DRAFT TOXICOLOGICAL PROFILE FOR HEXACHLOROETHANE 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 June 1994 *** DRAFT FOR PUBLIC COMMENT *** CAT. FOR DISCLAIMER Y EALTH 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. ***DRAFT FOR PUBLIC COMMENT *** ii KA 1242 F377 UPDATE STATEMENT T6e9 Toxicological profiles are revised and republished as necessary, but no less than once every three years. For | 3 9 ¢ information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry I 0 4 iL, Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 ***DRAFT FOR PUBLIC COMMENT *** nei prt ee Te “MEARE Slat sy : Nola tay 3 i ) JS SREARROORIE Fo A gr fn DLL : ) . ¢ reBet - pase, ® . 3 = ws - FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) amended the Comprehensive Environmental Response, Compensation, and Liability Act (CERCLA or Superfund). Section 211 of SARA also amended Title 10 of the U. S. Code, creating the Defense Environmental Restoration Program. Section 2704(a) of Title 10 of the U. S. Code directs the Secretary of Defense to notify the Secretary of Health and Human Services of not less than 25 of the most commonly found unregulated hazardous substances at defense facilities. Section 2704(b) of Title 10 of the U. S. Code directs the Administrator of the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare a toxicological profile for each substance on the list provided by the Secretary of Defense under subsection (b). 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 substance’s relevant toxicological properties. Following the public health statement is information conceming 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 the Environmental Protection Agency (EPA). The focus of the profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. *** DRAFT FOR PUBLIC COMMENT *** 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. We plan to revise these documents in response to public comments and as additional data become available. Therefore, we encourage comments that will make the toxicological profile series of the greatest use. Comments should be sent to: Agency for Toxic Substances and Disease Registry Division of Toxicology Mail Stop E-29 Atlanta, Georgia 30333 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 Prevention (CDC), and other Federal agencies. It has also been reviewed by a panel of nongovernment 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. David Satcher, M.D., Ph.D. Administrator Agency for Toxic Substances and Disease Registry *** DRAFT FOR PUBLIC COMMENT *** vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHOR(S): Cassandra Smith-Simon, M.S. ATSDR, Division of Toxicology, Atlanta, GA Joyce M. Donohue, Ph.D. Life Systems, Inc., Arlington, VA 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. ***DRAFT FOR PUBLIC COMMENT *** PA AR B rms ls, a= b ith ie = RE NRIED = lo CONTENTS FOREWORD . issu tn stam ds vs ws vivbu wn a'ssvawh evn vimanas esis tes v CONTRIBUTORS lls 4 4 vim vine le mini nove win snl aon ole line wigiinde]w walnie ih giwewinoipini ein oo vii LISTOF FIGURES . . «sr vu nsisins san ns vase ssmenns sors sasssnsonmnnsovaines sno xiii LAST OF TABLES vv vxnsussiatnsnsasnsntnnnsonsenshassrasiassss davai sion XV 1. PUBLIC HEALTH STATEMENT ........ PE SSE 1 1.1 WHATISHEXACHLOROETHANE? ......... 00s tvernnannnrsnennsvvns 1 1.2 WHAT HAPPENS TO HEXACHLOROETHANE WHEN IT ENTERS THEENVIRONMENTZ veo vviustsaransanerssnsnasssnsssssassnansnsonesy 2 1.3 HOW MIGHT I BE EXPOSED TO HEXACHLOROETHANE? . ............o0vnnn 3 1.4 HOW CAN HEXACHLOROETHANE ENTER AND LEAVE MYBODY? ........c0.t. 3 1.5 HOW CAN HEXACHLOROETHANE AFFECT MY HEALTH? ................o00 4 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO HEXACHLOROETHANE? . . . . ooo i tine es 5 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECTHUMANHEALTH? . ... iti iii icine 5 1.8 WHERE CAN I GET MORE INFORMATION? .........ccvnnnneenneneens 6 3 HEALTH EFFECTS vow rsimsnsnsmssrasarssasasbbanss men eraysssasaansiay 7 31 INTRODUCTION ...v'veasncnomunnnannsos vss 848th assimaat suse dial, 7 22 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE . ................ 7 2.2.1 Inhalation EXPOSUTE . . . «ov v tov meee iiien ess em eins ese 8 22.1.1 Death oo vo ee eee 8 2.21.2 SystemiCEBIfecIS cv vvvnrnsusersasnsnsasrniasanrasanminna. 8 2.2.1.3 Immunological Effects .............cciiiiiiii 17 2.2.1.4 Neurological Effects . . . ..... citi 17 2.2.1.5 Reproductive Effects ............ccvrr ruin 17 2.2.1.6 Developmental Effects . ......... oii 18 22.1.7 GenotoxiC Effects . . ovo viii 18 291.8 CaCET . «cc ttt vv vt sss strana sssssassennasssesssssaaanss 18 03 OrlBXpOMIC . s+ ss asurdrssstvssshuspmmnssnraisvosadvnnivivanee 18 22.2.1 Death «ov oe ee 18 2.222 SystemiCEffects ........ccccvsrrrrr i irnnarrrraeen 19 2.2.2.3 Immunological Effects ........... citi 32 2.2.24 Neurological Effects . . ........... iii, 32 2.225 Reproductive Effects ............ cctv 33 2.2.2.6 Developmental Effects . .......... cco 33 2.2.2.7 GenotoxiC Effects . . . voi iii 33 22.2.8 CANCEL + vv ov teat eee ete ieee 33 2.3.3 Dermal BRPOSUIE « ss su smrasnrssa bass ea mpasas sruee wads 40a nus 34 22.3.1 Death «vv te ee eee 34 2.23.2 SystemiC Effects ....vvu vicina 34 2.2.3.3 Immunological Effects ............ iii 36 2.2.3.4 Neurological Effects . . . . . o.oo vive 36 2.2.3.5 Reproductive Effects . ...... coi 36 2.2.3.6 Developmental Effects ..............oiiiiieen 36 22.37 GenotoXiC Effects . . . vv viii ieee 36 ***DRAFT FOR PUBLIC COMMENT*** 3; 4. 3. R.213.8 JOMCLE va W les in 1 Ye a hs a te dae are a als Sa NS 36 23 TOXICORINBTICS vail: co nt Fda wt a a saa adn tl ed rats 36 2.3.0 LADSOIDHONL. i wus eis 2h daa can » ein nin ws wn eS es eee 3 ae ae ia ret Ny 37 2.3.14 CInhalaliONEXPOSUIE uo osu vs vst usw snide aio as nies ronan 37 2.3.0.2 OPAL BIPOSUTE i viva's s thine nas ies niu vin wie wililn sia ns ans ssn oie 37 2.3.1.3 Dermal BRposure 1h by ne de se kk 0 as wea aa 38 2.3.2 DISIbOtON ©. 4 SE Lr A Ih si sa ra bn sm nad Pn TA are Die sad 38 23.2.1 Inhalation BRPOSUIE +. + vv sus vss us bins man'sivsns non sd on asin 38 2322 “OMBLEXPOBUIE . vv viv vv: sn vummme mime dads nsie omens sme 38 232.3 Dermal BXpOSUIE . ... 0 uv cv trv vnnsnsnrarasenanissnsense 38 2.3.2.4 Other Routes of Exposure . ............... iin... 39 2.3.3 MeDOUSHE «co crn ras Rass sss mit sans tn a 39 2.34 EXCTEHON . «4 ov vv tna vss r manson snnnss Cw ne me ww shea ele 41 2.3.4.1 Inhalation Exposure . ................. i 41 234.2 OTA EXPOSUTE +1 v1 nt vininsmansnanmmssittnca sannbomdon oni 41 234.3 DEMABRPOSUTE +. v2 vi uunininivnmumunnessnrsinhomenssnsene 41 2.3.5 Mechanisms of ACtiOn . . . . ... 41 24 RELEVANCE TO PUBLIC HEALTH ............. iii. 42 2.5 BIOMARKERS OF EXPOSURE AND EFFECT... ........ ui. 51 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Hexachloroethane ........... 51 2.5.2 Biomarkers Used to Characterize Effects Caused by Hexachloroethane . ........... 52 2.6 INTERACTIONS WITH OTHER SUBSTANCES . . ......... iii. 52 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE ...................... 53 2.8 METHODS FOR REDUCING TOXIC EFFECTS . . . . . . o.oo iit 53 2.8.1 Reducing Peak Absorption Following Exposure . ......................... 53 2.8.2 Reducing Body Burden ................... 54 2.8.3 Interfering with the Mechanism of Action for Toxic Effects . .................. 54 2.9 ADEQUACY OF THE DATABASE . . . . . ite 54 2.9.1 Existing Information on Health Effects of Hexachloroethane .................. 55 2.9.2 Identificationof Data Needs ...................... uuu... 55 293 On-going Studies .............c.00iiiiiiiii iii eee, 60 CHEMICAL AND PHYSICAL INFORMATION . .......... iii, 61 30 CHEMICAL IDENTITY ..utuunvassscornnummunrnnsnrnassssssnsnsn onsen 61 3.2 PHYSICAL AND CHEMICAL PROPERTIES . . . ....... citi. 61 PRODUCTION, IMPORT/EXPORT, USE, AND DISPOSAL ............. uuu... 65 4.1 PRODUCTION sc 2c co vt vt 5% £8 55 24 ohm vn vnsmmns nasa stots osssnseses 65 4.2 IMPORT/EXPORT . ....... iit iti ieee ee eee eee 65 B.3 USE uit tnemtassrsnrassnnssstssntnsentsstsntnoassiesosesmonsesn 65 44 DISPOSAL, oc v1 n sr sus hn sn nu sss: 0s as BPMs Rimi rnsnstmens use nn ork 67 POTENTIAL FOR HUMAN EXPOSURE . ........... iii, 69 5.1 OVERVIEW iii it tits tts e ieee e ai 69 5.2 RELEASES TO THE ENVIRONMENT ...................... Ma ars wn ws gw Te 69 Os 69 ER 72 5.23080l von vu vines imssintndarnrnrnsm snr urns shin sui nurses 72 5.3 ENVIRONMENTAL FATE ......... itt, 72 5.3.1 Transport and Partitioning . . ................ ui 72 5.3.2 Transformation and Degradation . . . . ...................... 0.0... ... 73 Bh ON 73 5.322 WHEE viv iiiuininianassrnemsnnmsisins sss sesss ssn 73 ***DRAFT FOR PUBLIC COMMENT *** xi 5.3.2.3 “Sediment and iSO. ic wei inti ain mamas 5,00 7 hile ety aE a we Sh aR ve 74 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT . . . .............. 74 Sd AIL iia a a RR ew RRR Re Pa a do wel a of eed aa lake ane 74 SAS Sediment and SOL: ii. c co vinrvimeie sols v3 sini swe Swe ine woawents dn pele alien 75 S44 OtherEnvironmental Media ....... cit iincievsrssonstnassssstnnns 75 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ................... 75 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES . . .................... 75 5.7 ADEQUACY OF THEDATABASE . ......... iii 75 5.7.1 Identificationof Data Needs . .. . .. . . ct iti ities ieee 76 572 On-going Studies ...........c vr rrrn teresa trnearaerrreanens 77 6. ANALYTICAL METHODS . . citi titi titties sisi ie eee e ans 79 6.1 BIOLOGICAL MATERIALS . . . eee 79 6.2 ENVIRONMENTAL SAMPLES ....coovusunsntnrvrnsassvsvsonsraisssanes 79 6.3 ADEQUACY OF THE DATABASE . . ...... iii 83 6.3.1 Identification of Data Needs . . . . . . cu iit iit tit it ete te ete 83 63.2 OngoingStudies ...........c. ttre aa aa 84 7. REGULATIONS AND ADVISORIES . . ... iii seein ees 85 8. REFERENCES ......... iii i iii ities 89 0. GLOSSARY © .vcntrssrsanenrssmenpsnsnsesiditisssonsosnsunmsestnssoniionns 101 APPENDICES A. USER'S GUIDE . . . ct ttt titi titi ts tsar stn er staan nanssneseas A-1 B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS . ............... i... B-1 C. PEER REVIEW . ott i tt eee et ee eee ie sissies ee eas C-1 ***DRAFT FOR PUBLIC COMMENT*** Be xiii LIST OF FIGURES 2-1 Levels of Significant Exposure to Hexachloroethane - Inhalation ..................o000.. 12 2-2 Levels of Significant Exposure to Hexachloroethane - Oral . . ............ccvuvvnen.. 26 2-3 Proposed Pathways for Hexachloroethane Metabolism . . .......ccvvvvvennennnnneee 40 2-4 Existing Information on Health Effects of Hexachloroethane . ............covvvvveeen. 56 5-1 Frequency of NPL Sites with Hexachloroethane Contamination . .............coveenn 70 ***DRAFT FOR PUBLIC COMMENT*** 4-1 5-1 6-1 7-1 Xv LIST OF TABLES Levels of Significant Exposure to Hexachloroethane - Inhalation ........................ 9 Levels of Significant Exposure to Hexachloroethane - Oral . ..............covvvnnnnn 20 Levels of Significant Exposure to Hexachloroethane - Dermal . ......................... 35 Genotoxicity of Hexachloroethane In Vitro . . .........cooiviinie. 49 Chemical Identity of Hexachloroethane . ............. cotinine nnn. 62 Physical and Chemical Properties of Hexachloroethane . .................ooonnnnnnnnn 63 Facilities that Manufacture or Process Hexachloroethane ............................. 66 Releases to the Environment from Facilities that Manufacture or Process HexachlOTOBhANE . . . ot vv tt it ee ete ee ete eee tte ee eee eee 71 Analytical Methods for Determining Hexachloroethane in Biological Materials . ............... 80 Analytical Methods for Determining Hexachloroethane in Environmental Samples . . . ........... 81 Regulations and Guidelines Applicable to Hexachloroethane ...................ooonnn. 86 ***DRAFT FOR PUBLIC COMMENT*"** 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about hexachloroethane and to emphasize the human health effects that may result from exposure to it.” The Environmental Protection Agency (EPA) has identified 1,350 hazardous waste sites as the most serious in the nation. These sites comprise the "National Priorities List" (NPL): Those sites which are targeted for long-term federal cleanup activities. Hexachloroethane has been found in at least 44 of the sites on the NPL. However, the number of NPL sites evaluated for hexachloroethane is not known. As EPA evaluates more sites, the number of sites at which hexachloroethane is found may increase. This information is important because exposure to hexachloroethane may cause harmful health effects and because these sites are potential or actual sources of human exposure to hexachloroethane. When a substance is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment. This release does not always lead to exposure. You can be exposed to a substance only when you come in contact with it. You may be exposed by breathing, eating, or drinking substances containing the substance or by skin contact with it. If you are exposed to a substance such as hexachloroethane, many 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, gender, nutritional status, family traits, life-style, and state of health. 1.1 WHAT IS HEXACHLOROETHANE? Hexachloroethane is a colorless solid that gradually evaporates when it is exposed to air. This compound is also called perchloroethane, carbon hexachloride, and HCE. It is sold under the trade names Avlothane, Distokal, Distopan, and Distopin. In the United States, about half of the hexachloroethane is used by the military for smoke-producing devices. It is also sold as degassing pellets that are used to remove the air bubbles in melted aluminum. Hexachloroethane may be present as an ingredient in some fungicides, insecticides, lubricants, plastics, and cellulose. At one time, hexachloroethane was prescribed for deworming animals. Hexachloroethane does not occur naturally in the environment. It is made by adding chlorine to tetrachloroethylene and is a by-product in the high temperature synthesis of tetrachloroethylene from carbon tetrachloride. Hexachloroethane is no longer made in the United States, but it is formed as a by-product in the production of some chemicals. Some hexachloroethane can also be formed by incinerators when materials containing chlorinated hydrocarbons are burned. Hexachloroethane itself is not flammable. Some ***DRAFT FOR PUBLIC COMMENT*** 2 1. PUBLIC HEALTH STATEMENT hexachloroethane can also be formed when chlorine reacts with carbon compounds in drinking water. Hexachloroethane vapors smell like camphor. You can begin to smell it in air when there are 150 parts present in a billion parts of air (ppb). You can smell it in water when 10 ppb are present. Neither a description of the taste nor the amount of hexachloroethane that gives a taste to water were found. More information on the properties and uses of hexachloroethane is found in Chapters 3, 4, and S. 1.2 WHAT HAPPENS TO HEXACHLOROETHANE WHEN IT ENTERS THE ENVIRONMENT? Hexachloroethane is released to the air during military operations and training exercises when smoke-producing devices containing hexachloroethane are used. Most of the hexachloroethane in a smoke pot or grenade is used up by the smoke-producing reaction. Only small amounts (5% or less) remain after the smoke has formed. However, these small amounts can collect in the atmosphere and in the soil. At one military training site, about 14,700 pounds of hexachloroethane were released to the air over a 2-year period. Hexachloroethane also enters the environment as part of the waste from companies that make or use this material. Vapors can be released to the air during production, use, or transport. Solid wastes containing hexachloroethane are buried in landfills or burned. The hexachloroethane buried in landfills can dissolve in underground water because it does not bind strongly to soil. Once dissolved, it can reach rivers, lakes, streams, or well water. Hexachloroethane in the air does not break down to other compounds. It gradually escapes into space. Some hexachloroethane that is in lakes or streams and surface soils will evaporate into the air. Some will be broken down by microorganisms. Microbes can break down hexachloroethane more easily without oxygen than with oxygen. That is why hexachloroethane buried in the soil or trapped in underground water will break down more quickly than hexachloroethane near the surface. In one study, it took only 4 days for 99% of the hexachloroethane in soil to break down when oxygen was not present. It took 4 weeks when oxygen was present. Hexachloroethane does not appear to collect in plants or animals used for food. It has a slight tendency to build up in fish, but the fish break it down quickly, so the amount found in fish from polluted waters is very low. Rainbow trout from Lake Ontario had only 0.03 parts hexachloroethane per trillion (ppt) parts of fish. More information on what happens to hexachloroethane in the environment is found in Chapters 4 and S. ***DRAFT FOR PUBLIC COMMENT *** 3 1. PUBLIC HEALTH STATEMENT 1.3 HOW MIGHT | BE EXPOSED TO HEXACHLOROETHANE? You can be exposed to hexachloroethane from the air. The amount of hexachloroethane in the air ranges from 5 to 7 ppt. Larger amounts may be found near military bases where smoke pots and grenades that contain hexachloroethane are used during training. Higher-than-average amounts can occur near aluminum smelters that use hexachloroethane as a degassing agent. Incinerators that burn industrial wastes containing chlorine can release hexachloroethane to the air. If you live near a hazardous waste site, you might be exposed to hexachloroethane by breathing or drinking contaminated water. Private wells near one hazardous waste site contained 4.6 ppb hexachloroethane. Children who play in soil near a waste site that contains hexachloroethane could be exposed if they put soil or soiled fingers into their mouths. You are not likely to be exposed to hexachloroethane from your food. However, you might be exposed if you use insecticides, fungicides, or plastics that contain this chemical. You may also be exposed to small amounts of this chemical from your drinking water if chlorine is used to kill germs. Hexachloroethane has been reported in drinking water at concentrations of 0.03-4.3 ppb in some locations. If you work in an industry that uses hexachloroethane, such as aluminum smelting, you could be exposed by breathing or touching it. If you work at a chemical plant where hexachloroethane is used, you could also be exposed. People who work with smoke-producing devices that contain hexachloroethane are exposed to it in the smoke. They can contact it through smoke particles on plants and in the soil. More information on how you can be exposed to hexachloroethane is found in Chapter 5. 