United States kS^laMIjk Environmental Protection ^J^iniiil m11 Agency EPA/690/R-04/002F Final 11-23-2004 Provisional Peer Reviewed Toxicity Values for Benzothiazole (CASRN 95-16-9) 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 BENZOTHIAZOLE (CASRN 95-16-9) Derivation of a Subchronic or Chronic Oral RfD 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 subchronic or chronic RfD for benzothiazole is not available on IRIS (U.S. EPA, 2002a), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002b). No relevant documents were located in the CARA list (U.S. EPA, 1991, 1994). The Office of Drinking Water produced a Toxicological Profile for benzothiazole (U.S. EPA, 1989) that provided a synopsis of toxicological information for the chemical, but no risk assessment. Neither ATSDR (2002), NTP (2002), IARC (2002), nor WHO (2002) have produced documents regarding benzothiazole. Literature searches of the following databases were conducted from 1965 through May 2004 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. 2 ------- 11-23-2004 REVIEW OF PERTINENT DATA Human Studies No data regarding the toxicity of benzothiazole to humans following chronic or subchronic oral exposure were located. Animal Studies No data regarding the toxicity of benzothiazole to animals following chronic or subchronic oral exposure were located. The only data found were acute animal studies. Investigators reported oral LD50 values of 380-492 mg/kg for benzothiazole in male and female Fischer 344 (Mayhew and Muni, 1986) and Sprague-Dawley (Younger Laboratories, 1964, 1976) rats, and an oral LD50 of 375 mg/kg in male rats of an unspecified strain (Lorke, 1983). A dermal LD50 of 126-200 mg/kg was found for male and female New Zealand Albino rabbits (Younger Laboratories, 1976). Benzothiazole was a mild to moderate skin irritant and a severe eye irritant in rabbits (Younger Laboratories, 1964, 1976). FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC OR CHRONIC RfD FOR BENZOTHIAZOLE The lack of chronic or subchronic oral toxicity data for humans or animals precludes derivation of a subchronic or chronic p-RfD for benzothiazole. It was considered that systemic toxicity values might be obtained by analogy to 2-mercaptobenzothiazole (MBT), which has toxicity and carcinogenicity information. However, the pharmacokinetic data on MBT (Colucci and Buyske, 1965; El Dareer et al., 1989; Larsen et al., 1988; Nagamatsu et al., 1979) do not suggest that biotransformation to benzothiazole would occur, and no obvious pathways for biotransformation of benzothiazole to MBT were identified. In addition, there is some evidence that the sulfur-containing mercapto group is involved in MBT carcinogenicity (NTP, 1988) and other aspects of MBT toxicity (Feinman, 1987). REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Colucci, D.F. and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14: 457-466. 3 ------- 11-23-2004 El Dareer, S.M., J.R. Kalin, K.F. Tillery et al. 1989. Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally and topically and in guinea-pigs dosed topically. J. Toxicol. Environ. Health. 27(1): 65-84. Feinman, S.E. 1987. Sensitivity to rubber chemicals. J. Toxicol.-Cut. Ocular Toxicol. 6(2): 117-153. 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 Larsen, G.L., J.E. Bakke, V.J. Feil and J.K. Huwe. 1988. In vitro metabolism of the methylthio group of 2-methylthiobenzothiazole by rat liver. Xenobiotica. 18(3): 313-322. Lorke, D. 1983. A new approach to practical acute toxicity testing. Arch. Toxicol. 54(4): 275- 288. Mayhew, D.A. and I.A. Muni. 1986. Dermal, eye and oral toxicological evaluations. Phase II report. Acute oral LD50 determinations of benzothiazole, dithiane, and oxathiane. Report submitted by American Biogenics Corp. to U.S. Army Medical Research and Development Command. NTIS AD-A172647. Nagamatsu, K., Y. Kido, G. Urakubo et al. 1979. Absorption, distribution, excretion and metabolism of 2-mercaptobenzothiazole in guinea pig. Eisei Kagaku. 25:59-65. (Cited in NTP, 1988) NTP (National Toxicology Program). 1988. Technical Report on the Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice. National Toxicology Program, Research Triangle Park, NC. NTP TR 332. NTIS PB 88245154. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html NTP (National Toxicology Program). 2002. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ U.S. EPA. 1989. Toxicological Profile for Benzothiazole. Criteria and Standards Division, Office of Drinking Water, Washington, DC. NTIS PB95-182655. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. 4 ------- 11-23-2004 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 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 Younger Laboratories. 1964. Toxicological investigation with benzothiazole in rats and rabbits. Initial submission with cover letter dated 8/19/92. Submitted by Monsanto Co. to U.S. EPA. OTS 0545424. Younger Laboratories. 