United States Environmental Protection Agency EPA/690/R-05/021F Final 6-17-2005 Provisional Peer Reviewed Toxicity Values for Superfund Health Risk Technical Support Center National Center for Environmental Assessment Office of Research and Development U.S. Environmental Protection Agency Cincinnati, OH 45268 2,3-Toluenediamine (CASRN 2687-25-4) ------- 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 ------- 6-17-2005 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR 2,3-TOLUENEDIAMINE (CASRN 2687-25-4) 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 ------- 6-17-2005 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 No RfD, RfC, or cancer assessment for 2,3-toluenediamine is available in the HEAST (U.S. EPA, 1997), which includes a comment that data for this chemical were inadequate for quantitative risk assessment. 2,3-Toluenediamine is not listed on IRIS (U.S. EPA, 2003) or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). The CARA list (U.S. EPA, 1991, 1994) includes a Health and Environmental Effects Profile (HEEP) for Selected Toluenediamine (U.S. EPA, 1984), which was the source document for the HEAST listing. ATSDR (2003) has not produced a Toxicological Profile that includes 2,3-toluenediamine. An Environmental Health Criteria Document for Diaminotoluenes (WHO, 1987) is available, but does not include derivation of quantitative risk values. Neither NTP (2003) nor IARC (2003) has assessed the carcinogenicity of 2,3-toluenediamine. ACGIH (2003), NIOSH (2003), and OSHA (2003) have not recommended occupational exposure limits for 2,3-toluenediamine. Literature 2 ------- 6-17-2005 searches were conducted from 1983 through 2004 for studies relevant to the derivation of provisional toxicity values for 2,3-toluenediamine. Databases searched included: TOXLINE (supplemented with BIOSIS and NTIS updates), MEDLINE, CANCERLIT, TSCATS, RTECS, CCRIS, DART, EMIC/ EMICBACK, HSDB, and GENETOX. 2,3-Toluenediamine is one of six diaminotoluene isomers that are components of crude or commercial grade mixtures used as intermediates in the production of dyes and pigments for commercial products (WHO, 1987). The crude mixture contains all six isomeric forms, while the two commercial mixtures are composed primarily of two isomers each. One commercial mixture, meta-diaminotoluene, contains the 2,4- and 2,6- isomers (80:20 or 65:35), and the other, ortho-diaminotoluene, contains the 2,3- and 3,4- isomers (40:60). REVIEW OF PERTINENT DATA Human Studies No data regarding the toxicity of 2,3-toluenediamine to humans following chronic or subchronic exposure by any route were located. Epidemiological studies of male workers exposed to diaminotoluene and dinitrotoluene mixtures were inconclusive as to whether there was an increased risk of reproductive effects (sperm production and viability of wife's pregnancies were evaluated) in the exposed workers (WHO, 1987). Animal Studies No data regarding the toxicity of 2,3-toluenediamine to animals following chronic or subchronic exposure by any route were located. One relevant study of the o-toluenediamine mixture (approximately 40% 2,3-toluenediamine) was located that evaluated developmental effects of the mixture in rats and rabbits (Becci et al., 1983). In the rat experiment, groups of 22 pregnant Sprague-Dawley females were given o- toluenediamine at doses of 0, 10, 30, 100, or 300 mg/kg-day by gavage in corn oil on gestation days 6 through 15 (Becci et al., 1983). Observations were conducted daily for general appearance, behavior, and mortality. Body weights of the dams were recorded on gestation days 0, 6, 9, 12, 15, and 20. On gestation day 20, all females were sacrificed and uterine contents were removed and examined. One-half of the fetuses were examined for soft tissue anomalies and the remaining fetuses were examined for skeletal anomalies. No treatment-related effects on appearance or behavior were observed in treated dams, and all dams survived the duration of the study. There was a statistically significant decrease in weight gain (-17%) during gestation for treated dams receiving 300 mg/kg-day compared to controls. No significant differences in number of live fetuses, implantation sites, or resorption sites were indicated. Fetal effects 3 ------- 6-17-2005 indicative of developmental delay were significant reductions in fetal body weight (-18%) in the 300 mg/kg-day group, and significant increases in skeletal variations (missing sternebrae at 300 mg/kg-day and incomplete ossification of vertebrae at 100 and 300 mg/kg-day). No maternal or developmental effects were seen at 30 mg/kg-day or below. The rabbit experiment included groups of 15 pregnant female Dutch-Belted rabbits given o-toluenediamine at doses of 0, 3, 10, 30, or 100 mg/kg-day