United States Environmental Protection 1=1 m m Agency EPA/690/R-15/006F Final 9-03-2015 Provisional Peer-Reviewed Toxicity Values for 1,1 -Dichloropropene (CASRN 563-58-6) 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 Dan D. Petersen, PhD, DABT National Center for Environmental Assessment, Cincinnati, OH DRAFT DOCUMENT PREPARED BY National Center for Environmental Assessment, Cincinnati, OH This document was externally peer reviewed under contract to Eastern Research Group, Inc. 110 Hartwell Avenue Lexington, MA 02421-3136 Questions regarding the contents of this document may be directed to the U.S. EPA Office of Research and Development's National Center for Environmental Assessment, Superfund Health Risk Technical Support Center (513-569-7300). li 1,1 -Dichloropropene ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS AND ACRONYMS iv BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVs 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 4 DERIVATION 01 PROVISIONAL VALUES 5 DERIVATION 01 ORAL REFERENCE DOSES 5 Feasibility of Deriving Subchronic and Chronic p-RfDs 5 DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 5 Feasibility of Deriving Subchronic and Chronic p-RfCs 5 CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 5 MODE-OF-ACTION (MOA) DISCUSSION 5 ALTERNATIVE METHODS 5 REFERENCES 7 in 1,1 -Dichloropropene ------- COMMONLY USED ABBREVIATIONS AND ACRONYMS a2u-g alpha 2u-globulin MN micronuclei ACGIH American Conference of Governmental MNPCE micronucleated polychromatic Industrial Hygienists erythrocyte AIC Akaike's information criterion MOA mode of action ALD approximate lethal dosage MTD maximum tolerated dose ALT alanine aminotransferase NAG N-acetyl-P-D-glucosaminidase AST aspartate aminotransferase NCEA National Center for Environmental atm atmosphere Assessment ATSDR Agency for Toxic Substances and NCI National Cancer Institute Disease Registry NOAEL no-observed-adverse-effect level BMD benchmark dose NTP National Toxicology Program BMDL benchmark dose lower confidence limit NZW New Zealand white (rabbit breed) BMDS benchmark dose software OCT ornithine carbamoyl transferase BMR benchmark response ORD Office of Research and Development BUN blood urea nitrogen PBPK physiologically based pharmacokinetic BW body weight PCNA proliferating cell nuclear antigen CA chromosomal aberration PND postnatal day CAS chemical abstracts service POD point of departure CASRN chemical abstracts service registry PODadj duration-adjusted POD number QSAR quantitative structure-activity CBI covalent binding index relationship CHO Chinese hamster ovary (cell line cells) RBC red blood cell CL confidence limit RDS replicative DNA synthesis CNS central nervous system RfC inhalation reference concentration CPN chronic progressive nephropathy RfD oral reference dose CYP450 cytochrome P450 RGDR regional gas dose ratio DAF dosimetric adjustment factor RNA ribonucleic acid DEN diethylnitrosamine SAR structure activity relationship DMSO dimethylsulfoxide SCE sister chromatid exchange DNA deoxyribonucleic acid SD standard deviation EPA Environmental Protection Agency SDH sorbitol dehydrogenase FDA Food and Drug Administration SE standard error FEVi forced expiratory volume of 1 second SGOT glutamic oxaloacetic transaminase, also GD gestation day known as AST GDH glutamate dehydrogenase SGPT glutamic pyruvic transaminase, also GGT y-glutamyl transferase known as ALT GSH glutathione SSD systemic scleroderma GST glutathione-S-transferase TCA trichloroacetic acid Hb/g-A animal blood-gas partition coefficient TCE trichloroethylene Hb/g-H human blood-gas partition coefficient TWA time-weighted average HEC human equivalent concentration UF uncertainty factor HED human equivalent dose UFa interspecies uncertainty factor i.p. intraperitoneal UFh intraspecies uncertainty factor IRIS Integrated Risk Information System UFS subchronic-to-chronic uncertainty factor IVF in vitro fertilization UFd database uncertainty factor LC50 median lethal concentration U.S. United States of America LD50 median lethal dose WBC white blood cell LOAEL lowest-observed-adverse-effect level iv 1,1 -Dichloropropene ------- Final 09-03-2015 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR 1,1-DICHLOROPROPENE (CASRN 563-58-6) BACKGROUND A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant scientific literature using established Agency guidance on human health toxicity value derivations. All PPRTV assessments receive internal review by a standing panel of National Center for Environment Assessment (NCEA) scientists and an independent external peer review by three scientific experts. The purpose of this document is to provide support for the hazard and dose-response assessment pertaining to chronic and subchronic exposures to substances of concern, to present the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to characterize the overall confidence in these conclusions and toxicity values. It is not intended to be a comprehensive treatise on the chemical or toxicological nature of this substance. The PPRTV review process provides needed toxicity values in a quick turnaround timeframe while maintaining scientific quality. PPRTV assessments are updated approximately on a 5-year cycle for new data or methodologies that might impact the toxicity values or characterization of potential for adverse human health effects and are revised as appropriate. It is important to utilize the PPRTV database flittp://hhpprtv.ornl.gov) to obtain the current information available. When a final Integrated Risk Information System (IRIS) assessment is made publicly available on the Internet (http://www.epa.eov/iris). the respective PPRTVs are removed from the database. DISCLAIMERS The PPRTV document provides toxicity values and information about the adverse effects of the chemical and the evidence on which the value is based, including the strengths and limitations of the data. All users are advised to review the information provided in this document to ensure that the PPRTV used is appropriate for the types of exposures and circumstances at the site in question and the risk management decision that would be supported by the risk assessment. Other U.S. Environmental Protection Agency (EPA) programs or external parties who may choose to use PPRTVs are advised that Superfund resources will not generally be used to respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program. This document has been reviewed in accordance with U.S. EPA policy and approved for publication. Mention of trade names or commercial products does not constitute endorsement or recommendation for use. QUESTIONS REGARDING PPRTVs Questions regarding the contents and appropriate use of this PPRTV assessment should 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). 1 1,1 -Dichloropropene ------- Final 09-03-2015 INTRODUCTION 1,1-Dichloropropene (1,1-DCPe) (CASRN 563-58-6) is an industrial chemical found at some Superfund sites. No repeat-dose studies are available in the scientific literature on which to base a hazard identification or a dose-response evaluation for the derivation of toxicity values. The related compound 1,3-dichloropropene is used as a pesticide, while the other four dichloropropenes have no reported uses and are present in lower concentrations (ATSDR. 2008). 1,1-DCPe is on the Tox 21 list [10,000 chemicals, U.S. EPA (2015b)1 currently undergoing in vitro toxicity testing. The molecular formula of 1,1-DCPe is C3H4CI2 (see Figure 1). A list of physicochemical properties is provided in Table 1. CI Figure 1. 1,1-Dichloropropene Structure Table 1. Physicochemical Properties of 1,1-Dichloropropene (CASRN 563-58-6)a Property (unit) Value Boiling point (°C) 76.5 Melting point (°C) ND Density (g/cm3 at 20°C) ND Vapor pressure (lmnHg at 20°C) 90.8 pH (unitless) ND Solubility in water (mg/L at 25 °C) 749 Relative vapor density (air = 1) ND Molecular weight (g/mol) 110.97 aChemIDplus (2015). ND = no data. Table 2 provides a summary of available toxicity values for 1,1-DCPe (CASRN 563-58-6) from U.S. EPA and other regulatory agencies or organizations. 2 1,1 -Dichloropropene ------- Final 09-03-2015 Table 2. Summary of Available Toxicity Values for 1,1-Dichloropropene (CASRN 563-58-6) Sou rce/Parameterab Value (applicability) Reference Noncancer ACGIH NV ACGIH (2015) ATSDR NV ATSDR (2015) Cal/EPA NV Cal/EPA (2015b): Cal/EPA (2014) NIOSH NV NIOSH (2015) OSHA NV OSHA (2011): OSHA (2006) IRIS NV U.S. EPA (2015a) DWSHA NV U.S. EPA (2012) HEAST NV U.S. EPA (2011) CARA HEEP NV U.S. EPA (1994) WHO NV WHO (2015) Cancer IRIS NV U.S. EPA (2015a) HEAST/WOE NV U.S. EPA (2011) IARC NV IARC (2015) NTP NV NTP (2014) Cal/EPA NV Cal/EPA (2015a): Cal/EPA (2011) aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; CARA = Chemical Assessments and Related Activities; DWSHA = Drinking Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables; HEEP = Health and Environmental Effects Profile; IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information Systems; NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; WHO = World Health Organization. ' Parameters: WOE = cancer weight of evidence (U.S. EPA. 1986). NV = not available. Literature searches were conducted on sources published from 1900 through April 2015 for studies relevant to the derivation of provisional toxicity values for 1,1-DCPe (CASRN 563-58-6). Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO) database of scientific literature. HERO searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR: Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through the National Service Center for Environmental Publications [NSCEP] and National Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET 3 1,1 -Dichloropropene ------- Final 09-03-2015 (Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC, EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER, LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and TSCATS; Virtual Health Library; Web of Science (searches Current Content database among others); World Health Organization; and Worldwide Science. The following databases outside of HERO were searched for toxicity values: ACGIH, ATSDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) The available data on 1,1-DCPe (CASRN 563-58-6) primarily focuses on its biodegradation, biotransformation by soil organisms, and use in the development of analytical methods. 1,1-DCPe is a contaminant in some drinking water sources. Because of this and the fact that no toxicological data were available for this compound, which is structurally similar to the rodent carcinogen 1,3-dichloropropene (1,3-DCPe), 1,1-DCPe was placed on the EPA's Contaminant Candidate List. No information is available on repeated-dose oral or inhalation exposure of humans or animals to 1,1-DCPe. A genetic toxicology study was conducted in several Salmonella strains (Granville et at.. 2005). The study evaluated mutagenicity using the Salmonella assay, the deoxyribonucleic acid (DNA) damage (comet assay), and the apoptotic (caspase assay) activities in human lymphoblastoid cells. In Salmonella, 1,1-DCPe was not mutagenic in strains TA98, TA100, TA1535, or TA104 ±S9 mix. However, it was clearly mutagenic in strain RSJ 100, which expresses the rat GSTT1-1 gene. 1,1-DCPe did not induce DNA damage in GSTTl-l-deficient human lymphoblastoid cells, and it induced apoptosis in these cells only at 5 mM. Consistent with its mutagenesis in RSJ 100, 1,1-DCPe reacted with glutathione (GSH) in vitro, suggesting an addition-elimination mechanism to account for the detected GSH conjugate. 1,1-DCPe was approximately 5,000 times more mutagenic than 1,1 -dichloroethylene (1,1-DCE). Neither 1,1-DCE nor 1,3-DCPe showed enhanced mutagenicity in strain RSJ 100, indicating a lack of activation of these congeners by GSTT1-1. Thus, 1,1-DCPe appears to be a base-substitution mutagen, requiring activation by GSTT1-1, and possibly involving the production of a reactive episulfonium ion. This bioactivation mechanism of 1,1-DCPe is thus different from that of its congeners 1,1-DCE and 1,3-DCPe. 1,1-DCPe also has caused genotoxicity in fish (Winn et aL 2006). It is being tested as part of Tox 21, and is in the NTP 1408 compound library. However, following EPA guidance, the available mechanistic studies do not provide endpoints that are currently usable for identifying a point of departure (POD). 4 1,1 -Dichloropropene ------- Final 09-03-2015 DERIVATION OF PROVISIONAL VALUES DERIVATION OF ORAL REFERENCE DOSES Feasibility of Deriving Subchronic and Chronic p-RfDs No sub chronic-duration, chronic-duration, developmental toxicity, reproductive toxicity, or carcinogenicity studies on 1,1-dichloropropene via the oral route were identified. Thus, no oral reference doses (RfDs) could be derived. However, as noted below, a computational toxicological surrogate approach was attempted. DERIVATION OF INHALATION REFERENCE CONCENTRATIONS Feasibility of Deriving Subchronic and Chronic p-RfCs No sub chronic-duration, chronic-duration, developmental toxicity, reproductive toxicity, or carcinogenicity studies on 1,1-dichloropropene via the inhalation route were identified. Thus, no inhalation reference doses (RfCs) could be derived. However, as noted below, a computational toxicological surrogate approach was attempted. CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR Limitations in the available data preclude development of a weight-of-evidence (WOE) descriptor. MODE-OF-ACTION (MOA) DISCUSSION Limitations in the available data preclude determination of a mode-of-action (MOA) discussion. ALTERNATIVE METHODS The surrogate