1976. Toxicologic investigation of benzothiazole (Final report). Initial submission with cover letter dated 11/26/91. Submitted by Monsanto Co. to U.S. EPA. OTS 0534825. 5 ------- 11-23-2004 Provisional Peer Reviewed Toxicity Values for Benzothiazole (CASRN 95-16-9) 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 BENZOTHIAZOLE (CASRN 95-16-9) Derivation of a Subchronic or Chronic Inhalation RfC 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 subchronic or chronic RfC for benzothiazole is not available on IRIS (U.S. EPA, 2002) or in the HEAST (U.S. EPA, 1997). No relevant documents were located in the CARA list (U.S. EPA, 1991, 1994). The Office of Drinking Water produced a Toxicological Profile for benzothiazole (U.S. EPA, 1989) that provided a synopsis of toxicological information for the chemical, but no risk assessment. ACGIH (2001), NIOSH (2002) and OSHA (2002) have not recommended occupational exposure limits for benzothiazole. ATSDR (2002), NTP (2002), IARC (2002), and WHO (2002) have not produced documents for this chemical. Literature searches of the following databases were conducted from 1965 through May 2004 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. 2 ------- 11-23-2004 REVIEW OF THE PERTINENT DATA Human Studies No data regarding the toxicity of benzothiazole to humans following chronic or subchronic inhalation exposure were located. Animal Studies No data regarding the toxicity of benzothiazole to animals following chronic or subchronic inhalation exposure were located. An acute inhalation study was conducted in which four male Sprague-Dawley rats survived a 6-hour exposure to a concentrated vapor of benzothiazole (Younger Laboratories, 1964). The exposure concentration was not estimated. FEASIBILITY OF DERIVING A PROVISIONAL SUBCHRONIC OR CHRONIC RfC FOR BENZOTHIAZOLE The lack of chronic or subchronic inhalation data for humans or animals precludes derivation of a subchronic or chronic p-RfC for benzothiazole. It was considered that systemic toxicity values might be obtained by analogy to 2-mercaptobenzothiazole (MBT), which has toxicity and carcinogenicity information. However, the pharmacokinetic data on MBT (Colucci and Buyske, 1965; El Dareer et al., 1989; Larsen et al., 1988; Nagamatsu et al., 1979) do not suggest that biotransformation to benzothiazole would occur, and no obvious pathways for biotransformation of benzothiazole to MBT were identified. In addition, there is some evidence that the sulfur-containing mercapto group is involved in MBT carcinogenicity (NTP, 1988) and other aspects of MBT toxicity (Feinman, 1987). REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2001. 2001 Threshold Limit Values for Chemical Substances and Physical Agents and 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 Colucci, D.F. and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14: 457-466. 3 ------- 11-23-2004 El Dareer, S.M., J.R. Kalin, K.F. Tillery et al. 1989. Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally and topically and in guinea-pigs dosed topically. J. Toxicol. Environ. Health. 27(1): 65-84. Feinman, S.E. 1987. Sensitivity to rubber chemicals. J. Toxicol.-Cut. Ocular Toxicol. 6(2): 117-153. 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 Larsen, G.L., J.E. Bakke, V.J. Feil and J.K. Huwe. 1988. In vitro metabolism of the methylthio group of 2-methylthiobenzothiazole by rat liver. Xenobiotica. 18(3): 313-322. Nagamatsu, K., Y. Kido, G. Urakubo et al. 1979. Absorption, distribution, excretion and metabolism of 2-mercaptobenzothiazole in guinea pig. Eisei Kagaku. 25: 59-65. (Cited in NTP, 1988) 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). 1988. Technical Report on the Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice. National Toxicology Program, Research Triangle Park, NC. NTP TR 332. NTIS PB 88245154. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/A [J. SRCH/iH ATI, SRCH Frames.html NTP (National Toxicology Program). 2002. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ OSHA (Occupational Safety and Health Administration). 2002. OSHA Standard 1910.1000 TableZ-1. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html U.S. EPA. 1989. Toxicological Profile for Benzothiazole. Criteria and Standards Division, Office of Drinking Water, Washington, DC. NTIS PB95-182655. 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. 4 ------- 11-23-2004 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. 2002. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http ://www. epa. gov/ iris/ 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 Younger Laboratories. 1964. Toxicological investigation with benzothiazole in rats and rabbits. Initial submission with cover letter dated 8/19/92. Submitted by Monsanto Co. to U.S. EPA. OTS 0545424. 