£% jT%J^ United States I^bTSp^ Environmental Protection Jf % Agency EPA/690/R-02/004F Final 5-31-2002 Provisional Peer Reviewed Toxicity Values for 1,2-Dichloroethylene (mixture) (CASRN 540-59-0) Derivation of an Inhalation RfC Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit 1 ------- NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor microgram (imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 1,2-DICHLOROETHYLENE (mixture) (CASRN 540-59-0) Derivation of an Inhalation RfC Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. INTRODUCTION 1,2-Dichloroethylene (CASRN 540-59-0), a mixture of cis and trans isomers, is not listed on IRIS (U.S. EPA, 2001), and an RfC is not available in the HEAST (U.S. EPA, 1997). The CARA list (U.S. EPA, 1991a, 1994) includes a Health and Environmental Effects Profile (HEEP) on dichloroethenes (U.S. EPA, 1986) and a Health and Environmental Effects Document (HEED) on 1,2-dichloroethylene (mixed isomers) (U.S. EPA, 1991b). Both documents declined to derive an RfC due to insufficient reporting and contradictory results in the limited data available. The ACGIH (1991, 2001) lists a TLV-TWA of 200 ppm (793 mg/m3) for all forms of 1,2-dichloroethylene based on liver toxicity of the trans isomer in a study by Freundt et al. (1977). NIOSH (1981, 2001) established a recommended exposure limit of 200 ppm (790 mg/m3) and OSHA (1999, 2000) established a permissible exposure limit of 200 ppm (790 mg/m3) for all forms of 1,2-dichloroethylene to protect against irritation of the eye and respiratory system, and depression of the central nervous system. ATSDR (1996, 2001) has not established inhalation MRLs for mixed isomers of 1,2-dichloroethylene or for the cis isomer, but 2 ------- 5-31-2002 has established an intermediate inhalation MRL of 0.2 ppm for the trans isomer based on hepatic effects. Neither IARC (2001) nor the WHO (2001) have written toxicological review documents on 1,2-dichloroethylene. A toxicity review on unsaturated halogenated hydrocarbons (Lemen, 2001), and the NTP (2001a, 2001b) management status report and health and safety report for 1,2-dichloroethylene were consulted for relevant information. Literature searches were conducted from 1994 to June 2001 for studies relevant to the derivation of an RfC for 1,2-dichloroethylene. The databases searched were: TOXLINE, MEDLINE, CANCERLIT, TOXLIT/BIOSIS, RTECS, HSDB, GENETOX, CCRIS, TSCATS, EMIC/EMICBACK, and DART/ETICB ACK. REVIEW OF THE PERTINENT LITERATURE Human Studies No pertinent data regarding the inhalation toxicity of 1,2-dichloroethylene in humans following subchronic or chronic exposures were found in the available review documents (U.S. EPA, 1986, 1991b; AT SDR, 1996; Lemen, 2001). Animal Studies The U.S. EPA (1986, 1991b) considered an available subchronic inhalation study on the mixed isomers by Torkelson (1965) to be an inadequate basis for risk assessment because of its lack of detail and because its negative results were discordant with those of Freundt et al. (1977) for the trans isomer. Torkelson (1965) reported no effects in rats, rabbits, guinea pigs, and dogs exposed to 500 or 1000 ppm of mixed isomers (60% cis, 40% trans) for 7 hrs/day, 5 days/week for 6 months, whereas Freundt et al. (1977) reported a LOAEL of 200 ppm for pulmonary and liver histopathology in female Wistar rats exposed to the trans isomer for 8 hours/day, 5 days/week for 16 weeks. However, a report of the Torkelson (1965) study submitted to the EPA in 1994 (Dow Chemical, 1962) indicated that statistically significant increases in organ weights relative to body weight were observed in the kidney of male rats and the liver of female rats at 500 and 1000 ppm, and the kidney of female rats at 1000 ppm. In addition, increased relative liver weight was also observed in a small group of male and female rabbits. (Absolute organ weights and histopathological results were not reported.) Rather than contradicting the Freundt et al. (1977) results, the reported organ weight changes in the Dow Chemical (1962) report lend some support to the histopathological observations in Freundt et al. (1977). However, too few details of methods and results are available regarding the Torkelson/Dow study to use this study for risk assessment. No additional subchronic or chronic duration studies of inhalation toxicity of 1,2-dichloroethylene (mixed isomers) in animals were found in the available review documents (ATSDR, 1996; Lemen, 2001) or in the literature search. 