710, 1,065, or 1,420 mg/kg (24 hours apart) and killed 6 hours after the second injection. Males only were tested. — = negative result; + = positive result; DNA = deoxyribonucleic acid Ly 48 2. HEALTH EFFECTS rats compared with that in either vehicle controls or historical controls (NTP 1987). Based on this rat study, 1,4-dichlorobenzene was found to be carcinogenic in male rats because of the finding of renal tumors. 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 with other hepatocellular carcinomas but not in vehicle 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 subject of current research. Toxicologists at CIIT have hypothesized that the male rat kidney is susceptible to the induction of certain tumors because it contains the protein a-2p-globulin, which has not been found at significant levels in female rats or in mice or humans (Charbonneau et al. 1987, 1989a, 1989b; Olson et al. 1990). They have demonstrated that a-2p-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 (1991) have concluded that renal tumors in male rats associated with «-2p-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. 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 2.4x10? (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 49 2. HEALTH EFFECTS 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 a-2p-globulin and hyalin droplet formation. Humans do not secrete a-2p-globulin in their urine and are, accordingly, not susceptible to renal tumorigenesis by way of the hyalin droplet mechanism. Based on the q,* of 2.4x10 (mg/kg/day)” for liver tumors, oral doses associated with upper-bound risks of 10%, 10%, 10%, and 10” would be 0.0042, 0.00042, 0.000042, and 0.0000042 mg/kg/day. These values are currently under review by EPA and have not been included in the IRIS database. It is unlikely that levels of 1,4-dichlorobenzene in the drinking water in any location would be high enough to cause a concern for cancer. 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators 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). 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 or cell that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid 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 more than one 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 biologic 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 2.5.1. 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 often not 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 2.5.2. 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, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "Populations That Are Unusually Susceptible.” 50 2. HEALTH EFFECTS 2.5.1 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. 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). Measurements of adipose concentrations of 1,4-dichlorobenzene provide information on long-term exposure, since 1,4-dichlorobenzene accumulates in fat (Morita et al. 1975). Information on the analytical methods commonly used to detect and quantify 1,4-dichlorobenzene in biological samples is presented in 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 test species. 25.2 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. 2.6 INTERACTIONS WITH OTHER CHEMICALS No studies have been located regarding the interactions of 1,4-dichlorobenzene with other chemicals. 2.7 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 include genetic make- up, developmental stage, health and nutritional status, and chemical exposure history. These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic and renal) or the pre-existing compromised function of target organs. For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations With Potentially High Exposure." No population has been identified as exhibiting 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, and individuals having a genetic susceptability to methemoglobin formation may be at increased risk from inhalation or oral exposure to 1,4-dichlorobenzene. 51 2. HEALTH EFFECTS 2.8 MITIGATION OF 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. 2.8.1 Reducing Peak Absorption Following Exposure Human exposure to 1,4-dichlorobenzene can occur by inhalation, ingestion, or by dermal contact. General recommendations for reducing absorption of 1,4-dichlorobenzene following acute inhalation exposure have included moving the patient to fresh air, and administration of 100% humidified supplemental oxygen with assisted ventilation (HSDB 1992). 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 1992). 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 1992). For dermal exposure the removal of contaminated clothing and a thorough washing of any exposed areas with soap and water has been recommended (HSDB 1992). 2.8.2 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. Methods designed to alter metabolism of 1,4-dichlorobenzene to promote formation of metabolites that are more easily excreted could potentially be developed. However, the current lack of knowledge of the metabolism 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. These methylated conjugates are excreted less rapidly than nonmethylated conjugates (Kimura et al. 1979). Since little is known concerning the toxicity of these conjugates, it is not possible to determine the consequences of promoting formation of these metabolites. 2.8.3 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-450 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 P-450 mediated oxidation, although it should be noted that the P-450 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 52 2. HEALTH EFFECTS 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-2u-globulin mediated nephropathy specific to male rats) or hematotoxic effects have not been clearly demonstrated, and with the available information it is difficult to speculate on how 1,4-dichlorobenzene might be causing 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. 29 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA 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. 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 or eliminate 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. 2.9.1 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 2-3. 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 imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs" information (i.e., data gaps that must necessarily be filled). Some limited information (i.e., anecdotal, single acute exposure, and workplace exposure) is available on the health effects of human exposure to 14-dichlorobenzene via inhalation and the oral route. For persons exposed via inhalation, there is information on death, systemic effects resulting from intermediate- and chronic-duration exposure, and neurologic effects. 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 developmental, genotoxic, and carcinogenic effects. Only lethality data are available in studies using the dermal route. 