NSF 4-CHLORO-1 2-2006 4-CHLORO-1 2-BENZENEDIAMINE CAS # 95-83-0 ORAL RISK ASSESSMENT DOCUMENT.pdf

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1、 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 4-CHLORO-1,2-BENZENEDIAMINE CAS # 95-83-0 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI July 2006 Copyright 2006 NSF International 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 iTABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PR

2、OPERTIES.3 2.1 Organoleptic Properties4 3.0 PRODUCTION AND USE .4 3.1 Production4 3.2 Use.4 4.0 ANALYTICAL METHODS.5 4.1 Analysis in Water 5 4.2 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

3、.5 6.0 COMPARATIVE KINETICS 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 8.2 Single-Exposure Studies7 8.3 Short-Term Exposure Stud

4、ies7 8.4 Long-Term and Chronic Exposure Studies 7 8.4.1 Subchronic Studies 7 8.4.2 Chronic Studies8 8.5 Studies of Genotoxicity and Related End-Points12 8.5.1 Mutagenicity Assays 12 8.5.2 Assays of Chromosomal Damage15 8.5.3 Other Assays of Genetic Damage17 8.6 Reproduction and Developmental Toxicit

5、y Studies .19 8.7 Studies of Immunological and Neurological Effects.20 8.7.1 Immunological Effects 20 8.7.2 Neurological Effects 20 9.0 RISK CHARACTERIZATION .20 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 ii9.1 Hazard Assessment20 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .20 9

6、.1.2 Weight-of-Evidence Evaluation and Cancer Characterization21 9.1.3 Selection of Key Study and Critical Effect22 9.1.4 Identification of Susceptible Populations .24 9.2 Dose-Response Assessment.24 9.2.1 Benchmark Dose Modeling.24 9.2.2 Cancer Risk Level Calculation25 9.3 Exposure Assessment 27 9.

7、4 TAC Derivation .27 9.5 STEL Derivation27 10.0 RISK MANAGEMENT 28 10.1 SPAC Derivation.28 11.0 RISK COMPARISONS AND CONCLUSIONS 28 12.0 REFERENCES 29 13.0 APPENDICES .34 13.1 Animal Dose Conversions.34 13.2 Salmonella Reverse Mutation Assay Results 37 13.3 Human Equivalent Dose Conversions.38 13.4

8、Benchmark Dose Results 39 14.0 PEER REVIEW HISTORY .41 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 iiiAUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Author: NSF Toxicology Services 1.800.NSF.MARK NSF International 789 Dixboro Road Ann Arbor, MI 48105 Disclaimer: The responsibility for the content of t

9、his 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 constitute an endorsement by NSF International, nor does it imply that other products ma

10、y not be equally suitable. Internal NSF Peer Reviewers: Gwendolyn Ball, Ph.D. Clif McLellan, M.S. Carolyn Gillilland, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on the NSF Health Advisory Board in providing peer review. These peer reviewers serve o

11、n 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) Director, Health and Ecological Criteria Division Office of Science and Technology/Office of Water U.S. E

12、nvironmental Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairman, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Director, Environmental Health Science Safe Environments Programme Health Canada Steven Bursian, Ph.D. Professor Mich

13、igan State University Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 ivJennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/WED Calvin Willhite, Ph.D. Department of Toxic Substances Control State

14、of California 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 vEXECUTIVE SUMMARY 4-CHLORO-1,2-BENZENEDIAMINE Oral Risk Assessment CAS # 95-83-0 PARAMETER LEVEL UNITS DERIVED BMDL10(95% confidence limit at 10% response level) 45 mg/kg-day From a chronic feeding study in rats 10-5Cancer Risk Level 0.005 mg

15、/kg-day From the BMDL10Oral Slope Factor 0.0022 mg/kg-day-1From the BMDL10Drinking Water Unit Risk (at the 1 x 10-6cancer risk level) 0.063 x 10-6 g/L-1From the oral slope factor TAC (total allowable concentration) 0.2 mg/L For a 70 kg adult drinking 2 L/day SPAC (single product allowable concentrat

16、ion) 0.02 mg/L From the TAC, assuming 10 potential sources of 4-chloro-1,2-benzenediamine in drinking water STEL (short term exposure level) Not applicable Not applicable The STEL is not derived for a genotoxic carcinogen KEY STUDY National Toxicology Program (NTP)/National Cancer Institute (NCI). 1

17、978. Bioassay of 4-Chloro-o-phenylenediamine For Possible Carcinogenicity. DHEW Publication No. (NIH) 78-1313, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014. CRITICAL EFFECT Combined urinary bladder tumors and precursor effects, including urinary blad

18、der transitional cell carcinomas, papillary carcinomas, transitional cell papillomas, papillomas not otherwise specified, and urinary bladder papillomatosis in male and female rats. UNCERTAINTY FACTORS No uncertainty factors were applied in this risk assessment, since an oral RfD was not determined.