3 ------- 5-31-2002 Other Studies Acute exposures to high concentrations (>1000 ppm) of trans-1,2-dichlorocthylcnc have been reported to cause eye irritation, nausea, vertigo, or narcosis (ACGIH, 1991; OSHA, 1999). One human fatality, presumably from depression of the central nervous system, was reported following exposure to an unknown quantity of 1,2-dichloroethylene vapor (isomer composition unreported) in an enclosed area (ATSDR, 1996). 1,2-Dichloroethylene has been used as an anesthetic in humans and animals (ACGIH, 1991; Lemen, 2001). FEASIBILITY OF DERIVING A PROVISIONAL RfC FOR 1,2-DICHLOROETHYLENE (MIXED ISOMERS) Quantitative data regarding the inhalation toxicity of 1,2-dichloroethylene are lacking for humans and the available subchronic animal study is inadequate. Thus, it is not possible to derive a provisional RfC for 1,2-dichloroethylene. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 1991. 1,2-Dichloroethylene. Documentation of the Threshold Limit Values and Biological Exposure Indices, 6th ed. ACGIH, Cincinnati, OH. p. 429-431. ACGIH (American Conference of Governmental Industrial Hygienists). 2001. 2001 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. p. 26. ATSDR (Agency for Toxic Substances and Disease Registry). 1996. Toxicological Profile for 1,2-Dichloroethene (Update). TP-95/04. August 1996. Atlanta, GA. ATSDR (Agency for Toxic Substances and Disease Registry). 2001. Minimal Risk Levels (MRLs) for Hazardous Substances. Dated April 2001. Examined July 2001. Online. http://www.atsdr.cdc.gov/mrls.html Dow Chemical Co. 1962. The toxicity of 1,2-dichloroethylene as determined by repeated exposures in laboratory animals. OTS0557247. Freundt, K.J., G.P. Liebaldt and E. Lieberwirth. 1977. Toxicity studies on trans- 1,2- dichloroethylene. Toxicology. 7: 141-153. IARC (International Agency for Research on Cancer). 2001. Search IARC agents and summary evaluations. Examined July, 2001. Online, http://monographs.iarc.fr/ 4 ------- 5-31-2002 Lemen, R.A. 2001. Unsaturated halogenated hydrocarbons. In: Patty's Toxicology, 5th ed., E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley, New York. Vol.5, p. 205-297. NIOSH (National Institute for Occupational Safety and Health). 1981. Occupational Health Guideline for 1,2-Dichloroethylene. Version dated September 1978. Occupational Health Guidelines for Chemical Hazards. Department of Health and Human Services (NIOSH) Publication No. 81-123. January 1981. Examined July 2001. Online. http://www.cdc.gov/niosh/pdfs/0195 .pdf NIOSH (National Institute for Occupational Safety and Health). 2001. 1,2-Dichloroethylene. CAS No. 540-59-0. NIOSH Pocket Guide to Chemical Hazards. Examined July 2001. Online. http://www.cdc.gov/niosh/npg/npgd0195.html NTP (National Toxicology Program). 2001a. Health and Safety Information for 1,2- Dichloroethylene. Examined July 2001. Online. http://ntp-server.niehs.nih.gov/htdoct/CHEM H&S/NTP Chem5/Radian540-59-0.html NTP (National Toxicology Program). 2001b. Testing status. Examined July 2001. Online. http://ntp-server.niehs.nih.gov/htdocs/Results Status/Resstatd/10110-X.Html OSHA (Occupational Safety and Health Administration). 1999. Occupational Safety and Health Guideline for 1,2-Dichloroethylene. (Developed under protocol by OSHA, the National Institute for Occupational Safety and Health and the Department of Energy). Version dated April 1999. Examined July 2001. Online. http://www.osha-slc.gOv/SLTC/healthguidelines/l 2-dichloroethylene/index.html OSHA (Occupational Safety and Health Administration). 