53 2. HEALTH EFFECTS FIGURE 2-3. Existing Information on Health Effects of 1,4-Dichlorobenzene SYSTEMIC / S/o se SE SE 4, /é SEES ES ESE ESE J mhatation | ®| | of of | ® Oral ol 6 © Dermal HUMAN SYSTEMIC / ” Ng ANS (E/E ES ES ESE SS ES 8 5 Inhalation e000 Oral o| © 6 © vA o| 0 Dermal @ ANIMAL @ Existing Studies 54 2. HEALTH EFFECTS 2.9.2 Identification of Data Needs Acute-Duration Exposure. The only information available for humans exposed to 1,4-dichlorobenzene for this duration 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-dichlorobenzene 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 all 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 MRL for oral exposure. The only available study using the dermal route is a lethality study that attempted to determine a dermal LD,, 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. Data on the effects of acute-duration exposure to 1,4-dichlorobenzene via inhalation would be extremely useful because inhalation of 1,4-dichlorobenzene by persons using consumer products containing 1,4-dichlorobenzene 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, may prove useful. As mentioned above, any further studies conducted by any route should investigate methemoglobinemia as a potential toxic end point. 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-dichlorobenzene via inhalation and the oral route for this exposure duration. 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). A considerable amount of data is available on the renal and hepatic effects of intermediate-duration inhalation exposure on a variety of laboratory animals (rats, mice, rabbits, guinea pigs, and monkeys) (Hollingsworth et al. 1956). These data were derived from a single large study with several inconsistent 55 2. HEALTH EFFECTS variables (discussed in Section 2.2.1.2). The data from the exposure of rats to concentrations of 1, 96, and 158 ppm showing enlargement and degeneration of hepatic parenchymal cells were used as the basis of an oral MRL (Hollingsworth et al. 1956). However, additional studies that follow current standards of good laboratory practice would be valuable for confirming these observations. Several animal studies were located using the oral route for this duration period 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 NOAEL of 18.8 mg/kg/day from a study where the LOAEL was 188 mg/kg/day for increased liver weights in rats accompanied by increased liver weights, necrosis, and slight cirrhosis at a dose of 376 mg/kg/day. Since kidney effects involve hyaline droplet nephropathy, they 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. Studies using the dermal route for this duration period 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 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). The only data located relating to chronic oral human exposure to 1,4-dichlorobenzene is a case study of a 19-year-old woman who developed skin discoloration as a result of eating 1,4-dichlorobenzene moth pellets daily for about 2.5 years (Frank and Cohen 1961). 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. 56 2. HEALTH EFFECTS The data are not considered adequate to derive an MRL for inhalation exposure for this duration because the available quantitative information is limited to a cursory occupational health survey that contains few details on exposure levels and health effects parameters studied and one animal inhalation study with inconclusive results. 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 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. Data on the effects of chronic dermal exposure to 1,4-dichlorobenzene may be useful if dermal absorption and systemic distribution of 1,4-dichlorobenzene can be demonstrated, 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 occurs in many U.S. communities. Any further testing by any route for this 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 or the oral or dermal route. 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 (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-dichlorobenzene 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-dichlorobenzene in humans exposed via inhalation, orally or by the dermal route. Several in vivo studies in animals and in vitro studies are available that generally indicate that the mechanism of carcinogenesis is that it acts as a tumor promoter rather than as a mutagen (Charbonneau et al. 1989b; Steinmelz and Spanggord 1987a, 1987b). There is no apparent need for further data in this area. Reproductive Toxicity. No information has been located on potential reproductive effects in humans exposed to 1,4-dichlorobenzene via inhalation, orally, or by the dermal route. 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 that were 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 1,4-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. 57 2. HEALTH EFFECTS Developmental Toxicity. No studies have been located regarding developmental effects on the offspring of humans exposed to 1,4-dichlorobenzene via the inhalation, oral, or dermal routes. 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). It was not possible to determine the role of maternal toxicity in the effects on the offspring. 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 1,4-dichlorobenzene could be demonstrated in toxicokinetic studies. Immunotoxicity. No studies were located that directly assess the potential immunotoxic effects of 1,4-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 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. In any future intermediate or chronic duration animal studies by any route of exposure, it would be useful to assess the potential immunotoxic effects of 1,4-dichlorobenzene. Neurotoxicity. Neurological effects including dizziness, weakness, headaches, nausea, vomiting, numbness, clumsiness, speech difficulties, and altered patterns of certain brainwaves have been reported to occur in case studies of persons exposed to 1,4-dichlorobenzene via inhalation (Cotter 1953; Miyai et al. 1988). 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-dichlorobenzene 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. Biomarkers of Exposure and Effect. 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. 1989; Langhurst and Nestrick 1979; Pellizzari et al. 1989; Pagnotto and Walkley 1965). Additional data with which to correlate these measurements to exposure levels and potential health effects would be useful. 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. 58 2. HEALTH EFFECTS 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 metabolized mainly by oxidation to 2,5-dichlorophenol and is rapidly eliminated, primarily in urine (Azouz et al. 1955; Hawkins et al. 1980). 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. Comparative Toxicokinetics. There are no available studies that compare the toxicokinetics of 1,4-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 compare most directly with humans with regard to other toxic effects in response to 1,4-dichlorobenzene exposure. Methods for Reducing Toxic Effects. Based on the chemical and physical properties of 1,4-dichlorobenzene, its absorption occurs most likely 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 1992), 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 in developing methods for interfering with the mechanism of action. 2.9.3 On-going Studies There are no known on-going studies related to the toxicity or toxicokinetics of 1,4-dichlorobenzene. 59 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Table 3-1 lists common synonyms, trade names, and other pertinent identification information for 1,4-dichlorobenzene. 3.2 PHYSICAL AND CHEMICAL PROPERTIES Table 3-2 lists important physical and chemical properties of 1,4-dichlorobenzene. 