United States Environmental Protection 1=1 m m Agency EPA/690/R-04/007F Final 11-23-2004 Provisional Peer Reviewed Toxicity Values for 3,5-Dinitroaniline (CASRN 618-87-1) 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 ------- 11-23-04 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 3,5-DINITROANILINE (CASRN 618-87-1) 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 ------- 11-23-04 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 3,5-dinitroaniline is not available on IRIS (U.S. EPA, 2003), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002a). No relevant documents were located in the CARA list (U.S. EPA, 1991, 1994). Neither ATSDR (2003), NTP (2003), IARC (2003), nor WHO (2003) have produced documents regarding 3,5-dinitroaniline. Literature searches of the following databases were conducted from 1965 through June, 2003 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. Additional literature searches from June 2003 through September 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. 2 ------- 11-23-04 REVIEW OF PERTINENT DATA Human Studies No data regarding the toxicity of 3,5-dinitroaniline to humans following oral exposure were located. Animal Studies No data regarding the toxicity of 3,5-dinitroaniline to animals following oral exposure were located. Other Studies Potential surrogates for 3,5-dinitroaniline were investigated. The other isomers of dinitroaniline, 2,4-dinitroaniline and 2,6-dinitroaniline, are chemical intermediates used in the production of azo dyes. Limited data are available for the toxicity of 2,4-dinitroaniline, and no information regarding the toxicity of 2,6-dinitroaniline was located (NLM, 2002). Animal lethality data for 2,4-dinitroaniline include oral LD50s of 285, 370, and 1050 mg/kg in rat, mouse, and guinea pig, respectively (Lewis, 2000). 2,4-Dinitroaniline is listed as a mild skin and eye irritant to rabbits (NIOSH, 2000). In an excerpt of study results, rats orally administered 2,4-dinitroaniline were reported to show toxic effects that included nervous system effects, weak met- and sulf- hemoglobinemia, and decreased thiol groups in the blood (Vasilenko et al., 1975; HSDB, 2003). No other study details were provided. In a metabolic study, no toxic effects were observed in male Fischer-344 rats administered a single dose of 1.0, 10.0, or 90.0 [imol/kg of radiolabeled [14C] 2,4-dinitroaniline orally or 10.0 [imol/kg intravenously (Matthews et al., 1986). 2,4-Dinitroaniline was readily absorbed from the gastrointestinal tract and rapidly distributed to all major tissues. Distribution and excretion were similar across the dose range studied and routes of administration. Approximately 70 to 85% of the doses cleared from most tissues within 6 hours post- administration. The primary metabolite, a sulfate conjugate of 2,4-dinitrophenylhydroxylamine, was excreted primarily via the urine. The authors concluded that within the dose range studied, the potential for bioaccumulation of 2,4-dinitroaniline in animal tissues is low. 3 ------- 11-23-04 FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC RfDs FOR 3,5-DINITROANILINE The database for 3,5-dinitroaniline is inadequate for derivation of a p-RfD. No subchronic or chronic data examining the effects of oral exposure to 3,5-dinitroaniline were located. Derivation of a p-RfD by analogy to the isomers 2,4-dinitroaniline and 2,6-dinitroaniline was considered. However, due to the lack of toxicity data, a derivation by analogy is not feasible. The U.S. EPA (2002b) guidance for development of toxicity values indicated that in the absence of human data, effect levels from animals studies involving mortality or other extremely severe toxicity would not be adequate to derive a reference value. REFERENCES ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Budavari, S. 2001. The Merck Index 13th ed. Merck & Co., Inc. Whitehouse Station, N.J. p. 575. HSDB (Hazardous Substances Data Bank). 2003. National Library of Medicine TOXNET system. Online, http://toxnet.nlm.nih.gov/cgi-bin/sis/search I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ Lewis, R.J. Sr. 2000. SAX's Dangerous Properties of Industrial Materials. Tenth edition on CD- ROM [version 1999 John Wiley & Sons, Inc.] Matthews, H. B., H.M Chopade, R.W. Smith, and L.T. Burka. 