United States Environmental Protection fm Agency EPA/690/R-04/003F Final 11-23-2004 Provisional Peer Reviewed Toxicity Values for /?-Bromofluorobenzene (CASRN 460-00-4) Derivation of Subchronic and Chronic Oral RfDs Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level 1 ------- MTD maximum tolerated dose MTL median threshold limit NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor Hg microgram |j,mol micromoles voc volatile organic compound 11 ------- 11-23-2004 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR p-BROMOFLUOROBENZENE (CASRN 460-00-4) Derivation of Subchronic and Chronic Oral RfDs Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) 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 (PPRTV) 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 Integrated Risk Information System (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 two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes request that a frequently used PPRTV be reassessed. 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 manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 11-23-2004 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 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. 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 manuscript 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 An RfD for/>-bromofluorobenzene (C6H4BrF) is not listed on IRIS (U.S. EPA, 2002a), the Drinking Water Standards and Health Advisories table (U.S. EPA, 2002b), or the HEAST (U.S. EPA, 1997). No pertinent documents are listed in the CARA database (U.S. EPA, 1991, 1994). A Drinking Water Toxicity Profile for /;-bromof1uorobcnzcnc (U.S. EPA, 1992) did not contain sufficient information supporting an RfD derivation. ATSDR (2002) has not published a toxicological profile for /;-bromof1uorobcnzcnc and this chemical was not listed in the NTP (2002) Management Status Reports. IARC (2002) and WHO (2002) have not published a review for /;-bromofluorobcnzcnc. No information pertinent to an RfD derivation for p-bromofluorobenzene was found in a review by Leber and Bus (2001). Literature searches of the following databases were conducted from 1994 to September 2002 for relevant studies: TOXLINE, MEDLINE, TSCATS, GENETOX, EMIC/EMICBACK, DART/ETICBACK, 2 ------- 11-23-2004 HSDB, RTECS, CCRIS, and BIOSIS. Previous literature searches of TOXLINE (1965-1994), TSCATS and RTECS were conducted in November 1994. An updated literature search was conducted through April 2004 and no relevant information was found. Literature search strategy employed for this compound was based on the CASRN and at least one common name. REVIEW OF PERTINENT LITERATURE Human Studies No studies were located regarding the toxicity of/>-bromofluorobenzene in humans following oral exposure. Animal Studies No studies were located regarding the toxicity of/>-bromofluorobenzene in animals following subchronic or chronic oral exposure. One acute oral lethality study was found (DuPont, 1985; U.S. EPA, 2002c). Groups of 10 male Sprague Dawley rats were administered 1000, 2000, 3000, or 5000 mg/kg of p- bromofluorobenzene via gavage in corn oil and sacrificed after a 14-day observation period. The LD50 was 2700 mg/kg (95% CI: 2200-3200 mg/kg). At non-lethal doses (specific levels not reported), tremors, limpness, and weight loss (3-19%) were observed 1-2 days after dosing. At lethal doses, death occurred within 3 days of dosing, preceded by tremors, absence of righting and/or grasping reflex, limpness, ataxia, lung noise, clear ocular discharge, and body weight loss (8-21%>). No other endpoints (including gross and histological pathology) were examined. FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC OR CHRONIC RfD FOR p-BROMOFLUOROBENZENE The lack of chronic or subchronic oral toxicity data for humans or animals precludes derivation of a subchronic or chronic p-RfD for /;-bromofluorobcnzcne. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html 3 ------- 11-23-2004 DuPont De Nemours & Co. 1985. Median lethal dose toxicity study with INY-1059-1 in rats. Haskell Laboratory. U.S. EPA/OTS Public Files, 8ECP submission. FicheNo. OTS0540497. IARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Leber, A.P. and J.S. Bus. 2001. Halogenated Benzenes. In: Patty's Toxicology. 5th ed. E. Bingham, B. Cohrssen and C.H. Powel, Ed. John Wiley and Sons, New York. 5: 499. NTP (National Toxicology Program). 2002. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1992. Drinking Water Toxicity Profiles. Office of Science and Technology, Office of Water, Washington, DC. September. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. 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. July. EPA/540/R-97/036. NTIS 97-921199. U.S. EPA. 2002a. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa.gov/iris/ U.S. EPA. 2002b. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. EPA 822-R-02-038. Online. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf U.S. EPA. 2002c. TSCATS (Toxic Substance Control Act Testing Submission database). Online, http://www.svrres.com/esc/tscats.htm WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria Series. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html 4 ------- 11-23-2004 Provisional Peer Reviewed Toxicity Values for /?-Bromofluorobenzene (CASRN 460-00-4) Derivation of Subchronic and Chronic Inhalation RfCs Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level 1 ------- MTD maximum tolerated dose MTL median threshold limit NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor Hg microgram |j,mol micromoles voc volatile organic compound 11 ------- 11-23-2004 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR p-BROMOFLUOROBENZENE (CASRN 460-00-4) Derivation of Subchronic and Chronic Inhalation RfCs Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) 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 (PPRTV) 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 Integrated Risk Information System (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 two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes request that a frequently used PPRTV be reassessed. 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 manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 11-23-2004 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 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. 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 manuscript 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 An RfC for /;-bromofluorobcnzcne (C6H4BrF) is not listed on IRIS (U.S. EPA, 2002) or in the HEAST (U.S. EPA, 1997). No documents for this chemical were listed in the CARA database (U.S. EPA, 1991, 1994). ATSDR (2002) has not published a toxicological profile for /;-bromof1uorobcnzcnc and this chemical was not listed in the NTP (2002) Management Status Reports. ACGIH (2002), NIOSH (2002) and OSHA (2002a,b) have not established occupational exposure limits for />bromofluorobcnzcnc. IARC (2002) and WHO (2002) have not published relevant reviews. No information pertinent to an RfC derivation for /;-bromof1uorobcnzcnc was found in a review by Leber and Bus (2001). Literature searches of the following databases were conducted from 1994 to September 2002 for relevant studies: TOXLINE, MEDLINE, TSCATS, GENETOX, EMIC/EMICBACK, DART/ETICBACK, HSDB, RTECS, CCRIS, and BIOSIS. Previous literature searches of TOXLINE (1965-1994), TSCATS and RTECS were conducted in 2 ------- 11-23-2004 November 1994. An updated literature search was conducted through April 2004 and no relevant information was found. Literature search strategy employed for this compound was based on the CASRN and at least one common name. REVIEW OF PERTINENT LITERATURE Human Studies No studies were located regarding the toxicity of/>-bromofluorobenzene in humans following inhalation exposure. Animal Studies No studies were located regarding the toxicity of/>-bromofluorobenzene in animals following subchronic or chronic inhalation exposure. Two acute inhalation studies were found (DuPont, 1985; Rhone-Poulenc, 1987; U.S. EPA, 2002b). Groups of 10 male Sprague-Dawley rats were exposed to 7.1, 14, 19, 22, or 26 mg/L air of/?-bromofluorobenzene for 4 hours and sacrificed after a 14-day observation period (DuPont, 1985). The LC50 was 18 mg/L (95% CI: 15-21 mg/L). Exposure to 14 mg/L or greater resulted in loss of righting reflex, diminished startle response, lethargy, tremors, spasms, labored or rapid breathing, red nasal discharge, and darkened eyes. A slight-to-moderate body weight loss (up to 8%) was observed in rats exposed to 7.1 mg/L and a slight-to-severe weight loss (4.1- 17.5%) was observed in the rats exposed to 14 mg/L or greater. No other endpoints (including gross and histopathology) were examined. The second study was conducted at a lower concentration. Groups of 10 albino Wistar rats (5/sex/group) were exposed (whole-body as opposed to nose only) to 0 (clear air control) or 5.95 mg/L of /;-b ro m o fl uo rob c n zene for 4 hours (Rhone-Poulenc, 1987). There were no deaths during the study. Clinical signs during exposure were consistent with a mildly irritant vapor and included abnormal respiratory pattern and body posture. During the post exposure observation period, signs included abnormal respiratory pattern and fascicular tremors. Four of five female rats exposed to />-bromofluorobenzene developed hair loss from the back during the observation period, compared to a single female with hair loss from the head. Food and water consumption, body weight and relative lung weight were unaffected by exposure to />-bromofluorobenzene. There were no macroscopic or microscopic findings attributable to exposure to/>-bromofluorobenzene. 