1.4 HOW CAN HEXACHLOROETHANE ENTER AND LEAVE MY BODY? Hexachloroethane can enter your body through your lungs if you breathe its vapors. Only a small amount will enter through your lungs. It can enter your body if you eat or drink something contaminated with it. Based on studies in animals, about half of the hexachloroethane you eat will get into your bloodstream. Very little will enter your body if you get it on your skin. The hexachloroethane that enters your body will go to your liver where it is turned into other compounds. Some of these compounds are harmful and will affect your health in almost the same way hexachloroethane does. If you are exposed to carbon tetrachloride, your liver can make hexachloroethane from it. ***DRAFT FOR PUBLIC COMMENT *** 4 1. PUBLIC HEALTH STATEMENT When hexachloroethane gets into your body, some goes to your body fat and stays there a short time. Most of it leaves your body in 1 or 2 days in the air you breathe out, in your urine, and in your feces. Additional information on how hexachloroethane enters and leaves your body is found in Chapter 2. 1.5 HOW CAN HEXACHLOROETHANE AFFECT MY HEALTH? There are no studies of hexachloroethane in humans. However, results of animal studies can be used to show how hexachloroethane can affect your health. Based on the animal data, hexachloroethane in the air can irritate your nose and lungs and cause some buildup of mucus in your nose. This might make it easier for you to catch a cold or some other respiratory infection. Hexachloroethane can irritate your eyes and make them tear. If you are in an area that contains a large amount of hexachloroethane vapor, your facial muscles may twitch or you may have difficulty moving. These effects have been observed in animals during exposure. Hexachloroethane is not a highly toxic substance. If you are exposed to a large amount for a long time, some of your liver cells could be destroyed and fat could build up in your liver. There is also a slight chance that your kidneys could be damaged. No results from animal studies suggest that hexachloroethane would make it hard for you to become pregnant or hurt your baby while you are pregnant. However, the animal studies that looked at the effects of hexachloroethane during pregnancy are limited. Liver tumors developed in mice that were orally exposed to hexachloroethane for their whole lifetime. Tumors of this kind are common in mice. Hexachloroethane will not necessarily have the same effect on people. Male rats that were exposed to hexachloroethane for their lifetime developed kidney tumors. This type of tumor is not found in people, so it is unlikely that exposure to hexachloroethane would cause you to develop cancer of the kidney. The International Agency for Research on Cancer (IARC) has determined that hexachloroethane is not classifiable as to its carcinogenicity in humans. EPA has determined that hexachloroethane is a possible human carcinogen. More information on the health effects from hexachloroethane exposure is found in Chapter 2. ***DRAFT FOR PUBLIC COMMENT *** 5 1. PUBLIC HEALTH STATEMENT 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO HEXACHLOROETHANE? Samples of your blood, urine, or feces can be tested to see if you were exposed to hexachloroethane. The tests for hexachloroethane are not routinely available at most doctors’ offices, but your doctor can collect blood, urine, or fecal samples and send them to a special laboratory for testing. These tests are useful only if you were exposed 24-48 hours before you saw the doctor. Your body changes hexachloroethane to the same compounds that it makes from other chemicals like tetrachloroethylene or pentachloroethane. If the laboratory finds hexachloroethane in your body fluids or excretions, your doctor will ask you if you were exposed to carbon tetrachloride. Your body can also make hexachloroethane from carbon tetrachloride. Additional information on medical tests that can be used to determine if you have been exposed to hexachloroethane is found in Chapters 2 and 6. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? : The federal government is concerned about the amount of hexachloroethane that you are exposed to in the environment. The government has established standards and guidelines to prevent you from being overexposed. The Occupational Safety and Health Administration (OSHA) has set a limit of 1 part per million (ppm) for the hexachloroethane in workplace air over an 8-hour workday. The National Institute for Occupational Safety and Health (NIOSH) considers hexachloroethane as a potential occupational carcinogen and recommends 1 ppm in air as a tolerance value. The EPA recommends that children not drink water with more than 5 ppm hexachloroethane for more than 10 days or more than 100 ppb for any longer than 7 years. Adults should not drink water with more than 450 ppb any longer than 7 years. EPA suggests that water consumed over a lifetime contain no more than 1 ppb hexachloroethane. Industrial releases of more than 100 pounds of hexachloroethane into the environment must be reported to EPA. Additional information on government regulations for hexachloroethane is found in Chapter 7. **xDRAFT FOR PUBLIC COMMENT*** 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 (404) 639-6000 This agency can also provide you with information on the location of occupational and environmental health clinics. These clinics specialize in the recognition, evaluation, and treatment of illness resulting from exposure to hazardous substances. ***DRAFT FOR PUBLIC COMMENT *** 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 hexachloroethane. It contains descriptions and evaluations of toxicological studies and epidemiological investigations and provides conclusions, where possible, on the relevance of toxicity and toxicokinetic data to public health. A glossary and list of acronyms, abbreviations, and symbols can be found at the end of this profile. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals and others address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure — inhalation, oral, and dermal; and then by health effect — death, systemic, immunological, neurological, reproductive, developmental, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods — acute (14 days or less), intermediate (15 - 364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELS) or lowest-observed-adverse- effect levels (LOAELS) reflect the actual doses (levels of exposure) used in the studies. LOAELSs have been classified into "less serious" or "serious" effects. "Serious" effects are those that evoke failure in a biological system and can lead to morbidity or mortality (e.g., acute respiratory distress or death). "Less serious" effects are those that are not expected to cause significant dysfunction or death, or those whose significance to the organism is not entirely clear. ATSDR acknowledges that a considerable amount of judgment may be required in establishing whether an end point should be classified as a NOAEL, "less serious" LOAEL, or "serious" LOAEL, and that in some cases, there will be insufficient data to decide whether the effect is indicative of significant dysfunction. However, the Agency has established guidelines and policies that are used to classify these end points. ATSDR believes that there is sufficient merit in this approach to warrant an attempt at distinguishing between "less serious” and "serious" effects. The distinction between "less serious” effects and "serious" effects is considered to be important because it helps the users of the profiles to identify levels of exposure at which major health effects start to appear. LOAELs or NOAELs should also help in determining whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the Levels of Significant Exposure (LSE) tables and figures may differ depending on the user’s perspective. Public health officials and others concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAELSs) or exposure levels below which no adverse effects (NOAELs) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels or MRLs) may be of interest to health professionals and citizens alike. Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of hexachloroethane are indicated in Table 2-2 and Figure 2-2. Because cancer effects could occur at lower exposure levels, Figure 2-2 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10 to 107), as developed by EPA. Estimates of exposure levels posing minimal risk to humans (Minimal Risk Levels or MRLs) have been made for hexachloroethane. An MRL is defined as an estimate of daily human exposure to a substance that is likely to be without an appreciable risk of adverse effects (noncarcinogenic) over a specified duration of exposure. MRLs are derived when reliable and sufficient data exist to identify the target organ(s) of effect ***DRAFT FOR PUBLIC COMMENT *** 8 2. HEALTH EFFECTS or the most sensitive health effect(s) for a specific duration within a given route of exposure. MRLs are based on noncancerous health effects only and do not consider carcinogenic effects. MRLs can be derived for acute, intermediate, and chronic duration exposures for inhalation and oral routes. Appropriate methodology does not exist to develop MRLs for dermal exposure. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1990), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. A User’s Guide has been provided at the end of this profile (see Appendix A). This guide should aid in the interpretation of the tables and figures for Levels of Significant Exposure and the MRLs. 2.2.1 Inhalation Exposure Hexachloroethane is a solid that sublimes at ambient air temperatures. At 20°C the saturated vapor concentration is 670-700 ppm (Weeks et al. 1979); thus, there is a limitation on the vapor concentration that can be used in studies using the inhalation route of exposure. In circumstances where the saturation threshold is exceeded, microcrystalline hexachloroethane forms in the atmosphere and is inhaled by the exposed animals along with the volatilized hexachloroethane. 2.2.1.1 Death No studies were located regarding lethality in humans after inhalation exposure to hexachloroethane. Rats were exposed to vapor concentrations of either 260 or 5,900 ppm hexachloroethane for 8 hours (Weeks et al. 1979). The 5,900 ppm vapor concentration was generated at 50°C and crystallized as it entered the exposure chamber. At the higher concentration the exposed animals showed signs of distress (staggering gait) during exposure, and 2 of 6 were dead at the end of 8 hours. No animals died at the lower exposure concentration. Following 6 weeks of inhalation exposure to 15-260 ppm, no deaths in quail were reported; however, 2 of 50 rats, 4 of 10 guinea pigs, and 1 of 4 dogs died with the 260 ppm concentration (Weeks et al. 1979). Based on clinical signs, the dogs seemed to be particularly sensitive to hexachloroethane exposure. The animals developed tremors and ataxia and closed their eyes. The one dog that died experienced convulsions before death. The rats and guinea pigs that succumbed to exposure died during weeks 4 or 5 and, thus, appear to be less sensitive. The quail were the most resistant to death following hexachloroethane exposure. All identified LOAEL values for lethality in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. These values indicate that hexachloroethane is lethal to animals exposed intermittently to 260 ppm for 6 weeks; however, no deaths occurred in animals acutely exposed for 8 hours to the same concentration. Concentrations of 48 ppm and lower were not lethal in rats, guinea pigs, dogs, or quail. 2.2.1.2 Systemic Effects No studies were located regarding systemic effects in humans after inhalation exposure to hexachloroethane. ***DRAFT FOR PUBLIC COMMENT *** xx INSWWOD OIN8Nd HO 14VHA xxx TABLE 2-1. Levels of Significant Exposure to Hexachloroethane - Inhalation Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference ACUTE EXPOSURE Death 1 Rat 8 hr 5900 (2/6 males died) Weeks et al. 1979 Systemic 2 Rat 8 hr Resp 260 5900 (interstitial Weeks et al. pneumonitis in 1979 2/4 survivors) Cardio 5900 Gastro 5900 Musc/skel 5900 Hepatic 5900 Renal 5900 Other 5900 (reduced body weight gain, quantitative data not provided) Other 5900 (adrenal) Neurological 3 Rat 6 hr 260 5900 (staggered gait in Weeks et al. 1 of 6 animals) 1979 4 Rat 11d 48° 260 (tremors) Weeks et al. Gd 6-16 1979 6hr/d Developmental 5 Rat 11d 260 Weeks et al. Gd 6-16 6hr/d 1979 S103443 HLTV3H 2 xxx INFWWOD O118Nd HOH L4VHA xxx TABLE 2-1. Levels of Significant Exposure to Hexachloroethane - Inhalation (continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure” Species frequency System (ppm) (ppm) (ppm) Reference Reproductive 6 Rat 1d 260 Weeks et al. Gd 6-16 1979 6hr/d INTERMEDIATE EXPOSURE Death 7 Gn pig 6 wk 260 (4/10 animals died) Weeks et al. 5d/wk 1979 6hr/d 8 Dog 6 wk 260 (1/4 males died) Weeks et al. 5d/wk 1979 6hr/d Systemic 9 Rat 6 wk Resp 48° 260 (diminished Weeks et al. 5d/wk resistance to 1979 6hr/d mycoplasia infection) Cardio 260 Gastro 260 Musc/skel 260 Hepatic 260 Renal 260 Derm/oc 260 Other 48 260 (reduced body weight in young males, quantitative data not provided) 10 Rat 6 wk Resp 260 Weeks et al. 5d/wk Hepatic 260 1979 6hr/d Renal 260 Other 48 260 (mean body weights decreased 11% in older males) S103443 HIVaH 2 ol »»» LNIWINOD J178Nd HO LdVHA « « « TABLE 2-1. Levels of Significant Exposure to Hexachloroethane - Inhalation (continued) Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure’ Species frequency System (ppm) (ppm) (ppm) Reference 1 Gn pig 6 wk Resp 260 Weeks et al. 5d/wk Cardio 260 1979 6hr/d Gastro 260 Musc/skel 260 Hepatic 260 Renal 260 Derm/oc 260 Other 48 260 (reduced body weight gain, quantitative data not provided) 12 Dog 6 wk Resp 260 Weeks et al. 5d/wk Cardio 260 1979 6hr/d Musc/skel 260 Hepatic 260 Renal 260 Derm/oc 260 Other 260 (body wt) Neurological 13 Rat 6 wk 260 Weeks et al. 5d/wk 1979 6hr/d 14 Rat 6 wk 48 260 (tremors) Weeks et al. 5d/wk 1979 6hr/d 15 Dog 6 wk 48 260 (tremors, ataxia, Weeks et al. 5d/wk fasciculations) 1979 6hr/d ’The number corresponds to entries in Figure 2-1. ®Used to derive an acute inhalation MRL of 0.5 ppm. An uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). ‘Used to derive an intermediate inhalation MRL of 0.09 ppm; concentration 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). Cardio = cardiovascular; d = days(s); Derm/oc = dermal/ocular; Gastro = gastrointestinal; Gd = gestation day(s); Gn pig = guinea pig; hr = hour(s); LOAEL = lowest-observed-adverse-effect level; Musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; ppm = parts per million; Resp = respiratory; wk = week(s); wt = weight S103443 H1TV3H 'C LL »»» LNJWWOD O118Nd HOH LIVHA wx» FIGURE 2-1 Levels of Significant Exposure to Hexachloroethane — Inhalation 0.1 0.01 0.001 0.0001 0.00001 ACUTE (<14 Days) Systemic N A: & > S$ oF & 8° & & 2 &F F&F © » & © C&O Na < So FP & XL FH & & & © > © E pom) FF & WF Oo < F< @r Pr QO2r Q2r O22 Q2r Q2r P2r O2r Pr L Oar Or @« Os Qer Ow« i | | | 1 1 1 1 I J——; | I 1 Nv Key B d Dog @ LOAEL for serious effects (animals) i Minimal risk level g Guinea Pig ( LOAEL for less serious effects (animals) J Lon aliscis otrier p- r Rat O NOAEL (animals) The number next to each point corresponds to entries in Table 2-1. 0.000001 S103443 H1TV3H °C zl xxx INFWWOD O118Nd HO LIVHA xxx. FIGURE 2-1 Levels of Significant Exposure to Hexachloroethane — Inhalation (Continued) INTERMEDIATE (15-364 Days) Systemic N » ¥ rd > S » & ©° al 7 & Gil © A © & NO NJ & oR © oy 5 & 10,000 — 1,000 — Qe @7n O12 Otig Por Oror O12d Ove Ow QOig Or Q124a Otig Qor QOr2d Og Oar Ortor 100 — or i 10 ] 1 1 ‘ 1 1 1 1 0.1} w 0.01 — Key 0.001 |— ) . i BL ’ d Dog @ LOAEL for serious effects (animals) : Mins yisk level i : i i 1 for effects other g Guinea Pig ( LOAEL for joss serious effects (animals) han cafooy 0.0001 — r Rat O NOAEL (animals) The number next to each point corresponds to entries in Table 2-1. 0.00001 [— 0.000001 L— S$103443 HLTV3H C el »»» LNIWWOD 2178Nd HOH 14VHA « « « FIGURE 2-1 Levels of Significant Exposure to Hexachloroethane — Inhalation (Continued) INTERMEDIATE (15-264 Days) Systemic a N N & X ¥ NS > & & © N XX Nn 2 @ Q 10,000 — 1,000— O12d O11g Or Otor Q12d Ot11g Qor Q120 11g Bor Por @ 154 Qir @14r 100[— Qitg Qo Otor Qi1sd Q1ar 10— 1 _—— 0.1 0.01 — Key 0.001 — . . ry ; d Dog @ LOAEL for serious effects (animals) 1 Minimal risk level g Guinea Pig ( LOAEL for less serious effects (animals) J Sn stiects cer 0.0001 — r Rat O NOAEL (animals) The number next to each point corresponds to entries in Table 2-1. 0.00001 [— 0.000001 L_ S103443 HLvVaH 'T vl 15 2. HEALTH EFFECTS Data are available pertaining to respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal/ocular, and other effects in animals. These effects are discussed below. The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Respiratory Effects. Acute exposure of rats to 5,900 ppm hexachloroethane for 8 hours caused interstitial pulmonary pneumonitis (Weeks et al. 1979). At this exposure concentration there were hexachloroethane particles present in the exposure chamber that were inhaled and probably contributed to the lung irritation. Changes in lung histopathology were noted when the animals were sacrificed after a 14-day recovery period. There were no changes in relative lung weights or tissue histopathology in animals that were exposed to 260 ppm for the same time period. When pregnant female rats were exposed to 0, 15, 48, or 260 ppm hexachloroethane on gestation days 6-16, 85% of the animals in the 48 ppm dose group displayed nasal exudate and all animals in the 260 ppm dose group were affected. When exposures occurred for 11 days, the excess mucus in the nasal cavity was not clearly associated with respiratory tract infection. With a longer- duration exposure (6 weeks) to the same dose, infection was present as discussed in the following paragraph. In rats exposed to 260 ppm hexachloroethane for 6 weeks, there was a significant decrease in oxygen consumption as compared to the controls (Weeks et al. 1979). The authors hypothesized that the decrease in oxygen consumption could have been a normal response to inhalation of a respiratory tract irritant. There were no significant changes in lung weights, but there was an increase in mycoplasma lesions of the nasal turbinates, trachea, and lungs; lymphoid hyperplasia of the trachea; and pneumonitis of the bronchi when the animals were sacrificed after the 6-week exposure period. These changes were not seen in the animals exposed to 15 or 48 ppm or in rats exposed to 260 ppm and sacrificed after a 12-week recovery period. The authors hypothesized that the respiratory tract lesions were the result of hexachloroethane potentiation of an endemic mycoplasma infection rather than systemic effects from inhalation exposure to hexachloroethane. The infection could be the result of lowered host resistance due to either compromised immune defenses or a weakened mucosal barrier along the respiratory epithelium. The NOAEL (48 ppm) from this study was used to calculate an intermediate inhalation MRL of 0.09 ppm as described in the footnote in Table 2-1. In older rats (12-14 weeks), there was a significant increase in relative lung weights as compared to controls following 6 weeks of exposure to 260 ppm hexachloroethane. Oxygen consumption was not measured in these animals, and it is not clear if the tissues were examined histologically (Weeks et al. 1979). In dogs, there were no significant changes in pulmonary function with exposure to 15-260 ppm hexachloroethane for 6 weeks (Weeks et al. 1979). Intrapleural