2000. Chemical Sampling Information for 1,2-Dichloroethylene. Version dated May 15 2000. Examined July 2001. Online. http://www.osha-slc.gov/dts/chemicalsampling/data/CH 233600.html Torkelson, T.R. 1965. Communication to TLV committee. Animal experiments on the toxicity of a vinyl chloride and vinylidene chloride copolymer and of the two substances that can be used to stabilize dispersions. Dow Chemical Co., Midland, MI. (Cited in ACGIH, 1991) U.S. EPA. 1986. Health and Environmental Effects Profile for Dichloroethenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991a. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. 5 ------- 5-31-2002 U.S. EPA. 1991b. Health and Environmental Effects Document for 1,2-Dichloroethylene (mixed isomers). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. May. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July 1997. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Examined July, 2001. Online, http://www.epa.gov/iris/ WHO (World Health Organization). 2001. Online catalogs for the Environmental Health Criteria series. Examined July 2001. Online, http://www.who.int/dsa/cat97/zehc.htm and http ://www,who.int/dsa/justpub/add.htm 6 ------- 5-31-2002 Provisional Peer Reviewed Toxicity Values for 1,2-Dichloroethylene (mixture) (CASRN 540-59-0) Derivation of an Oral Slope Factor Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit 1 ------- NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor microgram (imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 1,2-DICHLOROETHYLENE (mixture) (CASRN 540-59-0) Derivation of an Oral Slope Factor Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. INTRODUCTION 1,2-Dichloroethylene (CASRN 540-59-0), a mixture of cis and trans isomers, is not listed on IRIS (U.S. EPA, 2001), in the HEAST cancer table (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories List (U.S. EPA, 2000). The CARA list (U.S. EPA, 1991a, 1994) includes a Health and Environmental Effects Profile (HEEP) on dichloroethenes (U.S. EPA, 1986) and a Health and Environmental Effects Document (HEED) on 1,2-dichloroethylene (mixed isomers) (U.S. EPA, 1991b). The HEED assigned 1,2- dichloroethylene to Group D because of a lack of data regarding its carcinogenicity in humans or animals. Neither IARC (2001) nor the WHO (2001) have written a toxicological review document on 1,2-dichloroethylene. A Toxicological Profile on 1,2-dichloroethylene (ATSDR, 1996), a toxicity review on unsaturated halogenated hydrocarbons (Lemen, 2001), and the NTP (2001 a,b) management status report and health and safety report for 1,2-dichloroethylene were also consulted for relevant information. Literature searches were conducted from 1994 to June 2001 for studies relevant to the derivation of an oral slope factor for 1,2-dichloroethylene. The 2 ------- 5-31-2002 databases searched were: TOXLINE, MEDLINE, CANCERLIT, TOXLIT/BIOSIS, RTECS, HSDB, GENETOX, CCRIS, TSCATS, and EMIC/EMICBACK. REVIEW OF THE PERTINENT LITERATURE Human Studies No data regarding carcinogenicity of 1,2-dichloroethylene in humans following oral exposure were found in the available review documents (U.S. EPA, 1986, 1991b; ATSDR, 1996; Lemen, 2001). The literature search located one relevant human epidemiological study. A case- control study of 63,097 persons who died from pancreatic cancer between 1984 and 1993 found no association between occupational exposure to 1,2-dichloroethylene and death from pancreatic cancer (Kernan et al., 1999). No human studies were located that reported levels of exposure to 1,2-dichloroethylene. Animal Studies No data regarding carcinogenicity in animals following oral exposure to 1,2-dichloroethylene were located in the available reviews (U.S. EPA, 1986, 1991b; ATSDR, 1996; Lemen, 2001) or the literature search. Other Studies 1,2-Dichloroethylene did not produce reverse mutations in Salmonella typhimurium (strains TA98, TA100, TA1535, TA1537) or Saccharomyces cerevisiae D7 with or without metabolic activation, and did not produce reverse or forward mutations in Escherichia coli K12 with activation (U.S. EPA, 199 lb). At a high concentration, it was weakly positive for mitotic recombination in Saccharomyces cerevisiae D7 (U.S. EPA, 1991b). 