60 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-1. Chemical Identity of 1,4-Dichlorobenzene Characteristic Information Reference Chemical name 1,4-Dichlorobenzene Howard 1990 Synonym(s) p-Dichlorobenzene; HSDB 1990 benzene, 1,4-dichloro-; p-chlorophenyl chloride Registered trade name(s) Paracide Sittig 1985 Chemical formula CH.Cl, Howard 1990 Chemical structure cl Cl Identification numbers: CAS registry 106-46-7 Howard 1990 NIOSH RTECS CZ4550000 HSDB 1990 EPA hazardous waste u072 HSDB 1990 OHM /TADS No data DOT/UN/NA/IMCO shipping UN1592 HSDB 1990 IMCO 6.1 HSDB 523 HSDB 1990 NCI C54955 HSDB 1990 CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/International Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank; NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances 61 3. CHEMICAL AND PHYSICAL INFORMATION TABLE 3-2. Physical and Chemical Properties of 1,4-Dichlorobenzene Property Information Reference Molecular weight 147.01 Howard 1990 Color Colorless or white Verschueren 1983 Physical state Solid Verschueren 1983 Melting point 531°C Howard 1990 Boiling point 174°C Howard 1990 Density 1.458 g/mL Verschueren 1983 Odor Aromatic Verschueren 1983 Odor threshold: Water 0.011 ppm Amoore and Hautala 1983 Air 0.18 ppm (1.1 mg/m?) Amoore and Hautala 1983 Solubility: Water 49 mg/L at 22°C Verschueren 1983 Organic solvent(s) Partition coefficients: Log K_, Log K_. Vapor pressure Henry’s law constant Autoignition temperature Flashpoint Flammability limits Conversion factors Explosive limits 79 mg/L at 25°C Soluble in alcohol, benzene and ether 3.52 2.44-3.26 0.6 mmHg at 20°C 1.76 mmHg at 25°C 10 mmHg at 54.8°C 0.0015 atm-m®/mol at 20°C No data 150° F (65.5°C) (closed cup) 128.8°F (53.8°C) (open cup) No data 1 mg/m® = 0.166 ppm 1 ppm = 6.01 mg/m’ No data Verschueren 1983 Sax and Lewis 1987 Howard 1990 Bahnick and Doucette 1988; Newsom 1985; Schwarzenbach and Westfall 1981; Wilson et al. 1981 Verschueren 1983 Howard 1990 Sax and Lewis 1987 Howard 1990 Sax and Lewis 1987 Clayton and Clayton 1981 Verschueren 1983 63 4. PRODUCTION, IMPORT, 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 (HSBD 1990; IRPTC 1990). The volume of 1,4-dichlorobenzene produced in the United States in 1990 is expected to be about 132 million pounds (Chemical Marketing Reporter 1990; SRI 1990). The production of 1,4-dichlorobenzene has steadily increased over the past decade (1980-1989) at a rate of about 2% per year. It is anticipated that 1,4-dichlorobenzene production will continue to increase over the next 4 years (1990-1994) at an annual rate of about 2-4% (Chemical Marketing Reporter 1990). 1,4-Dichlorobenzene is produced by five U.S. companies at five different locations, including Monsanto Company, in Sauget, Illinois; PPG Industries, Inc., in Natrium, West Virginia; Standard Chlorine of Delaware, Inc, in Delaware City, Delaware; Vista Chemical Company, Lake Charles, Louisiana; and Specialty Organics in Irwindale, California. Unlike the other four facilities, Specialty Organics is a 1,4-dichlorobenzene processor, isolating 1,4-dichlorobenzene from purchased crude chlorobenzenes (Chemical Marketing Reporter 1990; SRI 1990). Table 4-1 summarizes the information on U.S. companies that reported the manufacture and use of 1,4-dichlorobenzene in 1988 (TRISS 1990). The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 4.2 [IMPORT/EXPORT The United States imports very little, if any, 14-dichlorobenzene. In 1978, about 22,000 pounds of 1,4-dichlorobenzene were imported; but since 1980, no imports of 1,4-dichlorobenzene have been reported (HSDB 1990; NTP 1989). The United States exports about 25% (about 33 million pounds) of its 1,4-dichlorobenzene production volume (Chemical Marketing Reporter 1990). Exports of 1,4-dichlorobenzene have expanded through the 1980's at about 1-2% per year due to the growth in production of polyphenylene sulfide (PPS) resin overseas (HSDB 1990; NTP 1989). 4.3 USE For the past 20 years, 14-dichlorobenzene has been used principally (35-50% 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 used in the production of PPS resin (approximately 20% of its total use) and as an intermediate in the production of other chemicals (approximately 10%). Minor uses of 1,4-dichlorobenzene include its use in the control of certain tree-boring insects and in the control of mold in tobacco seeds (Chemical Marketing Reporter 1990; HSDB 1990). TABLE 4-1. Facilities That Manufacture or Process Dichlorobenzne® Range of maximum amounts Facility Location on site in pounds Activities and uses Standard Chlorine Of Delaware Inc. Crest Products Inc. I. Schneid Inc. Zep Manufacturing Co. Sureco Inc. Monsanto Co. Hysan Corp. Frank J. Curran Co. Fuller Brush Co. Vista Chemical Co. Lake Charles Chemical Plant Stanhome Inc. Norton Co. Dow Chemical Co. Michigan Div. Willert Home Products Inc. Willert Home Products Inc. Petrokem Corp. Fresh Products Inc. Pestco Inc. Allied Block Industries Inc. Hardwicke Chemical Co. Phillips 66 Co. Philtex/Ryton Complex Carroll Co. P. P. G Industries Inc. Delaware City, DE Oldsmar, FL Atlanta, GA Atlanta, GA Fort valley, GA Cahokia, IL Chicago, IL Downers Grove, IL Great Bend, KS Westlake, LA Easthampton, MA Worcester, MA Midland, MI Saint Louis, MO Saint Louis, MO Paterson, NJ Toledo, OH Braddock, PA New Eagle, PA Elgin, SC Borger, TX Garland, TX New Martinsville, WV 1,000,000-9,999,999 10,000-99,999 10,000-99,999 39. 99, 9%, -99, 100, 000-999 100, 000-999 10,000-99, 100, 000-999, 100, 000-999 10,000-99 10,000-99,999 383888 8333 1,000-9,999 10,000-99,999 10,000-99,999 100, 000-999, 999 100,000-999,999 1,000,000-9,999,999 Produce; for sale/distribution For sale/distribution; in re- packaging As a formulation component; in re- packaging As a formulation component As a formulation component Produce; for sale/distribution As a formulation component In re-packaging In re-packaging Produce; as a byproduct As a formulation component As a manufacturing aid Import; as a byproduct As an article component As an article component As a formulation component Import; for sale/distribution; as an article component For on-site use/processing; as a formulation component In re-packaging As a reactant As a reactant As a formulation component Produce; for sale/distribution ‘Derived from TRIB8 (1990) IVSOdSIA ANV '3SN ‘1HOdWI ‘NOILONAOHd 'v 65 4. PRODUCTION, IMPORT, 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 (see Chapter 7) (HSDB 1990; IRPTC 1990). Incineration by appropriate means is the recommended method for the disposal of waste 1,4-dichlorobenzene (HSDB 1990). 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 (TRI88 1990), 6,153 pounds of waste 1,4-dichlorobenzene were landfilled and 37,997 pounds of waste 1,4-dichlorobenzene were sent to publicly- owned treatment works in 1988. 67 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 and moth repellant. 1,4-Dichlorobenzene is degraded in the atmosphere by reaction with hydroxyl radicals, with an atmospheric lifetime (theoretically calculated) of about 1 month. The compound is expected to be somewhat mobile in soil and to volatilize from surface water to the atmosphere. Biodegradation, sorption, volatilization, 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 inhalation, with an average daily intake from ambient air estimated at about 35 pg. Recent data suggest that exposure from indoor air may be an order of magnitude higher. Occupational and consumer contact with 1,4-dichlorobenzene is a frequent means of exposure, with the highest exposure resulting from production or processing of 1,4-dichlorobenzene. 1,4-Dichlorobenzene has been identified at 244 of the 1,300 hazardous waste sites that have been proposed for inclusion on the NPL (MIS 1990). The frequency of these sites within the United States can be seen in Figure 5-1. 