United States Environmental Protection 1=1 m m Agency EPA/690/R-12/013F Final 3-20-2012 Provisional Peer-Reviewed Toxicity Values for O, (9-Diethyl phosphorodithioate (CASRN 298-06-6) 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 J. Phillip Kaiser, PhD, 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). l 0,0-Diethyl phosphorodithioate ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS iii BACKGROUND 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVS 1 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) 3 DERIVATION 01 PROVISIONAL VALUES 4 CANCER WOE DESCRIPTOR 4 MODE-OF-ACTION DISCUSSION 4 REFERENCES 4 li 0,0-Diethyl phosphorodithioate ------- 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 111 0,0-Diethyl phosphorodithioate ------- FINAl 3-20-2012 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR 6>,6>-DIETHYL PHOSPHORODITHIOATE (CASRN 298-06-6) 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 (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 (9,0-Diethyl phosphorodithioate ------- FINAl 3-20-2012 INTRODUCTION No reference dose (RfD), reference concentration (RfC), or cancer assessment for 0,0-diethyl phosphorodithioate is included in the U.S. Environmental Protection Agency (U.S. EPA) Integrated Risk Information System (IRIS) (U.S. EPA, 201 la) or on the Drinking Water Standards and Health Advisories List (U.S. EPA, 201 lb). The Health Effects Assessment Summary Tables (HEAST) (U.S. EPA, 201 lc) does not report any RfD or RfC values. The Chemical Assessments and Related Activities (CARA) list does not include any EPA documents for 0,0-diethyl phosphorodithioate (U.S. EPA, 1994). The toxicity of 0,0-diethyl phosphorodithioate has not been reviewed by the Agency for Toxic Substances and Disease Registry (ATSDR, 2011) or the World Health Organization (WHO, 2011). The California Environmental Protection Agency (CalEPA, 2008, 2011) has not derived toxicity values for exposure to 0,0-diethyl phosphorodithioate. No occupational exposure limits for 0,0-diethyl phosphorodithioate have been derived or recommended by the American Conference of Governmental Industrial Hygienists (ACGIH, 2011), the National Institute for Occupational Safety and Health (NIOSH, 2007), or the Occupational Safety and Health Administration (OSHA, 2006). The HEAST (U.S. EPA, 201 lc) does not report a U.S. EPA (1986) cancer weight-of- evidence (WOE) classification of 0,0-diethyl phosphorodithioate. The International Agency for Research on Cancer (IARC, 2011) has not reviewed the carcinogenic potential of 0,0-diethyl phosphorodithioate. 0,0-Diethyl phosphorodithioate is not included in the 12th Report on Carcinogens (NTP, 2011). CalEPA (2009) has not prepared a quantitative estimate of the carcinogenic potential of 0,0-diethyl phosphorodithioate. Literature searches were conducted on sources published from 1900 through September 2011 for studies relevant to the derivation of provisional toxicity values for 0,0-diethyl phosphorodithioate, CAS No. (298-06-6). 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 (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 risk assessment values: ACGIH, ATSDR, CalEPA, 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. 2 0,0-Diethyl phosphorodithioate ------- FINAl 3-20-2012 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER) No information is available regarding repeat-dose human or animal studies of short-term or chronic duration for 0,0-diethyl phosphorodithioate. There are a limited number of acute-duration animal studies for 0,0-diethyl phosphorodithioate that are summarized in Table 1. However, these studies cannot be used for derivation of a reference value because they do not provide repeat-dose toxicity information. Table 1. Summary of Acute Toxicity Data for 0,0-Diethyl Phosphorodithioate (CASRN 298-06-6) Category Number of Male/Female, Strain, Species, Study Type, Study Duration Dosimetry Effects Reference (Comments) Human 1. Oral (mg/kg-day) No studies were located. 