1,2-Dichloroethylene altered chromosomal segregation, resulting in aneuploidy, in Aspergillus nidulans diploid strain PI (Crebelli et al., 1992, 1995; Rosenkranz and Klopman, 1996). This effect of 1,2-dichloroethylene and other haloalkanes was attributed to a direct or indirect interaction with spindle microtubules (Crebelli et al., 1992). In freshly isolated human lymphocytes with or without metabolic activation, 1,2-dichloroethylene induced micronucleus formation and also caused DNA breakage in the alkaline single cell gel electrophoresis (comet) assay (Tafazoli and Kirsch-Volders, 1996). 1,2-Dichloroethylene also induced micronucleus formation in 2 out of 3 human cell lines that stably express cytochromal enzymes: positive in parental human B lymphoblastoid line AHH-1 Tk+/- and line h2El, but negative in line MCL-5 (Doherty et al., 1996; Parry et al., 1996). At injected doses high enough to elicit clinical signs in CD-I mice, 1,2-dichloroethylene (purity 98%) did not induce micronucleus formation in bone marrow cells (Crebelli et al., 1999). 3 ------- 5-31-2002 FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR 1,2-DICHLOROETHYLENE Since the available literature contains no information regarding carcinogenicity in humans or animals following oral exposure to 1,2-dichloroethylene, there is no basis for the derivation of an oral slope factor. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 1996. Toxicological Profile for 1,2-Dichloroethene (Update). August 1996. Atlanta, GA. Crebelli, R., C. Andreoli, A. Carere et al. 1992. The induction of mitotic chromosome malsegregation in Aspergillus nidulans. Quantitative structure activity relationship (QSAR) analysis with chlorinated aliphatic hydrocarbons. Mutat. Res. 266: 117-134. Crebelli, R., C. Andreoli, A. Carere et al. 1995. Toxicology of halogenated aliphatic hydrocarbons: Structural and molecular determinants for the disturbance of chromosome segregation and the induction of lipid peroxidation. Chem.-Bio. Interact. 98: 113-129. Crebelli, R.C., A. Carere, P. Leopardi et al. 1999. Evaluation of 10 aliphatic halogenated hydrocarbons in the mouse bone marrow micronucleus test. Mutagenesis. 14: 207-215. Doherty, A.T., S. Ellard, E.M. Parry and J.M. Parry. 1996. An investigation into the activation and deactivation of chlorinated hydrocarbons to genotoxins in metabolically competent human cells. Mutagenesis. 11:247-274. IARC (International Agency for Research on Cancer). 2001. Search IARC agents and summary evaluations. Examined July, 2001. Online, http://monographs.iarc.fr/ Kernan, G.J., B.-T. Ji, M. Dosemeci et al. 1999. Occupational risk factors for pancreatic cancer: A case-control study based on death certificates from 24 U.S. states. Am. J. Ind. Med. 36: 260- 270. Lemen, R.A. 2001. Unsaturated halogenated hydrocarbons. In: Patty's Toxicology, 5th ed., E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley, New York. Vol.5, p. 205-297. NTP (National Toxicology Program). 2001a. Health and Safety Information for 1,2- Dichloroethylene. Examined July 2001. Online. http://ntp-server.niehs.nih.gov/htdoct/CHEM H&S/NTP Chem5/Radian540-59-0.html 4 ------- 5-31-2002 NTP (National Toxicology Program). 2001b. Testing status. Examined July 2001. Online. http://ntp-server.niehs.nili.gov/litdocs/Results Status/Resstatd/10110-X.Html Parry, J.M., E.M. Parry, R. Bourner et al. 1996. The detection and evaluation of aneugenic chemicals. Mutat. Res. 353:11-46. Rosenkranz, H.S. and G. Klopman. 1996. A study of the structural basis of the ability of chlorinated alkanes and alkenes to induce aneuploidy and toxicity in the mold Aspergillus nidulans. Mutat. Res. 354:183-193. Tafazoli, M. and M. Kirsch-Volders. 