United States Environmental Protection 1=1 m m Agency EPA/690/R-08/015F Final 7-24-2008 Provisional Peer Reviewed Toxicity Values for delta-Hexachlorocyclohexane (CASRN 319-86-8) 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 NAAQS National Ambient Air Quality Standards NOAEL no-ob served-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-ob served-effect level OSF oral slope factor p-IUR provisional inhalation unit risk p-OSF provisional oral slope factor p-RfC provisional inhalation reference concentration 1 ------- 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 ------- 7-24-2008 PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR DELTA-HEXACHLOROCYCLOHEXANE (CASRN 319-86-8) 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. 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. 1 ------- 7-24-2008 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 IRIS (U.S. EPA, 2008) does not report an RfD or RfC for delta-hexachlorocyclohexane (delta-HCH). The HE AST (U.S. EPA, 1997) states that data are inadequate for quantitative risk assessment for delta-HCH based on a Health and Environmental Effects Profile (HEEP) for hexachlorocyclohexanes (U.S. EPA, 1987). Delta-HCH is not included in the Drinking Water Standards and Health Advisory list (U.S. EPA, 2006). The CARA list (U.S. EPA, 1991, 1994) includes only the previously mentioned HEEP (U.S. EPA, 1987). ATSDR (2005) developed a Toxicological Profile for alpha-, beta-, gamma-, and delta-HCH but did not derive oral or inhalation MRLs for delta-HCH. There is no Environmental Health Criteria Document available for delta-hexachlorocyclohexane (WHO, 2008). ACGIH (2007), OSHA (2007), and NIOSH (2008) have not established occupational health standards for delta-HCH. On IRIS (U.S. EPA, 2008), delta-HCH is assigned to cancer Weight-of-Evidence Group D, "Not Classifiable as to Human Carcinogenicity," based on no available human data and inadequate animal data (verification date: 12/17/86). IARC (1987) did not assess the carcinogenicity of delta-HCH in its assessment of hexachlorocyclohexane isomers. Additionally, the carcinogenicity of delta-HCH has not been assessed by NTP (2005, 2008). Delta hexachlorocyclohexane (DeltaHCH) is one of a series of isomers of the pesticide lindane. Lindane itself (Gamma hexachlorocyclohexane (GammaHCH)), or the technical grade mixture which is comprised approximately 8% of the delta isomer, has significantly more toxicity information available than the delta isomer. In vivo testing of DeltaHCH, a lipophilic neurodepressant agent has been largely inconclusive. In vivo results looked negative for cancer in rats (Ito, et al., 1973, 1975) and negative for bodyweight changes and body temperature changes (Camon, et al., 1988). In vitro studies in CHO cells showed some additivity between delta and gamma isomers. In vitro studies point two mechanisms of toxicity, although there is 2 ------- 7-24-2008 cross-talk between the two pathways. The first appears to be related to the other HCH isomers well known interaction with the GABA receptor in neuronal tissue. Unlike the gamma isomer however, which is a GABA antagonist (like picrotoxin), delta is a partial allosteric agonist for the GABA receptor. While GammaHCH appears to bind near the picrotoxin site, DeltaHCH appears to involve (or overlap with) the binding site for barbiturates (Aspinwall et al 1997). Tissue specificity of the DeltaHCH response is explained by a lack of responsiveness to GABA receptors containing alpha 4, beta 1 or gamma 2L subunits. A chronic effects mechanism for carcinogenesis would appear to be related to its action on Ca signaling. The delta isomer has been repeatedly shown to cause the influx of calcium, and causing the activation of the protein kinase C pathway, and the activation of c-fos. Literature searches were conducted from the 1960s through December 2007 for studies relevant to the derivation of provisional toxicity values for delta-HCH. Databases searched include MEDLINE, TOXLINE (Special), BIOSIS, TSCATS/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. FEASIBILITY OF DERIVING A PROVISIONAL RfD FOR DELTA-HEXACXHLOROC Y CLOHEXANE The data are inadequate to derive a p-RfD for delta-HCH. No