United States Environmental Protection 1=1 m m Agency EPA/690/R-11/034F Final 3-23-2011 Provisional Peer-Reviewed Toxicity Values for ?7-Methyl Dicyclohexylamine (CASRN 7560-83-0) 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 Scott C. Wesselkamper, 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). ------- TABLE OF CONTENTS COMMONLY USED ABBREVIATIONS ii BACKGROUND 1 HISTORY 1 DISCLAIMERS 1 QUESTIONS REGARDING PPRTVS 2 INTRODUCTION 2 REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NON-CANCER) 3 DERIVATION 01 PROVISIONAL VALUES 4 CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 4 MODE-OF-ACTION DISCI SSION 4 REFERENCES 4 l ------- 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 11 ------- FINAL 3-23-2011 PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR ft-METHYL DICYCLOHEXYLAMINE (CASRN 7560-83-0) 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 provisional toxicity values receive internal review by a panel of six EPA scientists and external peer review by three independently selected scientific experts. 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 1 //-Methyl Dicyclohexylamine ------- FINAL 3-23-2011 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 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 No reference dose (RfD), reference concentration (RfC), or cancer assessment for //-methyl dicyclohexylamine is included in the IRIS database (U.S. EPA, 2010b) or on the Drinking Water Standards and Health Advisories List (U.S. EPA, 2009). No RfD or RfC values are reported in the HEAST (U.S. EPA, 2010a). The Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1994) does not include a Health and Environmental Effects Profile (HEEP) for //-methyl dicyclohexylamine. The toxicity of //-methyl dicyclohexylamine has not been reviewed by the ATSDR (2010) or the World Health Organization (WHO, 2010). CalEPA (2008, 2009a,b) has not derived toxicity values for exposure to //-methyl dicyclohexylamine. No occupational exposure limits for //-methyl dicyclohexylamine have been derived by the American Conference of Governmental Industrial Hygienists (ACGIH, 2010), the National Institute of Occupational Safety and Health (NIOSH, 2005), or the Occupational Safety and Health Administration (OSHA, 2010). The HEAST (U.S. EPA, 2010a) does not report any values for «-methyl dicyclohexylamine. //-Methyl dicyclohexylamine has not been evaluated under the Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005). The International Agency for Research on Cancer (IARC, 2010) has not reviewed the carcinogenic potential of //-methyl dicyclohexylamine. //-Methyl dicyclohexylamine is not included in the 11th Report on Carcinogens (NTP, 2005). CalEPA (2009c,d) has not prepared a quantitative estimate of carcinogenic potential for //-methyl dicyclohexylamine. Literature searches were conducted on sources published from 1900 through October 8, 2010, for studies relevant to the derivation of provisional toxicity values for 2 //-Methyl Dicyclohexylamine ------- FINAL 3-23-2011 //-methyl dicyclohexylamine, CAS No. 7560-83-0. Searches were conducted using EPA's Health and Environmental Research Online (HERO) evergreen 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, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW, EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS. REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NON-CANCER) The literature search revealed no usable human or animal studies (acute-, short term-, subchronic-, or chronic-duration) for development of toxicity values for //-methyl dicyclohexylamine. In an unpublished inhalation study by McGregor et al. (1981), dominant lethal and cytogenetic tests were conducted in CD rats, and a sperm abnormality test was conducted in B6C3Fi mice. Briefly, male and female CD rats and male B6C3Fi mice (30/sex/group) were exposed to //-methyl dicyclohexylamine (98% purity) through whole-body inhalation exposure at 0, 5, or 25 ppm (0, 40, or 200 mg/m3), 7 hours/day, for 5 consecutive days. A single-exposure cytogenetic test was also conducted in male and female CD rats (10/sex/group) employing 0, 5, or 20 ppm (0, 40, or 160 mg/m3) for 7 hours. There were no signs of dominant lethal mutation inducing potential or anti-fertility effects in male rats, nor did inhalation exposure to //-methyl dicyclohexylamine increase the frequency of aberrant cells in rat bone marrow. Additionally, there were no effects upon the frequency of abnormal sperm in mice. The study authors qualitatively reported that both mice and rats showed signs of severe -3 systemic toxicity during exposure to 200 or 160 mg/m , including reduced response to auditory stimuli, subdued behavior, nervous system effects (e.g., ataxia, convulsions), and mortality (in mice). However, due to their qualitative nature, these study data cannot be used to develop toxicity values. 