1996. In vitro mutagenicity and genotoxicity study of 1,2- dichloroethylene, 1,1,2-trichloroethane, 1,3-dichloropropane, 1,2,3-trichloropropane and 1,1,3- trichloropropene, using the micronucleus test and the alkaline single cell gel electrophoresis technique (comet assay) in human lymphocytes. Mutat. Res. 371:185-202. U.S. EPA. 1986. Health and Environmental Effects Profile for Dichloroethenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991a. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1991b. Health and Environmental Effects Document for 1,2-Dichloroethylene (mixed isomers). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. May. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July 1997. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer, 2000. EPA 822-B-00-001. Examined July, 2001. Online. http://www.epa. gov/ost/drinking/standards/dwstandards.pdf U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Examined June, 2001. Online, http://www.epa.gov/iris/ 5 ------- 5-31-2002 WHO (World Health Organization). 2001. Online catalogs for the Environmental Health Criteria series. Examined July 2001. Online, http://www.who.int/dsa/cat97/zehc.htm and http ://www,who.int/dsa/justpub/add.htm 6 ------- 5-31-2002 Provisional Peer Reviewed Toxicity Values for 1,2-Dichloroethylene (mixture) (CASRN 540-59-0) Derivation of an Inhalation Unit Risk Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level MTD maximum tolerated dose MTL median threshold limit 1 ------- NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor microgram (imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 1,2-DICHLOROETHYLENE (mixture) (CASRN 540-59-0) Derivation of an Inhalation Unit Risk Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human health toxicity values for Superfund risk assessments, establishing the following three tiers as the new hierarchy: 1. EPA's Integrated Risk Information System (IRIS). 2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund Program. 3. Other (peer-reviewed) toxicity values, including: ~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease Registry (ATSDR), ~ California Environmental Protection Agency (CalEPA) values, and ~ EPA Health Effects Assessment Summary Table (HEAST) values. A PPRTV is defined as a toxicity value derived for use in the Superfund Program when such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are developed according to a Standard Operating Procedure (SOP) and are derived after a review of the relevant scientific literature using the same methods, sources of data, and Agency guidance for value derivation generally used by the EPA IRIS Program. All provisional toxicity values receive internal review by two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program consensus review provided for IRIS values. This is because IRIS values are generally intended to be used in all EPA programs, while PPRTVs are developed specifically for the Superfund Program. Because new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 Disclaimers Users of this document should first check to see if any IRIS values exist for the chemical of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional Superfund and RCRA program offices are advised to carefully review the information provided in this document to ensure that the PPRTVs used are appropriate for the types of exposures and circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically updated; therefore, users should ensure that the values contained in the PPRTV are current at the time of use. It is important to remember that a provisional value alone tells very little about the adverse effects of a chemical or the quality of evidence on which the value is based. Therefore, users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may choose of their own initiative to use these PPRTVs are advised that Superfund