United States Environmental Protection 1=1 m m Agency EPA/690/R-11/020F Final 2-03-2011 Provisional Peer-Reviewed Toxicity Values for cis-1,2-Dichloroethylene (CASRN 156-59-2) Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- AUTHORS, CONTRIBUTORS, AND REVIEWERS CHEMICAL MANAGER Jon Reid, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH Note: Because the subchronic p-RfD presented in this document is based solely on the 2010 IRIS information, no external review was performed. All of the information provided in this PPRTV document was available to peer reviewers during the standard IRIS peer review process. ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS iv BACKGROUND 1 HISTORY 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVS 2 INTRODUCTION 2 HUMAN AND ANIMAL STUDIES 2 DERIVATION 01 PROVISIONAL VALUES 3 DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES 3 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 6 CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 6 DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 6 APPENDIX A. REFERENCES 7 in cis-1,2-Dichloroethylene ------- COMMONLY USED ABBREVIATIONS BMC benchmark concentration BMD benchmark dose BMCL benchmark concentration lower bound 95% confidence interval BMDL benchmark dose lower bound 95% confidence interval HEC human equivalent concentration HED human equivalent dose IUR inhalation unit risk LOAEL lowest-observed-adverse-effect level LOAELadj LOAEL adjusted to continuous exposure duration LOAELhec LOAEL adjusted for dosimetric differences across species to a human NOAEL no-ob served-adverse-effect level NOAELadj NOAEL adjusted to continuous exposure duration NOAELhec NOAEL adjusted for dosimetric differences across species to a human NOEL no-ob served-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional reference concentration (inhalation) p-RfD provisional reference dose (oral) POD point of departure RfC reference concentration (inhalation) RfD reference dose (oral) UF uncertainty factor UFa animal-to-human uncertainty factor UFC composite uncertainty factor UFd incomplete-to-complete database uncertainty factor UFh interhuman uncertainty factor UFl LOAEL-to-NOAEL uncertainty factor UFS subchronic-to-chronic uncertainty factor WOE weight of evidence iv cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR CIS-1,2-DICHLOROETHYLENE (CASRN 156-59-2) BACKGROUND HISTORY On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) 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 (PPRTVs) 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 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 of the information provided in this PPRTV document was available to peer reviewers during the standard IRIS peer review process. PPRTVs differ from IRIS values in that PPRTVs do not receive the multiprogram 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 5-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 documents conclude that a PPRTV cannot be derived based on inadequate data. 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 Resource Conservation and Recovery Act (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. 1 cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 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 document 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 On September 30, 2010, IRIS (U.S. EPA, 2010) posted a chronic RfD of 0.002 mg/kg-day for cis-1,2-dichloroethylene based on a sub chronic-duration oral rat study (90 days) by McCauley et al. (1995, 1990), using a point of departure (POD) from a benchmark dose level (BMDLio) of 5.1 mg/kg-day and a combined UF of 3000 (UFh = 10; UFa = 10; UFl = 1; UFS = 10; and UFD = 3). Development of the subchronic p-RfD in this PPRTV document has been accomplished using only information provided in the IRIS toxicological review of cis-1,2-dichloroethylene (CASRN 156-59-2) (U.S. EPA, 2010). All of the information provided in this PPRTV document was available to peer reviewers during the standard IRIS peer review process. IRIS does not generally post subchronic-duration values. However, because the IRIS chronic value was developed from a subchronic-duration study by utilizing the UFS of 10, a subchronic p-RfD is presented in this PPRTV document based on this same study. The PPRTV duplicates only the key information necessary to succinctly support the derivation of a subchronic p-RfD. Full details are available on the IRIS database (see the References section—U.S. EPA [2010]), but omits much of the detailed information and the reader is directed to the IRIS online document for details. HUMAN AND ANIMAL STUDIES Refer to the IRIS toxicological review of cis-1,2-dichloroethylene (U.S. EPA, 2010) for summaries of human and animal studies. 