pressure, transpulmonary pressure, air flow, and tidal volume were measured to obtain scores for compliance and resistance. When the animals were sacrificed at either 6 weeks or after a 12-week recovery period, there were no histopathological changes observed in the lungs. There were also no apparent effects on the respiratory system in guinea pigs from exposure to 15-260 ppm hexachloroethane. Exposure of quail to 260 ppm was associated with increased mucus in the nasal turbinates in 2 of the 10 animals, but this increased mucus did not appear to be associated with a respiratory infection. These changes were considered to be the direct effect of hexachloroethane on the epithelium of the nasal cavity and are discussed in Section 2.2.3.2. Exposure to hexachloroethane vapors can cause irritation to the respiratory system. Acute exposure to 260 ppm hexachloroethane had no apparent effect on the lungs and air passages in rats, but acute exposure to a concentration where particulate hexachloroethane was present in the atmosphere caused lung irritation (Weeks et al. 1979). On the other hand, intermediate-duration exposure to 260 ppm hexachloroethane appeared to cause some irritation of the respiratory epithelium which increased susceptibility to respiratory infection with 6-week, but not 11-day, exposures. When exposure ceased, the animals recovered, so there were no histopathological indications of tissue damage after a 12-week recovery period. Lesions of the nasal passages, trachea, and bronchi; increased mycoplasma infections; mucus in the nasal cavities; and decreased oxygen consumption were indicators of respiratory tract irritation from repeated episodes of hexachloroethane exposure. ***DRAFT FOR PUBLIC COMMENT *** 16 2. HEALTH EFFECTS Cardiovascular Effects. There were no histopathological changes in the heart for rats, guinea pigs, dogs, or quail that were exposed to concentrations of 0, 260, or 5,900 ppm hexachloroethane for 8 hours or to 0, 15, 48, or 260 ppm hexachloroethane for 6 weeks (Weeks et al. 1979). Gastrointestinal Effects. There were no histopathological changes in the stomach, small intestines, or large intestines for rats, guinea pigs, dogs, or quail that were exposed to concentrations of 0, 260, or 5,900 ppm hexachloroethane for 8 hours or to 0, 15, 48, or 260 ppm hexachloroethane for 6 weeks (Weeks et al. 1979). Hematological Effects. There were no effects on the red blood cell count of dogs exposed to 0, 15, 48, or 260 ppm hexachloroethane for 6 weeks (Weeks et al. 1979). Although other hematological parameters were apparently determined, the red cell count was the only parameter that was specified. Accordingly, it is not possible to speculate whether inhalation exposure to hexachloroethane has any effect on other hematological parameters. Musculoskeletal Effects. There were no treatment-related gross or histopathological lesions of the skeletal muscle or bone in rats, guinea pigs, dogs, or quail exposed to 0, 15, 48, or 260 ppm hexachloroethane for 6 weeks (Weeks et al. 1979). Hepatic Effects. A single exposure of rats to 260 ppm hexachloroethane had no effect on relative liver weight or tissue histopathology (Weeks et al. 1979). A single exposure to 5,900 ppm did not cause histopathological changes. Organ weights were not determined for the higher exposure concentration. The relative liver weight was increased in guinea pigs and rats, but not dogs or quail, that were exposed to 260 ppm for 6 weeks (Weeks et al. 1979). Since the increase in liver weight was not accompanied by any histological abnormalities, it is classified as a NOAEL rather than a LOAEL in Table 2-1 and Figure 2-1. There were no changes in liver weights or histopathology in any species exposed to concentrations of 15 or 48 ppm for 6 weeks. Renal Effects. A single exposure of rats to 260 ppm hexachloroethane had no effect on relative kidney weight or tissue histopathology (Weeks et al. 1979). A single exposure to 5,900 ppm did not cause histopathological changes. Organ weights were not determined for the higher exposure concentration. The relative kidney weight was increased in male rats, but not female rats, guinea pigs, dogs, or quail, that were exposed to 260 ppm for 6 weeks (Weeks et al. 1979). Since the increase in kidney weight was not accompanied by any histological abnormalities, it is classified as a NOAEL rather than a LOAEL in Table 2-1 and Figure 2-1. There were no changes in kidney weights or histopathology in any species exposed to 15 or 48 ppm hexachloroethane for 6 weeks. Dermal/Ocular Effects. Dogs that were exposed to 260 ppm hexachloroethane for 6 hours per day, 5 days per week, kept their eyes closed during each exposure (Weeks et al. 1979). Since this effect occurred throughout the 6-week study, it can be regarded as an acute effect that was most likely the result of vapor contact with the eye. In rats, a red exudate appeared about the eyes starting with week 4. This may have been a systemic effect. There were no reported effects on the eyes of guinea pigs or quail after 6 weeks of exposure to hexachloroethane. Other Systemic Effects. Rats exposed to a concentration of 5,900 ppm hexachloroethane for 8 hours had a decreased weight gain over the 14-day, postexposure observation period when compared to controls (Weeks et al. 1979). There were no differences in the weight gain for animals exposed to 260 ppm under the same conditions. Guinea pigs and male rats had decreased weight gains starting at week 2 or 3 of a 6-week exposure to 260 ppm hexachloroethane, but there were no effects on dogs or quail (Weeks et al. 1979). Exposure to 15 or 48 ppm hexachloroethane for 6 weeks had no effect on weight gain in rats, dogs, guinea pigs, or quail. ***DRAFT FOR PUBLIC COMMENT *** 17 2. HEALTH EFFECTS 2.2.1.3 Immunological Effects No studies were located regarding immunological effects in humans after inhalation exposure to hexachloroethane. There were no treatment-related gross or histopathological lesions of the thymus and spleen and no changes in spleen weight in rats that were exposed to 260 or 5,900 ppm hexachloroethane for 8 hours, nor were there any effects on thymus and spleen histopathology in rats, guinea pigs, dogs, and quail that were exposed to 260 ppm for 6 weeks (Weeks et al. 1979). The relative spleen weight was higher than that for the controls in young male rats but was not affected in older male rats or any of the other species evaluated. No effects were seen in the 15 and 48 ppm dose groups. There was an increased incidence of a mycoplasma respiratory tract infection in rats exposed to 260 ppm hexachloroethane for 6 weeks but not in rats exposed to lower doses or in other species. This could indicate compromised immune function or a weakened mucosal barrier along the respiratory epithelium. There were no studies identified that evaluated a wide range of immunological parameters. Therefore, there are no reliable LOAELs or NOAELs for this end point. Increases in spleen weights are not classified as LOAELSs since they were not accompanied by histopathological changes. 2.2.1.4 Neurological Effects No studies were located regarding neurological effects in humans after inhalation exposure to hexachloroethane. Acute 8-hour exposures to 5,900 ppm, but not 260 ppm, resulted in a staggering gait in one of six rats (Weeks et al. 1979). Tremors were also noted in pregnant rats exposed to 260 ppm starting on the 6th day of an 11-day exposure period but not in animals exposed to 15 or 48 ppm (Weeks et al. 1979). The 48 ppm NOAEL in pregnant rats was used to derive an MRL of 0.5 ppm for acute exposure to hexachloroethane as described in the footnote in Table 2-1 and plotted in Figure 2-1. When male rats were exposed to concentrations of 0, 15, 48, or 260 ppm hexachloroethane for 6 weeks, foot shock avoidance behavior and spontaneous motor activity were not different from controls when measured at 1 day, 3 weeks, or 6 weeks (Weeks et al. 1979). However, a group of male and female rats exposed to 260 ppm experienced tremors beginning at 4 weeks and persisting for the remainder of the 6-week exposure period. Recovery was evident during the 12-week post-exposure period (Weeks et al. 1978). Dogs were apparently quite sensitive to neurological effects during hexachloroethane exposure (Weeks et al. 1979). The animals displayed tremors, ataxia, head bobbing, and fasciculation of the facial muscles with a 260 ppm exposure. Symptoms disappeared in the interval between exposures but returned intermittently over the 6-week exposure period. There were no differences in serum cholinesterase activity between control and exposed animals. Apparently, the levels of the neurotransmitter acetylcholine were not affected by hexachloroethane. There were no neurological responses in guinea pigs or quail with a 260 ppm exposure, and none of the species evaluated showed any overt neurological response with a 15 or 48 ppm exposure. The highest NOAEL values and all LOAEL values from each reliable study for neurological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Acute exposures to hexachloroethane appear to cause mild neurological impairment during exposure, but symptoms do not persist during the intervals between exposures or after exposure ceases. 2.2.1.5 Reproductive Effects No studies were located regarding reproductive effects in humans after inhalation exposure to hexachloroethane. ***DRAFT FOR PUBLIC COMMENT *** 18 2. HEALTH EFFECTS In rats, hexachloroethane was maternally toxic at doses of 48 and 260 ppm administered on gestation days 6-16 based on decreased maternal body weight gain, but it was not embryotoxic or fetotoxic (Weeks et al. 1979). There were no treatment-related gross or histopathological lesions of the testes in rats, dogs, guinea pigs, and quail that were exposed to concentrations of hexachloroethane up to 260 ppm for 6 weeks. However, relative testes weights were increased in rats when compared to controls. No other reproductive organs were evaluated (Weeks et al. 1979). The highest NOAEL from each reliable study for reproductive effects in each species and duration category is recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.6 Developmental Effects No studies were located regarding developmental effects in humans after inhalation exposure to hexachloroethane. In animals, hexachloroethane did not cause skeletal or soft tissue abnormalities in offspring of rat dams that were exposed to vapors of hexachloroethane (15-260 ppm) during gestation days 6-16 (Weeks et al. 1979). The highest NOAEL value from this study for developmental effects in rats is recorded in Table 2-1 and plotted in Figure 2-1. 2.2.1.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans or animals after inhalation exposure to hexachloroethane. Genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer Studies in humans regarding carcinogenic effects of exposure to hexachloroethane are limited. One case study was identified where a man who had been occupationally exposed to hexachloroethane was treated for a liver tumor (Selden et al. 1989). Exposure had occurred over a period of 6 years as a result of the presence of hexachloroethane in a degassing agent used during aluminum smelting. However, the hexachloroethane reacted at the 700°C use-temperature, releasing a gas that was 96% hexachlorobenzene with small amounts of other chlorinated compounds. Because there was occupational exposure to a mixture of chlorinated compounds rather than just hexachloroethane, it is highly unlikely that the tumor was the result of hexachloroethane exposure alone. Occupational exposure to mineral oil mists for 20 years was also part of the subject’s employment history. No studies were located regarding cancer incidence in animals after inhalation exposure to hexachloroethane. EPA has derived an inhalation unit risk (cancer slope factor) of 1.4x10? (mg/kg/day)” for hexachloroethane (IRIS 1993). This inhalation unit risk was calculated using data from oral studies (see Section 2.2.2.8) and Figure 2-2. 2.2.2 Oral Exposure 2.2.2.1 Death No studies were located regarding lethality in humans after oral exposure to hexachloroethane. ***DRAFT FOR PUBLIC COMMENT *** 19 2. HEALTH EFFECTS When hexachloroethane was administered to rats by gavage with oil as the solvent, the LD, value was 5,160 mg/kg for males and 4,460 mg/kg for females (Weeks et al. 1979). When the hexachloroethane was dissolved in aqueous methyl cellulose solution, the LD, was 7,690 mg/kg for males and 7,080 mg/kg for females. The lower LD, for the corn oil solvent indicates that the absorption from this hydrophobic medium is greater than that from a hydrophilic medium such as methyl cellulose solution. The LD, of 4,970 mg/kg for male guinea pigs given hexachloroethane in corn oil is similar to that for rats (Weeks et al. 1979). With repeated administration of hexachloroethane, a dose of 750 mg/kg/day in corn oil was lethal to 1 of 5 male rats and 2 of 5 females within 15 days (NTP 1989). The earliest death occurred in a male rat on day 5. All animals died between day 2 and day 8 with doses of 1,500 and 3,000 mg/kg/day. With 6-week hexachloroethane exposures, there were some deaths among rats given a dose of 1,000 mg/kg/day in corn oil, and all animals died with a dose of 1,780 mg/kg/day (NTP 1977). The number of animals that died at the 1,000 mg/kg/day dose level was not specified and the time of death was not given for any of the doses. There were no deaths in animals given doses of 562 mg/kg/day or lower. Mice were more resistant to hexachloroethane exposure than rats because all of the mice survived doses of 1,000 mg/kg/day in corn oil for 6 weeks (NTP 1977). Some male mice died with a 1,780 mg/kg/day dose, but the exact number was not specified. With a 13-week exposure duration, doses of 750 mg/kg/day in corn oil were lethal to some male and female rats (NTP 1989). The earliest death occurred among the males at 7 weeks. Between 7 weeks and 13 weeks (the end of the exposure period), 5 of 10 males died; during week 13, 2 of 10 females died. Chronic (2-year) exposure of male rats to 20 mg/kg/day hexachloroethane and female rats to 160 mg/kg/day had no effect on survival (NTP 1989), but the longevity of rats exposed to doses of 212 and 423 mg/kg/day for 66 weeks was decreased as compared to controls (NTP 1977; Weisburger 1977). The hexachloroethane was given by gavage in corn oil for both studies. Doses of 750 mg/kg/day and greater can be lethal with both acute- and intermediate-duration exposures, and a chronic intake of 212 mg/kg/day or greater can shorten the lifespan of rats. There were no apparent effects on lifespan with chronic administration of a 160 mg/kg/day dose in female rats or a dose of 20 mg/kg/day in male rats. All identified LOAEL values for lethality in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects No studies were located regarding systemic effects in humans after oral exposure to hexachloroethane. Data are available pertaining to respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, dermal/ocular, and other effects in animals. These effects are discussed below. The highest NOAEL values and all LOAEL values from each reliable study for systemic effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Respiratory Effects. Pregnant female rats were given 100 or 500 mg/kg/day hexachloroethane in corn oil for 11 days (gestation days 6-16) (Weeks et al. 1979). In the high dose group, 75% of the animals showed an increased incidence of upper respiratory tract irritation compared to only 10% of the controls. Subclinical pneumonitis was evident in 20% of the animals in the high dose group as was increased mucous in the nasal turbinates. There were no effects on the respiratory tract for the animals exposed to 100 mg/kg/day when compared to the controls. ***DRAFT FOR PUBLIC COMMENT *** xxx INGWWOD O1N8Nd HOH 14vHQA xxx TABLE 2-2. Levels of Significant Exposure to Hexachloroethane - Oral 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 ACUTE EXPOSURE Death 1 Rat (G)* Once 7080 (LD50 - females) Weeks et al. 1979 2 Rat (G)’ Once 7690 (LD50 - males) Weeks et al. . 1979 3 Rat (GO) Once 5160 (LD50 - males) Weeks et al. 1979 4 Rat (GO) Once 4460 (LD50 - females) Weeks et al. 1979 5 Gn pig (GO) Once 4970 (LD50) Weeks et al. 1979 Systemic 6 Rat (G0) 11d Resp 100 500 (increased mucus in Weeks et al. Gd 6-16 nasal turbinates, 1979 subclinical pneumonitis) Other 100 500 (reduced body weight gain, quantitative data not provided) 7 Rabbit (GW) 12 d Resp 1000 Weeks et al. Cardio 1000 1979 Gastro 1000 Musc/skel 1000 Hepatic 100° 320 (hepatocellular 1000 (coagulation, degeneration) necrosis, hemorrhage) Renal 100 320 (tubular nephrosis; tubular nephrocalinosis) Other 100 320 (reduced body weight, quantitative data not provided) S103443 H1TVaH ¢ xxx INTJWWNOD O118Nd HOS 14vHA xxx TABLE 2-2. Levels of Significant Exposure to Hexachloroethane - Oral (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 8 Sheep (GO) Once Hepatic 500 (elevated sorbital Fowler 1969b dehydrogenase, glutamate dehydrogenase and ornithine carbamoyl transferase; decreased brom- sulphthalein clearance from the liver) Neurological 9 Rat (GO) 11d 100 500 (tremors) Weeks et al. Gd 6-16 1979 Developmental 10 Rat (GO) 11d 100 500 (delayed Weeks et al. Gd 6-16 development) 1979 Reproductive 1" Rat (GO) 11d 100 500 (increased fetal Weeks et al. Gd 6-16 resorptions; 1979 reduced gestation indices, INTERMEDIATE EXPOSURE Death 12 Rat (GO) 13 wk 5d/wk quantitative data not provided) 750 (death of 5/10 males and 2/10 females) NTP 1989 S103443 H1TV3aH ¢ Ie xxx INFWWOO ON8Nd HOS 14vHQA xxx TABLE 2-2. Levels of Significant Exposure to Hexachloroethane - Oral (continued) Exposure Key to duration/ figure® Species Route frequency System (mg/kg/day) NOAEL LOAEL (effect) Less serious Serious (mg/kg/day) (mg/kg/day) Reference 13 Rat (Go) 2-16 d 5d/wk Systemic 14 Rat (GO) 6 wk 5d/wk 15 Rat (Go) 2-16 d 5d/wk 16 Rat (F) 16 wk Other Resp Renal Derm/oc Other Resp Cardio Gastro Hemato Musc/skel Hepatic Renal Other (body wt) 316 375 375 —-— 62 750 (death of 1/5 males NTP 1989 and 2/5 females) 1500 (100% mortality) 562 (decreased body NTP 1977 weight gain - males amount not specified) 750 (shortness of NTP 1989 breath) 187 (hyaline droplet formation, granular cast) 750 (lacrimation) 750 (mean body weight decreased 24% in females; males gained 24% of the amount gained by controls) Gorzinski et al. 1985 15 (swelling of hepatocytes in 6/10 males) 15 (increased kidney weight 10%, relative kidney weight 5.5%, tubular atrophy and hypertrophy in males) S103443a HIWW3H 2 »»x INFJWWOD OIN8Nd HOS 14vHA xxx TABLE 2-2. Levels of Significant Exposure to Hexachloroethane - Oral (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 17 Rat (GO) 7 wk Hepatic 497 (significantly Milman et al. 5d/wk increased mean 1988; Story et liver weight) al. 1986 18 Rat (GO) 13 wk Resp 750 NTP 1989 5d/wk Cardio 750 Gastro 750 Hepatic 9% 188 (centrilobular necrosis and increased liver weight in females) Renal 47 (hyaline droplets, tubular degeneration) Derm/oc 750 Other 750 (19% reduction in mean male body weight) 19 Mouse (GO) 6 wk Other 1000 1780 (reduced body weight NTP 1977 5d/wk gain, quantitative data not