3 //-Methyl Dicyclohexylamine ------- FINAL 3-23-2011 DERIVATION OF PROVISIONAL VALUES Limitations in the available data preclude development of both cancer and noncancer toxicity values for //-methyl dicyclohexylamine. CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR Limitations in the available data preclude development of a WOE descriptor. MODE-OF-ACTION DISCUSSION Limitations in the available data preclude determination of a mode-of-action discussion. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). (2010) Threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, Ohio. As cited in HSDB (Hazardous Substances Data Bank). Available online at http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7HSDB. Accessed on 10/8/2010. ATSDR (Agency for Toxic Substances and Disease Registry). (2010) 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 10/8/2010. 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.gov/air/ allrels.html. Accessed on 10/8/2010. CalEPA (California Environmental Protection Agency). (2009a) OEHHA/ARB approved chronic reference exposure levels and target organs. Office of Environmental Health Hazard, Sacramento, CA. Available online at http://www.arb.ca.gov/toxics/healthval/chronic.pdf. Accessed on March 8, 2011. CalEPA (California Environmental Protection Agency). (2009b) OEHHA toxicity criteria database. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gOv/risk//ChemicalDB/index.asp. Accessed on 10/8/2010. 4 //-Methyl Dicyclohexylamine ------- FINAL 3-23-2011 CalEPA (California Environmental Protection Agency). (2009c) 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/pdf/CPFs042909.pdf. Accessed on 10/8/2010. CalEPA (California Environmental Protection Agency). (2009d) Hot spots unit risk and cancer potency values. Appendix A. Office of Environmental Health Hazard Assessment, California, CA. Available online at http://www.oehha.ca.gov/air/hot_spots/2009/AppendixA.pdf. Accessed on 10/8/2010. IARC (International Agency for Research on Cancer). (2010) IARC Monographs on the evaluation of carcinogenic risks to humans. Available online at http://monographs.iarc.fr/ENG/ Monographs/PDFs/index.php. Accessed on 10/8/2010. McGregor, DB. (1981). Tier II mutagenic screening of 13 NIOSH priority compounds. Individual compound report «-methyl dicyclohexylamine, Report No. 36. National Institute for Occupational Safety and Health (NIOSH), Cincinnati, OH. Available online at http://www.ntis.gov/search/product.aspx?ABBR=PB83126607. Accessed on 2/18/2011. NIOSH (National Institute for Occupational Safety and Health). (2005) NIOSH pocket guide to chemical hazards. Centers for Disease Control and Prevention, Atlanta, GA. Index by CASRN. Available online at http://www.cdc.gov/niosh/npg/npgdcas.html. Accessed on 10/8/2010. NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. 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/tocl 1.html. Accessed on 10/8/2010. OSHA (Occupational Safety and Health Administration). (2010) Air contaminants: occupational safety and health standards for shipyard employment, subpart Z, toxic and hazardous substances. U.S. Department of Labor, Washington, DC. OSHA Standard 1915.1000. Available online at http://www.osha.gov/pls/oshaweb/owadisp.show_document7p_ table=STANDARDS&p_id=10286. Accessed on 10/8/2010. U.S. EPA (Environmental Protection Agency). (1986) Guidelines for carcinogen risk assessment. Prepared by the Risk Assessment Forum, U.S. Environmental Protection Agency. Washington, DC. Available online at http://www.epa.gov/raf/publications/pdfs/CA%20 GUIDELINE S_1986 PDF U.S. EPA (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.cgi?Dockey= 60001G8L.txt. 5 //-Methyl Dicyclohexylamine ------- FINAL 3-23-2011 U.S. EPA (Environmental Protection Agency). (2005) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register 70(66): 17765-17817. Available online at http://www.epa.gov/raf/publications/pdfs/ CANCER_GUIDELINES_FINAL_3 -25-05 PDF U.S. EPA (Environmental Protection Agency). (2009) 2009 edition of the drinking water standards and health advisories. Office of Water, Washington, DC; EPA 822-R-06-013. Available online at http://www.epa.gov/waterscience/drinking/standards/dwstandards2009.pdf. Accessed on 10/8/2010. U.S. EPA (Environmental Protection Agency). (2010a) Health effects assessment summary tables (HEAST). Office of Research and Development, National Center for Environmental Assessment, Cincinnati, Ohio: For the Office of Emergency and Remedial Response, Washington, DC; EPA 540-R-97-036. Available online at http://epa-heast.ornl.gov/. Accessed on 10/8/2010. U.S. EPA (Environmental Protection Agency). (2010b) 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 10/8/2010. WHO (World Health Organization). (2010) Online catalogs for the Environmental Health Criteria Series. Available online at http://www.who.int/ipcs/publications/ehc/en/. Accessed on 10/8/2010. 6 //-Methyl Dicyclohexylamine ------- |