resources will not generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund Program. Questions Regarding PPRTVs Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed to the EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI. INTRODUCTION 1,2-Dichloroethylene (CASRN 540-59-0), a mixture of cis and trans isomers, is not listed on IRIS (U.S. EPA, 2001), in the HEAST cancer table (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories List (U.S. EPA, 2000). The CARA list (U.S. EPA, 1991a, 1994) includes a Health and Environmental Effects Profile (HEEP) on dichloroethenes (U.S. EPA, 1986) and a Health and Environmental Effects Document (HEED) on 1,2-dichloroethylene (mixed isomers) (U.S. EPA, 1991b). The HEED assigned 1,2- dichloroethylene to Group D because of a lack of data regarding its carcinogenicity in humans or animals. Neither IARC (2001) nor the WHO (2001) have written a toxicological review document on 1,2-dichloroethylene. A Toxicological Profile on 1,2-dichloroethylene (ATSDR, 1996), a toxicity review on unsaturated halogenated hydrocarbons (Lemen, 2001), and the NTP (2001 a,b) management status report and health and safety report for 1,2-dichloroethylene were also consulted for relevant information. Literature searches were conducted from 1994 to June 2001 for studies relevant to the derivation of an inhalation unit risk for 1,2-dichloroethylene. The 2 ------- 5-31-2002 databases searched were: TOXLINE, MEDLINE, CANCERLIT, TOXLIT/BIOSIS, RTECS, HSDB, GENETOX, CCRIS, TSCATS, and EMIC/EMICBACK. REVIEW OF THE PERTINENT LITERATURE Human Studies No data regarding carcinogenicity of 1,2-dichloroethylene in humans following inhalation exposure were found in the available review documents (U.S. EPA, 1986, 1991b; ATSDR, 1996; Lemen, 2001). The literature search located one relevant human epidemiological study. A case- control study of 63,097 persons who died from pancreatic cancer between 1984 and 1993 found no association between occupational exposure to 1,2-dichloroethylene and death from pancreatic cancer (Kernan et al., 1999). No human carcinogenicity study was located that reported levels of exposure to 1,2-dichloroethylene. Animal Studies No data regarding carcinogenicity in animals following inhalation exposure to 1,2-dichloroethylene were located in the available reviews (U.S. EPA, 1986, 1991b; ATSDR, 1996; Lemen, 2001) or the literature search. Other Studies 1,2-Dichloroethylene did not produce reverse mutations in Salmonella typhimurium (strains TA98, TA100, TA1535, TA1537) or Saccharomyces cerevisiae D7 with or without metabolic activation, and did not produce reverse or forward mutations in Escherichia coli K12 with activation (U.S. EPA, 199 lb). At a high concentration, it was weakly positive for mitotic recombination in Saccharomyces cerevisiae D7 (U.S. EPA, 1991b). 1,2-Dichloroethylene altered chromosomal segregation, resulting in aneuploidy, in Aspergillus nidulans diploid strain PI (Crebelli et al., 1992, 1995; Rosenkranz and Klopman, 1996). This effect of 1,2-dichloroethylene and other haloalkanes was attributed to a direct or indirect interaction with spindle microtubules (Crebelli et al., 1992). In freshly isolated human lymphocytes with or without metabolic activation, 1,2-dichloroethylene induced micronucleus formation and also caused DNA breakage in the alkaline single cell gel electrophoresis (comet) assay (Tafazoli and Kirsch-Volders, 1996). 1,2-Dichloroethylene also induced micronucleus formation in 2 out of 3 human cell lines that stably express cytochromal enzymes: positive in parental human B lymphoblastoid line AHH-1 Tk+/- and line h2El, but negative in line MCL-5 (Doherty et al., 1996; Parry et al., 1996). At injected doses high enough to elicit clinical signs in CD-I mice, 1,2-dichloroethylene (purity 98%) did not induce micronucleus formation in bone marrow cells (Crebelli et al., 1999). 