3 ------- 11-23-2004 FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC OR CHRONIC RfC FOR />-BROMOFLU OROBEN ZENE The lack of chronic or subchronic inhalation toxicity data for humans or animals precludes derivation of a subchronic or chronic p-RfC for /j-bromofluorobcnzcnc. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2002. TLVsŪ and BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological Exposure Indices. Cincinnati, OH. ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html DuPont De Nemours & Co. 1985. Inhalation median lethal concentration toxicity study with INY-1059-1 in rats. Haskell Laboratory. U.S. EPA/OTS Public Files, 8ECP submission. Fiche No. OTS0540496. IARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Leber, A.P. and J.S. Bus. 2001. Halogenated Benzenes. In: Patty's Toxicology. 5th ed. E. Bingham, B. Cohrssen and C.H. Powel, Ed. John Wiley and Sons, New York. 5: 499. NIOSH (National Institute for Occupational Safety and Health). 2002. NIOSH Pocket Guide to Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/.html NTP (National Toxicology Program). 2002. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ OSHA (Occupational Safety and Health Administration). 2002a. OSHA Standard 1910.1000 Table Z-l. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html OSHA (Occupational Safety and Health Administration). 2002b. OSHA Standard 1915.1000 for Air Contaminants. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OshStd data/1915 1000.html 4 ------- 11-23-2004 Rhone-Poulenc, Inc. 1987. Parabromofluorobenzene Acute Inhalation Study in Rats 4-Hour Exposure. Neuilly s/Seine Cedex, France. January 12, 1987. U.S. EPA/OTS Public Files, 8ECP submission. Fiche No. OTS0571350. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. 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. July. EPA/540/R-97/036. NTIS 97-921199. U.S. EPA. 2002a. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http ://www. epa. gov/ iris/ U.S. EPA. 2002b. TSCATS (Toxic Substance Control Act Testing Submission database). Online, http://www.svrres.com/esc/tscats.htm WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria Series. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html 5 ------- 11-23-2004 Provisional Peer Reviewed Toxicity Values for /?-Bromofluorobenzene (CASRN 460-00-4) Derivation of a Carcinogenicity Assessment Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 ------- Acronyms and Abbreviations bw body weight cc cubic centimeters CD Caesarean Delivered CERCLA Comprehensive Environmental Response, Compensation and Liability Act of 1980 CNS central nervous system cu.m cubic meter DWEL Drinking Water Equivalent Level FEL frank-effect level FIFRA Federal Insecticide, Fungicide, and Rodenticide Act g grams GI gastrointestinal HEC human equivalent concentration Hgb hemoglobin i.m. intramuscular i.p. intraperitoneal i.v. intravenous IRIS Integrated Risk Information System IUR inhalation unit risk kg kilogram L liter LEL lowest-effect level LOAEL lowest-observed-adverse-effect level LOAEL(ADJ) LOAEL adjusted to continuous exposure duration LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human m meter MCL maximum contaminant level MCLG maximum contaminant level goal MF modifying factor mg milligram mg/kg milligrams per kilogram mg/L milligrams per liter MRL minimal risk level 1 ------- MTD maximum tolerated dose MTL median threshold limit NAAQS National Ambient Air Quality Standards NOAEL no-observed-adverse-effect level NOAEL(ADJ) NOAEL adjusted to continuous exposure duration NOAEL(HEC) NOAEL adjusted for dosimetric differences across species to a human NOEL no-observed-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration p-RfD provisional oral reference dose PBPK physiologically based pharmacokinetic PPb parts per billion ppm parts per million PPRTV Provisional Peer Reviewed Toxicity Value RBC red blood cell(s) RCRA Resource Conservation and Recovery Act RDDR Regional deposited dose ratio (for the indicated lung region) REL relative exposure level RfC inhalation reference concentration RfD oral reference dose RGDR Regional gas dose ratio (for the indicated lung region) s.c. subcutaneous SCE sister chromatid exchange SDWA Safe Drinking Water Act sq.cm. square centimeters TSCA Toxic Substances Control Act UF uncertainty factor Hg microgram |j,mol micromoles voc volatile organic