United States Environmental Protection 1=1 m m Agency EPA/690/R-13/006F Final 4-25-2013 Provisional Peer-Reviewed Toxicity Values for 2,2-Difluoropropane (CASRN 420-45-1) 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 CONTRIBUTOR Jon Reid, 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). ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS ii BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVs 1 INTRODUCTION 2 DERIVATION OF PROVISIONAL REFERENCE VALUES 7 ALTERNATIVE METHODS 7 CANCER WEIGHT OF EVIDENCE (WOE) DESCRIPTOR 7 REFERENCES 7 l 2,2-Difluoropropane ------- COMMONLY USED ABBREVIATIONS BMC benchmark concentration BMCL benchmark concentration lower bound 95% confidence interval BMD benchmark dose 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 POD point of departure p-OSF provisional oral slope factor p-RfC provisional reference concentration (inhalation) p-RfD provisional reference dose (oral) 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 11 2,2-Difluoropropane ------- FINAL 4-25-2013 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR 2,2-DIFLUOROPROPANE (CASRN 420-45-1) 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 (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. 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 2,2-Difluoropropane ------- FINAL 4-25-2013 INTRODUCTION 2,2-Difluoropropane (CASRN 420-45-1) is a gas that belongs to a class of chemicals called hydrofluorocarbons (HFCs) (British Columbia Ministry of Environment, 1999). HFCs were introduced to replace ozone-depleting substances such as CFCs (chlorofluorocarbons) (Blowers and Lownsbury, 2010) and are mainly used for refrigeration, air conditioning, and insulating foams, with minor uses in other applications such as fire protection systems and medical inhalers (Tsai, 2005). Table 1 provides physicochemical properties of 2,2-difluoropropane. Table 1. Physicochemical Properties of 2,2-Difluoropropane (CASRN 420-45-1)3 Property (unit) Value Boiling point (°C) -0.4 Melting point (°C) -105 "3 Density (g/cm ) 0.92 g/mL at 20°C Vapor pressure (Pa at 25°C) ND pH (unitless) ND Solubility in water (g/100 mL at 25°C) ND Relative vapor density (air =1) ND Molecular weight (g/mol) 80.0765 aChemIDplus (2011); Chemspider (2011). ND = no data. A summary of available relevant health information for 2,2-difluoropropane from U.S. EPA and other agencies/organizations is provided in Table 2. 2 2,2-Difluoropropane ------- FINAL 4-25-2013 Table 2. Summary of Available Toxicity Values for 2,2-Difluoropropane (CASRN 420-45-1) Source/Parameter" Value (Applicability) Notes Reference Date Accessed Cancer IRIS NV NA U.S. EPA (2011a) 4-25-2013 HEAST NV NA U.S. EPA (2011b) 4-25-2013 IARC NV NA IARC (2011) 4-25-2013 NTP NV NA NTP (2011) 4-25-2013 CalFPA NV NA CalEPA (2009) 4-25-2013 Noncancer ACGIH NV NA ACGIH (2011) 4-25-2013 ATSDR NV NA ATSDR (2011) 4-25-2013 CalEPA NV NA CalEPA (2008, 2011) 4-25-2013 NIOSH NV NA NIOSH (2007) 4-25-2013 OSHA NV NA OSHA (2006) 4-25-2013 IRIS NV NA U.S. EPA (2011a) 4-25-2013 Drinking water NV NA U.S. EPA (2011c) 4-25-2013 HEAST NV NA U.S. EPA (2011b) 4-25-2013 CARA HEEP NV NA U.S. EPA (1994) 4-25-2013 WHO NV NA WHO (2011) 4-25-2013 aSources: Integrated Risk Information System (IRIS) database; Health Effects Assessment Summary Tables (HEAST); International Agency for Research on Cancer (IARC); National Toxicology Program (NTP); California Environmental Protection Agency (CalEPA); American Conference of Governmental Industrial Hygienists (ACGIH); Agency for Toxic Substances and Disease Registry (ATSDR); National Institute for Occupational Safety and Health (NIOSH); Occupational Safety and Health Administration (OSHA); Chemical Assessments and Related Activities (CARA) list; Health and Environmental Effects Profile (HEEP); World Health Organization (WHO). NA = not applicable; NV = not available. Literature searches were conducted on sources published from 1900 through April 2013 for studies relevant to the derivation of provisional toxicity values for 2,2-difluoropropane, CASRN (420-45-1). 