1986. Disposition of 2,4- dinitroaniline in the male F-344 rat. Xenobiotica. 16(1): 1-10. NIOSH (National Institute for Occupational Safety and Health). 2000. Registry of Toxic Effects of Chemical Substances (RTECS). Aniline, 2,4-dinitro- RTECS #:BX9100000. National Library of Medicine. Cincinnati, OH. Online, http://www.cdc.gov/niosh/rtecs/bx8adae0.html 4 ------- 11-23-04 NLM (National Library of Medicine). 2002. National Institutes of Health, U.S. Department of Health and Human Services. Online, http://toxnet.nlm.nih.gov/ NTP (National Toxicology Program). 2003. 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. 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 PB97-921199. U.S. EPA. 2002a. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer 2002. EPA 822-R-02-038. Online. http://www.epa. gov/waterscience/drinking/ standards/dwstandards .pdf U.S. EPA. 2002b. A review of the Reference Dose and Reference Concentration processes. Final report prepared for the Risk Assessment Forum, U.S. EPA, Washington, DC. EPA/630/P- 02/002F. U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http ://www. epa. gov/ iris/ Vasilenko N.M., V.I. Zvezdai and F.A. Kolodub. 1975. Peculiarities of the toxicodynamics of 2,4-dinitroaniline and 6-chlor-2,4-dinitroaniline in the comparative aspect. Gig. Sanit. 8: 106-7. [Rus.; Cited in HSDB, 2003] WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm 5 ------- 11-23-04 Provisional Peer Reviewed Toxicity Values for 3,5-Dinitroaniline (CASRN 618-87-1) 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 ------- 11-23-04 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 3,5-DINITROANILINE (CASRN 618-87-1) 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 ------- 11-23-04 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 3,5-dinitroaniline is not available on IRIS (U.S. EPA, 2003) or in the HEAST (U.S. EPA, 1997). No relevant documents were located in the CARA list (U.S. EPA, 1991, 1994). ACGIH (2003), NIOSH (2003), and OSHA (2003) have not recommended occupational exposure limits for 3,5-dinitroaniline. ATSDR (2003), NTP (2003), IARC (2003), and WHO (2003) have not produced documents for this chemical. Literature searches of the following databases were conducted from 1965 through June, 2003 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. Additional literature searches from June 2003 through September 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. 2 ------- 11-23-04 REVIEW OF THE PERTINENT DATA Human Studies No data regarding the toxicity of 3,5-dinitroaniline to humans following inhalation exposure were located. Animal Studies No data regarding the toxicity of 3,5-dinitroaniline to animals following inhalation exposure were located. Other Studies Potential surrogates for 3,5-dinitroaniline were investigated. The other isomers of dinitroaniline, 2,4-dinitroaniline and 2,6-dinitroaniline, are chemical intermediates used in the production of azo dyes. Limited data are available for the inhalation toxicity of 2,4-dinitroaniline, and no information regarding the toxicity of 2,6-dinitroaniline was located (NLM, 2002). A synopsis of an acute exposure inhalation study (Khipko et al., 1982; HSDB, 2003) for 2,4-dinitroaniline examining developmental effects was located. Pregnant rats were exposed to 17mg/cu.m of 2,4- dinitroaniline for 4 hours/day within the first 7 or 19 days of pregnancy. Increased mortality of rat embryos and decreased embryo length on the 20th day of pregnancy was reported in exposed animals relative to controls. In addition, the 7-day exposure decreased alpha 2-globulin formation. No other study details were provided. No subchronic or chronic data are available for either possible surrogate chemical via the inhalation route of exposure. In a metabolic study, no toxic effects were observed in male Fischer-344 rats administered a single dose of 1.0, 10.0, or 90.0 [imol/kg of radiolabeled [14C] 2,4-dinitroaniline orally or 10.0 [imol/kg intravenously (Matthews et al., 1986). 