provided) Neurological 20 Rat (GO) 13 wk 47 94 (post gavage 375 (convulsions) NTP 1989 5d/wk hyperactivity) CHRONIC EXPOSURE Death - 21 Rat (GO) 66 wk 212 (26/50 males and NTP 1977; 5d/wk 23/50 females died before the end of the study) Weisburger 1977 S103443 H1TV3H ¢ €2 xxx INGWWOO OIM8Nd HOS 14VHA xxx TABLE 2-2. Levels of Significant Exposure to Hexachloroethane - Oral (continued) Exposure Key to duration/ NOAEL figure® Species Route frequency System (mg/kg/day) LOAEL (effect) Less serious (mg/kg/day) Serious (mg/kg/day) Reference Systemic 22 Rat (GO) 66 wk Renal 5d/wk Other 23 Rat (GO) 2 yr Resp 5d/wk Cardio Gastro Hepatic Renal 24 Mouse (GO) 78 wk Renal 5d/wk Other (body wt) Cancer 25 Rat (GO) 2 yr 5d/wk 160 160 160 160 590 212 (30% reduction of weight gain in males) 10 (mineralization of renal papillae; renal tubule hyperplasia in males) 212 (tubular necrosis, NTP 1977; interstitial Weisburger 1977 nephritis, regenerative epithelium, fibrosis and casts) NTP 1989 20 (necrosis, regenerative epithelium, interstitial fibrosis in males) 590 (tubular NTP 1977; nephropathy, Weisburger 1977 degeneration of the tubular epithelium, inflammation, fibrosis, and calcium deposits) 10 (CEL: renal adenoma NTP 1989 in males only) 20 (CEL: renal adenocarcinoma in males only) S103443 H1TVaH 2 ve xxx INWOOD OMEN HOH L3VHA xxx TABLE 2-2. Levels of Significant Exposure to Hexachloroethane - Oral (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 26 Mouse (GO) 78 wk 590 (CEL: hepatocellular NTP 1977; carcinomas in males Weisburger 1977 and females) 5d/wk The number corresponds to entries in Figure 2-2. "Administered in methylcellulose solution. ‘Used to derive an acute oral MRL of 1 mg/kg/day; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). dUsed to derive an intermediate oral MRL of 0.01 mg/kg/day; dose divided by an uncertainty factor of 100 (10 for extrapolation from animals to humans and 10 for human variability). Cardio = cardiovascular; CEL = cancer effect level; d = day(s); Derm/oc = dermal/ocular; f = diet; G = gavage; Gastro = gastrointestinal; Gd = gestation day(s); Gn pig = guinea pig; GO = gavage (oil); GW = gavage (water); Hemato = hematological; LD50 = lethal dose (50% kill); LOAEL = lowest-observed-adverse-effect level; mg/kg/day = milligrams per kilograms per day; musc/skel = musculoskeletal; NOAEL = no-observed-adverse-effect level; Resp = respiratory; wk = week(s); wt = weight; yr = year(s) S103443 HITV3H 2 Ge xx» INSWWNOD ON8Nd HOH L14VHA xxx FIGURE 2-2 Levels of Significant Exposure to Hexachloroethane — Oral ACUTE (<14 Days) Systemic & & 2 A > & 8° » & &N 2° F&F $ © Q PF ° 5 > a o& FP & & FP & & 5° & o¥ of (mgkg/day) © & FW Ff 3 F< 10,000 — | El) Bb: mz Wa 1,000 — Om Om Om Om @nm Qs ond* on Qer on Qo Qior @1rr 100 — Qsr Qm Om Qs Om Qe Qior Qtr i I 1 10— ' | I I | 1 — A "4 0.1 — 0.01 — Key g Guinea Pig I LD50 i Minimal risk level 0.001 (— m Mouse @ LOAEL for serious effects (animals) Sk afiscs Spier r Rat (D LOAEL for less serious effects (animals) h Rabbit O NOAEL (animals) 0.0001 [— a Sheep @ CEL - Cancer Effect Level (animals) The number next to each point corresponds to entries in Table 2-2. 0.00001 — *Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 0.000001 L_ S103443 H1TV3H 2 FIGURE 2-2 Levels of Significant Exposure to Hexachloroethane — Oral (Continued) INTERMEDIATE (15-364 Days) Systemic s ? N 2 3 > . : &° . Kg & v4 © 9 N OS > & A oS a & RI F&F KR & & © > (mg/kg/day) © Ns o © 24 A NS < Q oS N . 10,000 — ¥ @ @ om > 1,000 @ir @1r @iur Oter Ore Orer 1 Qs Ore 9M py D5 Per 3 O sr OQ 1sr 1ar O81 @ 20r 3 @ir ise — 18r 20 2 100 O 16r O1ter Oter Q1ter Oier Ors Q ter O ter Qu 32 (LD50) Weeks et al. g/kg 1979 Systemic Rabbit 24 hr Derm/oc 132 Weeks et al. mg/kg 1979 Rabbit Once Derm/oc 100 (corneal opacity; Weeks et al. mg iritis) 1979 INTERMEDIATE EXPOSURE Immunological Gn pig 3 wk 1000 (no skin Weeks et al. ppm sensitization) 1979 Dermal/oc = dermal/ocular; g/kg = grams/kilograms; Gn pig = guinea pig; hr = hour(s); LD50 = lethal dose (50% kill); LOAEL = lowest-observed-adverse-effect level; mg/kg = milligrams per kilograms; NOAEL = no-observed-adverse-effect level; ppm = parts per million; wk = week(s) S103443 H1TV3H ¢ SE 36 2. HEALTH EFFECTS Contact with crystalline hexachloroethane caused swelling, iritis, corneal opacity, and discharge when placed in rabbit eyes overnight. All signs of ocular irritation were reversed 72 hours later (Weeks et al. 1979). Contact with hexachloroethane vapors at a concentration of 260 ppm was apparently irritating to the eyes of dogs because the animals kept their eyes closed during all exposure periods (Weeks et al. 1979). In rats, a red exudate was observed about the eyes after 4 weeks of exposure to hexachloroethane vapors, and in rabbits, after a single dermal exposure to a water paste of hexachloroethane (Weeks et al. 1979). The red exudate did not appear until after 4 weeks of exposure to hexachloroethane vapor and, thus, may be a systemic effect rather than the effect of direct contact of the eye with hexachloroethane. 2.2.3.3 Immunological Effects No studies were located regarding immunological effects in humans following dermal exposure to hexachloroethane. Hexachloroethane did not act as a sensitizer in guinea pigs when a challenge dose was given 2 weeks after the end of a 3-week sensitization period. Accordingly, it did not stimulate antibody formation during sensitization. The NOAEL for dermal sensitization is reported in Table 2-3. 2.2.3.4 Neurological Effects No studies were located regarding neurological effects in humans following dermal exposure to hexachloroethane. Rats that died after dermal exposure to unspecified doses of hexachloroethane during an LD, test protocol displayed ataxia, tremors, and convulsions before death (Weeks et al. 1979). A LOAEL for neurological effects is recorded in Table 2-3. No studies were located regarding the following heath effects in humans or animals after dermal exposure to hexachloroethane: 2.2.3.5 Reproductive Effects 2.2.3.6 Developmental Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer 2.3 TOXICOKINETICS Overview There are no data on the absorption of hexachloroethane by the inhalation and dermal routes. Based on the minimal effects seen on target tissues (liver and kidney), absorption from the lungs seems to be limited. Dermal absorption was also estimated to be low based on calculated dermal penetration rates. Data on absorption across the gastrointestinal tract are inconsistent. Absorption estimates based on excretory products in rabbits suggest that a moderate portion of a 500 mg/kg dose (perhaps 40-50%) is absorbed. Data on excretory products from rats and mice indicate that a much larger portion (62-88%) of this same dose is absorbed. ***DRAFT FOR PUBLIC COMMENT *** 37 2. HEALTH EFFECTS Hexachloroethane distributes preferentially to the adipose tissue. Relatively high concentrations are also found in male rat kidneys. Moderate concentrations of hexachloroethane are found in the liver, female kidney, and blood and small amounts in muscle, lungs, and brain. If the hexachloroethane is generated endogenously from carbon tetrachloride, the concentration in the rat liver exceeds that in the kidneys. Hexachloroethane is metabolized by the mixed function oxidase system by way of a two-step reduction reaction involving cytochrome P-450 and either reduced nicotinamide adenine dinucleotide phosphate (NADPH) or cytochrome by as an electron donor. The first step of the reduction reaction results in the formation of the pentachloroethyl free radical. In the second step, tetrachloroethene is formed as the primary metabolite. Two chloride ions are released. Pentachloroethane is a minor metabolic product that is generated from the pentachloroethyl free radical. The primary metabolites of hexachloroethane are eventually oxidized to form trichloroethanol and trichloroacetic acid. These ultimate metabolites are excreted along with unchanged hexachloroethane, tetrachloroethene, and pentachloroethane. A small amount of the absorbed hexachloroethane is oxidized completely to carbon dioxide. Hexachloroethane and its metabolites are removed from the body in exhaled air, urine, and bile. In rats and mice, 60-70% of the radiolabeled hexachloroethane was in exhaled air and was present as volatiles other than carbon dioxide. 2.3.1 Absorption 2.3.1.1 Inhalation Exposure No information was located regarding absorption in either humans or animals after inhalation exposure to hexachloroethane. The minor effects of hexachloroethane on organs other than the lungs in animal studies indicates that absorption does occur, but is probably minimal. Given the lipophilic nature of hexachloroethane, absorption across the lung epithelium is possible. 2.3.1.2 Oral Exposure No studies were located regarding absorption in humans following oral exposure to hexachloroethane. When sheep were administered a dose of 500 mg/kg hexachloroethane dissolved in olive oil and emulsified in water, absorption was slow based on the appearance of hexachloroethane in the venous blood (Fowler 1969b). The maximum concentration in blood was observed 24 hours after compound administration in one sheep. Based on the amount of label found in rabbit urine and exhaled air, 19-29% of a 500 mg/kg dose was absorbed (Jondorf et al. 1957). Since some hexachloroethane would be excreted in bile and found in fecal matter, the actual amount absorbed was larger than 30%, perhaps 40-50%. Data from studies in rats and mice using radiolabeled hexachloroethane suggest that much higher proportions of a 500 mg/kg/day dose of hexachloroethane were absorbed (Mitoma et al. 1985). Rats exhaled 65% of the radiolabel in exposed air and 6% in the excreta. This indicates that more than 65-70% of the hexachloroethane was absorbed. Comparable data from mice given 999 mg/kg/day indicate that more than 72-88% of the dose was absorbed. The radiolabel in expired air was 72% of the dose in mice and there was 16% of the label in the excreta (Mitoma et al. 1985). Hexachloroethane is apparently absorbed to a greater extent when administered in corn oil than when administered in an aqueous medium, based on the fact that the LD, values for hexachloroethane dissolved in methyl cellulose solution are higher than those for an oil solvent in both male and female rats (Weeks ***DRAFT FOR PUBLIC COMMENT *** 38 2. HEALTH EFFECTS et al. 1979). The ratio of LD, values suggests that about one-third less material is absorbed from an aqueous medium. 2.3.1.3 Dermal Exposure No information was located regarding absorption in humans or animals after dermal exposure to hexachloroethane. Absorption of a saturated hexachloroethane solution across human skin was estimated to be 0.0230 mg/cm?/hr based on the physical properties of hexachloroethane (Fiserova-Bergerova et al. 1990). 2.3.2 Distribution 2.3.2.1 Inhalation Exposure No information was located regarding distribution in humans or animals following inhalation exposure to hexachloroethane. 2.3.2.2 Oral Exposure No information was located regarding distribution in humans following oral exposure to hexachloroethane. After oral exposure of rats to hexachloroethane for 8-16 weeks, the largest concentration of hexachloroethane was found in the adipose tissues (Gorzinski et al. 1985; Nolan and Karbowski 1978). The kidneys of male rats, but not females, also contained high concentrations of hexachloroethane. When rats were given doses of 3, 30, or 100 mg/kg/day for 110-111 days, the concentration in the male kidney was four times larger than that in the female kidney at the lowest dose and 48 times larger at the highest dose (Nolan and Karbowski 1978). These proportions are very much like the relationship found with doses of 1, 15, or 62 mg/kg/day given to rats where the male kidney contained four times as much label as the female kidney at the low dose and 45 times as much as the female kidney at the high dose (Gorzinski et al. 1985). Hexachloroethane is also found in the liver and blood after oral exposure to hexachloroethane, although the levels found in these tissues are much lower than those found in the adipose deposits and male kidney (Gorzinski et al. 1985; Nolan and Karbowski 1978). With a dose of 1 mg/kg/day, adipose tissue samples from male rats contained 3.15 pg/g; the kidneys contained 1.36 pg/g; the liver, 0.29 ug/g; and the blood, 0.08 pg/g after 16 weeks of exposure (Gorzinski et al. 1985). In the female, the adipose tissue contained 2.59 pg/g; the kidneys, 0.39 ug/g; the liver, 0.26 pg/g; and the blood, 0.07 pg/g. As the doses were increased, the concentrations in the tissues also increased. There is a relatively rapid turnover of hexachloroethane in the tissues. In studies where doses of 62 or 100 mg/kg/day hexachloroethane were fed in the diet for about 8 weeks, the level in the tissue decayed with a half-life of 2.3-2.7 days following first order kinetics (Gorzinski et al. 1985; Nolan and Karbowski 1978). In sheep fed hexachloroethane in olive oil emulsified in water, the hexachloroethane was found primarily in the liver, kidneys, and adipose tissue 8 hours after exposure; much smaller amounts were found in brain and muscle 8 hours after exposure. The maximum concentration of hexachloroethane in blood occurred 24 hours after dosing (Fowler 1969b). 2.3.2.3 Dermal Exposure No information was located regarding distribution in humans or animals after dermal exposure to hexachloroethane. ***DRAFT FOR PUBLIC COMMENT *** 39 2. HEALTH EFFECTS 2.3.2.4 Other Routes of Exposure The tissue distribution of intraperitoneal “C hexachloroethane in male rats differed from that in male mice based on the concentrations that were bound to DNA, RNA, and protein (Lattanzi 1988). In both species the highest concentrations of label were found in the kidney, followed by the liver, lungs, and stomach in descending order. The amount of bound label in the mice, however, was about twice that in the rat for both kidney and liver. The higher concentration of label in mouse liver may help to explain why hepatocellular cancer has been seen in mice but not in rats. Hexachloroethane can be generated endogenously from exposure to carbon tetrachloride. Hexachloroethane is formed in the liver through the union of two trichloromethyl free radicals. The tissue distribution of endogenously generated hexachloroethane differed from that of exogenous hexachloroethane. After oral administration of 1 mL/kg carbon tetrachloride to rabbits, adipose tissue contained the highest concentration of hexachloroethane (1.6, 16.5, and 6.8 pg/g) at 6, 24, and 48 hours (Fowler 1969a). This was similar to the distribution found after oral and intraperitoneal exposure to hexachloroethane (Gorzinski et al. 1985; Lattanzi 1988; Nolan and Karbowski 1978). However, the amount in the liver was about twice that in the kidney at both 6 and 24 hours. At 6 hours, the liver contained 1.6 pg/g and the kidney 0.7 pg/g, while at 24 hours the liver contained 4.2 pg/g and the kidney contained 2.2 pg/g. Only small amounts were found in the muscle. 2.3.3 Metabolism Most of the information on the metabolism of hexachloroethane has been collected by in vitro techniques using rat liver slices or rat liver microsomes. Figure 2-3 summarizes the results of these studies. The identification of tetrachloroethene and pentachloroethane as the initial metabolites of hexachloroethane metabolism in vitro agrees with in vivo data from sheep that were orally exposed to doses of 500-1,000 mg/kg hexachloroethane (Fowler 1969b). The initial steps of hexachloroethane metabolism take place in liver microsomes under anaerobic conditions (Nastainczyk et al. 1982; Salmon et al. 1981, 1985; Town and Leibman 1984). Cytosolic enzymes are minimally involved with hexachloroethane metabolism (Town and Leibman 1984). Hexachloroethane is dechlorinated in a two-step reduction reaction. In the first step, cytochrome P-450 contributes one electron to hexachloroethane, leading to the loss of a chloride ion and the formation of a pentachloroethyl free radical. In the second step, a second electron is contributed by either NADPH or cytochrome b, and a second chloride is lost, producing tetrachloroethene (Nastainczyk et al. 1982). A smaller amount of the pentachloroethyl free radical becomes pentachloroethane by abstraction of a hydrogen atom from a hydrogen donor. In studies using liver microsomes, approximately 99.5% of the hexachloroethane was converted to tetrachloroethene at physiological pHs (Nastainczyk et al. 1982). When the reaction occurred at higher pHs (8.4-8.8), the ratio of pentachloroethane to tetrachloroethene was increased. The specific cytochrome P-450 involved in this series of reactions was stimulated by phenobarbital and not by 3-methylchloanthrene (Nastainczyk et al. 1982; Salmon et al. 1985; Thompson et al. 1984; Town and Leibman 1984). Both tetrachloroethene and pentachloroethane undergo subsequent hepatic metabolism. Pentachloroethane is reductively dechlorinated by microsomes to yield trichloroethene. (Reductive dechlorination was favored when there were three chlorines on one carbon and at least one chlorine on the vicinal carbon [Thompson et al. 1984), a characteristic shared by hexachloroethane and pentachloroethane). Trichloroethene and tetrachloroethene were then oxidized by hepatic enzymes to form trichloroethanol and trichloroacetic acid as terminal reaction products. Apparently, additional dechlorination reactions can occur since labeled ***DRAFT FOR PUBLIC COMMENT *** 40 2. HEALTH EFFECTS FIGURE 2-3. METABOLISM OF HEXACHLOROETHANE ¢ ¢ Cl we os ¢ a + Cl Ci Hexachloroethane “ Cytochrome P-450 ClI™ < < UT Cl Ci Pentachloroethyl Free Radical 2 NADPH or MN Cl C Cl I CI he a / AN Cl—C—C—H Cl Cl | | Cl Cli Tetrachloroethene Pentachloroethane y \ Cl Cl “ N / \, C=C / N Le Cl H : "" Trichloroethene Cl v Cl H | © | Ci—C —C c—C—G—oH | c OH Cl H Trichloroacetic Acid Trichloroethanol *** DRAFT FOR PUBLIC COMMENT *** 41 2. HEALTH EFFECTS dichloroethanol, dichloroacetic acid, monochloroacetic acid, and oxalic acid have been found in urine of animals given an oral dose of labeled hexachloroethane (Jondorf et al. 1957; Mitoma et al. 1985). Some hexachloroethane (about 2%) was completely dechlorinated and metabolized to carbon dioxide in rats and mice (Mitoma et al. 1985). 2.3.4 Excretion 2.3.4.1 Inhalation Exposure No data were located regarding excretion in humans or animals after inhalation exposure to hexachloroethane. 