1、di-tert-Butyl Peroxide 1/03 di-tert-BUTYL PEROXIDE CAS # 110-05-4 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI January 2003 2003 NSF International di-tert-Butyl Peroxide 01/03 i TABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organoleptic Properties4
2、3.0 PRODUCTION AND USE .4 3.1 Production4 3.2 Use.5 4.0 ANALYTICAL METHODS.5 4.1 Assay Method.5 4.2 Analysis in Water 5 4.3 Analysis in Biological Matrices 5 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .5 5.1 Sources of Human Exposure 5 5.2 Sources of Environmental Exposure .6 6.0 COMPARATIVE KI
3、NETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS6 7.0 EFFECTS ON HUMANS .6 7.1 Case Reports 6 7.2 Epidemiological Studies6 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS6 8.1 Limited-Exposure Effects .7 8.1.1 Irritation and Sensitization Studies.7 8.1.2 Ocular Exposure Studies.7 8
4、.2 Single-Exposure Studies7 8.3 Short-Term Exposure Studies8 8.4 Long-Term and Chronic Exposure Studies 9 8.4.1 Subchronic Studies 9 8.4.2 Chronic Studies10 8.4.3 In Vitro Studies10 8.5 Studies of Genotoxicity and Related End Points 10 8.5.1 Mutagenicity Assays 11 8.5.2 Assays of Chromosomal Damage1
5、1 8.5.3 Other Assays of Genetic Damage13 8.6 Reproductive and Developmental Toxicity Studies13 di-tert-Butyl Peroxide 01/03 ii 8.7 Studies of Immunological and Neurological Effects.13 9.0 RISK CHARACTERIZATION .14 9.1 Hazard Assessment14 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Actio
6、n .14 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization14 9.1.3 Selection of Key Study and Critical Effect15 9.1.4 Identification of Susceptible Populations .15 9.2 Dose-Response Assessment.15 9.2.1 Oral RfD Derivation 15 9.3 Exposure Assessment 15 9.4 TAC Derivation .16 9.5 STEL Deriv
7、ation16 10.0 RISK MANAGEMENT 16 10.1 SPAC Derivation.16 11.0 RISK COMPARISONS AND CONCLUSIONS 16 12.0 REFERENCES 17 13.0 PEER REVIEW HISTORY .20 2003 NSF di-tert-Butyl Peroxide 01/03 iii AUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Author: NSF Toxicology Services 1.800.NSF.MARK NSF International 78
8、9 Dixboro Road Ann Arbor, MI 48105 Disclaimer: The responsibility for the content of this document remains solely with NSF International, and the author noted above should be contacted with comments or for clarification. Mention of trade names, proprietary products, or specific equipment does not co
9、nstitute an endorsement by NSF International, nor does it imply that other products may not be equally suitable. Internal NSF Peer Reviewers: Clif McLellan, M.S. Maryann Sanders, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on the NSF Health Advisory
10、 Board in providing peer review. These peer reviewers serve on a voluntary basis, and their opinions do not necessarily represent the opinions of the organizations with which they are affiliated. Edward Ohanian, Ph.D. (Chairman, NSF Health Advisory Board) Acting Director, Health and Ecological Crite
11、ria Division Office of Science and Technology/Office of Water U.S. Environmental Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairman, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Acting Director, Environmental Health Science Saf
12、e Environments Programme Health Canada Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industries, Inc. Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. 2003 NSF di-tert-Butyl Peroxide 01/03 iv Jennifer Orme-Zavaleta, M.S.