2,4-Dinitroaniline was readily absorbed from the gastrointestinal tract and rapidly distributed to all major tissues. Distribution and excretion were similar across the dose range studied and routes of administration. Approximately 70 to 85% of the doses cleared from most tissues within 6 hours post- administration. The primary metabolite, a sulfate conjugate of 2,4-dinitrophenylhydroxylamine, was excreted primarily via the urine. The authors concluded that within the dose range studied, the potential for bioaccumulation of 2,4-dinitroaniline in animal tissues is low. 3 ------- 11-23-04 FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC RfCs FOR 3,5-DINITROANILINE The database for 3,5-dinitroaniline is inadequate for derivation of a p-RfC. No subchronic or chronic data examining the effects of inhalation exposure to 3,5-dinitroaniline were located. Derivation of a p-RfC by analogy to the isomers 2,4-dinitroaniline and 2,6-dinitroaniline was considered. However, due to the lack of toxicity data, a derivation by analogy is not feasible. The U.S. EPA (2002) guidance for development of toxicity values indicated that in the absence of human data, effect levels from animal studies involving mortality or other extremely severe toxicity would not be adequate to derive a reference value. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2003. 2003 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. Cincinnati, OH. ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Budavari, S. 2001. The Merck Index 13th ed. Merck & Co., Inc., Whitehouse Station, N.J. p.575. HSDB (Hazardous Substances Data Bank). 2003. National Library of Medicine TOXNET system. Online, http://toxnet.nlm.nih.gov/cgi-bin/sis/search I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ Khipko, S.E., N.M. Vasilenko, M.Y. Kudrya and F.A. Kolodub. 1982. Gig. Tr. Prof. Zabol. 6: 47. (Cited in HSDB, 2003) Matthews, H. B., H.M Chopade, R.W. Smith and L.T. Burka. 1986. Disposition of 2,4- dinitroaniline in the male F-344 rat. Xenobiotica. 16(1): 1-10. 4 ------- 11-23-04 NIOSH (National Institute for Occupational Safety and Health). 2003. NIOSH Pocket Guide to Chemical Hazards. Online. http://www.cdc.gOv/niosh/npg/npgd0000.html#F NLM (National Library of Medicine). 2002. National Institutes of Health, U.S. Department of Health and Human Services. Online, http://toxnet.n1m.nih.gov/ NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ OSHA (Occupational Safety and Health Administration). 2003. 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 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 PB97-921199. U.S. EPA. 2002. A review of the Reference Dose and Reference Concentration processes. Final report prepared for the Risk Assessment Forum, U.S. EPA, Washington, DC. EPA/630/P- 02/002F. U.S. EPA. 2003. 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). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm 5 ------- 11-23-04 Provisional Peer Reviewed Toxicity Values for 3,5-Dinitroaniline (CASRN 618-87-1) 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 ------- 11-23-04 PROVISIONAL PEER REVIEWED TOXICITY VALUE FOR 3,5-DINITROANILINE (CASRN 618-87-1) 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 ------- 11-23-04 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 3,5-dinitroaniline is not available on IRIS (U.S. EPA, 2003), the HEAST (U.S. EPA, 1997), or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). No relevant documents were located in the CARA list (U.S. EPA, 1991, 1994). Neither ATSDR (2003), NTP (2003), IARC (2003), nor WHO (2003) have produced documents regarding 3,5-dinitroaniline. Literature searches of the following databases were conducted from 1965 through September 2002 in order to locate relevant studies: TOXLINE, CANCERLIT, MEDLINE, CCRIS, GENETOX, HSDB, DART/ETICBACK, EMIC/EMICBACK, RTECS and TSCATS. Additional literature searches from June 2003 through September 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. 