United States kS^laMIjk Environmental Protection ^J^iniiil m11 Agency EPA/690/R-11/014F Final 3-25-2011 Provisional Peer-Reviewed Toxicity Values for 1 -Bromo-4-Ethylbenzene (CASRN 1585-07-5) 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). ------- 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 NONCANCER) 3 DERIVATION 01 PROVISIONAL VALUES 3 CANCER WOE DESCRIPTOR 3 MODE-OF -ACTION DISCUSSION 3 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 NOAELrec 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 3-25-2011 PROVISIONAL PEER-REVIEWED TOXICITY VALUES l-BROMO-4-ETHYLBENZENE (CASRN 1585-07-5) 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 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 1 -Bromo-4-Ethylbenzene ------- FINAL 3-25-2011 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 No Reference Dose (RfD), Reference Concentration (RfC), or cancer assessment for l-bromo-4-ethylbenzene 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, 201 la). The CARA list (U.S. EPA, 1994) does include a Health and Environmental Effects Profile (HEEP) for l-bromo-4-ethylbenzene (U.S. EPA, 1994) that declined to derive noncancer toxicity values due to inadequate noncancer data and potential carcinogenicity of the chemical. The toxicity of l-bromo-4-ethylbenzene has not been reviewed by the AT SDR (2010) or the World Health Organization (WHO, 2010). The CalEPA (2008, 2009a,b,c,d) has not derived toxicity values for exposure to l-bromo-4-ethylbenzene. No occupational exposure limits for l-bromo-4-ethylbenzene 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, 201 la) does not report an EPA (1986) cancer weight-of-evidence classification or an oral slope factor for l-bromo-4-ethylbenzene. l-Bromo-4-ethylbenzene 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 l-bromo-4-ethylbenzene. l-Bromo-4-ethylbenzene is not included in the 11th Report on Carcinogens (NTP, 2005). CalEPA (2009c,d) has not prepared a quantitative estimate of carcinogenic potential for 1 -bromo-4-ethylbenzene. Literature searches were conducted on sources published from 1900 through February 22, 2010, for studies relevant to the derivation of provisional toxicity values for l-bromo-4-ethylbenzene, CAS No. 1585-07-5. Searches were conducted using EPA's Health and Environmental Research Online (HERO) evergreen database of scientific literature. HERO 2 1 -Bromo-4-Ethylbenzene ------- FINAL 3-25-2011 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 NONCANCER) The literature search revealed no human or animal studies of acute-, short-term-, or chronic duration for l-bromo-4-ethylbenzene. 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 weight-of-evidence descriptor. MODE-OF-ACTION DISCUSSION A study by Toranzo et al. (1977) examined the toxic effects of substituted bromobenzenes on the liver of rats. Specifically, male Holtzman rats received ip injections of a series of ortho-substituted bromobenzes—including o-bromoethylbenzene—and were sacrificed 24 hours later at which time livers were removed. Four rats were treated with o-bromoethylbenzene at a dose of 0.15 ml/kg (unknown purity) while six rats were received an ip injection of sesame oil (unknown purity), representing the control group. The study authors 3 1 -Bromo-4-Ethylbenzene ------- FINAL 3-25-2011 determined o-bromoethylbenzene to be hepatotoxic as indicated by the presence of necrotic lesions in the liver. The study authors suggested that the toxic liver effects of o-bromoethylbenzene were due to its metabolism to a reactive metabolite. An in vitro study by Gottschall et al. (1983) determined the toxicity of ortho-substituted bromobenzenes on hepatocytes. Specifically, rat hepatocytes were incubated with various derivatives of bromobenzenes—including o-bromoethylbenzene—for 2-4 hours at various concentrations. o-Bromoethylbenzene was tested at concentrations of 1.5 and 2.5 millimolar. By monitoring changes in indices of toxicity (e.g., intracellular potassium, etc), study authors determined that o-bromoethylbenzene was the most hepatotoxic of the deritaves tested. Gottschall et al. (1983) suggested that the observed liver toxicity was most likely due to a reactive metabolite formed during the metabolism of o-bromoethylbenzene. These studies (i.e., Toranzo et al. 1977 and Gottschall et al. 1983) provide information on a possible mode of action for o-bromoethylbenzene-induced toxicity. However, these studies cannot be used for derivation of a reference value because they do not provide repeated-dose toxicity information. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). (2010) Threshold limit values for chemical substances and physical agents and biological exposure indices. Cincinnati, OH. As cited in HSDB (Hazardous Substances Data Bank). Available online at http://toxnet.nlm.nih.eov/cei-bin/sis/htmleen7HSDB. Accessed on October 4, 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.eov/toxprofiles/index.asp. Accessed on October 4, 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.eov/air/allrels.html. CalEPA (California Environmental Protection Agency). (2009a) OEHHA/ARB approved chronic reference exposure levels and target organs. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.arb.ca.eov/toxics/healthval/chronic.pdf. CalEPA (California Environmental Protection Agency). (2009b) OEHHA Toxicity Criteria Database. Office of Environmental Health Hazard Assessment (OEHHA), Sacramento, CA. Available online at http://www.oehha.ca.eov/riskAChemicalDB/index.asp. Accessed on October 12, 2010. 4 1 -Bromo-4-Ethylbenzene ------- FINAL 3-25-2011 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/TSDlookup2002.pdf. CalEPA (California Environmental Protection Agency). (2009d) Technical support document for describing available cancer potency factors. Appendix I. Office of Environmental Health Hazard Assessment, Sacramento, CA. Available online at http://www.oehha.ca.gov/air/hot spots/pdf/Appendix%20I2002.pdf. Gottschall DW, Wiley RA, Hanzlik RP. (1983) Toxicity of ortho-substituted bromobrenzenes to isolated hepatocytes: comparison to in vivo results. Toxicol Appl Pharmacol. 69(l):55-65. IARC (International Agency for Research on Cancer). (2010) Agents classified by the IARC monographs, volumes 1-100. IARC monographs on the evaluation of carcinogenic risks to humans. Available online at http://monographs.iarc.fr/ENG/Classification/ClassificationsCASOrder.pdf. Accessed on October 4, 2010. NIOSH (National Institute for Occupational Safety and Health). (2005) NIOSH pocket guide to chemical hazards. Index by CASRN. Available online at http://www.cdc.gov/niosh/npg/npgdcas.html. Accessed on October 4, 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-server.niehs.nih.gov/index.cfm?obiectid= 32BA9724-F1F6-975E-7FCE50709CB4C932. Accessed on October 4, 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 document?p table=STANDARDS&p id=102 86. Toranzo, EG; Gillesse, T; Mendenhall, M; et al. (1977) Effect of substituents on arene oxide- mediated liver toxicity among substituted bromobenzenes. Toxicol Appl Pharmacol 40(3):415-425. 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%20GUIDELINES 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 http://nepis.epa. gov/Exe/ZyPURL.cgi?Dockev=6000 lG8L.txt. 5 1 -Bromo-4-Ethylbenzene ------- FINAL 3-25-2011 U.S. EPA (Environmental Protection Agency). (2005) Guidelines for carcinogen risk assessment. Risk Assessment Forum, Washington, D.C.; 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 October 12, 2010. U.S. EPA (Environmental Protection Agency). (201 la) 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; EPA 540-R-97-036. Available online at http://epa-heast.ornl.gov/. Accessed on October 4, 2010. U.S. EPA (Environmental Protection Agency). (201 lb) 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 October 4, 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 October 4, 2010. 6 1 -Bromo-4-Ethylbenzene ------- |