United States Environmental Protection 1=1 m m Agency EPA/690/R-02/005F Final 5-31-2002 Provisional Peer Reviewed Toxicity Values for Dinoseb (CASRN 88-85-7) Derivation of an Oral Slope Factor 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 IRIS Integrated Risk Information System IUR inhalation unit risk i.v. intravenous 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 MTD maximum tolerated dose MTL median threshold limit 1 ------- 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 microgram (.imol micromoles voc volatile organic compound 11 ------- 5-31-2002 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR DINOSEB (CASRN 88-85-7) Derivation of an Oral Slope Factor 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 new information becomes available and scientific methods improve over time, PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS value for a specific chemical becomes available for Agency review, the analogous PPRTV for that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a PPRTV cannot be derived based on inadequate data. 1 ------- 5-31-2002 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 Dinoseb is classified on IRIS in cancer weight-of-evidence Group D - not classifiable as to human carcinogenicity (U.S. EPA, 2001). The assessment, verified on 5/3/89, was based on lack of human and inadequate animal carcinogenicity data, comprising two studies in mice (Innes et al., 1969; Dow Chemical Co., 1981) and one in rats (Dow Chemical Co., 1977). Dinoseb is also listed in Group D on the Drinking Water Standards and Health Advisories list (U.S. EPA, 2000). A cancer assessment for dinoseb is not included in the HEAST (U.S. EPA, 1997). The CARA list (U.S. EPA, 1991, 1994) includes a Health and Environmental Effects Profile (HEEP) for Dinoseb (U.S. EPA, 1984) that found no evidence for carcinogenicity of this chemical. IARC (2001) has not reviewed the carcinogenicity of dinoseb. ATSDR (2001) has not produced a Toxicological Profile for dinoseb and no Environmental Health Criteria Document is available (WHO, 2001). NTP (2001) has not studied the carcinogenic potential of dinoseb. Updated literature searches for cancer data were conducted from 1983 to 2001. The databases searched 2 ------- 5-31-2002 were: TOXLINE, MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and EMIC/EMICBACK. REVIEW OF THE PERTINENT LITERATURE Human Studies Case-control studies in Swedish cancer patients, described in U.S. EPA (1984), found no evidence of increased risk of malignant lymphomas or malignant mesenchymal soft tissue tumors associated with dinoseb exposure (Eriksson et al., 1979; Hardell et al., 1981). Animal Studies Long-term studies of dinoseb exposure in mice (Innes et al., 1969; Dow Chemical Co., 1981) and rats (Dow Chemical Co., 1977) did not show an increase in tumors and/or were inadequate studies of carcinogenicity (U.S. EPA, 1984, 2001). No additional studies subsequent to the 1989 IRIS review were located. Other Studies Genotoxicity assays of dinoseb have generally shown no mutagenic activity, but have demonstrated an ability to interact with DNA and RNA (U.S. EPA, 1984, 2001). In bacteria, dinoseb was not mutagenic in multiple assays in Salmonella typhimurium and Escherichia coli, but produced positive results in differential toxicity tests comparing growth of repair- /recombination-deficient and proficient strains of S. typhimurium, E. coli and Bacillus subtilis. Assays for mitotic gene conversion in the yeast Saccharomyces cerevisiae produced mixed results. A sex-linked recessive lethality assay in Drosophila was negative. Results were also negative for unscheduled DNA synthesis in cultured human lung fibroblasts. Sperm morphology studies showed an increase in the occurrence of abnormal sperm in treated rats, but no effect in mice. FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR DINOSEB A provisional oral slope factor for dinoseb cannot be derived due to lack of human and inadequate animal cancer data. 3 ------- 5-31-2002 REFERENCES ATSDR (Agency for Toxicological Substances Disease Registry). 2001. Internet HazDat Toxicological Profile Query. U.S. Department of Health and Human Services, Public Health Service. Atlanta, GA. Examined October 10, 2001. Online. http://www.atsdr.cdc.gov/gsql/toxprof.script Dow Chemical Company. 1977. Available from EPA. Write to FOI, EPA, Washington, DC 20460. (Cited in U.S. EPA, 2001) Dow Chemical Company. 1981. Available from EPA. Write to FOI, EPA, Washington, DC 20460. (Cited in U.S. EPA, 2001) Eriksson, M., N.O. Berg, L. Hardell et al. 1979. Case control study of malignant mesenchymal soft-tissue tumors and exposure to chemical substances. Lakartidningen. (Swe.) 76(4): 3872- 3875. (Cited in U.S. EPA, 1984) Hardell, L., M. Eriksson., P. Lenner et al. 1981. Malignant lymphoma and exposure to chemicals, especially organic solvents, chlorophenols, and phenoxy acids: A case controlled study. Br. J. Cancer. 43:169-176. (Cited in U.S. EPA, 1984) IARC (International Agency for Research on Cancer). 2001. Cumulative Cross Index to IARC Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Examined October 10, 2001. Online. http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html Innes, J.R.M., M.G. Valerio, L. Petruceli et al. 1969. Bioassay of pesticides and industrial chemicals for tumorigenicity in mice. A preliminary note. J. Natl. Cancer Inst. 42: 1104-1114. (Cited in U.S. EPA, 1984, 2001) NTP (National Toxicology Program). 2001. Management Status Report. Examined October 10, 2001. Online. http://ntp-server.niehs.nih.gov/cgi/iH Indexes/ALL SRCH/iH ALL SRCH Frames.html U.S. EPA. 1984. Health and Environmental Effects Profile for Dinoseb. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington, DC. U.S. EPA. 1989. Notes of the 6/13/89 CRAVE Work Group Meeting (summary sheet dated 5/5/89). Available from: National Center for Environmental Assessment, Washington, DC. U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and Environmental Assessment, Washington, DC. April. 4 ------- 5-31-2002 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. EPA/540/R-97/036. NTIS PB 97-921199. U.S. EPA. 2000. Drinking Water Standards and Health Advisories. Summer 2000. Office of Water, Washington, DC. Online, http://www.epa.gov/ost/drinking/standards/ U.S. EPA. 2001. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Examined October 10, 2001. Online, http://www.epa.gov/iris/ WHO (World Health Organization). 2001. World Health Criterial Publications catalogue. Examined October 10, 2001. Online, http://www.who.int/dsa/cat98Zzehc.htm 5 ------- |