dose-response information pertinent to any target organs is available in the current database; thus, the database lacks a study that could serve as a suitable basis for derivation of an RfD for delta-HCH. FEASIBILITY OF DERIVING A PROVISIONAL RfC FOR DELTA-HEXACXHLOROC Y CLOHEXANE No inhalation toxicity data in humans or animals are identified; thus, no p-RfC could be derived for delta-HCH. PROVISIONAL CARCINOGENICITY ASSESSMENT FOR DELTA-HEXACXHLOROC Y CLOHEXANE Because of the lack of carcinogenic data in humans or animals, under the 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005), this PPRTV document classifies delta-HCH as having "Inadequate Information to Assess Carcinogenic Potential." FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR OR INHALATION UNIT RISK FOR DELTA-HEXACXHLOROCYCLOHEXANE Neither a p-OSF nor a p-IUR could be derived for delta-HCH because of the lack of suitable oral or inhalation in both humans and animals. 3 ------- 7-24-2008 REFERENCES ACGIH (American Conference of Governmental Industrial Hygienists). 2007. 2007 Threshold Limit Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH, Cincinnati, OH. Aspinwall, L.S., I. Bermudez, L. A. King and K. A. Wafford, 1997. The Interactions of H ex a ch1 orocy cl oh ex an e Isomers with Human T-Aminobutyric Acid \ Receptors Expressed in Xenopus Oocytes. Pharm. Exp. Theraputics Vol. 282:1557-1564. ATSDR (Agency for Toxic Substances and Disease Registry). 2005. Toxicological Profile for Alpha-, Beta-, Gamma-, and Delta-Hexachlorocyclohexanes (HCH). Update. U.S. Department of Health and Human Services, Public Health Service, Atlanta, GA. Camon, L., Martinez, E., Artigas, F., Sola, C., Rodriguez-Farre, E., 1988. The Effect of Non- Convulsant Doses of Lindane on Temperature and Body Weight. Toxicology, Vol. 49, Nos. 2/3, Part 2, pages 389-394. IARC (International Agency for Research on Cancer). 1987. Overall Evaluation of Carcinogenicity: An Updating of IARC Monographs. 1-42(7): 220. Online. http://193.51.164.1 l/htdocs/Indexes/Suppl7Index.html. Ito, N., Nagasaki, H., Arai, M., Sugihara, S., and Makiura, S. 1973. Histologic and ultrastructural studies on the hepatocarcinogenicity of benzene hexachloride in mice. Journal of the National Cancer Institute. 51: 817-826. Ito, N., Nagasaki, H., Aoe, H., Sugihara, S., Miyata, Y., Arai, M., Shirai, T. 1975. Brief Communication: Development of hepatocellular carcinomas in rats treated with benzene hexachloride. Journal of the National Cancer Institute. 54(3): 801-805. NIOSH (National Institute for Occupational Safety and Health). 2008. NIOSH Pocket Guide to Chemical Hazards. Index by CASRN. Available at http://www2.cdc.gov/nioshtic- 2/nioshtic2.htm. NTP (National Toxicology Program). 2005. 11th Report on Carcinogens. U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health, Research Triangle Park, NC. Available at http://ntp-server.niehs.nih.gov. NTP (National Toxicology Program). 2008. Management Status Report. Online. http://ntp.niehs.nih.gov/index.cfm?obiectid=78CC7E4C-FlF6-975E-72940974DE301C3F. OSHA (Occupational Safety and Health Administration). 2007. 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. 4 ------- 7-24-2008 U.S. EPA. 1987. Health and Environmental Effects Profile for Hexachlorocyclohexanes. Prepared by the Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, 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. 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. 2005. Guidelines for Carcinogen Risk Assessment. Risk Assessment Forum, Washington, DC; EPA/630/P-03/001F. Federal Register 70(66): 17765-17817. Available online at http://www.epa.gov/raf. U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office of Water, Washington, DC. EPA 822-R-06-013. Washington, DC. http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf. U.S. EPA. 2008. Integrated Risk Information System (IRIS). Office of Research and Development, National Center for Environmental Assessment, Washington, DC. Online. http ://www. epa. gov/iri s/. WHO (World Health Organization). 2008. Online catalogs for the Environmental Health Criteria Series. Online. http://www.who.int/ipcs/publications/ehc/ehc alphabetical/en/index.html. 5 ------- |