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: 3 2,2-Difluoropropane ------- FINAL 4-25-2013 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 (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 relevant health information: ACGM, AT SDR, CalEPA, U.S. EPA IRIS, U.S. EPAHEAST, U.S. EPA HEEP, U.S. EPA OW, U.S. EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. Table 3 provides an overview of the toxicity database for 2,2-difluoropropane and includes potentially relevant repeated short-term-, subchronic-, and chronic-duration studies. 4 2,2-Difluoropropane ------- FINAL 4-25-2013 Table 3. Summary of Potentially Relevant Data for 2,2-Difluoropropane (CASRN 420-45-1) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL BMDL/ BMCL LOAEL Reference Comments Human 1. Oral Acuteb ND Short-term0 ND Long-termd ND Chronic6 ND 2. Inhalation Acuteb ND Short-term0 ND Long-termd ND Chronic0 ND Animal 1. Oral Subchronic ND Chronic ND Developmental ND Reproductive ND Carcinogenic ND 2. Inhalation Subchronic ND Chronic ND Developmental ND 5 2,2-Difluoropropane ------- FINAL 4-25-2013 Table 3. Summary of Potentially Relevant Data for 2,2-Difluoropropane (CASRN 420-45-1) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry3 Critical Effects NOAEL BMDL/ BMCL LOAEL Reference Comments Reproductive ND Carcinogenic ND aDosimetry: NOAEL, BMDL/BMCL, and LOAEL values are converted to an adjusted daily dose (ADD in mg/kg-d) for oral noncancer effects and a human equivalent concentration (HEC in mg/m3) for inhalation noncancer effects. Values are converted to a human equivalent dose (HED in mg/kg-d) for oral carcinogenic effects and a HEC for inhalation carcinogenic effects. All long-term exposure values (4 wk and longer) are converted from a discontinuous to a continuous (weekly) exposure. Values from animal developmental studies are not adjusted to a continuous exposure. bAcute = exposure for <24 hr (U.S. EPA, 2002) °Short-term = Repeated exposure for >24 hr <30 d (U.S. EPA, 2002). dLong-term = Repeated exposure for >30 d <10% lifespan (based on 70 yr typical lifespan) (U.S. EPA, 2002). "Chronic = Repeated exposure for >10% lifespan (U.S. EPA, 2002). ND = no data. 6 2,2-Difluoropropane ------- FINAL 4-25-2013 DERIVATION OF PROVISIONAL REFERENCE VALUES As shown in Table 3, no information is available regarding repeat-dose human or animal studies of short-term, subchronic, or chronic duration for 2,2-difluoropropane by any route of exposure. Thus, limitations in the available data preclude development of cancer and noncancer provisional toxicity values. ALTERNATIVE METHODS An attempt was made to identify potential surrogate chemicals that could be used to predict the toxicity of 2,2-difluoropropane (details regarding searches and methods are presented in Wang et al. [2012]). Limited information exists about the toxicity of other HFCs (Tsai, 2005; Brock et al., 2000) that could be used as potential surrogates. Several related structural analogs were found; the two most structurally related analogs are 1,1-difluoroethane (CASRN 75-37-6) and difluoromethane (CASRN 75-10-5). These analogs are selected based on similarity in chemical structure, carbon number, and most importantly, the position of fluorine atoms. Other haloalkanes, such as 2,2-dichloropropane, exhibit significant similarity (91%). Unfortunately, no repeat-dose toxicity information was available for any of those potential surrogates and commonality in endpoints and/or toxic effects could not be identified. Toxicity data are also available on other hydrofluoropropanes, such as 1,1,1,3,3-pentafluoropropane and 1,1,1,3,3,3-hexafluoropropane. However, those chemicals would likely not serve as good surrogates for 2,2-difluoropropane due to differences in fluorine atom position, which is expected to affect the toxicity properties of these compounds. CANCER WEIGHT OF EVIDENCE (WOE) DESCRIPTOR No human or suitable animal data on the carcinogenicity of 2,2-difluoropropane were identified. U.S. EPA (201 la) has not classified the carcinogenic potential of 2,2-difluoropropane, and no other agencies have reviewed or classified the carcinogenic potential of this chemical (IARC, 2011; NTP, 2011; CalEPA, 2009). Furthermore, no studies regarding the genotoxicity and mutagenicity of 2,2-difluoropropane were identified. Thus, the cancer WOE descriptor for 2,2-difluoropropane is "inadequate information to assess carcinogenic potentiaF. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 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