by gavage in corn oil on gestation days 6 through 18 (Becci et al., 1983). Observations were conducted daily for general appearance, behavior, and mortality. Body weights of the does were recorded on gestation days 0, 6, 9, 12, 15, 18, and 29. On gestation day 29, all females were sacrificed and uterine contents were removed and examined. All the fetuses were examined for both soft tissue and skeletal anomalies. Appearance and behavior of does were unaffected by treatment. All does survived the duration of the study. Body weight gain during gestation was significantly decreased (-60%) in treated does receiving 100 mg/kg-day compared to controls. Other observations at this dose were a significant increase in the incidence of resorptions, a 16% decrease in the mean number of liver fetuses/doe (reported as statistically significant in the text, but not in the table showing the data), and a significant 22% decrease in fetal body weight. No maternal or developmental effects were seen at 30 mg/kg-day or below. Other Studies Limited data are available on the genotoxicity of 2,3-toluenediamine. The chemical was weakly mutagenic in Salmonella typhimurium strain TA98 with or without metabolic activation (Cheung et al., 1996). Administration of 0.2 or 0.5 mg/kg of 2,3-toluenediamine by intraperitoneal injection had no effect on chromosomal aberrations or mitotic frequency in bone marrow or ascites tumor cells in male CFW mice (Mikstacki, 1985). DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD VALUES FOR 2,3-TOLUENEDIAMINE No subchronic or chronic studies were located regarding toxicity of 2,3-toluenediamine to humans or animals by oral exposure. Data on the o-toluenediamine mixture (approximately 40% 2,3-toluenediamine) showed that the mixture produced evidence of embryo/fetotoxicity in both rats and rabbits, primarily at doses that also reduced gestational body weight gain in maternal animals. Due to the absence of data for 2,3-toluenediamine itself, derivation of RfD values is precluded. 4 ------- 6-17-2005 DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION RfC VALUES FOR 2,3-TOLUENEDIAMINE No subchronic or chronic inhalation studies of 2,3-toluenediamine in humans or animals were located, precluding derivation of RfC values for 2,3-toluenediamine. DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT FOR 2,3-TOLUENEDIAMINE No long-term data in humans or animals are available to assess the carcinogenic potential of 2,3-toluenediamine. Limited data indicate that the chemical is weakly genotoxic in bacteria (Cheung et al., 1996), but not clastogenic in mice in vivo (Mikstacki, 1985). Under the U.S. EPA (2005) Guidelines for Carcinogen Risk Assessment, there is inadequate information to assess the carcinogenic potential of 2,3-toluenediamine. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2003. 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). 2003. Toxicological Profile Information Sheet. U.S. Department of Health and Human Services, Public Health Service. Online, http://www.atsdr.cdc.gov/toxpro2.html Becci, P.J., E.L. Reagan, M.J. Knickerbocker et al. 1983. Teratogenesis study of o- toluenediamine in rats and rabbits. Toxicol. Appl. Pharmacol. 71: 323-329. Cheung Y.L., J. Snelling, N.N. Mohammed et al. 1996. Interaction with the aromatic hydrocarbon receptor, CYP1A induction, and mutagenicity of a series of diaminotoluenes: implications for their carcinogenicity. Toxicol. Appl. Pharmacol. 139(1): 203-11. IARC (International Agency for Research on Cancer). 2003. Search IARC Monographs. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Mikstacki, A. 1985. Evaluation of mutagenicity of some aromatic amines used as hair dyes by chromosomal aberration tests in-vivo. Genet. Pol. 26(1): 109-116. 5 ------- 6-17-2005 NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket Guide to Chemical Hazards. Online, http://www.cdc.gov/niosh/npg/npgdcas.html NTP (National Toxicology Program). 2003. Management Status Report. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ATI, SRCH/iH ATI, SRCH Frames.html 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. 1984. Health and Environmental Effects Profile for Selected Toluenediamine. Prepared by the Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. EPA600/X-84/148. NTIS PB88- 131073/AS. 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. 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/ U.S. EPA. 2005. Guidelines for Carcinogen Risk Assessment. Office of Research and Development, National Center for Environmental Assessment, Washington, DC. EPA/63 0/P-03/001F. WHO (World Health Organization). 1987. Environmental Health Criteria 74. Diaminotoluenes. Online: http://www.inchem.org/documents/ehc/ehc/ehc74.htm#PartNumber:4 6 ------- |