2.3.4.2 Oral Exposure Orally ingested hexachloroethane is excreted in exhaled air, urine, and fecal matter. The portion of the hexachloroethane found in fecal matter is the result of excretion in bile. The results of studies that measured the amount of residual hexachloroethane in excreta can be misleading, since much of the absorbed hexachloroethane is metabolized to other compounds. Measurement of “C label after exposure to labeled compound presents a more complete picture of ultimate hexachloroethane fate and excretion than measurement of hexachloroethane. In rats and mice, 65-70% of an oral dose of radiolabeled hexachloroethane (500 mg/kg/day for rats and 999 mg/kg/day for mice) was present in exhaled air (Mitoma et al. 1985). Only about 2% of this amount was exhaled as carbon dioxide. The remainder was present as other volatile compounds. In rabbits, a much smaller portion of the label was found in exhaled air (14-24%) after oral administration of 500 mg/kg hexachloroethane. The amount of labeled carbon dioxide was not determined (Jondorf et al. 1957). Relatively little hexachloroethane, pentachloroethane, and tetrachloroethene was found in the urine of sheep after oral administration of 500 mg/kg hexachloroethane (Fowler 1969b), and relatively little label (5%) was found in the urine of rabbits given 500 mg/kg (Jondorf et al. 1957). The major urinary metabolites were trichloroethanol and trichloroacetic acid in rats, rabbits, and mice (Jondorf et al. 1957; Mitoma et al. 1985). In rabbits, smaller amounts of dichloroethanol, dichloroacetic acid, monochloroacetic acid, and oxalic acid were also present (Jondorf et al. 1957). In sheep, 80% of the hexachloroethane, tetrachloroethene, and pentachloroethane fecal excretions were excreted within 24 hours (Fowler 1969b). Some of this was unabsorbed hexachloroethane and the remainder was material that had been absorbed and was excreted with the bile. Hexachloroethane was present in bile within 15 minutes of dosing and the concentration in bile was 8-10 times greater than that in blood at that time. Traces of hexachloroethane, tetrachloroethene, and pentachloroethane were present in the 48-72 hour fecal collections. 2.3.4.3 Dermal Exposure No studies were located regarding excretion by humans or animals after dermal exposure to hexachloroethane. 2.3.5 Mechanisms of Action The kidney and liver are the primary target organs for hexachloroethane based on the results of toxicity testing and supported by toxicokinetic information from tissue distribution and binding studies (Lattanzi 1988). Male rats were more susceptible to kidney damage than female rats (NTP 1989), and the kidneys of male rats contained 4-45% more hexachloroethane radiolabel than the kidneys of female rats (Gorzinski et al. 1985). However, there were some effects on kidneys of both sexes. ***DRAFT FOR PUBLIC COMMENT *** 42 2. HEALTH EFFECTS The mechanism of toxicity leading to tubular nephropathy and renal tumorigenesis in male rats is related to the synthesis and excretion of the protein a2p-globulin. This protein is synthesized in the liver and secreted into the blood. It is filtered through the glomeruli of the kidneys and partially reabsorbed through the proximal tubules where it is partially hydrolyzed (Swenberg 1993). The remainder is excreted, comprising 26% of the urinary protein (NTP 1989; Olson et al. 1990). Other species of laboratory animals, female rats, and humans produce minimal amounts of an a«2p-globulin-type protein. In the presence of hexachloroethane and other nonpolar hydrocarbons or their metabolites, a2p-globulin accumulates in hyaline droplets in the tubular epithelium. The accumulation of hyaline droplets damages the epithelial cells, leading to exfoliation and the appearance of hyaline casts in the urine. Regenerative repair of the epithelium leads to hyperplasia and increases the risk for tumors when mutated cells divide before DNA repair can occur. Although binding of hexachloroethane to a2u-globulin can explain kidney damage in male rats, it does not explain the less severe kidney changes in female rats (NTP 1989). Thus, other mechanisms must be involved in the nephrotoxicity of hexachloroethane. When DNA, RNA, and protein were isolated from kidney cells of male rats, it was found that hexachloroethane was bound more strongly to RNA and protein than to DNA (Lattanzi 1988). The highest concentrations were found bound to RNA. Epigenetic interference with protein synthesis and cell function could lead to the kidney nephropathy seen in female rats and contribute to the damage in male rats. However, no studies were identified that would support this hypothetical mechanism. Liver necrosis is another concern following hexachloroethane exposure. Hexachloroethane is metabolized in the centrilobular area of the liver by way of the microsomal mixed function oxidase system. The relatively nonpolar pentachloroethyl free radical is an intermediate in this pathway. The reaction of the free radical with unsaturated lipids in the cellular or organelle membranes could contribute to hepatocyte damage and necrosis. Conjugated dienes and malondialdehyde serve as a markers for free radical-induced lipid peroxidation. There was a uniform increase in malondialdehyde in eight assays of rat liver microsomes that were incubated with hexachloroethane (Town and Leibman 1984). Conjugated dienes were increased in some, but not all, of the samples. No changes were seen in the concentration of conjugated dienes in the hepatic endoplasmic reticulum of male rats, 2 hours after hexachloroethane exposure (Reynolds 1972). The authors hypothesized that the poor solubility of hexachloroethane in body fluid and the use of a mineral oil solvent limited the concentration of hexachloroethane in the liver at 2 hours and, thus, the lack of its effects on conjugated dienes could not be used to eliminate the possibility of free radical cellular damage at a later point in time. Although limited, the data provide some support to a free radical mechanism for the hepatic toxicity of hexachloroethane. Clinical signs of neurotoxicity (tremors and ataxia) have been observed in sheep, dogs, and rats during or immediately after both oral and inhalation exposure. Sometimes tremors developed early in the treatment regime and other times the tremors became apparent only after repeated exposures. Fluke-infected sheep experienced tremors of the facial muscles, neck, and forelimbs and were unable to stand after treatment with hexachloroethane. They were successfully treated with calcium borogluconate. This suggests that the neurological action of hexachloroethane may be the result of interference with the availability of calcium within excitable cells. 2.4 RELEVANCE TO PUBLIC HEALTH Hexachloroethane is a solid crystalline material that has entered the environment as a result of its use in military pyrotechnics and as a component of smoke-producing devices used for screening or signaling purposes. It is an intermediate in the production of fluorocarbons, cleaning agents, and refrigerants and was once used in veterinary medicine to control liver flukes in sheep. It can be found at military disposal sites and at hazardous waste sites. In addition, hexachloroethane can be formed during incineration of chlorinated ***DRAFT FOR PUBLIC COMMENT *** 43 2. HEALTH EFFECTS and during chlorination of drinking water. Accordingly, there is some risk that humans can be exposed to this material. There have been no studies of hexachloroethane involving humans. The only case study identified was one where occupational exposure to a hexachloroethane-containing degassing agent was documented. However, during the degassing operation, the hexachloroethane reacted to produce a mixture of chlorinated compounds. The subject was exposed to the compounds in this mixture, including small amounts of hexachloroethane, rather than to hexachloroethane alone. Animal studies identify the kidney and liver as the primary target organs for hexachloroethane. Renal problems were most severe in male rats and were associated with o2u-globulin/hyaline droplet nephropathy. Minimal to mild lesions were also seen in female rat kidneys and in male and female mice, indicating that some mechanism, in addition to hyaline droplet formation, is involved in renal toxicity. The liver responds to hexachloroethane exposure with increases in liver weight, increases in serum levels of liver enzymes, centrilobular necrosis, fatty infiltration of the tissues, hemosiderin-laden macrophages, and hemorrhage. Effects on the liver and kidneys were mild with inhalation exposure and more pronounced with oral exposure. No data were available for effects on the liver and kidneys by the dermal exposure route. Hexachloroethane vapors and ingested hexachloroethane act as irritants on the lining of the lung, nasal cavity, trachea, and other tissues of the respiratory tract. Pulmonary irritation was associated with an increased incidence of mycoplasma infection in rats. Hexachloroethane exposure can also irritate the eyes. The irritation of the eye and respiratory tract are reversible once exposure has ceased. Both oral and inhalation exposures to high concentrations of hexachloroethane were associated with hyperactivity, ataxia, convulsions, and/or prostration in rats, sheep, and dogs. The mechanism for these neurological effects is not clear since there were no apparent histopathological lesions in the brains of the affected animals. Neurological effects were only noted with the high-dose exposures. There has been no comprehensive evaluation of the reproductive and developmental effects of hexachloroethane. Limited data indicate that it is maternally toxic and retards fetal development. It does not appear to be a teratogen. Minimal Risk Levels for Hexachloroethane Inhalation MRLs ® An MRL of 0.5 ppm has been derived for acute inhalation exposure to hexachloroethane. This MRL is based on a study in pregnant female rats exposed to doses of 0, 15, 48, or 260 ppm hexachloroethane for 6 hours/day on gestation days 6-16 (Weeks et al. 1979). Tremors were observed in the 260 ppm dose group during exposure starting on day 12 and persisting through day 16. Excess mucous was present in the nasal turbinates of all of the dams in the 260 ppm dose group and 85% of the dams in the 48 ppm dose group, but these effects were reported to be transient and mild. The excess mucus in the nasal turbinates cannot be clearly regarded as an adverse effect since there was a mycoplasma infection in the rat colony. The authors do not describe the incidence of this infection among pregnant females as being more severe than that in controls. Accordingly, 48 ppm was identified as a NOAEL and used to derive the MRL, employing an uncertainty factor of 100. The exposure was not normalized on the basis of pharmacokinetic data (Gorzenski et al. 1985) that suggest a rapid turnover of hexachloroethane in the tissues. ® An MRL of 0.09 ppm has been derived for intermediate inhalation exposure to hexachloroethane. ***DRAFT FOR PUBLIC COMMENT *** 44 2. HEALTH EFFECTS This MRL was derived from a study using groups of male and female rats and exposure concentrations of 0, 15, 48, or 260 ppm hexachloroethane for 6 hours per day, 5 days per week for 6 weeks (Weeks et al. 1979). The rats exposed to 260 ppm had an increased incidence of pulmonary mycoplasma infections, when compared to the controls and the other treatment groups, and decreased body weights. Two of the rats died. There were no effects for the 15 and 48 ppm exposure concentrations. The NOAEL of 48 ppm was used with an uncertainty factor of 100 to calculate the MRL after normalization to adjust for the 6-hour-per-day, 5-days-per-week exposure. A chronic MRL for inhalation exposure has not been derived because no data were located on the effects of long-term exposures in humans or animals. Oral MRLs ® An MRL of 1 mg/kg/day has been derived for acute oral exposure to hexachloroethane. This MRL was derived from a NOAEL of 100 mg/kg/day in a study where groups of 5 male New Zealand rabbits were given doses of 0, 100, 320, and 1,000 mg/kg/day hexachloroethane dissolved in methylcellulose solution by gavage for 12 days. Dose-dependant liver degeneration and necrosis were noted at dose levels of 320 and 1,000 mg/kg/day. Effects were characterized as fatty degeneration, coagulation necrosis, hemorrhage, ballooning degeneration, eosinophilic change, and hemosiderin-laden macrophages, and giant cells. Comparable effects were not seen in the 100 mg/kg/day dose group. Liver weights increased at the highest dose tested; however, quantitative data were not provided. Toxic tubular nephrosis and minimal nephrocalcinosis of the convoluted tubules were seen at dose levels of 320 and 1,000 mg/kg/day, however comparable effects were not seen at the lowest dose tested. Kidney weights increased significantly (p<0.05) at the highest dose tested. For the most part, serum clinical parameters (blood urea nitrogen, protein bilirubin, AST, ALT, AP, and sodium) were not affected significantly. Levels of potassium and glucose were decreased significantly at dose levels of 320 mg/kg/day or greater. Body weights were reduced significantly (p<0.05) at exposure levels of 320 and 1,000 mg/kg/day. Quantitative data were not provided for any of the effects noted in this study, although the degree of significance and the dose-related nature of the effects were included in the discussion of the results. ® An MRL of 0.01 mg/kg/day has been derived for intermediate oral exposure to hexachloroethane. The MRL was derived from a NOAEL of 1 mg/kg/day in a study where groups of 10 male and 10 female rats were given hexachloroethane at 1, 15, or 65 mg/kg/day in the diet for 16 weeks (Gorzinski et al. 1985). All rats survived the 16-week exposure period and there were no clinical signs of compound toxicity. Organ weights were not significantly different than controls except for absolute and relative liver weights and male kidney weights at the highest dose. Swelling of the hepatocytes was present in males at the two highest doses. At the 15 mg/kg dose, swollen hepatocytes were noted in 6 of 10 males, and 8 of 10 males were affected at the 62 mg/kg/day dose. Swollen hepatocytes were seen in 4 control males and in 3 males from the lowest dose group. Hepatocyte size was not affected in females, but absolute and relative liver weights were increased in the highest dose group. The male rats exhibited renal tubular atrophy, hypertrophy, dilation, and degeneration for both the 15 and 62 mg/kg/day doses. Atrophy and tubular degeneration was also present in 6 of 10 females at the 62 mg/kg/day dose and 2 of 10 females at the 15 mg/kg/day dose. The 15 mg/kg/day dose was identified as the LOAEL in this study with the 1 mg/kg/day dose as the NOAEL. This NOAEL was used with an uncertainty factor of 100 to derive the MRL. ***DRAFT FOR PUBLIC COMMENT *** 45 2. HEALTH EFFECTS The intermediate-duration MRL for hexachloroethane is protective against chronic exposures as well as exposures of shorter durations, based on the data provided (Gorzinski et al. 1985; NTP 1989). Accordingly, a chronic-duration exposure MRL was not derived. Death. No studies were located regarding lethality in humans after exposure to hexachloroethane. LD, values for animals range from 4,460 to 5,160 mg/kg when hexachloroethane is administered by gavage in corn oil and from 7,080 to 7,690 mg/kg when administered in an aqueous methyl cellulose solution (Weeks et al. 1979). The higher LD, value for the aqueous solution indicates that absorption from this medium is lower than from a digestible food oil. When exposures occurred by the inhalation route, 1 of 6 rats died during an 8-hour exposure to 5,900 ppm (Weeks et al. 1979). At this concentration, the inhalation chamber contained crystalline hexachloroethane as well as hexachloroethane vapors. The dermal LD, was greater than 32,000 mg/kg when hexachloroethane was applied to shaved rabbit skin for 24 hours (Weeks et al. 1979). This suggests poor dermal absorption of hexachloroethane and agrees with a calculated low dermal absorption rate of 0.023 mg/cm?/hr based on physical properties (Fiserova-Bergerova et al. 1990). There were some deaths among dogs, rats, and guinea pigs with exposure to 260 ppm in air for 6 weeks (Weeks et al. 1979). When exposures were oral, death occurred in rats at doses of 750 mg/kg/day (NTP 1989) and in mice at 1,780 mg/kg/day (NTP 1977). Lower doses were nonlethal. Chronic oral exposure to 212 mg/kg/day shortened the life expectancy of male and female rats (NTP 1977), but doses of 20 mg/kg/day in males and 160 mg/kg/day in females did not (NTP 1989). Although mice were exposed to oral doses of 590 and 1,170 mg/kg/day hexachloroethane for 78 weeks, poor survival among male controls made it difficult to evaluate the effects of hexachloroethane. Survival for the high-dose females was slightly less than that for vehicle controls, but the differences were not significant (NTP 1977). LD, values and the lowest lethal doses for acute- and intermediate-duration exposures classify hexachloroethane as moderately toxic. It is unlikely that exposures to hexachloroethane at levels found at hazardous waste sites would cause death in humans. Systemic Effects There are no data for systemic effects in humans following exposure to hexachloroethane by any route. Data are available for inhalation and oral exposures in several animal species. The only available dermal exposure data apply to dermal/ocular effects. Respiratory Effects. Acute exposure to 5900 ppm hexachloroethane (a combination of gaseous and microcrystalline material) resulted in interstitial pulmonary pneumonitis (Weeks et al. 1979). These pulmonary lesions were seen after a 14-day recovery period. The entrapment of solid hexachloroethane particles in the lungs could have contributed to the symptoms observed. Excess mucous in the nasal turbinates, irritation of the epithelium, and increased incidence of a bacterial respiratory infection were seen in rats with inhalation exposure to 260 ppm for 6 weeks and pulmonary irritation was present in pregnant rats with an oral dose of 500 mg/kg/day (Weeks et al. 1979). Effects on the respiratory epithelium were not apparent in the tissue of the lungs, nasal cavity, nasal turbinates, larynx, trachea, or bronchi based on histopathological examination (NTP 1977, 1989; Weeks ct al. 1979). Exposure to hexachloroethane, especially in its vaporous state, may weaken the effectiveness of respiratory tract mucus as an antimicrobial barrier and, thus, increase the incidence of pulmonary infections in exposed animals. Alternatively, it may weaken disease resistance by some other mechanism. Humans exposed to hexachloroethane vapors in the environment could experience an increased risk of respiratory tract infections. ***DRAFT FOR PUBLIC COMMENT *** 46 2. HEALTH EFFECTS Cardiovascular Effects. There were no histopathological effects on the heart after inhalation or oral exposure at any concentration tested (15-5,900 ppm for the inhalation route and 1-750 mg/kg/day for the oral route) and with acute, intermediate, or chronic exposure durations (Gorzinski et al. 1985; NTP 1977, 1989; Weeks et al. 1979). The risk that humans will experience adverse effects on the cardiovascular system as the result of exposure to hexachloroethane through the environment seems to be relatively low. Gastrointestinal Effects. There were no histopathological effects on the stomach, small intestines, or large intestines with inhalation or oral exposure to hexachloroethane at any concentration tested (15-5,900 ppm for the inhalation route and 1-750 mg/kg/day for the oral route) and with acute, intermediate, or chronic exposure durations (Gorzinski et al. 1985; NTP 1977, 1989; Weeks et al. 1979). The risk that humans will experience adverse effects on the gastrointestinal system as the result of exposure to hexachloroethane in the environment seems to be relatively low. Hematological