2 cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 DERIVATION OF PROVISIONAL VALUES DERIVATION OF PROVISIONAL ORAL REFERENCE DOSES On September 30, 2010, IRIS (U.S. EPA, 2010) posted an RfD of 0.002 mg/kg-day based on a subchronic-duration oral rat study (90 days) by McCauley et al. (1995, 1990), using a POD from a BMDLio of 5.1 mg/kg-day and a combined UF of 3000 (UFh = 10; UFa = 10; UFl = 1; UFS = 10; and UFD = 3). Background on the principal study provided in the IRIS file (i.e., EPA [2010], Section I. A.2) is indicated below: McCauley et al. (1995, 1990) administered 0, 32, 97, 291, or 872 mg/kg-day cis-l,2-DCE by corn oil gavage to male andfemale Spr ague-Daw ley rats (10 rats/sex/group) for 90 days. At the end of the 90-day exposure period, animals were sacrificed and the brain, gonads, heart, kidneys, adrenals, liver, spleen, and thymus were weighed and examined for gross pathology. Blood samples were collectedfor hematological and clinical chemistry examinations. Tissues from controls and the high-dose group animals were examinedfor histopathologic changes. Clinical observations during the study were reported by the authors as minimal and not compound-related. Gavage deaths were present in both the treated and control groups (1/10 female rats at 32 mg/kg-day; 1/10 female rats at 97 mg/kg-day; 1/10 male controls; 3/10 male rats at 291 mg/kg-day; 4/10 male rats at 872 mg/kg-day). Terminal body weights in male rats at the two highest dose groups were lower than controls by 10-11%, but were not considered by the author as statistically significant; no treatment-related effects on body weight were reported in female rats. Absolute liver weights were statistically significantly increased by 10, 15[] and 24% in female rats at doses of97, 291, and 872 mg/kg-day, respectively. The increases in absolute liver weight of 6, 13, 5[] and 15% in male rats of the 32[-], 97[~], 291[-] and 872[-]mg/kg-day dose groups, respectively, were not statistically significant nor dose related. Relative liver weights were statistically significantly increased in a dose-related manner in males andfemales. The increases were 15, 17, and 32% for males and 14, 19, and 30% for females at 97, 291, and 872 mg/kg-day, respectively. Histopathological evaluation revealed no specific hepatic injury. The authors concluded that there was a consistent, dose-related increase in relative liver weight in both sexes and that this effect, in light of the negative histopathology findings, may reflect hypertrophy and hyperplasia. Absolute kidney weights in female rats were increased by 3, 16, 17, and 17% compared to the control at doses of32, 97, 291, and 872 mg/kg-day, respectively, but were not statistically significant. In male rats increases in absolute kidney weight of 9, 17, 7, and 14% for the 32, 97, 291, and872 mg/kg-day dose groups, respectively, were not statistically significantly elevated compared to the control 3 cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 nor dose related. Statistically significant increases in relative kidney weights were recorded in male rats in all dose groups (14, 19, 19, and 27% at 32, 97, 291, and 872 mg/kg-day, respectively). Female rats exhibited increased (although not statistically significant) relative kidney weights in the three highest doses (19, 23, and 23% at 97, 291, and 872 mg/kg-day, respectively). Relatively large variances in the female dose groups may explain why relative kidney weight increases in females were not statistically significant. Histopathological findings for kidney effects were negative, leading the authors to hypothesize that the increases in relative kidney weight may be due at least in part to decreased body weight gain. Sporadic changes (although noted as statistically significant) in some clinical chemistry parameters were observed. Blood urea nitrogen (BUN) levels were significantly decreased (40%) at the highest dose in males but not in females. Serum calcium levels were significantly elevated by 8 and 10% in males at the 32 and 97 mg/kg-day doses, respectively, and serum phosphorus was significantly decreased by 14% in males exposed to 32 mg/kg-day. In females, serum phosphorus was significantly increased by 34 and 25% in the groups dosed with 97 and 291 mg/kg-day, respectively. No significant changes were reported in AST activity. Hemoglobin and hematocrit level, and red blood cell (RBC) count were significantly decreased in female