5.2 RELEASES TO THE ENVIRONMENT Industrial manufacturers, processors, and users of 1,4-dichlorobenzene are required to report the quantities of this substance released to environmental media annually (EPA 1988b). The data currently available, compiled in the Toxics Release Inventory (TRI88 1990) for releases in 1988 to air, water, soil, and other media, are summarized in Table 5-1. Total releases of 1,4-dichlorobenzene to the environment reported in 1988 were 1,865,072 pounds. The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. Industrial releases contribute only a small fraction of the total environmental loading of 1,4-dichlorobenzene. Use of consumer products containing 1,4-dichlorobenzene is the major source of environmental release (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 highly volatile substance and sublimes at room temperature, most environmental releases are to the atmosphere. Industrial emissions of 1,4-dichlorobenzene reported for 1988 totalled 1,842,869 pounds (TRI88 1990). 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 (see Sections 4.1 and 4.3), about 51 million pounds of 1,4-dichlorobenzene will be released to the air in 1990 from these sources. 1,4-Dichlorobenzene may be emitted to air from other sources, such as hazardous waste sites, or during its use as a fumigant (EPA 1981). 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). FIGURE 5-1. FREQUENCY OF NPL SITES WITH 1,4 DICHLOROBENZENE CONTAMINATION * FREQUENCY BH 1 TO 3 SITES BEY 4 TO 9 SITES 10 TO 17 SITES BE 3: SITES Derived from HAZDAT 199 34NSOdX3 NYWNH HOH TVIINILOd 'S TABLE 5-1. Releases to the Enviroment from Facilities That Manufacture or Process Dichlorobenzene® Reported amounts released in pounds off-site Underground Total POTW waste Facility Location Air injection Water Land environment transfer transfer Standard Chlorine Of Delaware City, DE 49,946 0 403 0 50,349 0 0 Delaware Inc. Crest Products Inc. Oldsmar, FL 0 0 0 0 0 0 0 I. Schneid Inc. Atlanta, GA 0 0 0 0 0 0 0 Zep Manufacturing Co. Atlanta, GA 37 0 0 0 37 147 32 Sureco Inc. Fort valley, GA 2,200 0 750 0 2,950 0 250 Monsanto Co. Cahokia, IL 1,003,900 0 0 0 1,003,900 30,000 98,000 Hysan Corp. Chicago, IL 16,318 0 0 0 16,318 0 0 Frank J. Curran Co. Downers Grove, IL 250 0 0 0 250 0 0 Fuller Brush Co. Great Bend, KS 6,753 0 0 0 6,753 0 0 Vista Chemical Co. Lake Westlake, LA 250 0 250 0 500 0 250 Charles Chemical Plant Stanhome Inc. Easthampton, MA 10,000 0 0 0 10,000 250 250 Norton Co. Worcester, MA 462,561 0 0 0 462,561 0 0 Dow Chemical Co. Midland, MI 100 0 0 0 100 0 0 Michigan Div. Willert Home Products Saint Louis, MO 0 0 0 0 0 0 0 Inc. Willert Home Products Saint Louis, MO 250 0 0 0 250 0 0 Inc. Petrokem Corp. Paterson, NJ 250 0 0 0 250 0 0 Fresh Products Inc. Toledo, OH 7,400 0 0 0 7,400 7,600 0 Pestco Inc. Braddock, PA 0 0 0 0 0 0 0 Allied Block Industries New Eagle, PA 0 0 0 0 0 0 0 Inc. Hardwicke Chemical Co. Elgin, SC 204 0 0 0 204 0 0 Phillips 66 Co. Borger, TX 8,450 15,000 250 1,050 24,750 0 31,000 Philtex/Ryton Complex Carroll Co. Garland, TX 0 0 0 0 0 0 0 P. P. G Industries Inc. New Martinsvil, WV 274,000 0 4,500 0 278,500 0 9,100 Totals 1842869 15,000 6153 1050 1865072 37997 138882 ‘Derived from TRI88 (1990) POTW = Publicly owned treatment works 3HNSOdX3 NVYWNH HOH TVIIN3LOd 'S 70 5. POTENTIAL FOR HUMAN EXPOSURE 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 100 ppb (Perry et al. 1979; Young et al. 1983). Industrial releases to surface water and publicly-owned treatment works reported for 1988 were 6,153 and 37,997 pounds, respectively. ~~ Approximately 15,000 pounds were released to groundwater by underground injection (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), and 1,4-dichlorobenzene has been detected in both surface water and groundwater samples at about 5% of the hazardous waste sites included in the Contract Laboratory Program (CLP). Data from the CLP Statistical Database indicate 1,4-dichlorobenzene was found in surface water and groundwater samples at geometric mean concentrations for the positive samples of 6 and 37 ppb, respectively (CLPSD 1990). Note that the information used from the CLP Statistical Database includes data from both NPL and non-NPL sites. 5.2.3 Soil The principal source of 1,4-dichlorobenzene release to land is disposal of industrial waste in landfills. Industrial releases of 1,4-dichlorobenzene to land reported for 1988 total 1,050 pounds (TRIS8 1990). 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). 1,4-Dichlorobenzene has been detected in soil/sediment samples taken at 4% of the hazardous waste sites included in the CLP Statistical Database at a geometric mean concentration of 450 ppb for the positive samples (CLPSD 1990). 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 1.6x10° to 4.6x10° 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 non-aerated 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), of 1.5x10° atm-m®/mol at 20°C (Howard 1989), indicates that partitioning from air to water is likely to be minor relative to 7 5. POTENTIAL FOR HUMAN EXPOSURE 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 to soils and sediments. 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, be transported through groundwater, and migrate from surface water to groundwater through the soil (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. Measured mean bioconcentration factors of 370-720 for rainbow trout (Oliver and Niimi 1983) and 1,800 for guppies (Chiou 1985) were reported. 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. Data on biomagnification through the food chain 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 14-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. 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, '*C 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-dichlorobenzene sample was reported (Bouwer and McCarty 1982). The compound was completely mineralized to inorganic end products. Longer acclimation periods are required when 1,4-dichlorobenzene 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). 72 5. POTENTIAL FOR HUMAN EXPOSURE 5.3.2.3 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. 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air 1,4-Dichlorobenzene has been detected in ambient air samples in several monitoring studies, as shown in Table 5-2. Concentrations in urban areas and in the vicinity of hazardous waste sites generally average less than 4 pg/m?® but indoor air concentrations of 1,4-dichlorobenzene may be one to three 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). Concentrations in workplace air were the highest measured (IARC 1982). Data from the Total Exposure Assessment Methodology (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-dichlorobenzene, the authors assumed that the concentrations found are almost all 1,4-dichlorobenzene. 5.4.2 Water 1,4-Dichlorobenzene has generally been detected at low concentrations in surface water, groundwater, and finished drinking water in the United States. 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 (Staples et al. 1985) and in 100% of 91 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). In a New Jersey survey, 14-dichlorobenzene was detected in 6% of 463 surface water samples and 3% of 685 groundwater samples. The highest concentrations were 31 ppb and 995 ppb for surface water and groundwater, respectively (Page 1981). 