13、Associate Director for Science USEPA/NHEERL/WED Adi Pour, Ph.D. Director, Douglas County Health Department Omaha, Nebraska Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California 2003 NSF di-tert-Butyl Peroxide 01/03 v EXECUTIVE SUMMARY Di-tert-Butyl Peroxide Oral Risk Asse
14、ssment CAS # 110-05-4 PARAMETER LEVEL UNITS CALCULATED: NOAEL (no-observed-adverse-effect level) Not identified Oral RfD (oral reference dose) Not identified TAC (total allowable concentration) 0.01 mg/L Based on a qualitative risk assessment under NSF/ANSI 61 (2002). SPAC (single product allowable
15、concentration) 0.01 mg/L Based on a qualitative risk assessment under NSF/ANSI 61 (2002). STEL (short term exposure level) 0.01 mg/L Based on a qualitative risk assessment under NSF/ANSI 61 (2002). KEY STUDIES Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, and K. Mortelmans. 1988; and Microbiologic
16、al Associates, Inc. 1996. CRITICAL EFFECT There were insufficient data to identify a critical toxicological effect for this chemical. UNCERTAINTY FACTORS Since a quantitative risk assessment was not performed, no uncertainty factors were used. TOXICITY SUMMARY Di-tert-butyl peroxide was negative in
17、two Salmonella reverse mutation assays. A mouse bone marrow micronucleus assay produced weakly positive results at one dose level in two assays, but results of one of the assays was within the range of historical control results. Di-tert-butyl peroxide was also a weak inducer of short-term indices o
18、f tumor promotion, although it was not a tumor promoter in a 60-week dermal study. However, lack of human data and of oral data in laboratory animals, as well as very weak positive responses in several genetic toxicity studies, indicate that data are inadequate for an assessment of human carcinogeni
19、c potential of di-tert-butyl peroxide. Floyd and Stokinger (1958) reported results of numerous experiments on the acute and subacute non-cancer effects of di-tert-butyl peroxide. The acute toxicity of the chemical is low, with an oral LD50 25,000 mg/kg and an intraperitoneal LD50of 3,210 mg/kg. In a
20、 seven-week study during which five rats were dosed three times per week at one fifth of the oral LD50(5,000 mg/kg), one rat died during the second week and another during the third week. The three survivors failed to gain weight normally. Histopathology of rats dosed with organic peroxides revealed
21、 mild liver effects of questionable relevance to treatment. Non-lethal effects of orally administered di-tert-butyl peroxide are therefore limited to decreased body weight gain and possible liver effects, based on available studies. The number of toxicological endpoints examined was not sufficient t
22、o meet current guidelines for a repeated dose study from which a critical effect could be selected and an oral RfD calculated. CONCLUSIONS The available data are inadequate to quantitatively describe the risk to human health posed by di-tert-butyl peroxide. Based on genetic toxicity and dermal tumor
23、 promotion data suggesting that the carcinogenic potential of the chemical is weak or absent, a qualitative risk level of 0.01 mg/L is adequately protective of human health based on a weight of evidence approach consistent with NSF/ANSI 61 (2002), Table A3. 2003 NSF di-tert-Butyl Peroxide 01/03 1 1.
24、0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant di-tert-butyl peroxide in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/ANSI 61 (2002), or as a contaminant in a drinking water tre
25、atment chemical evaluated under NSF/ANSI 60 (2002). Both non-cancer and cancer endpoints have been considered, and risk assessment methodology developed by the U.S. Environmental Protection Agency (U.S. EPA) has been used. Non-cancer endpoints are evaluated using the reference dose (RfD) approach (B
26、arnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993), which assumes that there is a threshold for these endpoints that will not be exceeded if appropriate uncertainty factors (Dourson et al., 1996) are applied to the highest dose showing no significant effects. This highest dose is derived from h
27、uman exposure data when available but more often is derived from studies in laboratory animals. Either the no-observed-adverse-effect level (NOAEL) taken directly from the dose-response data, or the calculated lower 95% confidence limit on the dose resulting in an estimated 10% increase in response
28、(the LED10or BMDL from benchmark dose programs) can be used (U.S. EPA, 2001a). The lowest-observed-adverse-effect level (LOAEL) can also be used, with an additional uncertainty factor, although the benchmark dose approach is preferred in this case. The RfD is expressed in mg/kg-day. It is defined by
29、 the U.S. EPA as “an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime” (Barnes and Dourson, 1988; U.S. EPA, 1993; U.