rats dosed at 291 mg/kg-day, while only hematocrit was significantly decreased in females dosed with 872 mg/kg-day. In males, similar decreases (ranging from 6 to 10% compared with the control) occurred in hemoglobin in the 291[-] and 872[-]mg/kg-day groups and in hematocrit in the 97[~], 291[-] and 872[-]mg/kg-day groups. Overall, the changes in clinical chemistry and hematology parameters were considered by the authors to be marginal and of questionable biological significance. No noteworthy compound-related histopathological changes were observed in any dose group. IRIS utilized a BMD approach to develop the POD as indicated below: Increased relative kidney weight in male andfemale rats (McCauley et al. (1995, 1990) was identified as the critical effect. Benchmark dose (BMD) modeling methodology (U.S. EPA, 2000) was used to determine the point of departure (POD) by estimating the effective dose at a specified level of response (BMDx) and its 95% lower confidence limit (BMDLx). A 10% change in relative kidney weight compared with the control was selected as the benchmark response (BMR) level. A BMR of 10% change in relative kidney weight was selected by analogy to body weight, for which a 10% change is generally recognized as a minimally biologically significant change (U.S. EPA, 2000). All of the models for continuous data (i.e., linear, polynomial, power, and Hill models) in U.S. EPA's BMDS (version 2.1) were fit to relative kidney weight data. For the male rat, BMDS modeling of relative kidney weight data showed that only the Hill model adequately fit the data (test 4 y p> 0.1). The other continuous models fit to these data, the polynomial (linear and degree>2) and power models, exhibited significant lack of fit. The Hill model predicted a BMDio and BMDLio of 19.8 and 5.1 mg/kg-day, respectively. For the female rat, the Hill model 4 cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 provided the best fit of the relative kidney weight data (based on the model with the lowest Akaike Information Criteria (AIC) value and adequate visual fit of the data). The Hill model predicted a BMD w and BMDL w of 55.2 and 10.4 mg/kg-day, respectively. The POD for the RfD for cis-l,2-DCE was selected as 5.1 mg/kg-day based on male rat relative kidney weight, the lower of the male andfemale BMDLw values for this endpoint. A subchronic p-RfD is developed from IRIS's (2010) reporting of McAuley et al. (1995, 1990) (omitting the extrapolation to chronic duration, i.e., UFS of 10). Subchronic p-RfD = BMDLio UFc = 5.1 mg/kg-day ^ 300 = 0.017 or 2 x 10"2 mg/kg-day The discussion of the uncertainty factors utilized by IRIS is shown below: An intraspecies UF (UFh) of 10 was applied to account for potentially sensitive human subpopulations in the absence of quantitative information on the variability of response to cis-l,2-DCE in the human population. Factors that could contribute to a range of human response to cis-l,2-DCE were discussed in Section 4.8 of the Toxicological Review of cis-1,2-Dichloroethylene and trans-1,2-Dichloroethylene (U.S. EPA, 2010). Intrahuman variability in CYP450 levels that are responsible for metabolism of cis-1,2-DCE to reactive metabolites has been documented. This variation in CYP450 could alter susceptibility to cis-1,2-DCE toxicity. Individual variability in nutritional status, alcohol consumption, or the presence of underlying disease could also alter metabolism of cis-1,2-DCE. To account for these uncertainties, a factor of 10 was includedfor individual variability. An interspecies UF (UFa) of 10 was applied to account for the variability in extrapolating from laboratory animals to humans. No information was available to characterize the toxicokinetic or toxicodynamic differences between experimental animals and humans for cis-1,2-DCE. An UF of 1 was used for extrapolation from a LOAEL to a NOAEL (UFjJ because the current approach is to address this factor as one of the considerations in selecting a BMR for BMD modeling. In this case, a BMR of a 10% change in relative kidney weight compared with the control was selected under an assumption that it represents a minimally biologically significant change. An UF of 3 was used to account for database deficiencies (UFu). The study used in this RfD derivation, McCauley et al. (1995, 1990), is the only study of repeat-dose toxicity available for cis-1,2-DCE. The database for this isomer is missing studies of reproductive toxicity, including a two-generation reproductive toxicity study, and developmental toxicity; however, the developmental toxicity potential for cis-1,2-DCE is informed