Effects. The effects of acute exposures to hexachloroethane on hematological parameters were not evaluated in animal species. Inhalation doses of 260 ppm for 6 weeks had no effect on erythrocyte counts in dogs (Weeks et al. 1979) and oral exposures of up to 62 mg/kg/day for 16 weeks had no effect on red cell counts, hemoglobin concentrations, or white cell counts in rats (Gorzinski et al. 1985). These results suggest that hexachloroethane does not affect hematological parameters, but there are relatively few data upon which to base this conclusion. On the basis of the existing data, the occurrence of hexachloroethane at hazardous waste sites should not pose a significant hematological risk for humans. Musculoskeletal Effects. Neither inhalation nor oral exposures to hexachloroethane were associated with histopathological changes in skeletal muscle or bone in rats following acute-, intermediate-, or chronic- duration exposures with inhalation exposure concentrations of 15-5900 ppm or oral exposure concentrations of 1-750 mg/kg/day (Gorzinski et al. 1985; NTP 1977, 1989; Weeks et al. 1979). More comprehensive data pertaining to the musculoskeletal system were not identified. Based on the data available, there appears to be no risk for musculoskeletal effects for those who live or work near a hazardous waste site. Hepatic Effects. Hepatic tissues are moderately vulnerable to exposure to hexachloroethane especially when exposure occurs by the oral route. With acute- and intermediate-duration inhalation exposures, the only effects noted were an increase in liver weight in rats and guinea pigs, but not dogs or quail, after 6 weeks of exposure to 260 ppm (Weeks et al. 1979). There were no observable histopathological changes in the tissues that accompanied the organ weight change and no histopathological changes with acute exposure to an even higher hexachloroethane concentration (5,900 ppm). When exposures occurred by the oral route, increased liver weights, increases in serum liver enzyme levels, centrilobular necrosis, fatty degeneration, hemosiderin-laden macrophages, and hemorrhage were noted in animals following acute- and intermediate-duration exposures (Fowler 1969b; Gorzinski et al. 1985; NTP 1989; Weeks et al. 1979). The lowest LOAEL for these effects was a dictary dose of 15 mg/kg/day for 16 weeks which was associated with enlargement of the hepatocytes in males (Gorzinski et al. 1985). However, there were no observable adverse effects on tissue histopathology in male rats given 20 mg/kg/day for 2 years or in females given 160 mg/kg/day for the same period of time (NTP 1989). Organ weights were not determined for the chronic exposures. These data suggest that there is a potential for individuals who might be exposed to hexachloroethane from a contaminated drinking water supply to experience hepatic effects. The risk from other exposure routes (inhalation or dermal) due to contaminated hazardous waste sites is probably minimal. Renal Effects. Acute exposure to concentrations of 260-5,900 ppm hexachloroethane had minimal effects on the kidney. There was an increase in kidney weights in male rats exposed to 260 ppm hexachloroethane for 6 weeks but no discernable effects on tissue histopathology (Weeks et al. 1979). This same exposure concentration had no effect on female rats or on male or female dogs, guinea pigs, or quail under parallel exposure conditions. ***DRAFT FOR PUBLIC COMMENT *** 47 2. HEALTH EFFECTS Acute-, intermediate-, and chronic-duration exposures of male rats to doses of 10 mg/kg/day or greater were associated with renal tubular nephropathy (Gorzinski et al. 1985; NTP 1977, 1989; Weeks et al. 1979). Affected animals displayed tubular necrosis, hyaline droplets in tubular epithelial cells, regenerative tubular epithelium, interstitial nephritis, and fibrosis. The severity of the renal lesions varied with the dose and the duration of exposure. Hexachloroethane is a member of a family of compounds that bind to the excretory protein a2p-globulin and form hyaline droplets in the tubular epithelium leading to necrosis and repair hyperplasia (Borghoff 1993; Olson et al. 1990). The hexachloroethane metabolites tetrachloroethane and pentachloroethane are also members of this family of compounds (Borghoff 1993; Swenberg 1993). Female rats and laboratory animals from other species synthesize only minimal quantities of this protein and, thus, have a lower risk for renal effects. In male rats, a2p-globulin accounts for 26% of the urinary protein, and chemicals that bind with it have a strong tendency to accumulate in the kidney causing cellular damage. Mild to moderate nephropathy in female rats exposed to 80 or 160 mg/kg/day for 2 years, a high incidence of nephropathy in mice exposed to 590 or 1,179 mg/kg/day for 78 weeks, and nephrosis in rabbits exposed to 320 or 1,000 mg/kg/day for 12 days, indicate that hexachloroethane has an effect on the kidney that is independent of a2p-globulin (NTP 1977, 1989; Weeks et al. 1979). Thus, the public health risk for renal effects should be considered when evaluating the possible effects of human exposure to hexachloroethane at hazardous waste sites. Dermal/Ocular Effects. Inhalation and oral exposure of animals to hexachloroethane caused lacrimation and reddening of the eyes after oral exposure (NTP 1977, 1989), or closing of the eyes as an avoidance mechanism during inhalation exposure (Weeks et al. 1979). Overnight, direct contact of the eyes with crystalline hexachloroethane resulted in corneal opacity and iritis in rabbits, but recovery was complete 3 days later (Weeks et al. 1979). There was no evidence that crystalline hexachloroethane affected the skin of animals with either inhalation or oral exposures of acute, intermediate, or chronic durations (Fowler 1969b; Gorzinski et al. 1985; NTP 1977, 1989; Weeks et al. 1979). When a water paste was placed on the shaved skin of rabbits for 24 hours, there was only a slight redness as the result of contact (Weeks et al. 1979). The concentrations of hexachloroethane that might be found at hazardous waste sites are unlikely to act as skin irritants in humans; some eye irritation could occur from exposure to hexachloroethane vapors. Other Systemic Effects. Decreased weight gains occurred in response to both acute inhalation exposure to a high concentration of hexachloroethane (5,900 ppm) and intermediate-duration exposures to a lower concentration (260 ppm) (Weeks et al. 1979). Oral exposures were also associated with decreased weight gains with doses of 320 mg/kg/day or greater for 12 days in rabbits and with 562 mg/kg/day or greater for 6-16 weeks in rats (NTP 1977, 1989). Female rats exposed to 750 mg/kg/day for 16 days actually lost 25% of their initial body weight (NTP 1989). Decreased weight gain occurred in mice at doses of 1,760 mg/kg/day (NTP 1977). In light of these findings, the concentrations of hexachloroethane found at hazardous waste sites are unlikely to be of great enough magnitude to have an effect on body weight in humans. Immunological Effects. No studies were located regarding immunological effects in humans after exposure to hexachloroethane. In addition, there were no data from comprehensive studies of immune response in animals for exposure by any route and for any duration. When the tissue histopathology of the spleen, thymus, and, in one case, lymph nodes were evaluated, no abnormalities were noted (Gorzinski et al. 1985; NTP 1989; Weeks et al. 1979). After 6-week inhalation exposures to 260 ppm hexachloroethane, the relative spleen weight was increased in young, but not in older, male rats. Data on dermal sensitization indicate that exposure to low levels of hexachloroethane does not elicit antibody formation leading to an allergic dermatological response (Weeks et al. 1979). ***DRAFT FOR PUBLIC COMMENT *** 48 2. HEALTH EFFECTS An increased incidence in mycoplasma infections in rats exposed to 260 ppm hexachloroethane for 6 weeks suggests that hexachloroethane might weaken resistance to infection (Weeks et al. 1979). This could be the result of either a change in the quantity or consistency of the respiratory tract mucus or a systemic weakening of the immune system. The data are inadequate to formulate any hypothesis regarding the mechanism for diminished host resistance or to postulate whether hexachloroethane in the environment might lower the resistance of humans to respiratory infections. Neurological Effects. No studies were located regarding neurological effects in humans after exposure to hexachloroethane. Inhalation, oral, and dermal exposure of animals to moderate or high doses (260 ppm, 5,900 ppm, 375 mg/kg/day, 750 mg/kg/day) resulted in hyperactivity, tremors, fasciculation of the facial muscles, ataxia, convulsions, and/or prostration (Fowler 1969b; NTP 1977, 1989; Southcott 1951; Weeks et al. 1979). Inhalation exposure of rats to 260 ppm for 6 weeks did not have any effect on spontaneous motor activity or shock avoidance behavior. Ataxia, tremors, and prostration in sheep given hexachloroethane (170 or 338 mg/kg) for a liver fluke infection were successfully treated with calcium as calcium borogluconate. This suggests that the neurological action of hexachloroethane may be the result of interference with the availability of calcium within excitable cells. This mechanism would explain the transient nature of the hexachloroethane neurotoxicity and is compatible with the low affinity that hexachloroethane shows for brain tissue (Fowler 1969b). There were no effects at any of the doses tested on the histopathology of the brain for any duration or route of exposure (Gorzinski et al. 1985; NTP 1977, 1989; Weeks et al. 1979). This observation is consistent with tissue distribution studies which indicate that hexachloroethane has no particular affinity for the brain tissues (Fowler 1969b). Based on the available data, the concentrations of hexachloroethane at hazardous waste sites are unlikely to reach levels that would elicit a neurological response in humans. However, there have not been any comprehensive studies of brain or nerve function after exposure to hexachloroethane. Developmental Effects. No studies were located regarding the developmental effects of hexachloroethane in humans. One acute-duration oral study in rats did not reveal adverse effects on the rat embryo or fetus, and the compound did not cause malformations in offspring, although fetal development was delayed. In the absence of quantitative data, more specific information on particular parameters measured, and data on other animal species, it is not possible to speculate on the likelihood of hexachloroethane causing developmental effects in persons living near hazardous waste sites. Reproductive Effects. No studies of reproductive effects in humans were located. In animals, hexachloroethane adversely affected fertility following oral exposure, but no effects were reported following inhalation exposure. The absence of quantitative data on reproductive parameters, as well as evaluation of parameters that are pertinent to the assessment of reproductive risk, precludes any meaningful determination of the potential for hexachloroethane to cause adverse effects on human reproduction. Genotoxic Effects. No studies were located regarding the genotoxic effects of hexachloroethane in humans after inhalation, oral, or dermal exposure. In vitro studies of hexachloroethane using microbial, fungal, and rodent cell assays are summarized in Table 2-4. Tests of prokaryotic cell systems failed to detect gene mutation (Haworth et al. 1983; Roldan-Arjona et al. 1991; Simmon and Kauhanen 1978; Weeks et al. 1979) or DNA damage (Nakamura et al. 1987) following hexachloroethane treatment. Similar results were reported for eukaryotic cells. Hexachloroethane did not cause gene mutation in cells harvested from the stationary growth phase (Bronzetti et al. 1989b) or DNA damage in yeast (Saccharomyces cerevisiae) (Simmon and Kauhanen 1978), chromosomal aberrations in fungi (Aspergillus nidulans) (Crebelli et al. 1988), ***DRAFT FOR PUBLIC COMMENT *** xxx INTJWWOD O1M8Nd HOH L4VHA xxx TABLE 2-4. Genotoxicity of Hexachloroethane In Vitro Results With Without Species (test system) End point activation activation Reference Prokaryotic organisms: Salmonella typhimurium (TA98, Gene mutation ol - Haworth et al. TA100, TA1535, TA1537) 1983 S. typhimurium (TA98, TA100, Gene mutation - - Weeks et al. 1979 TA1535, TA1537, TA1538) S. typhimurium (BA13) Gene mutation ~ - Roldan-Arjona et al. 1991 S. typhimurium (TA98, TA100, Gene mutation - - Simon and TA1535, TA1537, TA1538) Kauhanen 1978 S. typhimurium (TA1535/psk1002) DNA damage - - Nakamura et al. 1987 Eukaryotic organisms: Fungi: Saccaromyces cerevisiaeD , Gene mutation = - Weeks et al. 1979 S. cerevisiaeD , DNA damage/repair - = Simmon and Kauhanen 1978 S. cerevisiae Gene mutation - - Bronzetti et al. 1989b Aspergillus nidulans diploid strain P1 Chromosomal aberration - Not tested Crebelli et al. 1988 Mammalian cells: Chinese hamster ovary Chromosomal aberration = - Galloway et al. 1987 Chinese hamster ovary Sister chromatid exchange + - Galloway et al. 1987 Mouse (Balb/C-3T3) Cell transformation Not tested - Tu et al. 1985 - = negative result; + = positive result S103443 H1TV3aH ¢ 6v 50 2. HEALTH EFFECTS chromosomal aberrations in Chinese hamster ovary cells (Galloway et al. 1987), or cell transformations in mouse cells (Tu et al. 1985). Hexachloroethane did cause sister chromatid exchanges in Chinese hamster ovary cells in the presence of activation; however, the overall importance of this response is reduced since these effects occurred at doses that were cytotoxic (e.g., induced cell cycle delay) (Galloway et al. 1987). Similarly, hexachloroethane induced a significant (p<0.01) increase of gene conversion in cells harvested from the logarithmic growth phase. Similar effects were not seen in stationary growth phase cells, both with and without metabolic activation (Bronzetti et al. 1989). Because cells of this sort contain a high level of cytochrome P-450, it is plausible that the positive responses were due to metabolites rather than the parent compound. Cancer. Only one report was located regarding an association between hexachloroethane and cancer in humans (Selden et al. 1989). In this study a liver tumor was found in an adult male who had used a product containing hexachloroethane at work for 6 years. However, under the conditions of use, the hexachloroethane reacted to form hexachlorobenzene and other chlorinated compounds which were as likely, or more likely, to have contributed to the tumorigenesis as the hexachloroethane. Lifetime exposure of rats to hexachloroethane resulted in renal carcinomas and adenomas in Fischer-344 male rats (NTP 1989). The incidence of adenomas was 0/50 for the controls, 2/50 for animals at a dose of 10 mg/kg/day, and 4/50 for animals at a dose of 20 mg/kg/day. In the animals from the high-dose group, there were also 3/50 renal carcinomas. The number of tumors was significantly greater in exposed rats than in both controls and historical controls using the Fisher Exact Test (NTP 1989). No tumors were seen in the female rats. In an earlier study, there were renal tubular cell adenomas in 5/50 Osborne-Mendel rats receiving doses of 212 mg/kg/day but no tumors in 49 animals receiving 423 mg/kg/day or in 20 vehicle control rats (Weisburger 1977). Despite the lack of tumors, there was a high incidence of nephropathy (18-66%) in exposed male and female rats. The male rat kidney is susceptible to the induction of tumors because of a2p-globulin excretion (Borghoff 1993; Olson et al. 1990). This protein is not made by female rats, other laboratory species, or humans in significant quantities, but large amounts are synthesized and excreted by male rats. EPA (1991a) has concluded that renal tumors in male rats that are associated with a2p-globulin should not be used in assessing the potential for any chemical to cause renal tumors in humans. Compounds that bind to a2p-globulin lead to the formation of hyaline droplets in the kidney causing cell damage and regenerative hyperplasia (Borghoff 1993; Olson et al. 1990). A statistically significant increase in hepatocellular carcinomas was seen in male and female mice that were dosed with 590 and 1,179 mg/kg/day hexachloroethane in corn oil by gavage for 78 continuous weeks (Weisburger 1977). The incidence of tumors in the exposed mice was greater than that in controls on the basis of both the Fisher Exact test and the Cochran-Armitage test. There were no hepatic tumors in male or female rats with chronic exposure to doses of 10-423 mg/kg/day (NTP 1977, 1989; Weisburger 1977). Hexachloroethane may function as a promoter rather than an inducer of hepatic tumors. When male rats were given a single dose of 497 mg/kg hexachloroethane followed by daily treatment with a known promotor (phenobarbital) for 7 weeks, there was no increase in the number of GGT + foci in the liver (Milman et al. 1988; Story et al. 1988). GGT + foci are markers for precarcinogenic cell changes. When a single dose of a known initiator dimethylnitrosamine was followed by 7 weeks of dosing with 497 mg/kg/day hexachloroethane, the number of GGT + foci was four times the number seen with a single dose of dimethylnitrosamine in the absence of hexachloroethane treatment. The fact that hexachloroethane does not appear to be mutagenic in short-term tests of genetic toxicity and that it has a low tendency to bind to DNA (Lattanzi et al. 1988) is consistent with classifying it as a promotor rather than a direct acting carcinogen. ***DRAFT FOR PUBLIC COMMENT *** 51 2. HEALTH EFFECTS NTP determined that there was clear evidence of carcinogenicity in male rats based on the increased incidence of renal neoplasms and no evidence of carcinogenic activity in female rats (NTP 1989). The EPA classified hexachloroethane as a possible human carcinogen (Group C). The slope factor calculated by EPA is 14x10 (mg/kg/day) for both the oral and inhalation routes of exposure (IRIS 1993). IARC has determined that hexachloroethane is not classifiable as to human carcinogenicity (Group 3). 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(s) or cell(s) that is measured within a compartment of an organism (NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid(s) or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to hexachloroethane 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 not often substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by hexachloroethane 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, a decrease in the biologically effective dose, or a target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "Populations That Are Unusually Susceptible." 