United States Environmental Protection 1=1 m m Agency EPA/690/R-04/01IF Final 11-23-2004 Provisional Peer Reviewed Toxicity Values for Nicotinonitrile (CASRN 100-54-9) 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 MTD maximum tolerated dose 1 ------- 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 NICOTINONITRILE (CASRN 100-54-9) 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 The HEAST (U.S. EPA, 1997) does not list subchronic or chronic reference dose (RfD) or reference concentration (RfC) values for nicotinonitrile (3-cyanopyridine; C6H4N2), noting that data were inadequate for quantitative risk assessment, and does not include any cancer assessment for the chemical. A Health and Environmental Effects Document (HEED) for Selected Nitriles (U.S. EPA, 1987), that was listed in the HEAST as a reference for subchronic and chronic toxicity, reported no chronic or subchronic toxicity studies of nicotinonitrile and assigned the chemical to U.S. EPA (1999) cancer weight-of-evidence Group D {not classifiable as to human carcinogenicity) based on no human or animal cancer data. Nicotinonitrile is not listed on IRIS (U.S. EPA, 2003) or the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). No relevant documents, other than the previously mentioned HEED, were located in the CARA list (U.S. EPA, 1991, 1994). IARC (2003), NTP (2003), and ACGIH 2 ------- 11-23-2004 (2002) have not assessed the carcinogenicity of nicotinonitrile. ACGIH (2002), NIOSH (2003) and OSHA (2003a,b) have not established occupational exposure limits for nicotinonitrile. ATSDR (2003) and WHO (2003) have not published toxicological review documents on nicotinonitrile. Patty's Toxicology (2001) was consulted for relevant information. Literature searches were conducted from 1986 thru December 2002 for studies relevant to the derivation of provisional toxicity values for nicotinonitrile. Databases searched included: TOXLINE, MEDLINE, CANCERLIT, BIOSIS, TSCATS, RTECS, CCRIS, DART/ETICBACK, EMIC/EMICBACK, HSDB and GENETOX. Additional literature searches from December 2002 through September 2004 were conducted by NCEA-Cincinnati using MEDLINE, TOXLINE, Chemical and Biological Abstracts databases. REVIEW OF PERTINENT DATA Human Studies No studies were located regarding the subchronic or chronic toxicity or carcinogenicity of nicotinonitrile in humans. Animal Studies No studies were located regarding the subchronic or chronic toxicity or carcinogenicity of nicotinonitrile in animals. Other Studies Nicotinonitrile was negative for induction of mutation in Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 when tested with or without S9 metabolic activation (Florin et al., 1980). DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD VALUES FOR NICOTINONITRILE Provisional subchronic or chronic oral RfD values for nicotinonitrile cannot be derived because human and animal toxicity data following subchronic or chronic oral exposure to nicotinonitrile are lacking. 3 ------- 11-23-2004 DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION RfC VALUES FOR NICOTINONITRILE Provisional subchronic or chronic inhalation RfC values for nicotinonitrile cannot be derived because human and animal toxicity data following subchronic or chronic inhalation exposure to nicotinonitrile are lacking. DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT FOR NICOTINONITRILE No data were located regarding the carcinogenicity of nicotinonitrile in humans or animals. Nicotinonitrile did not induce mutations in bacteria (Florin et al., 1980). Under the proposed U.S. EPA (1999) cancer guidelines, the data are inadequate for an assessment of human carcinogenic potential. Derivation of quantitative estimates of cancer risk for nicotinonitrile is precluded by the absence of pertinent carcinogenicity data. REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2002. TLVsŪ and BEIsŪ: Threshold Limit Values for Chemical Substances and Physical Agents, Biological Exposure Indices. ACGIH, 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 Florin, I., L. Rutberg, M. Curvall and C.R. Enzell. 1980. Screening of tobacco smoke constituents for mutagenicity using the Ames' test. Toxicology. 18: 219-232. I ARC (International Agency for Research on Cancer). 2003. IARC Agents and Summary Evaluations. Online, http://www-cie.iarc.fr/ NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket Guide to Chemical Hazards. Index by CASRN. Online, http://www.cdc.gov/niosh/srh-nsh.html http://ntp-server.ni ehs .nih. gov/cgi/iH Indexes/AI 4 ------- 11-23-2004 OSHA (Occupational Safety and Health Administration). 2003a. OSHA Standard 1910.1000 Table Z-l. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OsliStd data/1910 1000 TABLE Z-l.html OSHA (Occupational Safety and Health Administration). 2003b. OSHA Standard 1915.1000 for Air Contaminants. Part Z, Toxic and Hazardous Substances. Online. http://www.osha-slc.gov/OshStd data/1915 1000.html Patty's Toxicology. 2001. 5th ed. E. Bingham, B. Cohrssen and C.H. Powel, Ed. John Wiley and Sons, New York. U.S. EPA. 1987. Health and Environmental Effects Document for Selected Nitriles. Prepared by Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC. 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 Carcinogenic Risk Assessment. Risk Assessment Forum, National Center for Environmental Assessment, Office of Research and Development. Washington, DC. July 1999. Online, http://www.epa.gov/NCEA/raf/crasab.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/ WHO (World Health Organization). 2003. Online Catalogs for the Environmental Criteria Series. Online, http://www.who.int/dsa/cat98/zehc.htm 5 ------- |