by a series of range-finding studies of the developmental toxicity of a mixture of cis-1,2-DCE isomers (composition of isomers unknown) (NTP, 1991a, b, c). No evidence of developmental toxicity was 5 cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 observed in mice or rats based on the parameters evaluated in these range-finding studies (gravid uterus weight, fetal body weight, number of fetuses [live/dead], implantation sites, and resorptions). An UF of 1 was used since a subchronic exposure was utilized to develop a subchronic value (UFs). Confidence in the subchronic p-RfD value is identical to that of the chronic RfD value: low, based on a study confidence of medium and a database confidence of low. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS There is no suitable information for developing RfC values. IRIS did not develop an RfC value as indicated below: The inhalation toxicity database for cis-l,2-DCE does not support derivation of an RfC. No studies of the effects of cis-l,2-DCE by inhalation exposure in humans were identified. In experimental animals, investigation of the inhalation toxicity of cis-l,2-DCE is limited to an acute 4-hour inhalation LC50 study in rats (DuPont, 1999). There are no inhalation studies of subchronic, chronic, reproductive, or developmental toxicity of cis-1,2-DCE. Therefore, no inhalation RfC values were derivedfor cis-1,2-DCE. CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR The cancer WOE descriptor for c/.s- l ,2-dichloroethylene is provided in the IRIS toxicological review of as-1,2-dichloroethylene (U.S. EPA, 2010) as "Inadequate Information to Assess Carcinogenic Potential (both oral and inhalation)." This descriptor is based on the absence of epidemiological studies in humans and the lack of animal studies designed to evaluate the carcinogenic potential. DERIVATION OF PROVISIONAL CANCER POTENCY VALUES As indicated in the IRIS toxicological review of c/'s-1,2-dichloroethylene (U.S. EPA, 2010), the lack of data on carcinogenicity precludes the derivation of quantitative estimates for either oral (p-OSF) or inhalation (p-IUR) exposure. 6 cis-1,2-Dichloroethylene ------- FINAL 2-3-2011 APPENDIX A. REFERENCES DuPont. (1999) Initial submission: letter from DuPont Haskell Laboratory to U.S. EPA re results of 4-hour inhalation median lethality study (LC50) in rats w/cis-l,2-dichloroethylene, dated 8/26/99. E.I. DuPont de Nemours and Company, Wilmington, DE. Submitted under TSCA Section 8E; EPA Document No. 88990000257; NTIS No. OTS0559785. McCauley, PT; Robinson, M; Daniel, FB; et al. (1990) The effects of subacute and subchronic oral exposure to cis-l,2-dichloroethylene in rats. Health Effects Research Laboratory, U.S. Environmental Protection Agency, Cincinnati, OH and Toxic Hazards Division, Air Force Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, OH; unpublished report. McCauley, PT; Robinson, M; Daniel, FB; et al. (1995) The effects of subacute and subchronic oral exposure to cis-l,2-dichloroethylene in Sprague-Dawley rats. Drug Chem Toxicol 18:171-184. NTP (National Toxicology Program). (1991a) Range finding studies: developmental toxicity 1,2-dichloroethylene when administered via feed in Swiss CD-I mice. Public Health Service, U.S. Department of Health and Human Services; NTP TRP 91022. Available from the National Institute of Environmental Health Sciences, Research Triangle Park, NC. NTP (National Toxicology Program). (1991b) Range finding studies: developmental toxicity 1,2-dichloroethylene when administered via feed in CD Sprague-Dawley rats. Public Health Service, U.S. Department of Health and Human Services; NTP TRP 91032. Available from the National Institute of Environmental Health Sciences, Research Triangle Park, NC. NTP (National Toxicology Program). (1991c) Range finding studies: developmental toxicity 1,2-dichloroethylene (repeat) when administered via feed in CD Sprague-Dawley rats. Public Health Service, U.S. Department of Health and Human Services; NTP TRP 91033. Available from the National Institute of Environmental Health Sciences, Research Triangle Park, NC. U.S. EPA (Environmental Protection Agency). (2000) Benchmark Dose Technical Guidance Document. External review draft. EPA/63O/R-00/001. Available online at http://www.epa.gov/iris/backgr-d.htm. U.S. EPA (Environmental Protection Agency). (2010) Integrated Risk Information System (IRIS). Office of Research and Development. National Center for Environmental Assessment, Washington, DC. Examined Dec. 2010. Available online at http://www.epa.gov/iris/. Accessed 2010. 7 cis-1,2-Dichloroethylene ------- |