1,4-Dichlorobenzene has been reported in surface waters in the vicinity of hazardous waste sites (Elder et al. 1981; Oliver and Nicol 1982a). Finished drinking water samples from 20 of the 113 cities monitored in the National Organics Monitoring Survey (NOMS) had levels of 1,4-dichlorobenzene 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 three 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). 5.4.3 Soil Data on soil concentrations of 1,4-dichlorobenzene were not located. However, the compound was detected in 2% of 357 sediment samples recorded on the STORET database (Staples et al. 1985), in sediment samples from the Great Lakes at concentrations ranging from 2 to 210 ppb (Oliver and Nicol 1982a), and in 73 5. POTENTIAL FOR HUMAN EXPOSURE TABLE 5-2. Summary of 1,4-Dichlorobenzene Levels in Air oncentration m®)?* Location Maximum Mean References Rural United States No data 0° Shah and Heyerdahl 1988 Suburban No data 0.29° Shah and Heyerdahl 1988 United States Urban United States 120 0.12-9.6 Bozzelli and Kebbekus 1979; Harkov et al. 1984 Shah and Heyerdahl 1988; Wallace et al. 1986 Hazardous waste 25 0.18-3.2 Harkov et al. 1985; sites La Regina et al. 1986 Indoor 1.6x10° 1.7-56 Scuderi 1986; Shah and Heyerdahl 1988; Wallace et al. 1986 Workplace 4.4x10° 3.3x10%-2.9x10°% IARC 1982 1 pg/m® = 0.166 ppb ®Median value ‘Range of values 74 5. POTENTIAL FOR HUMAN EXPOSURE sediments near a hazardous waste site (Elder et al. 1981; Hauser and Bromberg 1982). 1,4-Dichlorobenzene has been reported to occur in soils as a result of lindane degradation (IARC 1982), so the presence of 1,4-dichlorobenzene may not be indicative of 1,4-dichlorobenzene disposal per se. 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 the pigs and hens to 14-dichlorobenzene (IARC 1982). 1,4-Dichlorobenzene was detected in trout from the Great Lakes at concentrations ranging from 1 to 4 ppb (Oliver and Nicol 1982a) and concentrations of 1,4-dichlorobenzene reported in mackerel, mussels, and other fish species from around the world ranged up to 0.4 ppm (IARC 1982). 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 outdoor levels for 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 ug/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 pg per day for an adult drinking 2 L of water per day. Dichlorobenzene (all isomers) was identified in 100% of 42 samples of human breast milk collected in five urban areas of the United States at concentrations of 0.04-68 ppb (Erickson et al. 1980). 1,4-Dichlorobenzene was detected in 100% of 46 composite human adipose tissue specimens analyzed for the National Human Adipose Tissue Survey (NHATS) at levels of 12-500 ppb (EPA 1989d; Stanley 1986). These measurements indicate widespread exposure of the general population to 1,4-dichlorobenzene. Occupational exposure to 1,4-dichlorobenzene may be important in several industries. Workers may be exposed to 1,4-dichlorobenzene during production, processing, and industrial use of the compound, including the production and packaging of space deodorants and moth repellents (IARC 1982). NIOSH estimated that about 34,000 workers were potentially exposed to 1,4-dichlorobenzene in the early 1980s (NOES 1990). 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). 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). Current control technology should limit workplace concentrations to this level. 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Individuals using space deodorants or moth repellents containing 1,4-dichlorobenzene in their homes have the potential for high exposure to this compound (Scuderi 1986). Indoor air concentrations resulting from the 75 5. POTENTIAL FOR HUMAN EXPOSURE use of these products in bathrooms and closets have been measured at levels up to 1.3 mg/m® (0.22 ppm) (Scuderi 1986). Those individuals living near industrial facilities or hazardous waste sites with higher than average levels of 1,4-dichlorobenzene in the air or water would also have potential above-average exposure. Currently, workers in the industries identified above (Section 5.5) have the highest potential exposure to 1,4-dichlorobenzene. 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA 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 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 or eliminate 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. On this basis, it does not appear that further research in this area is required. Production, Import/Export, Use, and Release and Disposal. Data on the production and uses of 1,4-dichlorobenzene in the United States are available (Chemical Marketing Reporter 1990; HSDB 1990; IRPTC 1990; SRI 1980; TRI88 1990). 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 PPS resins. Incineration is the recommended disposal method for 1,4-dichlorobenzene (HSDB 1990). Disposal of this compound is controlled by federal regulations (HSDB 1990; IRPTC 1990). 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 1988, became available in May of 1990. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Environmental Fate. The environmental fate of 14-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; Chiow et al. 1983; Cuppitt 1980; Howard 1990; Newsom 1985; Schwarzenbach and Westall 1981; Singh et al. 1981; Spain and Nishino 1987; Tabak et al. 1981). Volatilization, sorption, and biodegradation appear to be competing processes for 1,4-dichlorobenzene removal 76 5. POTENTIAL FOR HUMAN EXPOSURE 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. 1989). 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 or bathing in environmental waters that contain 1,4-dichlorobenzene. Food Chain Bioaccumulation. Bioconcentration of 1,4-dichlorobenzene has been documented for several aquatic species (Chiou 1985; Oliver and Niimi 1983). Based on the relatively high K_,, it appears that bioaccumulation does occur (Leo et al. 1971). No data were located on biomagnification through terrestrial or aquatic food chains. Additional information on bioconcentration by plants and biomagnification of 1,4-dichlorobenzene would be helpful in evaluating the potential importance of food chain bioaccumulation for human exposure. Exposure Levels in Environmental Media. Several studies are available documenting levels of 1,4-dichlorobenzene in air, water, and sediments in rural and urban areas and in the environs of hazardous waste sites (Coniglio et al. 1980; Dressman et al. 1977; Elder et al. 1981; Hauser and Bromberg 1982; IARC 1982; IJC 1989; Oliver and Nicol 1982a; Page 1981; Scudera 1986; Stables et al. 1985; Wallace et al. 1986). 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 estimate better the potential for current human exposure levels from these media, especially in the vicinity of hazardous waste sites. Although there is very little information on 1,4-dichlorobenzene levels in food (IARC 1982), it does not appear that this is an important source of human exposure. However, data on 1,4-dichlorobenzene levels in foodstuffs would be useful to confirm this assumption. 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 (EPA 1989d; Erickson et al. 1980; 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 past exposure (EPA 1989d; Stanley 1986). 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 1,4-dichlorobenzene to which humans have been exposed. Exposure Registries. No exposure registries for 1,4-dichlorobenzene were located. This compound is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The compound 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 the exposure to this compound. 