5 ------- 11-23-2004 Provisional Peer Reviewed Toxicity Values for Benzothiazole (CASRN 95-16-9) 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 BENZOTHIAZOLE (CASRN 95-16-9) 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 of benzothiazole is not available on IRIS (U.S. EPA, 2002a), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002b). No relevant documents were located in the CARA list (U.S. EPA, 1991, 1994). A toxicological profile on benzothiazole prepared by the Office of Drinking Water (U.S. EPA, 1989) did not locate carcinogenic study data for benzothiazole in humans or animals, but did include mutagenicity assay results in bacteria (Sano and Korte, 1985). Neither ATSDR (2002), NTP (2002), IARC (2002), nor WHO (2002) have produced documents regarding benzothiazole. Literature searches of the following databases were conducted from 1965 through May 2004 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. 2 ------- 11-23-2004 REVIEW OF THE PERTINENT DATA Human Studies No data regarding the possible carcinogenicity of benzothiazole in humans were located. Animal Studies No reports of animal studies examining the carcinogenicity of benzothiazole by any route of exposure were located. Supporting Studies Data regarding the genotoxicity of benzothiazole are limited to two reports of testing in the Ames assay. Benzothiazole did not induce an increase in revertant colony counts with or without an S-9 metabolic activation system in Salmonella typhimurium tester strains TA98, TA100, TA1535, TA1537, and TA1538 exposed to concentrations ranging from 3.2 x 10"4 to 1 jj.l/plate (Sano and Korte, 1985). In another study, benzothiazole was reported to have induced reverse mutations in strain TA1537 in the presence of an S-9 metabolic activation system, but the study was presented in an abstract that did not include any experimental details (Kinae et al., 1981). PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION There are no data on the carcinogenicity of benzothiazole in humans or animals and only limited genotoxicity data. It was considered that cancer toxicity values might be obtained by analogy to 2-mercaptobenzothiazole (MBT), which has toxicity and carcinogenicity information. However, the pharmacokinetic data on MBT (Colucci and Buyske, 1965; El Dareer et al., 1989; Larsen et al, 1988; Nagamatsu et al., 1979) do not suggest that biotransformation to benzothiazole would occur, and no obvious pathways for biotransformation of benzothiazole to MBT were identified. In addition, there is some evidence that the sulfur-containing mercapto group is involved in MBT carcinogenicity (NTP, 1988) and other aspects of MBT toxicity (Feinman, 1987). Under the proposed U.S. EPA (1999) cancer guidelines, the available data are inadequate for an assessment of human carcinogenic potential. QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK Derivation of quantitative estimates of cancer risk for benzothiazole is precluded by the lack of data demonstrating carcinogenicity associated with benzothiazole exposure. 3 ------- 11-23-2004 REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2002. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Colucci, D.F. and D.A. Buyske. 1965. The biotransformation of a sulfonamide to a mercaptan and to mercapturic acid and glucuronide conjugates. Biochem. Pharmacol. 14: 457-466. El Dareer, S.M., J.R. Kalin, K.F. Tillery et al. 1989. Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally and topically and in guinea-pigs dosed topically. J. Toxicol. Environ. Health. 27(1): 65-84. Feinman, S.E. 1987. Sensitivity to rubber chemicals. J. Toxicol.-Cut. Ocular Toxicol. 6(2): 117-153. 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 Kinae, N., H. Kawashima, R. Kawane et al. 1981. Detection and isolation of mutagenic substances from sea water. J. Pharmacobio-Dyn. 4: S-63. (Abstract) Larsen, G.L., J.E. Bakke, V.J. Feil and J.K. Huwe. 1988. In vitro metabolism of the methylthio group of 2-methylthiobenzothiazole by rat liver. Xenobiotica. 18(3): 313-322. Nagamatsu, K., Y. Kido, G. Urakubo et al. 1979. Absorption, distribution, excretion and metabolism of 2-mercaptobenzothiazole in guinea pig. Eisei Kagaku. 25:59-65. (Cited in NTP, 1988) NTP (National Toxicology Program). 1988. Technical Report on the Toxicology and Carcinogenesis Studies of 2-Mercaptobenzothiazole (CAS No. 149-30-4) in F344/N Rats and B6C3F1 Mice. National Toxicology Program, Research Triangle Park, NC. NTP TR 332. NTIS PB 88245154. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html NTP (National Toxicology Program). 2002. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ Sano, S.K. and D.W. Korte, Jr. 1985. Mutagenic Potential of Benzothiazole. Institute Report No. 205. U.S. Army Medical Research and Development Command, Letterman Army Institute of Research, Presidio of San Francisco, CA. NTIS ADA-164696. 4 ------- 11-23-2004 U.S. EPA. 1989. Toxicological Profile for Benzothiazole. Criteria and Standards Division, Office of Drinking Water, Washington, DC. NTIS PB95-182655. 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. 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. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html 5 ------- |