compound 11 ------- 11-23-2004 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR p-BROMOFLUOROBENZENE (CASRN 460-00-4) Derivation of a Carcinogenicity Assessment Background On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) 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 (PPRTV) 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 Integrated Risk Information System (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 two EPA scientists and external peer review by three independently selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the multi-program 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 science and available information evolve, PPRTVs are initially derived with a three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes request that a frequently used PPRTV be reassessed. 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 manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 11-23-2004 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 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. 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 manuscript 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 A carcinogenicity assessment for /;-bromof1uorobcnzcnc (C6H4BrF) is not listed on IRIS (U.S. EPA, 2002a), the Drinking Water Standards and Health Advisories table (U.S. EPA, 2002b), or the HEAST (U.S. EPA, 1997). No documents for this chemical are listed in the CARA database (U.S. EPA, 1991, 1994). A Drinking Water Toxicity Profile forp- bromofluorobenzene (U.S. EPA, 1992) contained no relevant information. ATSDR (2002) has not published a toxicological profile for /;-bromofluorobcnzcne and this chemical was not listed in the NTP (2002) Management Status Reports. ACGIH (2002), IARC (2002) and WHO (2002) have not assessed the carcinogenicity of />bromofluorobcnzcnc. No information pertinent to a carcinogenicity assessment for /j-bromofluorobcnzcnc was found in a review by Leber and Bus (2001). Literature searches of the following databases were conducted from 1994 to September 2002 for relevant studies: TOXLINE, MEDLINE, TSCATS, GENETOX, EMIC/EMICBACK, 2 ------- 11-23-2004 DART/ETICBACK, HSDB, RTECS, CCRIS, and BIOSIS. Previous literature searches of TOXLINE (1965-1994), TSCATS and RTECS were conducted in November 1994. An updated literature search was conducted through April 2004 and no relevant information was found. Literature search strategy for this compound was based on the CASRN and at least one common name. REVIEW OF PERTINENT LITERATURE Human Studies No studies of the potential carcinogenicity of /;-bromofluorobcnzcne in humans were located. Animal Studies No studies of the potential carcinogenicity of /;-bromofluorobcnzcnc in animals were located. Other Studies No genetic toxicity data were located for/>-bromofluorobenzene. PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION Under the proposed U.S. EPA (1999) guidelines, the data are inadequate for an assessment of human carcinogenic potential. QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK Derivation of quantitative estimates of cancer risk for />-bromofluorobenzene is precluded by the lack of data regarding carcinogenicity of this chemical. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2002. TLVsŪ and BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological Exposure Indices. Cincinnati, OH. 3 ------- 11-23-2004 ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html I ARC (International Agency for Research on Cancer). 2002. IARC Agents and Summary Evaluations. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Leber, A.P. and J.S. Bus. 2001. Halogenated Benzenes. In: Patty's Toxicology. 5th ed. E. Bingham, B. Cohrssen and C.H. Powel, Ed. John Wiley and Sons, New York. 5: 499. NTP (National Toxicology Program). 2002. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. U.S. EPA. 1992. Drinking Water Toxicity Profiles. Office of Science and Technology, Office of Water, Washington, DC. September. U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. December. U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. 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. July. EPA/540/R-97/036. NTIS 97-921199. U.S. EPA. 1999. Guidelines for Carcinogen Risk Assessment. Review Draft. Risk Assessment Forum, Washington, DC. July. U.S. EPA. 2002a. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa.gov/iris/ U.S. EPA. 2002b. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. EPA 822-R-02-038. Online. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf WHO (World Health Organization). 2002. Online Catalogs for the Environmental Criteria Series. 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