77 5. POTENTIAL FOR HUMAN EXPOSURE 5.7.2 On-going Studies Remedial investigations and feasibility studies at NPL sites that contain 1,4-dichlorobenzene will provide further information on environmental concentrations and human exposure levels near waste sites. No information was located regarding on-going studies of the environmental fate of 1,4-dichlorobenzene. As part of the Third National Health and Nutrition Evaluation Survey (NHANES III), the Environmental Health Laboratory Sciences Division of the Center for Environmental Health and Injury Control, Centers for Disease Control, will be analyzing human blood samples for 1,4-dichlorobenzene 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. 79 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring 1,4-dichlorobenzene in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify 1,4-dichlorobenzene. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect 1,4-dichlorobenzene in environmental samples are the methods approved by federal 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 refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS Gas chromatography (GC) is used most frequently to detect 1,4-dichlorobenzene in biological materials (Erickson et al. 1980; Langhorst and Nestrick 1979; Pellizzari et al. 1985), but gas-liquid chromatography (GLC) may also be employed (Jan 1983). The chromatograph separates complex mixtures of organic compounds and allows individual compounds to be identified and quantified by a detector. Detectors used to identify 1,4-dichlorobenzene in biological materials include the electron capture detector (ECD) (Bristol et al. 1982; Jan 1983) and the photoionization detector (PID) (Langhorst and Nestrick 1979). When unequivocal identification is required, a mass spectrometer (MS) coupled to the GC column may be employed (Antoine et al. 1986; Barkley et al. 1980; Cramer et al. 1988; Erickson et al. 1980; Pellizzari et al. 1985). These detection methods appear to be about equally sensitive for 1,4-dichlorobenzene. Table 6-1 summarizes the data for several representative methods for determining levels of 1,4-dichlorobenzene in biological fluids and tissues. 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 (Antoine et al. 1986; Barkley et al. 1980; Cramer et al. 1988; Erickson et al. 1980; Pellizzari et al. 1985). Breath samples are pumped directly through a sorbent cartridge to collect the organics components (Barkley et al. 1980). Additional clean-up steps may be required to separate the analyte from complex matrix materials (Jan 1983; Langhorst and Nestrick 1979). An important metabolite of 1,4-dichlorobenzene, 2,5-dichlorophenol, may be measured in urine by colorimetric or ultraviolet methods (Pagnatto and Walkley 1965). The colorimetric determination with 4-aminoantipyrine follows steam distillation of the phenol from acidified urine. The lowest reported concentration detected was 10 mg/L. This analysis may be employed to monitor for recent occupational exposure to 1,4-dichlorobenzene, since production of 2,5-dichlorophenal is specific to 1,4-dichlorobenzene (i.e., it is not produced from other endogenous substances). 6.2 ENVIRONMENTAL SAMPLES 1,4-Dichlorobenzene in air, water, soil/sediments and food is usually determined by GC analysis (APHA 1977, 1989; Daft 1989; EPA 1986a, 1986b, 1986c, 1986i, 1989b, 1989c, 1989i, 1989h; NIOSH 1984), but high-performance liquid chromatography (HPLC) may also be used for some media (Bush et al. 1984). Several representative methods appropriate for quantifying 1,4-dichlorobenzene in each of these media are summarized in Table 6-2. TABLE 6-1. Analytical Methods for Determining 1,4-Dichlorobenzene in Biological Materials Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Blood Heat sample, purge with helium, trap GC/MS 3 ppb 86.3+10.9° Pellizzari on sorbent trap, desorb thermally et al. 1985 Blood Extract with carbon tetrachloride, GC/PID 3.0 ppb 89 17 Langhorst and clean up on silica gel column Nestrick 1979 Blood Extract with hexane GC/ECD 2 ppb 81.6 Bristol et al. 1982 Urine Extract with carbon tetrachloride, GC/PID 0.75 ppb 8117 Langhorst and clean up on silica gel column Nestrick 1979 Human milk Heat sample, purge with helium, trap GC/MS 0.6 ppb 629° Erickson on sorbent trap, desorb thermally et al. 1980 Human milk Extract with hexane; clean up with GLC/ECD 5 ppb°© >80 Jan 1983 sulfuric acid, Florisil® Adipose tissue Extract with hexane; clean up with GLC/ECD 146 ppb*° >80 Jan 1983 sulfuric acid, Florisil®; elute with diethyl ether in hexane Adipose tissue Macerate in water, heat sample, purge =~ GC/MS 6 ppb 56.5 £25.7° Pellizzari with helium, trap on sorbent trap, et al. 1985 desorb thermally *Value is for m-dichlorobenzene ®Value is for chlorobenzene “Lowest level detected “Mean level detected ECD = electron capture detector; GC = gas chromatography; GLC = gas liquid chromatography; MS = mass spectrometry; PID = photoionization detector SAQOH.L3W TVOILATYNY 9 TABLE 6-2. Analytical Methods for Determining 1,4-Dichlorobenzene in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air Adsorb on charcoal, desorb with GC/FID 25 ppb® 90-110° APHA 1977 carbon disulfide Air Adsorb on charcoal, desorb with GC/FID 0.01 mg/ No data NIOSH 1984 carbon disulfide sample Water Purge with inert gas, trap on GC/HSD No data 90 EPA 198%h sorbent trap, desorb thermally Water Purge with inert gas, trap on HRGC/PID, 0.01 ppb 98-103 EPA 1989i sorbent trap, desorb thermally, ELCD backflush with helium Water Purge with inert gas, trap on GC/PID 0.006 ppb 91-107 EPA 1986h sorbent trap, desorb thermally, backflush with helium Water Purge with inert gas, trap on GC/MS 2 ppb 112 EPA 1989c sorbent trap, desorb thermally, backflush with helium Water Purge with inert gas, trap on HRGC/MS 0.03 ppb 103 EPA 198% sorbent trap, desorb thermally, backflush with helium SAOHL3W TVOILATYNY 9 18 TABLE 6-2 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Wastewater Extract with methylene chloride GC/MS 4.4 ppb 63 EPA 1982f Wastewater Extract with methylene chloride, GC/ECD 1.34 ppb 89 EPA 1982a hexane Soil/solid waste Purge with inert gas, trap on GC/HSD 2.4-300 ppb 42-143 EPA 1986a sorbent trap, desorb thermally Soil Purge with inert gas, trap on GC/PID 3-375 ppb 42-143 EPA 1986a sorbent trap, desorb thermally Soil /sediment Extract with methylene chloride GC/MS 75-660 ppb 20-124 EPA 1986b Food Extract with acetone/isooctane GC/ECD, No data 97-100 Daft 1989 HECD *Lowest value for various compounds reported during collaborative testing of this method ®Estimated accuracy of the method when the personal sampling pump is calibrated with a charcoal tube in the line ECD = electron capture detector; ELCD = electrolytic conductivity detector; FID = flame ionization detector; GC = gas chromatography; HECD = hall electroconductivity detector; HRGC = high resolution gas chromatography; HSD = halogen specific detector; MS = mass spectrometry; PID = photoionization detector SAOHL13W TVOLLATVNY 9 83 6. ANALYTICAL METHODS The EPA methods for analysis of drinking water, wastewater, and soil /sediment samples included in Table 6-2 are approved by the American Society for Testing and Materials (ASTM). Many of the APHA (1989) methods for water are equivalent to the EPA methods. In most analytical procedures, 1,4-dichlorobenzene is trapped on a solid sorbent material such as activated charcoal or Tenax®. Air samples are drawn directly through the sorbent (APHA 1977; NIOSH 1984). 