3 ------- 5-31-2002 FEASIBILITY OF DERIVING A PROVISIONAL INHALATION UNIT RISK FOR 1,2-DICHLOROETHYLENE Since the available literature contains no information regarding carcinogenicity in humans or animals following inhalation exposure to 1,2-dichloroethylene, there is no basis for the derivation of an inhalation unit risk. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 1996. Toxicological Profile for 1,2-Dichlorothene (Update). August 1996. Atlanta, GA. Crebelli, R., C. Andreoli, A. Carere et al. 1992. The induction of mitotic chromosome malsegregation in Aspergillus nidulans. Quantitative structure activity relationship (QSAR) analysis with chlorinated aliphatic hydrocarbons. Mutat. Res. 266: 117-134. Crebelli, R., C. Andreoli, A. Carere et al. 1995. Toxicology of halogenated aliphatic hydrocarbons: Structural and molecular determinants for the disturbance of chromosome segregation and the induction of lipid peroxidation. Chem.-Bio. Interact. 98: 113-129. Crebelli, R.C., A. Carere, P. Leopardi et al. 1999. Evaluation of 10 aliphatic halogenated hydrocarbons in the mouse bone marrow micronucleus test. Mutagenesis. 14: 207-215. Doherty, A.T., S. Ellard, E.M. Parry and J.M. Parry. 1996. An investigation into the activation and deactivation of chlorinated hydrocarbons to genotoxins in metabolically competent human cells. Mutagenesis. 11:247-274. IARC (International Agency for Research on Cancer). 2001. Search IARC agents and summary evaluations. Examined July, 2001. Online, http://monographs.iarc.fr/ Kernan, G.J., B.-T. Ji, M. Dosemeci et al. 1999. Occupational risk factors for pancreatic cancer: A case-control study based on death certificates from 24 U.S. states. Am. J. Ind. Med. 36: 260- 270. Lemen, R.A. 2001. Unsaturated halogenated hydrocarbons. In: Patty's Toxicology, 5th ed., E. Bingham, B. Cohrssen and C.H. Powell, Ed. John Wiley, New York. Vol.5, p. 205-297. NTP (National Toxicology Program). 2001a. Health and Safety Information for 1,2- Dichloroethylene. Examined July 2001. Online. http://ntp-server.niehs.nih.gov/htdoct/CHEM H&S/NTP Chem5/Radian540-59-0.html 4 ------- 5-31-2002 NTP (National Toxicology Program). 2001b. Testing status. Examined July 2001. Online. http://ntp-server.niehs.nili.gov/litdocs/Results Status/Resstatd/10110-X.Html Parry, J.M., E.M. Parry, R. Bourner et al. 1996. The detection and evaluation of aneugenic chemicals. Mutat. Res. 353:11-46. Rosenkranz, H.S. and G. Klopman. 1996. A study of the structural basis of the ability of chlorinated alkanes and alkenes to induce aneuploidy and toxicity in the mold Aspergillus nidulans. Mutat. Res. 354:183-193. Tafazoli, M. and M. Kirsch-Volders. 1996. In vitro mutagenicity and genotoxicity study of 1,2- dichloroethylene, 1,1,2-trichloroethane, 1,3-dichloropropane, 1,2,3-trichloropropane and 1,1,3- trichloropropene, using the micronucleus test and the alkaline single cell gel electrophoresis technique (comet assay) in human lymphocytes. Mutat. Res. 371:185-202. U.S. EPA. 1986. Health and Environmental Effects Profile for Dichloroethenes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. U.S. EPA. 1991a. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1991b. Health and Environmental Effects Document for 1,2-Dichloroethylene (mixed isomers). Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. May. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by the Office of Research and Development, National Center for Environmental Assessment, Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July 1997. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer, 2000. EPA 822-B-00-001. Examined July, 2001. Online. http://www.epa. gov/ost/drinking/standards/dwstandards.pdf U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Examined June, 2001. Online, http://www.epa.gov/iris/ 5 ------- 5-31-2002 WHO (World Health Organization). 2001. Online catalogs for the Environmental Health Criteria series. Examined July 2001. Online. http://www.who.int/dsa/cat97/zehc.htm and http://www.who.int/dsa/justpub/add.htm 6 ------- |