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Hexachloroethane Based on results from animal studies, urinary and fecal excretion of hexachloroethane can be used to identify recent exposures (Fowler 1969b; Jondorf et al. 1957). Recent exposure to hexachloroethane can also be determined by measuring the amount of hexachloroethane in the blood, but this would be a more invasive procedure than analyzing urine or fecal matter (Fowler 1969b). The concentrations of hexachloroethane in fecal matter were higher than those in urine in sheep for the 24-hour period following exposure (Fowler 1969b). Thus, fecal matter might be better for analysis than urine. Both hexachloroethane and its lipophilic metabolites can distribute to body fat. Only the hexachloroethane can be used to confirm compound exposure by way of a fat biopsy, since some of its metabolites are also produced from other chlorinated hydrocarbons or are present as contaminants in the environment. A ***DRAFT FOR PUBLIC COMMENT *** 52 2. HEALTH EFFECTS clearance half-life of 2.5 days was reported for hexachloroethane absorbed from the diet (Gorzinski et al. 1985). Hexachloroethane in body fat, accordingly, is more representative of current exposures than of exposures that occurred weeks or months before testing. 2.5.2 Biomarkers Used to Characterize Effects Caused by Hexachloroethane No information was located regarding adverse health effects of hexachloroethane in humans; therefore, no judgment can be made concerning possible biomarkers of exposure in humans. Renal toxicity appears to be the principal effect associated with exposure to hexachloroethane in animals. Lesions of the kidney (nephropathy, linear mineralization, and hyperplasia) were reported at 10 mg/kg/day or greater in male rats (NTP 1989). Urinalysis also revealed granular and cellular casts in rats exposed to hexachloroethane (47 mg/kg/day or greater) for 13 weeks (NTP 1989). Because other compounds cause similar effects and because some of these effects are unique to male rats, they are not valuable as biomarkers for human hexachloroethane exposure. The liver is also a target of hexachloroethane toxicity, but the effects are not as severe as for the kidneys. For the most part, effects in rats were confined to swelling of hepatocytes which occurred at dose levels of 15 mg/kg/day or greater following oral exposure (Gorzinski et al. 1985). Certain biochemical parameters that are commonly associated with chemically-induced liver damage were assessed in rabbits exposed to hexachloroethane by gavage for 12 days (Weeks et al. 1979) and in sheep given a single dose of 500 mg/kg (Fowler 1969b). There were no statistically significant alterations in serum enzymes (alanine amino transferase, aspartate aminotransferase, and alkaline phosphatase) or bilirubin in rabbits, but serum values were increased as compared to controls (Weeks et al. 1979). Plasma sorbitol dehydrogenase, glutamate dehydrogenase, and ornithine carbamoyl transferase concentrations increased in sheep (Fowler 1969b). Because these effects can also be caused by other chemicals, they cannot be considered specific biomarkers for hexachloroethane. 2.6 INTERACTIONS WITH OTHER SUBSTANCES Hexachloroethane is commonly used by the military for pyrotechnics and smoke screens. Hexachloroethane- containing, smoke-producing devices combine hexachloroethane with zinc oxide (Gordon et al. 1991). Small quantities of other materials such as calcium silicide can also be present. Hexachloroethane is generally about 44-47% of the reaction mixture. When a smoke pot or grenade is ignited, hexachloroethane reacts with zinc oxide to produce zinc chloride. Only small amounts (0.3-5%) of hexachloroethane remain. Other products of the reaction are tetrachloroethylene, carbon tetrachloride, phosgene, and hexachlorobenzene (Gordon et al. 1991). The environmental residues from smoke generation vary with the configuration of the device and its position when it ignites (upright or prone) (Schaeffer et al. 1988). A number of studies of the toxicity of zinc oxide /hexachloroethane smoke have been conducted (Brown et al. 1990; Karlsson et al. 1986; Marrs et al. 1983). These studies demonstrate that smoke exposure results in pulmonary inflammation and irritation. When male Porton Wistar rats were exposed to hexachloroethane/ zinc oxide smoke for 60 minutes, the lungs showed pulmonary edema, alveolitis, and areas of macrophage infiltration 3 days later. At 14 days, there was interstitial fibrosis and macrophage infiltration. At 28 days, increased fibrosis and macrophage infiltration were noted. However, these same symptoms occurred when the animals inhaled zinc chloride; there was no apparent synergism between the zinc chloride and residual hexachloroethane (Brown et al. 1990; Richard et al. 1989). This is consistent with the fact that smoke contains little hexachloroethane and the observation that acute exposure to 260 ppm hexachloroethane had no effects on the lungs of rats (Weeks et al. 1979). Environmental agents that influence microsomal reactions will influence hexachloroethane toxicity. The production of tetrachloroethene as a metabolite is increased by agents like phenobarbital that stimulate certain cytochrome P-450 isozymes (Nastainczyk et al. 1982; Thompson et al. 1984). Exposure to food ***DRAFT FOR PUBLIC COMMENT *** 53 2. HEALTH EFFECTS material or other xenobiotics that influence the availability of mixed function oxidase enzymes and/or cofactors will change the reaction rate and end products of hexachlorocthane metabolism and thus influence its toxicity. No other studies of interactions of hexachloroethane with other chemicals were identified in the published literature. However, the primary metabolites of hexachloroethane (tetrachloroethene and pentachlorocthane) are themselves toxic and would be expected to exacerbate hexachloroethane toxicity if they were present in a mixture with hexachloroethane. Concurrent carbon tetrachloride exposure would also be expected to exacerbate hexachloroethane toxicity. Both hexachloroethane and carbon tetrachloride are processed by microsomes to generate free radicals, and carbon tetrachloride also forms endogenous hexachloroethane in the liver (Fowler 1969a). 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to hexachloroethane than will most persons exposed to the same level of hexachloroethane in the environment. Reasons include genetic make-up, developmental stage, age, health and nutritional status (including dietary habits that may increase susceptibility, such as inconsistent diets or nutritional deficiencies), and substance exposure history (including smoking). These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic, renal, and respiratory) or the pre-existing compromised function of target organs (including effects or clearance rates and any resulting end-product metabolites). 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 studies were located regarding populations that are unusually susceptible to hexachloroethane toxicity. Because the kidney and liver are the primary target tissues, individuals with compromised liver or kidney function would have an increased risk from exposure. Susceptibility to pulmonary infections could be increased by exposure to hexachloroethane vapors and, thus, individuals that suffer from chronic respiratory problems could also have an increased risk from hexachloroethane exposure. The risk to overweight individuals consuming a high fat diet is likely to be greater than that for lean individuals. Excess deposits of body fat increase physiological exposure durations due to the affinity of the adipose tissue for hexachloroethane. Hexachloroethane collects in the adipose deposits during exposure and is released slowly to circulatory fluids after the exposure has ceased. Individuals consuming a high fat diet are likely to absorb increased quantities of hexachloroethane when exposure occurs through the oral route; absorption from a lipid matrix is favored over absorption from an aqueous medium. 2.8 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to hexachloroethane. 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 hexachloroethane. 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 Humans can be exposed to hexachloroethane by inhalation, ingestion, or skin contact. There are no specific treatments for hexachloroethane overexposure. However, treatments available for halogenated hydrocarbons may be useful. ***DRAFT FOR PUBLIC COMMENT *** 54 2. HEALTH EFFECTS When individuals have been exposed to vapors of hexachloroethane, they should be moved to fresh air. Additional treatment with oxygen may be beneficial. If hexachloroethane has been ingested, treatments designed to minimize absorption of halogenated hydrocarbons are appropriate. If the victim is alert, can swallow, and appears to have a good gag reflex, water (1-2 glasses) may be administered after ingestion of small amounts of hexachloroethane (Bronstein and Currance 1988; Stutz and Janusz 1988). Because many hydrocarbons may cause spontaneous vomiting, induced emesis is not recommended since it may result in aspiration of gastric contents. If large amounts of hexachloroethane have been ingested, gastric lavage may be useful if performed soon after exposure. Activated charcoal can be administered to bind hexachloroethane in the gastrointestinal tract and minimize absorption. Activated charcoal can be combined with cathartics to speed fecal excretion. Because hexachloroethane is lipid soluble, the administration of a fat-based substance or whole milk are not recommended as they may cause increased absorption. In order to minimize absorption through the skin, all contaminated clothing should be removed and the skin should be washed with mild soap and water (Bronstein and Currance 1988; Stutz and Janusz 1988). In cases where the compound has been splashed into the eyes, irrigation with large amounts of water for 15-30 minutes has been recommended. 2.8.2 Reducing Body Burden Hexachloroethane that is absorbed appears rapidly in the systemic circulation. It is distributed widely throughout the body, with the highest concentration in fat and kidney and the lowest in the muscle (Fowler 1969b; Gorzinski et al. 1985). There are no specific treatments available for reducing the body burden if hexachloroethane is absorbed. Because hexachloroethane causes renal injury, hemodialysis may be useful to reduce the plasma levels of hexachloroethane should renal failure occur in exposed persons. 2.8.3 Interfering with the Mechanism of Action for Toxic Effects No information is available on the adverse health effects of hexachloroethane in humans. Animal studies revealed that hexachloroethane primarily causes liver and kidney toxicity. Effects on the nervous system and lungs have also been reported. The mechanism by which these effects are mediated is not well characterized. Reductive metabolism by cytochrome P-450 and production of a free radical intermediate have been suggested as factors in hexachloroethane-induced hepatotoxicity (Nastainczyk et al. 1982; Thompson et al. 1984; Town and Leibman 1984). Accordingly, one possible approach may be to reduce free radical injury. To that end, oral administration of N-acetylcysteine can be used as a means of reducing free radical injury. Also, oral administration of vitamin E and vitamin C may be of value since they are free radical scavengers. The mechanism of renal toxicity is not clear. Because the spectrum of kidney lesions observed in male rats (Gorzinski et al. 1985; NTP 1989) resembled those for a2p-globulin nephropathy, hexachloroethane-induced kidney lesions may, in part, be due to hexachloroethane binding to this protein. On the other hand, renal toxicity was observed in female rats and did not present the same sequence of lesions. This suggests the effects in males may not be totally due to a2p-globulin. Specific methods to minimize renal toxicity, based on mechanism of action, cannot be proposed at this time. 2.9 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of hexachloroethane 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 hexachloroethane. ***DRAFT FOR PUBLIC COMMENT *** 55 2. HEALTH EFFECTS The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.9.1 Existing Information on Health Effects of Hexachloroethane The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to hexachloroethane are summarized in Figure 2-4. The purpose of this figure is to illustrate the existing information concerning the health effects of hexachloroethane. 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." A data need, as defined in ATSDR’s Decision Guide for Identifying Substance-Specific Data Needs Related to Toxicological Profiles (ATSDR 1989), is substance-specific information necessary to conduct comprehensive public health assessments. Generally, ATSDR defines a data gap more broadly as any substance-specific information missing from the scientific literature. As indicated by Figure 2-4, data available on the health effects of hexachloroethane in humans is extremely sparse. There is only one case study of a liver tumor in an individual who had used a hexachloroethane- containing degassing agent in his work for a period of 6 years (Selden et al 1989). However, during use the hexachloroethane reacted to form hexachlorobenzene and small amounts of other chlorinated compounds. Exposure to hexachloroethane was minimal compared to exposure to the reaction products. There are more data available concerning the effects of hexachloroethane in animals, particularly for exposure by the inhalation and oral routes. These studies identify the liver and kidney as target organs for hexachloroethane. There have been no studies of chronic exposure by the inhalation route. Although there are some data on neurological and immunological effects, there have been no well-designed, comprehensive studies of these systems. This is also true for reproductive and developmental effects. The data are limited and there has been no comprehensive multigeneration study of reproductive processes and only two studies of developmental effects. In vivo testing for mutagenic potential has also not been conducted. The carcinogenic potential for hexachloroethane has only been evaluated for the oral route. Data for the dermal route are limited to an LDs, study and data on dermal/ocular effects. A theoretical estimation of dermal transport of hexachloroethane indicated that absorption is low. 2.9.2 Identification of Data Needs Acute-Duration Exposure. No studies were located on the effects of hexachloroethane in humans after acute exposure by any route. Acute inhalation exposure in animals caused respiratory effects, but these effects occurred at concentrations that were lethal (Weeks et al. 1979). There were no effects on the liver and kidney after inhalation exposure to hexachloroethane. An MRL of 0.5 ppm was calculated for acute inhalation exposure based on the occurrence of neurological effects in pregnant rats. Acute oral exposure of animals was associated with kidney and liver damage (Fowler 1969b; NTP 1989; Weeks et al. 1979). An MRL of 1 mg/kg was derived for acute oral exposures based on a NOAEL for the absence of liver damage in rabbits (Weeks et al. 1979). Additional oral exposure studies to delineate the threshold for acute liver effects and help to clarify the indices that are predictive of liver damage would be useful. Studies of kidney effects in female rats and other laboratory animals using the oral route would also be helpful to differentiate between lesions associated with a2pu-globulin and those produced by other mechanisms. ***DRAFT FOR PUBLIC COMMENT *** 56 2. HEALTH EFFECTS FIGURE 2-4. Existing Information on Health Effects Inhalation Oral Dermal Inhalation Oral Dermal of Hexachloroethane N SYSTEMIC 7 / / 3 / / \ . & S oN Ni 3° & S$ & & & S & & oF /E//&/ eS SESS HUMAN NN SYSTEMIC 7 / /3/90 Fowler 1969b wash with water, sodium hydroxide, hydrochloric acid and water again Feces Macerate under warm hexane; GLC/ECD No data >90 Fowler 1969b successively wash with water, sodium hydroxide, hydrochloric acid and water again Blood, liver, Extract with hexane GC/ECD 0.001 pg/g No data Nolan and kidney, fat Karbowski 1978 * Typical or expected values for halocarbons by this method. Data were not reported for hexachloroethane. ECD = electron capture detector; GC = gas chromatography; GLC = gas liquid chromatography; MS = mass Spectroscopy. SAOHL3N TVOILATYNY ‘9 08 xxx INFWINOD OIN8Nd HO 14VHA xxx TABLE 6-2. Analytical Methods for Determining Hexachloroethane in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Air Collect on activated coconut GC/FID 0.01 mg/sample No data NIOSH 1984 shell charcoal in glass tube; desorb with carbon disulfide Water/ Extract with methylene chloride; GC/ECD 0.03 pg/L 99 EPA 1982 wastewater exchange to hexane; Florisil® cleanup, if required Wastewater Extract continuously with methylene Isotope dilution, 10 pg/L No data EPA 1990c chloride under alkaline and then capillary column acidic conditions GC/MS Water/wastewater Extract with methylene chloride Packed column 1.6 pg/L 40-113 APHA 1992 under alkaline and then acidic GC/MS conditions Water/soil/ Extract with methylene chloride; Capillary column 1.6ng/L? 83-96 EPA 1990a wastes exchange to hexane; Florisil® or GC/ECD GPC cleanup, if required Water/soil/ Extract with methylene chloride; Packed column 0.03 pg/L *® 14 EPA 1990b wastes exchange to hexane; Florisil® or GC/ECD GPC cleanup, if required SAOHL3IW TYOILATVNY 9 18 xxx INTJWWOD O1N8Nd HOH 14vHQA xxx TABLE 6-2. Analytical Methods for Determining Hexachloroethane in Environmental Samples (continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Food (fish, milk, Extract with acetonitrile; cleanup GC/ECD No data >80 Yurawecz and Puma 1986 butter, corn oil) with Florisil®, elute with petroleum ether and ethyl ether/petroleum ether 2 Method detection limit (MDL) in reagent water. Estimated quantitation limits for other matrices are: 10 MDL in groundwater, 670 MDL to 10,000MDL in soil, and 100,000MDL in nonaqueous wastes. ECD = electron capture detection; FID = Flame ionization detector; GC = gas chromatography; GPC = gel permeation chromatography; MS = mass spectroscopy SAOHL3IN TVOILATYNY 9 28 83 6. ANALYTICAL METHODS The electron capture detector (ECD) is most frequently used to identify hexachloroethane. A flame ionization detector (FID) may also be used (NIOSH 1984). When unequivocal identification is required, an MS coupled to the GC column may be employed. 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA, as amended, directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of hexachloroethane is available. Where adequate information is not available, ATSDR, in conjunction with the NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of hexachloroethane. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. The presence of hexachloroethane in exhaled air, blood, and tissues can be determined using GC/MS (Pellizzari et al. 1985a, 1985b). Separation by GC with electron capture detection and liquid chromatography have also been used to identify hexachloroethane in blood tissues, urine, and/or fecal matter (Fowler 1969b; Gorzinski et al. 1985; Jondorf et al. 1957; Mitoma et al. 1985; Nolan and Karbowski 1978). Since the metabolites of hexachloroethane are themselves xenobiotic compounds or are the metabolites of other xenobiotics, the parent compound serves as the only true biomarker of exposure. Endogenous production of hexachloroethane following carbon tetrachloride exposure necessitates the need for an exposure history even when hexachloroethane is detected in body tissues or fluids (Fowler 1969a). Additional studies to correlating levels of hexachloroethane in various biological media with environmental exposures would be useful. No data were located regarding methods that identify biomarkers of hexachloroethane’s toxic effects. Although hexachloroethane-induced hepatic damage can cause increases in serum levels of liver enzymes, these enzyme changes are not specific to hexachloroethane exposure (Fowler 1969b; Weeks et al. 1979). In male rats, exposure to hexachloroethane is associated with the presence of granular and cellular casts in the urine (NTP et al. 1989). These effects are related to the formation of hyaline droplets in the male rat kidney. The formation of hyaline droplets is unique in male rats and is not indicative of the toxic effect of hexachloroethane. Therefore, they are not useful as biomarkers of effect. There is a need to identify compound-specific biomarkers for the effects of hexachloroethane exposure. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. Analytical methods are available to detect and quantify hexachloroethane in air, water, soil, wastes, and food (APHA 1992; EPA 1982, 1990a, 1990b, 1990c; NIOSH 1984; Yurawecz and Puma 1986). Air is the medium of most concern for human exposure to this chemical. Exposure may also occur from water, especially in the vicinity of hazardous waste sites or industrial sources. The existing analytical methods can provide determinations for hexachloroethane at levels sufficiently low to meet regulatory requirements and evaluate health effects (EPA 1982, 1990a, 1990b, 1990c; NIOSH 1984). Improved methods of extraction and analysis that minimize losses due to volatilization would enhance recovery of hexachloroethane from environmental samples and provide a better estimate of environmental levels, especially in air and drinking water at hazardous waste sites and military training facilities. ***DRAFT FOR PUBLIC COMMENT *** 84 6. ANALYTICAL METHODS Methods are also available to measure degradation products of hexachloroethane in environmental samples, but these products (e.g., tetrachloroethylene) are released to the environment from many other sources and are therefore not useful determinants of the environmental impact of this chemical. 6.3.2 On-going Studies The Environmental Health Laboratory Sciences Division of the National Center for Environmental Health and Injury Control, Centers for Disease Control, is developing methods for the analysis of hexachloroethane and other volatile organic compounds in blood. These methods use purge and trap methodology, high resolution gas chromatography, and magnetic sector mass spectrometry which gives detection limits in the low parts per trillion (ppt) range. On-going studies to improve analytical methods for hexachloroethane and related compounds include the EPA "Master Analytical Scheme" being developed for organic compounds in water (Michael et al. 1988) and the research in supercritical fluid extraction (Lopez-Avila et al. 1991; Weiboldt et al. 1988). Research continues on improving extraction, concentration, and elution techniques, and detection devices (Eichelberger et al. 1983, 1990; Ho et al. 1993; Pankow and Rosen 1988; Valkenburg and Munslow 1989). These improvements are designed to overcome problems with sample preparation and increase sensitivity and reliability of the analyses. ***DRAFT FOR PUBLIC COMMENT *** 85 7. REGULATIONS AND ADVISORIES Because of its potential to cause adverse health effects in exposed people, numerous regulations, and advisories have been established for hexachloroethane by various international, national, and state agencies. Major regulations and advisories pertaining to hexachloroethane are summarized in Table 7-1. ATSDR has calculated an MRL of 0.5 ppm for acute inhalation exposure to hexachloroethane based on a NOAEL of 48 ppm from a study in pregnant rats. The critical effect was the occurrence of tremors during exposure starting on day 6 of an 11 day exposure period at a LOAEL of 260 ppm (Weeks et al. 1979). The exposure was not normalized on the basis of pharmacokinetic data (Gorzenski et al. 1985) that suggest a rapid turnover of hexachloroethane in the tissues. An intermediate-duration MRL of 0.09 ppm has been calculated for inhalation exposure to hexachloroethane based on a NOAEL of 48 ppm for a 6 week study in male and female rats (Weeks et al. 1979). The critical effect was an increase in the incidence of mycoplasma infections in rats exposed to 260 ppm. The NOAEL was normalized by adjusting for a 6 hour per day and 5 day per week exposure pattern. An acute oral MRL of 1 mg/kg/day has been calculated for oral exposure to hexachloroethane based on a NOAEL of 100 mg/kg/day from a study in male rabbits (Weeks et al. 1979). Hepatic necrosis and degeneration were observed in the treated animals at doses of 320 and 1,000 mg/kg/day. An intermediate-duration MRL of 0.01 mg/kg/day has been calculated for oral exposure to hexachloroethane in the diet based on a NOAEL of 1 mg/kg/day from a study in male and female rats (Gorzinski et al. 1985). Enlargement of the hepatocytes was seen in male rats at doses of 15 and 62 mg/kg/day. Relative liver weights were increased in males and females at the 62 mg/kg/day dose. EPA has derived a chronic oral RfD of 0.001 mg/kg/day for hexachloroethane (IRIS 1993). This value is based on a NOAEL of 1 mg/kg/day for atrophy and degeneration of the renal tubules in rats exposed for 16 weeks (Gorzinski et al. 1985). The NOAEL was divided by an uncertainty factor of 1,000 to account for interspecies extrapolation, human variability, and use of a subchronic study. EPA places medium confidence in this RfD (IRIS 1993). ***DRAFT FOR PUBLIC COMMENT*** 86 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachloroethane ***DRAFT FOR PUBLIC COMMENT *** Agency Description Information References INTERNATIONAL IARC Carcinogenic classification Group 3 IARC 1987 NATIONAL Regulations: a. Air EPA OAQPS Hazardous Air Pollutant Yes Public Law 101-549 Section 112 NESHAP for Source Categories: Yes EPA 1992 Organic HAPs from Synthetic Organic Chemical Manufacturing Industry (Proposed) Organic OSHA PEL TWA 1 ppm (10 mg/m®) OSHA 1989 skin (29 CFR 1910.1000) OSHA 1993 (29 CFR 1910.1000) b. Water: EPA OWRS General permits under NPDES Yes 40 CFR 122 General Pretreatment Regulations Yes 40 CFR 403 for Existing and New Sources of Pollution Hazardous substance Yes 40 CFR 116 Reportable quantity 100 pounds 40 CFR 117.3 c. Other: EPA OERR Reportable quantity 100 pounds EPA 1989 (40 CFR 302.4) EPA OSW Hazardous Waste Constituent Yes EPA 1980 (Appendix VIII) (40 CFR 261) Groundwater Monitoring List Yes EPA 1987 (Appendix IX) (40 CFR 264) Land Disposal Restrictions Yes EPA 1990, 1991, (40 CFR 268) Burning of Hazardous Waste in 3x102 mg/kg EPA 1991 Boilers and Industrial Furnaces- Residue Concentration Limit EPA OTS Toxic Chemical Release Reporting Rule Yes EPA 1988 (40 CFR 372) Health and Safety Data Reporting Rule Yes EPA 1988 (40 CFR 716.120) 87 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachloroethane (continued) Agency Description Information References Guidelines: a. Air: ACGIH TLV TWA 1 ppm (9.7 mg/m’) ACGIH 1992 A2 - Suspected human carcinogen NIOSH REL, TWA 1 ppm NIOSH 1992 occupational carcinogen b. Water: EPA ODW Health Advisories Gordon et al. 1991 One-day (child) 5 mg/L Ten-day (child) 5 mg/L Longer-term (child) 100 pg/L Longer-term (adult) 450 pg/L Lifetime (adult) 1 ug/L EPA OWRS Ambient Water Quality Criteria EPA 1980 Ingesting water and organisms: 1.9 pg/L’ Ingesting organisms only: 8.74 ug/L’ c. Other: EPA RfD (oral) 1x10” mg/kg-day IRIS 1993 Carcinogenic Classification Group C* IRIS 1993 Cancer slope factor (q,*) q,* (oral) 1.4x10? (mg/kg-day)™! q,* (inhalation) 1.4x10 (mg/kg-day)"! STATE Regulations and Guidelines: a. Air Acceptable ambient air concentrations NATICH 1991 Connecticut 50 pg/m’ (8 hr) Kansas 2.5x10"! pg/m® (annual) Massachusetts 5.3x10" ug/m’ (24 hr) 2.5x10" pg/m’ (annual) Nevada 2.38 mg/m’ (8 hr) North Dakota 9.7x102 mg/m® (8 hr) Oklahoma 2.0x10*? ug/m® (24 hr) Texas 9.7x10*" ug/m* (30 min) 1.0x10*" pg/m’ (annual) Vermont 2.5x10"! pg/m?® (annual) Virginia 1.6x10*2 ug/m® (24 hr) ***DRAFT FOR PUBLIC COMMENT *** 88 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Hexachloroethane (continued) Agency Description Information References b. Water: Drinking water standards and guidelines FSTRAC 1990 Kansas 1.9 pg/L Minnesota . 0.7 pg/L * Group 3: Not classifiable as to human carcinogenicity. ® Based on a lifetime incremental cancer risk of 1x10°. ¢ Group C: Possible human carcinogen. 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Profiles on occupational hazards for criteria document priorities. Menlo Park, CA: Stanford Research Institute, National Institute for Occupational Safety and Health. PB-274 073. *Staples CA, Werner AF, Hoogheem TJ. 1985. Assessment of priority pollutant concentrations in the United States using STORET database. Environ Toxicol Chem 4:131-142. *Story DL, Meierhenry EF, Tyson CA, et al. 1986. Differences in rat liver enzyme-altered foci produced by chlorinated aliphatics and phenobarbital. Toxicol Ind Health 2:351-362. Strong L, Wall R. 1990. The chemical control of livestock parasites: problems and alternatives. Parasitology Today 6:291-296. *Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-hospital care. Second edition. Beltsville, MD: Bradford Communications Corporation. *Suffet TH, Brenner L, Cairo PR. 1980. GC/MS identification of trace organics in Philadelphia drinking waters during a 2-year period. Water Res 14:853-867. *Swenberg JA. 1993. «2u-globuin mediated male rat kidney carcinogens. In: Coping with nongenotoxic carcinogens: mode of action, detection, and risk assessment. New Orleans, LA: Society of Toxicology. *Tabak HH, Quave SA, Mashni CI, et al. 1981. Biodegradability studies with organic priority pollutant compounds. J Water Pollut Control Fed 53:1503-1518. Tennant RW, Elwell MR, Spalding JW, et al. 1991. Evidence that toxic injury is not always associated with induction of chemical carcinogenesis. Mol Carcinog 4:420-440. *Thompson JA, Ho B, Mastovich SL. 1984. Reductive metabolism of 1,1,1,2-tetrachloroethane and related chloroethanes by rat liver microsomes. Chem Biol Interactions 51:321-333. *Thruston AD. 1978. High pressure liquid chromatography techniques for the isolation and identification of organics in drinking water extracts. J Chromatogr Sci 16:254-259. : *Thruston RV, Gilfoil TA, Meyn EL, et al. 1985. Comparative toxicity of ten organic chemicals to ten common aquatic species. Water Res 19:1145-1155. *Town C, Leibman KC. 1984. The in vitro dechlorination of some polychlorinated ethanes. Drug Metab Disp 12:4-8. Tracor Jitco, Inc. 1981. Environmental and health aspects of hexachlorocthane, a comprehensive bibliography of published literature 1930-1981. Washington, DC: Environmental Protection Agency, Office of Pesticides and Toxic Substances. PB81-249674. *TRI90. 1992. Toxic Chemical Release Inventory. National Library of Medicine, National Toxicology Information Program, Bethesda, MD. ) *Tu AS, Murray TA, Hatch KM, et al. 1985. In vitro transformation of BALB/c-3T3 cells by chlorinated ethanes and ethylenes. Cancer Lett 28:85-92. ***DRAFT FOR PUBLIC COMMENT *** 100 8. REFERENCES Valkenburg CA, Munslow WD. 1989. Evaluation of modifications to extraction procedures used in analysis of environmental samples from Superfund sites. J Assoc Off Anal Chem 72:602-608. Van Rossum P, Webb RG. 1978. Isolation of organic water pollutants by XAD resins and carbon. J Chromatogr 150:381-392. Van Dyke RA. 1977. Dechlorination mechanisms of chlorinated olefins. Environ Health Perspect 21:121-124. Van Dyke RA, Wineman CG. 1971. Enzymatic dechlorination. Dechlorination of chloroethanes and propanes in vitro. Biochem Pharmacol 20:463-470. *Verschueren K. 1983. Handbook of environmental data on organic chemicals. 2nd ed. New York: Van Nostrand Reinhold Company. Walker JD. 1987. Effects of chemicals on microorganisms. J Water Pollut Control Fed 59:614-625. *Weast RC, ed. 1986. CRC handbook of chemistry and physics. 67th ed. Boca Raton, FL: CRC Press. *Weeks MH, Angerhofer RA, Bishop R, et al. 1979. The toxicity of hexachloroethane in laboratory animals. Am Ind Hyg Assoc J 40:187-199. *Weisburger EK. 1977. Carcinogenicity studies on halogenated hydrocarbons. Environ Health Perspect 21:7-16. *Wiebolt RC, Adams GE, Later DW. 1988. Sensitivity improvement in infrared detection for supercritical fluid chromatography. Anal Chem 60:2422-2427. *Yaws C, Yang HC, Pan X. 1991. Henry's law constants for 362 organic compounds in water. Chemical Engineering 179-185. Young JY, Smart DA, Allen JT, et al. 1989. Field exposure of chemical school students and cadre to fog oil and hexachloroethane (HC) smokes. Frederick, MD: U.S. Army Biomedical Research & Development Laboratory. AD-A225-008. *Yurawecz MP, Puma BJ. 1986. Gas chromatographic determination of electron capture sensitive volatile industrial chemical residues in foods, using AOAC pesticide multiresidue extraction and cleanup procedures. J Assoc Off Anal Chem 69:80-86. ***DRAFT FOR PUBLIC COMMENT *** 101 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. In Vitro — Isolated from the living organism and artificially maintained, as in a test tube. ***DRAFT FOR PUBLIC COMMENT *** 102 9. GLOSSARY In Vivo — Occurring within the living organism. Lethal Concentratio (LG) — 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 is 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 Be caused death in humans or animals. Lethal Dosey, (LDg,) — 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). 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. ***DRAFT FOR PUBLIC COMMENT *** 103 9. GLOSSARY 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. ***DRAFT FOR PUBLIC COMMENT *** Fell Jd eh, oo blo wis r Ie ol nk 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 end point 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 (CELSs). 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. *** DRAFT FOR PUBLIC COMMENT *** (3). “@. 3) (6). . (8). 9). (10). Qn. 1D. 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 LOAELS can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table. 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 "18r" 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. LOAELSs 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. 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. *** DRAFT FOR PUBLIC COMMENT *** «x LINGWWOO 0118Nd HOH 14VHA «xs 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 INTERMEDIATE EXPOSURE Systemic 18 Rat 13 wk Resp 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE > Cancer i." m 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 Z 5d/wk organs) © 7hr/d x > 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 Sd/wk hemangiosarcomas) 6hr/d * The number corresponds to entries in Figure 2-1. b used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 10° 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) ev «+ LNIWWOD 0178Nd HOH 14vHa ... FIGURE 2-1. Levels of Significant Exposure to [Chemical X] - Inhalation INTERMEDIATE CHRONIC (15-364 Days) (> 365 Days) Systemic Systemic Id > s S & a oF S$ 3° oS © > & ; S ¢ EY &F i > > > S S$ - = 5 K & & £ & & F of & & EEE A SE (ppm) 10,000 [ 1,000 [- > RS 100 | @1or @17r 25m ® Deg BD o O2ir M24g P21r O22h oe Osem Bas ser Baer Pour . 3 25m 1or 3sr BEF. (Mp o wk O25m (iar @33m Osx Paem ® Qs4r O3ar Q34r O34 Parr @aom 3er x —=Q18r O1or > 1 1 1 1 = 1 0.1 ' 104 1 ooi I i 10-5 - Estimated Upper- <-— , Bound Human 0.001 | ' Cancer Risk ad 10-6 Levels 0.0001 p= Key 10-7 r Rat @ LOAEL for serious effects (animals) * - 0.00001 L m Mouse @ LOAEL for less serious effects (animals) ! Minimal risk level for h Rabbit O NOAEL (animals) , effects other than cancer g Guinea pig @ CEL - Cancer Effect Level (animals) ~~ h Monkey The number next to each point corresponds to entries in Table 2-1. * Doses represent the lowest dose tested per study that produced a tumorigenic response and do not imply the existence of a threshold for the cancer end point. 130017-1 vv A-5 APPENDIX A (13). 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. (14). Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. 1s. 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. (16). 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). (17). 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. (18). Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from EPA’s Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels @)). (19). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. 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. *** DRAFT FOR PUBLIC COMMENT *** A-6 APPENDIX A 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, -intermediate, - chronic). These MRLs are not meant to support regulatory action, but to acquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a 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) (Bames and Dourson 1988; EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. 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 poten- tial 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 continuous 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 infor- mation 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 of (1, 3, or 10) is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of (1, 3, or 10) are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and (1, 3, or 10) are used for inter- species variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. Generally an uncertainty factor of 10 is used; however, the MRL workgroup reserves the right to use uncertainty factors of (1, 3, or 10) based on scientific judgement. 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. *** DRAFT FOR PUBLIC COMMENT *** ACGIH ADME atm ATSDR BCF BSC CDC CEL CERCLA CFR CLP cm CNS DHEW DHHS DOL ECG EEG EPA EKG FAO FEMA FIFRA fpm ft FR GC gen HPLC hr 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 liquid chromatography lethal concentration, low lethal concentration, 50% kill ***DRAFT FOR PUBLIC COMMENT *** LD 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 STEL STORET TLV TSCA TRI TWA US. UF Lo B-2 APPENDIX B 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 short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor ***DRAFT FOR PUBLIC COMMENT *** WHO R RIA Avy pm Bg B-3 APPENDIX B 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 ***DRAFT FOR PUBLIC COMMENT*** vo - a i. 0 arf ee Sa oo = Mo de sly ition Rs Wt od » - be Yr: «i i IE 1 WP andes wu hid w C1 APPENDIX C PEER REVIEW A peer review panel was assembled for hexachloroethane. The panel consisted of the following members: Dr. Dominic Cataldo, Staff Scientist, Battelle Northwest, Richland, WA; Dr. Peter Van Voris, Senior Program Manager, Battelle Pacific Northwest Laboratories, Richland, WA; Mr. Lyman Skory, Private Consultant, Midland, MI. These experts collectively have knowledge of hexachloroethane’s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. % U.S. GOVERNMENT PRINTING OFFICE:1994-537-974 ***DRAFT FOR PUBLIC COMMENT *** U. C. BERKELEY LIBRARIES Co4725k6498