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 (APHA 1989; EPA 1986b, 1986¢, 1989b, 1989c, 1989h, 1989i). Thermal desorption or desorption by carbon disulfide can be used. Extraction procedures with methylene chloride or isooctane may also be used to separate 1,4-dichlorobenzene from wastewater, soil/sediment, or food samples (Daft 1989; EPA 1982a, 1982f, 1986b). Following separation of the organic compounds by GC, 1,4-dichlorobenzene can be detected by one of several types of instruments: a flame ionization detector (FID), halogen specific detector (HSD), electrolytic conductivity detector (ELCD), PID, ECD, or, for unequivocal identification, MS. Detection limits for these methods are in the low ppb range, which is probably well below levels of health concern. The most sensitive method appears to be PID. 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 1977). Interference by other volatile organic compounds 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(i)(5) of CERCLA 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 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 or eliminate 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. 84 6. ANALYTICAL METHODS 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Exposure to 1,4-dichlorobenzene 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. 1982; Jan 1983; Langhorst and Nestrick 1979; Pellizzari et al. 1985). Sensitive analytical methods are available for all of these measurements. However, development of methods with improved specificity and sensitivity would be valuable in identifying individuals with low level exposure. 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-dichlorobenzene. 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 (APHA 1977; Daft 1989; EPA 1989a, 1989b, 1989c, 1989f, 198%h, 1989i; NIOSH 1984). The accuracy and precision of the methods are well documented and mass spectrometry provides adequate specificity. Development of techniques to improve the accuracy and ease of sample preparation analyte and transfer for these methods is underway (see Section 6.3.2). Therefore, it does not appear that additional analytical methods for determining 1,4-dichlorobenzene in environmental media are required. 6.3.2 On-going Studies The Environmental Health Laboratory Sciences Division of the Center for Environmental Health and Injury Control, Centers for Disease Control, is developing methods for the analysis of 1,4-dichlorobenzene and other volatile organic compounds in blood. These methods use purge and trap methodology and magnetic sector mass spectrometry which gives detection limits in the low parts per trillion range. On-going studies to improve analytical methods for 1,4-dichlorobenzene and related compounds include the EPA "Master Analytical Scheme" being developed for organic compounds in water (Michael et al. 1988), the research in supercritical fluid extraction (King 1989) which is applicable to organohalide analytes, and the implementation of whole column cryotrapping techniques (Pankow and Rosen 1988; Pankow et al. 1988). These improvements are designed to simplify purge and trap sample preparation and increase sensitivity, reliability, and speed of the analyses. 85 7. REGULATIONS AND ADVISORIES Because of its potential to cause adverse health effects in exposed people, a number of regulations and guidelines have been established for various international, federal, and state agencies. These values are summarized in Table 7-1. The EPA has withdrawn the IRIS entry for 14-dichlorobenzene. Reference dose (RfD) and reference concentrations (RfC) values have not been determined. The ATSDR has calculated an intermediate inhalation MRL of 0.2 ppm based on a NOAEL of 96 ppm for liver effects in rats (Hollingsworth et al. 1956). The ATSDR has also calculated an intermediate oral MRL of 0.1 mg/kg/day based on a NOAEL of 18.8 mg/kg/day in rats (Hollingsworth et al. 1956). The critical effect was liver toxicity. 86 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to 1,4-Dichlorobenzene Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 2B IARC 1987 WHO Recommended drinking water 0.1ug/L WHO 1984a guideline NATIONAL Regulations: a. Air OSHA PEL TWA 75 ppm (450 mg/m®) OSHA 1989 STEL 110 ppm (675 mg/nt) (29 CFR 1910.1000) b. Water: EPA ODW MCL 0.075 mg/L EPA 1987f (40 CFR 141) SMCL (proposed) 0.005 mg/L EPA 1989f EPA OWRS General permits under NPDES Yes 40 CFR 122 General Pretreatment Regulations Yes 40 CFR 403 for Existing and New Sources of Pollution Effluent Guidelines and Standards Yes 40 CFR 401 Hazardous substance Yes 40 CFR 116 c. Other: EPA OERR Reportable quantity 100 Ib EPA 198% (40 CFR 3024) EPA OPP Pesticide required to be Yes EPA 1989g reregistered - List C Inert ingredient of toxicological Yes EPA 1987g concern EPA OSW Hazardous Waste Constituent Yes EPA 1980b (Appendix VIII) (40 CFR 261) Groundwater Monitoring List Yes EPA 1987¢ (Appendix IX) (40 CFR 264) Land Disposal Restrictions Yes EPA 1987d, 1988a, 1990 (40 CFR 268) 87 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References EPA OTS Toxic Chemical Release Reporting Rule Yes EPA 1988b (40 CFR 372) Test Rule Soil Adsorption and Reproductive Yes EPA 1986f, 1986¢ Effects (40 CFR 799.1052) Health and Safety Data Reporting Rule Yes EPA 1988c (40 CFR 716.120) Preliminary Assessment Information Yes EPA 1982a Reporting Rule (40 CFR 712.30) Guidelines: a. Air ACGIH TLV TWA 75 ppm (451 mg/m’) ACGIH 1990 STEL 110 ppm (661 mg/m’) NIOSH IDLH 1,000 ppm NIOSH 1985 b. Water: EPA ODW MCLG 0.075 mg/L EPA 1987f Health Advisories EPA 1987i One-day (child) 10.7 mg/L Ten-day (child) 10.7 mg/L Longer-term (child) 10.7 mg/L Longer-term (adult) 37.5 mg/L Lifetime (adult) 0.075 mg/L EPA OWRS Ambient Water Quality Criteria EPA 1980c Ingesting water and organisms: 0.4 mg/L Ingesting organisms only: 2.6 mg/L c. Other: EPA Cancer slope factor (q, *) q,* (oral) 2.4x102 (mg/kg/day)’ Battelle and Crump 1986 88 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References STATE Regulations and Guidelines: a. Air Acceptable ambient air concentrations NATICH 1989 Connecticut 9.0 mg/m® (8 hr) Massachusetts 42ug/m® (24 hr) Nevada 10.7 mg/m° (8 hr) North Carolina 66 mg/m (15 min) North Dakota 4.5 mg/m® (8 hr) 6.75 mg/m (1 hr) South Carolina : 4.50 mg/m’ (24 hr) Virginia 7.5 mg/m (24 hr) b. Water: Drinking water quality standards FSTRAC 1990 Alabama 75 ug/L Arizona 75 ug/L California Sug/L Connecticut 75 ug/L Maine 27ug/L Massachusetts Sug/L Minnesota 75 ug/L Rhode Island 75 ug/L Vermont 75 ug/L Wisconsin 75 ug/L ACGIH = American Conference of Governmental Industrial Hygienists; EPA = Environmental Protection Agency; IARC = International Agency for Research on Cancer; IDLH = Immediately Dangerous to Life or Health Level; MCL = Maximum Contaminant Level; MCLG = Maximum Contaminant Level Goal; NIOSH = National Institute for Occupational Safety and Health; NPDES = National Pollutant Discharge Elimination System; ODW = Office of Drinking Water; OERR = Office of Emergency and Remedial Response; OPP = Office of Pesticide Products; OSHA = Occupational Safety and Health Administration; OSW = Office of Solid Waste; OTS = Office of Toxic Substances; OWRS = Office of Water Regulations and Standards; PEL = Permissible Exposure Limit; RfD = Reference Dose; SMCL - Secondary Maximum Contaminant Level; STEL = Short Term Exposure Limit; TLV = Threshold Limit Value; TWA = Time-Weighted Average; WHO = World Health Organization 8. 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In: Detoxication mechanisms. 2nd ed. New York, NY: John Wiley and Sons, 237-258. 