30、S. EPA, 1999a). NSF uses the RfD to derive three product evaluation criteria for non-cancer endpoints. The total allowable concentration (TAC), generally used to evaluate the results of extraction testing normalized to static at-the-tap conditions, is defined as the RfD multiplied by the 70 kg weigh
31、t of an average adult assumed to drink two liters of water per day. A relative source contribution (RSC), to ensure that the RfD is not exceeded when food and other non-water sources of exposure to the chemical are considered, is also applied in calculating the TAC. The relative source contribution
32、should be data derived, if possible. Alternately, a 20% default contribution for water can be used (U.S. EPA, 1991a). The TAC calculation is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70 kg total contribution of other sources (mg/day) 2L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2
33、L/day The single product allowable concentration (SPAC), used for water treatment chemicals and for water contact materials normalized to flowing at-the-tap conditions, is the TAC divided by the estimated total number of sources of the substance in the drinking water treatment and distribution syste
34、m. In the absence of source data, a default multiple source factor of 10 is used. 2003 NSF di-tert-Butyl Peroxide 01/03 2 This accounts for the possibility that more than one product in the water and/or its distribution system could contribute the contaminant in question to drinking water. Finally,
35、a short-term-exposure level (STEL), at a higher level than the TAC, may be calculated for contaminants such as solvents expected to extract at higher levels from new product, but also expected to decay rapidly over time. The STEL is calculated from the NOAEL or the LED10of an animal study of 14- to
36、90-days duration, with uncertainty factors appropriate to the duration of the study. The contaminant level must decay to the TAC or below under static conditions, or to the SPAC or below under flowing conditions within 90 days, based on the contaminant decay curve generated from over-time laboratory
37、 extraction data. Endpoints related to cancer are evaluated using modeling to fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999b). If there is sufficient evidence to use a non-linear model, the LED10or BMDL, divided by the anticipated exposure, is calculated to give
38、a margin of exposure. If there is insufficient evidence to document non-linearity, a linear model drawing a straight line from the LED10or BMDL to zero, is used as a default. If a linear model (generally reflecting a genotoxic carcinogen) is used, a target risk range of 10-6to 10-4is considered by t
39、he U.S. EPA to be safe and protective of public health (U.S. EPA, 1991a). For the purposes of NSF/ANSI 60 (2002) and 61 (2002), the TAC is set at the 10-5risk level, and the SPAC is set at the 10-6risk level. Use of a higher risk level is not ruled out but would generally require documentation of a
40、benefit to balance the additional risk. The minimum data set for a quantitative risk assessment is described in NSF/ANSI 60 (2002) and 61 (2002) Annex A as consisting of a gene mutation assay, a chromosomal aberration assay, and a subchronic toxicity study. If the subchronic study is not available,
41、a qualitative risk assessment may be performed under the requirements of Annex A, Table A3. These requirements specify that the TAC may be set at 10 g/L (0.01 mg/L) if the weight of evidence review of the required genetic toxicity studies and all other relevant toxicity data concludes that the chemi
42、cal is not a hazard to human health at that level. Further, the TAC may be set up to 50 g/L (0.05 mg/L) if, in addition, there is a repeated dose study of less than subchronic duration that is of suitable quality. The RfD, TAC, SPAC, and STEL values derived in this document are based on available he
43、alth effects data and are intended for use in determining compliance of products with the requirements of NSF/ANSI 60 (2002) and 61 (2002). Application of these values to other exposure scenarios should be done with care and with a full understanding of the derivation of the values and of the compar
44、ative magnitude and duration of the exposures. These values do not have the rigor of regulatory values, as data gaps are generally filled by industry or government studies prior to regulation. Data gaps introduce uncertainty into an evaluation and require the use of additional uncertainty factors to
45、 protect public health. The general guidelines for this risk assessment include those from the National Research Council (1983) and from The Presidential/Congressional Commission on Risk Assessment and Risk Management (1997a, 1997b). Other guidelines used in the development of this assessment may in
46、clude the following: Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986), Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996a), draft revised Guidelines for 2003 NSF di-tert-Butyl Peroxide 01/03 3 Carcinogen Risk Assessment (U.S. EPA, 1999b), Guidelines for Developmental Toxic
47、ity Risk Assessment (U.S. EPA, 1991b), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996b), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998), Recommendations for and Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988), and Health Effects Tes
48、ting Guidelines (OPPTS series 870, U.S. EPA 1996c; 40 CFR Part 798, U.S. EPA, 2002a). The literature search strategy employed for this compound was based on the Chemical Abstract Service Registry Number (CASRN) and at least one common name. As a minimum, the following data banks were searched: ChemI
49、D Plus Registry of Toxic Effects of Chemical Substances (RTECS) Hazardous Substances Data Bank (HSDB) GENE-TOX Environmental Mutagen Information Center (EMIC) Developmental and Reproductive Toxicology (DART/ETIC) TOXLINE Toxicology Literature from Special Sources (TOXLIT) CANCERLIT Chemical Carcinogenesis Research Information System (CCRIS) Medline (via PubMed) Integrated Risk Information System (IRIS) Syracuse Research Corporation Online Toxic Substance Control Act Database (TSCATS) 2.0 PHYSI