2 ------- 11-23-04 REVIEW OF THE PERTINENT DATA Human Studies No data regarding the possible carcinogenicity of 3,5-dinitroaniline in humans were located. Animal Studies No reports of animal studies examining the carcinogenicity of 3,5-dinitroaniline by any route of exposure were located. Other Studies Positive findings for 3,5-dinitroaniline were reported in Salmonella typhimurium strains TA1537, TA1538, TA98, and TA100 without metabolic activation and in TA1535 with or without metabolic activation (Spanggord et al., 1982). In the same study, 3,5-dinitroaniline was not mutagenic in strain TA100NR3 (without nitroreductase activity), with or without activation. Increased mutagenic potential was seen in 3,5-dinitroaniline, compared to the isomers 2,4- dinitroaniline or 2,6-dinitroaniline, in S. typhimurium strains TA98 and TA100, with or without metabolic activation (Apmann et al.,1997; Kawai et al., 1987). Other investigators reported that both the position and spatial relationship of the substituted nitro group on the ring influence the mutagenic potential of the nitroaromatic compounds (Vance and Levin, 1984; and Shimizu and Yano, 1986). Garner and Nutman (1977) reported increased mutagenic activity in the ring-substituted anilines containing at least two positions substituted with either an amino or nitro group for Salmonella typhimurium strain TA1538. PROVISIONAL WEIGHT-OF-EVIDENCE CLASSIFICATION No studies examining the carcinogenic potential of 3,5-dinitroaniline in humans or animals were located. Genotoxicity data indicate 3,5-dinitroaniline to be mutagenic in in vitro bacterial studies, but no information is available regarding in vivo genotoxicity in mammals. As the available data are insufficient to assess carcinogenic potential in animals or humans, they are consistent with the hazard descriptor, "inadequate information to assess carcinogenic potential," as specified by the updated U.S. EPA (1999). 3 ------- 11-23-04 QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK Derivation of quantitative estimates of cancer risk for 3,5-dinitroaniline is precluded by the lack of data demonstrating carcinogenicity associated with 3,5-dinitroaniline exposure. REFERENCES Assmann, N., M. Emmrich, G. Kampf and M. Kaiser. 1997. Genotoxic activity of important nitrobenzenes and nitroanilines in the Ames test and their structure-activity relationship. Mutat. Res. 395: 139-144. ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Toxicological Profile Information Sheet. Online, http://www.atsdr.cdc.gov/toxpro2.html Garner, R.C. and C.A. Nutman. 1977. Testing of some azo dyes and their reduction products for mutagenicity using Salmonella typhimurium TA1538. Mutat. Res. 44: 9-19. IARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ Kawai, A., S. Goto, Y. Matsumoto and H. Matsushita. 1987. Mutagenicity of aliphatic and aromatic nitro compounds. Jpn. J. Ind. Health. 29: 34-54. NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nih.gov/ Shimizu, M. and E. Yano. 1986. Mutagenicity of mono-nitrobenzene derivatives in the Ames test and rec assay. Mutat. Res. 170:11-22. (Cited in Assmann et al., 1997) Spanggord, R.J., K.E. Mortelmans, A.F. Griffin and V.F. Simmon. 1982. Mutagenicity in Salmonella typhimurium and structure-activity relationships of wastewater components emanating from the manufacture of trinitrotoluene. Environ. Mutagen. 4: 163-179. 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 ------- 11-23-04 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 PB97-921199. U.S. EPA. 1999. Guidelines for Carcinogen Risk Assessment. Preliminary Draft. Risk Assessment Forum, Washington, DC. July. Online. http:// cfpub .epa. gov/NCEA/raf/cancer.htm U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. Summer 2002. EPA 822-R-02-038. Online. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf U.S. EPA. 2003. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http://www.epa.gov/iris/ Vance, W.A. and D.E. Levin. 1984. Structural features of nitroaromatics that determine mutagenic activity in Salmonella typhimurium. Mutagenesis. 6:797-811 (Cited in Assmann et al„ 1997) WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/pcs/pubs/pub ehc alph.htm 5 ------- |