107 8. REFERENCES *Wilson JT, Enfield CG, Dunlap WJ, 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. 109 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. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. 110 9. GLOSSARY In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. In Vivo -- Occurring within the living organism. Lethal Concentration, (LC) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentratio (LCs) -- A calculated concentration of a chemical in air to which exposure for a specific length of time 1s expected to cause death in 50% of a defined experimental animal population. Lethal Dose, (LD,;) -- 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, (LD) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time, (LT) -- 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. 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). 111 9. GLOSSARY 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 (TD) -- 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. A-1 APPENDIX A USER'S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance 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 substance. 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 by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. 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 (LOAELSs) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate 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. The LSE tables and figures can be used 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. The legends presented below demonstrate the application of these tables and figures. A representative example 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 exist, 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. (2) Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. (3). 4). (5). (6). (7). (8). 9). (10). (11). (12). A-2 APPENDIX A Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological. developmental, reproductive, and cancer. NOAELs and LOAELSs 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. 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 define a NOAEL and a Less Serious LOAEL (also see the two "18" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. 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 LOAELSs from different studies. In this case (key number 18). rats were exposed to [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. 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, one systemic effect (respiratory) was investigated in this study. 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 exposure level 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 end point used to quantify the adverse effect accompanies the LOAEL. The "Less Serious” respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. Reference The complete reference citation is given in Chapter 8 of the profile. CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELs for cancer, but the text may report doses which did not cause a measurable increase in cancer. 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. A-3 APPENDIX A LEGEND See LSE 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 levels for particular exposure duration. (13). (14). (15). (16). (17). (18). (19). Exposure Duration 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. Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m® or ppm and oral exposure is reported in mg/kg/day. NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates 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). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. 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 EPA’s Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q;"). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. [} +> TABLE 2-1. Levels of Significant Exposure to [Chemical x] - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure® Species duration System (ppm) (ppm) (ppm) Reference [2}— INTERMEDIATE EXPOSURE gee @ 0 ; [4}— 1s Rat 13 wk Resp 3 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE Cancer ul 2 m 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 = > 5d/wk organs) > Thr/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 2 The number corresponds to entries in Figure 2-1. [12}— b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 1073 ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk = week(s) vv [] ———— —— INTERMEDIATE (15-384 Days) 100 1 @e OW ore Pe [re] — Yc“ ——— Qe On oy © 0000 §- FIGURE 2-1. Ot Gry GeO 1% Cotetere 000 0 0 0% % % 0% 0% % 0 "s ea or» @n= 0 Orem fos manmmwe Key fir © (10461 te soins flocs jardmals) @ LOAEL tor hess serine sfiocm fardmals) NOAEL jerdmate) @ cel - Concw Elect Lovet he rmumber nest io each pain con espands ie entries bv Tete 2 | ‘ [esas ropeasert ha ewes Sone teoted por $hudy That produto navsdperte 100p0r0e Grd Se pot imply Bre teluience of 4 Prahdld be Be Sunow ond pant Levels of Significant Exposure to [Chemical X]-Inhalation Ome Be Bsc Pree Ose Ose QO Ome Os On PO V XION3ddV Sv H Cones A-6 APPENDIX A Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, 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 discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and 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. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, -interimediate, - chronic). These MRLs are not meant to support regulatory action, but to aquaint 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 substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, "Interactions with Other Chemicals" and 2.7, "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 used by the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. A-7 APPENDIX A To derive an MRL, ATSDR generally selects the end point 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 effects (e.g.. systemic, neurological, and developmental). In order to compare NOAELSs and LOAELS for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.e., 7 days/week). If the information and reliable quantitative data on the chosen end point 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. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used 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 adjusted 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. ACGIH ADME atm ATSDR BCF BSC CDC CEL CERCLA CFR CLP cm CNS DHEW DHHS DOL ECG EEG EPA EKG FAO FEMA FIFRA fpm GC gen HPLC IDLH IARC ILO B-1 APPENDIX B 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 liter LC LC, LC,, LD Lo LD, 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 B-2 APPENDIX B 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 STEL STORET TLV TSCA TRI TWA U.S. UF yr WHO wk R {IANA |v YV pm Hg B-3 APPENDIX B 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 micron microgram CA APPENDIX C PEER REVIEW A peer review panel was assembled for 1,4-dichlorobenzene. The panel consisted of the following members: Dr. James Polland, Private Consultant, Las Vegas, Nevada; Mr. Lyman Skory, Skory Consulting, Midland, Michigan; Dr. James Withey, Environmental Health Centre, Ottawa, Ontario, Canada; 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. In addition, Section 2.8 was peer reviewed by Dr. Alan Hall, Private Consultant, Evergreen, Colorado; Dr. James Gallo, University of Georgia, College of Pharmacy, Athens, Georgia; and Dr. Peter Lacouture, The Purdue Frederick Company, Norwalk, Connecticut. 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. % U.S. GOVERNMENT PRINTING OFFICE: 1993 738-201 10.11 U. C. BERKELEY LIBRARIES I C08La&Aa5Y5]