2. Inhalation (mg/m3) No studies were located. Animal 1. Oral (mg/kg) Acute 10/10, Sprague-Dawley rat, single gavage followed by a 14-day observation period 1260, 1580, 2000, or 2510 Weight loss, mortality, increasing weakness, collapse, hemorrhagic lungs, liver discoloration, and acute gastrointestinal inflammation Information from IUCLID (2007); Primary reference for this study is not available 10/10, Sprague-Dawley rat, single gavage 316,398, 501, or 631 Tremors, salivation, dyspnea, increasing weakness, and inflammation of the gastric mucosa with renal and liver hyperemia Information from IUCLID (2007); Primary reference for this study is not available 2. Inhalation (mg/L) Acute 30/30, Sprague-Dawley rat, 4 hours followed by a 14-day observation period 0.98, 1.02, 10.4, 1.35, 1.60, or 2.10 Cholinesterase inhibition;, clear nasal discharge; lacrimation; breathing difficulties; hypoactivity; fur discoloration; breathing difficulties; chromodacryorrhea around the mouth, nose, and eyes; weight loss; mortality; tremors; petechial hemorrhage of the thymus and lungs; alopecia Information from IUCLID (2007); Primary reference for this study is not available 6/0, Sprague-Dawley rat, 6 hours followed by a 14-day observation period 0.7 Mortality, ocular erythema, increasing weakness , tremors, nasal bleeding, and hemorrhagic lungs Information from IUCLID (2007); Primary reference for this study is not available 3 0,0-Diethyl phosphorodithioate ------- FINAl 3-20-2012 DERIVATION OF PROVISIONAL VALUES Limitations in the available data preclude development of cancer and noncancer toxicity values. CANCER WOE DESCRIPTOR Limitations in the available data preclude development of a WOE descriptor. MODE-OF-ACTION DISCUSSION Mutagenicity studies of diethyl phosphorodithioate, technical grade (92%) or the sodium salt, were conducted by FMC Corporation (1985, 1986, 1987) using the Ames assay with or without S-9 metabolic activation at doses ranging from 50 |ig to 1000 |ig per plate. Technical grade diethyl phosphorodithioate was mutagenic in Salmonella typhimurium strain TA1535; the mutagenic response was nearly twice as great without activation (41-fold increase with 1000 |ig/plate over solvent controls versus 23.9-fold increase with activation). A repeat experiment produced quantitatively similar results, suggesting that the chemical is detoxified by oxidative metabolism. A positive response was also observed in strain TA100 without activation, although it was of lesser magnitude. No increase in revertant colonies, either with or without metabolic activation, was observed in strains TA98, TA1537, or TA1538, which are sensitive to frame-shift mutagens. No positive responses with the sodium salt of diethyl phosphorodithioate were observed with or without metabolic activation in any of the five strains tested (i.e., TA98, TA100, TA1535, TA1537, TA1538). These studies (i.e., FMC Corporation, 1985, 1986, 1987) provide information on a possible mode of action for 0,0-diethyl phosphorodithioate-induced toxicity. However, these studies cannot be used for derivation of a reference value because they do not provide repeat-dose toxicity information. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). (2011) 2011 TLVs and BEIs: Based on the documentation of the threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH: ACGIH. Available online at http://www.acgih.org/store/ProductDetail.cfm?id=2147. 783980. ATSDR (Agency for Toxic Substances and Disease Registry). (2011) Toxicological profile information sheet. U.S. Department of Health and Human Services, Public Health Service. Available online at http://www.atsdr.cdc.gov/toxprofiles/index.asp. Accessed on 09/22/2011. 684152. 4 (9,0-Diethyl phosphorodithioate ------- FINAl 3-20-2012 CalEPA (California Environmental Protection Agency). (2008) All OEHHA acute, 8-hour and chronic reference exposure levels (chRELs) as of December 18, 2008. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.eov/air/allrels.html. Accessed on 09/22/2011. 595416. CalEPA (California Environmental Protection Agency). (2009) Hot spots unit risk and cancer potency values. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/air/hot spots/2009/AppendixA.pdf. Accessed on 09/22/2011. 684164. CalEPA (California Environmental Protection Agency). (2011) OEHHA toxicity criteria database. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/tcdb. Accessed on 9/22/2011. 783987. FMC Corporation. (1985) Preliminary results of a Ames salmonella/microsome mutagenicity test with 0,0-diethyl phosphorodithioate with cover letter dated 12-02-85. Document I.D. FYIOTS-1285-0465. Microfiche No. OTS0000465-0. Available online at http ://www. nti s. gov/ search/Index. aspx. FMC Corporation. (1986) Salmonella/mammalian-microsome plate incorporation mutagenicity assay (Ames Test) for test articles FMC 87059 and FMC 1007 with cover letter dated 6-25-86. EPA Document No. FYI-OTS-0786-0465. NTIS OTS0000465-1. Available online at http ://www. nti s. gov/ search/Index. aspx. FMC Corporation. (1987) Salmonella/mammalian-microsome plate incorporation mutagenicity assay (Ames Test) with 0,0-diethyl phosphorodithioate with cover letter dated 7-31-87. Document I.D. FYI-OTS-0687-0465. Microfiche No. OTS0000465-2. Available online at http ://www. nti s. gov/ search/Index. aspx. IARC (International Agency for Research on Cancer). (2011) IARC monographs on the evaluation of carcinogenic risks to humans. Lyon, France: IARC. Available online at http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php. Accessed on 09/22/2011. 783869. IUCLID (International Uniform Chemical Information Database). (2007) 0,0-diethyl hydrogen phosphorodithioate. CAS No. 298-06-6. Available online at http://www.epa.gov/hpv/pubs/summaries/oodiphos/cl4864rr.pdf. Accessed on 1/4/2012. NIOSH (National Institute for Occupational Safety and Health). (2007) NIOSH pocket guide to chemical hazards. Index by CASRN. Available online at http://www.cdc.gov/niosh/docs/2005- 149/. Accessed on 09/22/2011. 192177. NTP (National Toxicology Program). (2011) Report on carcinogens, twelfth edition. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC. Available online at http://ntp.niehs.nih.gov/ntp/roc/twelfth/rocl2.pdf. Accessed on 9/22/2011. 737606. 5 (9,0-Diethyl phosphorodithioate ------- FINAl 3-20-2012 OSHA (Occupational Safety and Health Administration). (2006) Table Z-l limits for air contaminants: occupational safety and health standards, subpart Z, toxic and hazardous substances. U.S. Department of Labor, Washington, DC; OSHA Standard 1910.1000. Available online at http://63.234.227.130/pls/oshaweb/owadisp.show document?p table=STANDARDS& p id=9992. Accessed on 9/22/2011. 670067. U.S. EPA (U.S. Environmental Protection Agency). (1986) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/R-00/004. September 1986. Available online at http://epa.gov/raf/publications/pdfs/CA%20GUIDELINES 1986.PDF. 199530. U.S. EPA (U.S. Environmental Protection Agency). (1994) Chemical assessments and related activities (CARA). Office of Health and Environmental Assessment, Washington, DC; EPA/600/R-94/904. Available online at nepis.epa.gov/Exe/ZyPURL.cai?Dockey=6000lG8L.txt. 596444. U.S. EPA (Environmental Protection Agency). (201 la) Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Available online at http://www.epa.gov/iris/. Accessed on 9/22/2011. 003752. U.S. EPA (Environmental Protection Agency). (201 lb) 2011 Edition of the drinking water standards and health advisories. Office of Water, Washington, DC; EPA/820/R-11/002. Available online at http://water.epa.gov/action/advisories/drinking/drinking index.cfm. Accessed on 9/22/2011. 783978. U.S. EPA (Environmental Protection Agency). (201 lc) Health effects assessment summary tables (HEAST). 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. Available online at http://epa-heast.ornl.gov/. Accessed on 9/12/2011. 595422. WHO (World Health Organization). (2011) Online catalogs for the Environmental Health Criteria Series, WHO, Geneva, Switzerland. Available online at http://www.who.int/ipcs/publications/ehc/en/. Accessed on 9/22/2011. 783977. 6 (9,0-Diethyl phosphorodithioate ------- |