approach allows for the use of data from related compounds to calculate screening values when data for the compound of interest are limited or unavailable. Details regarding searches and methods for surrogate analysis are presented in Wane et al. (2012). Three types of potential surrogates (structural, metabolic, and toxicity) are identified to facilitate the final surrogate chemical selection. The surrogate approach may or may not be route-specific or applicable to multiple routes of exposure. All information was considered together as part of the final weight-of-evidence (WOE) approach to select the most suitable surrogate both toxicologically and chemically. An initial surrogate search focused on the identification of structurally similar chemicals with toxicity values from the Integrated Risk Information System (IRIS), PPRTV, and Health Effects Assessment Summary Tables (HEAST) databases to take advantage of the well-characterized chemical-class information. This was accomplished by searching the US EPA's DSSTox database (DSSTox. 2012) at similarity levels >60%, and the National Library of Medicine's C hem 1 Dpi us database (ChcmlDplus. 2015) at similarity levels >70%. Both ChemlDplus (which uses 3D QSAR models) and DSSTox (which uses 2D QSAR models) identified an overlapping list of analogs (see Table 3). 5 1,1 -Dichloropropene ------- Final 09-03-2015 Table 3. Structural Analogues for 1,1-Dichloropropene Chemical Name Structural Similarity Information Source 1 -B ro mo -1 -chloropropene 90% CliemlDDlus (2015) 1,1 -Dibromopropene 88% 1,1 -Dichlorobutene 87% T richloroethylene 80% 1,1,2-Trichloropropene 77% 1,2 -Dichloro-1 -flouroethy lene 76% 2-Bromo-l, 1 -dichloroethylene 75% 1,1 -Dichloroethylene 74% 1-Chloropropene 80% DSSTox (2012) 1,1-DCE 70% Dimethylvinyl chloride 67% T etrachloroethylene 64% T richloroethylene 64% 1,3 -Dichloropropene 62% While there was in vivo repeat-dose information on some of these closely related compounds, including 1,1-DCE, 1,3-DCPe, tetrachloroethylene, and trichloroethylene, there was no data on the parent compound 1,1-DCPe to match health effects. The structurally closely related chemicals' toxicity profiles also showed no consistent pattern of target organ toxicity, as shown in Table 4. Due to a lack of matching repeat-dose toxicity information for any of the potential structural surrogates, derivation of risk values (e.g., RfD, RfC, and oral cancer slope factor [OSF]) based on the computational toxicological surrogate approach Wane et al. (2012) is not feasible for 1-DCPe. Table 4: The Target Organs and RfD of Potential Surrogates Potential Surrogate Chemical Target Organ RfD T richloroethylene Immune system 5 x 10 4 mg/kg-d T etrachloroethylene Nervous system 6 x 10 3 mg/kg-d 1,1-DCE Liver 5 x 10 2 mg/kg-d 1,3-DCPe Nasal respiratory epithelium chronic irritant 3 x 10 2 mg/kg-d 6 1,1 -Dichloropropene ------- Final 09-03-2015 REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). (2015). 2015 TLVs and BEIs. Based on documentation of the threshold limit values for chemical substances and physical agents and biological exposure indices. 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Research Triangle Park, NC: U.S. Department of Health and Human Services, Public Health Service, http://ntp.niehs.nih.gov/pubhealth/roc/rocl3/index.html 7 1,1 -Dichloropropene ------- Final 09-03-2015 OSHA (Occupational Safety & Health Administration). (2006). Table Z-l limits for air contaminants. Occupational safety and health standards, subpart Z, toxic and hazardous substances. (OSHA standard 1910.1000). Washington, DC: U.S. Department of Labor. http://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&p id=9992 OSHA (Occupational Safety & Health Administration). (201 1). Air contaminants: occupational safety and health standards for shipyard employment, subpart Z, toxic and hazardous substances. (OSHA Standard 1915.1000). Washington, DC: U.S. Department of Labor. http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=10286 U.S. EPA (U.S. Environmental Protection Agency). (1986). 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Geneva, Switzerland: World Health Organization (WHO). http://www.who.int/ipcs/publications/ehc/en/ Winn. RN; Norris. MB; I .othenbach. D; Flynn. K; Hammermeister. D; Whiteman. F; Sheedv. 6; Johnson. R. (2006). Sub-chronic exposure to 1,1 -dichloropropene induces frameshift mutations in lambda transgenic medaka. Mutat Res 595: 52-59. http ://dx. doi. org/10.1016/i .mrfmmm .2005.10.009 8 1,1 -Dichloropropene ------- |