19、 The carcinogenic effects observed in chronic animal studies were analyzed using linear extrapolation. TOXICITY SUMMARY No human data were located. Hepatic focal hyperplasia and renal pyelonephritis were among the non-neoplastic effects observed in rats at dose-related increased incidences compared

20、to controls after dietary administration of 4-chloro-1,2-benzenediamine for 78 weeks. Urinary bladder tumors and precursor effects were among the neoplastic effects observed in male and female rats. Uterine/endometrial hyperplasia was observed in female mice at an increased incidence compared to con

21、trols after chronic dietary administration of 4-chloro-1,2-benzenediamine for 78 weeks, and combined hepatocellular adenomas and carcinomas were observed in male or female mice at a statistically increased incidence compared to controls. No kinetic or metabolism studies in humans or laboratory anima

22、ls were identified for 4-chloro-1,2-benzenediamine. The weight of evidence suggests that 4-chloro-1,2-benzenediamine is genotoxic in vivo and in vitro. 4-Chloro-1,2-benzenediamine caused mutations in Salmonella typhimurium with metabolic activation and in hepatocytes isolated from Big Blue mice expo

23、sed in vivo. 4-Chloro-1,2-benzenediamine also caused chromosomal aberrations in vivo in mouse bone marrow cells and produced dose-related increases in micronucleated polychromatic erythrocytes in the in vivo mouse bone marrow micronucleus assay. Sister chromatid exchanges were also observed in vivo,

24、 but the effect was not dose-related. Positive results in an in vivo alkaline single cell (Comet) assay were observed in the liver, but not in other organs. Unscheduled DNA synthesis was detected in an in vitro DNA repair assay in primary rat hepatocytes. 4-Chloro-1,2-benzenediamine was positive in

25、an in vitro microscreen prophage-induction assay with metabolic activation in Escherichia coli for the ability to induce DNA damage. A 10-5cancer risk level for 4-chloro-1,2-benzenediamine was extrapolated from the chronic feeding BMDL10of 45 mg/kg-day, which was based on the combined incidence of u

26、rinary bladder tumors and precursors in rats, since these tumors represented the most sensitive endpoint in laboratory animals. CONCLUSIONS Based on the statistically increased tumor incidences in rats and mice chronically administered 4-chloro-1,2-benzenediamine, and its positive in vitro and in vi

27、vo genotoxicity data, the weight of evidence supports that 4-chloro-1,2-benzenediamine is likely to be carcinogenic to humans. The drinking water action levels derived in this risk assessment are protective of public health since they were based on chronic oral data for 4-chloro-1,2-benzenediamine f

28、rom the most sensitive endpoint and laboratory animal species. 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant 4-chloro-1,2-benzenediamine in drinking water, as an extractant from one or mor

29、e drinking water system components evaluated under NSF/ANSI 61 (2005), or as a contaminant in a drinking water treatment chemical evaluated under NSF/ANSI 60 (2005). Both non-cancer and cancer endpoints have been considered, and risk assessment methodology developed by the U.S. Environmental Protect

30、ion Agency (U.S. EPA) has been used. Non-cancer endpoints are evaluated using the reference dose (RfD) approach (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993; U.S. EPA, 2002), which assumes that there is a threshold for these endpoints that will not be exceeded if appropriate uncertainty

31、factors (Dourson et al., 1996; U.S. EPA, 2002; WHO/IPCS, 2005) are applied to the highest dose showing no significant effects. This highest dose is derived from human exposure data when available, but more often is derived from studies in laboratory animals. Either the no-observed-adverse-effect lev

32、el (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 (the LED10or BMDL10from benchmark dose programs) can be used (U.S. EPA, 2003a). The lowest-observed-adverse-effect level (LOAEL) can also

33、 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 the U.S. EPA as “an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (inc

34、luding 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.S. EPA, 2003b). NSF uses the RfD to derive three product evaluation criteria for non-cancer endpoints. The total allowable concentration

35、 (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 weight 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

36、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 should be data derived, if possible. Alternately, a 20% default contribution for water can be used (U.S. EPA, 1991a). The TAC calculatio

37、n is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70 kg total contribution of other sources (mg/day) 2 L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2 L/day The single product allowable concentration (SPAC), used for water treatment chemicals and for water contact materials normalized

38、 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 system. In the absence of source data, a default multiple source factor of 10 is used. 2006 NSF 4-Chloro-1,2-benzenediamine 07/06 2This acc

39、ounts 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, a short-term-exposure level (STEL), at a higher level than the TAC, may be calculated for contaminants such as solvents expected t

40、o 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 90-days duration, with uncertainty factors appropriate to the duration of the study. The contaminant level must decay to a level a

41、t or below the TAC under static conditions, or to a level at or below the SPAC under flowing conditions within 90 days, based on the contaminant decay curve generated from over-time laboratory extraction data. Endpoints related to cancer are evaluated using modeling to fit a curve to the appropriate

42、 dose-response data (U.S. EPA, 1996a, U.S. EPA, 1999; U.S. EPA, 2003c; U.S. EPA, 2005a). If there is sufficient evidence to use a non-linear model, the LED10or BMDL10, divided by the anticipated exposure, is calculated to give a margin of exposure. If there is insufficient evidence to document non-l

43、inearity, a linear model drawing a straight line from the LED10or BMDL10to 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 the U.S. EPA to be safe and protective of public health (U.S. EPA, 1991a)

44、. For the purposes of NSF/ANSI 60 (2005) and 61 (2005), 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 benefit to counteract the additional risk. The RfD, TAC, SPAC, and STEL

45、 values derived in this document are based on available health effects data and are intended for use in determining compliance of products with the requirements of NSF/ANSI 60 (2005) and 61 (2005). Application of these values to other exposure scenarios should be done with care, and with a full unde

46、rstanding of the derivation of the values and of the comparative 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 evaluati

47、on, and require the use of additional uncertainty factors to protect public health. The general guidelines for this risk assessment include those from the National Research Council (NRC, 1983) and from the Presidential/Congressional Commission on Risk Assessment and Risk Management (1997a; 1997b). O

48、ther guidelines used in the development of this assessment may include 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 Carcinogen Risk Assessment (U.S. EPA, 1999), draft fina

49、l Guidelines For Carcinogen Risk Assessment (U.S. EPA, 2003c), Guidelines For Carcinogen Risk Assessment (U.S. EPA, 2005a), Guidelines for Developmental Toxicity 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), A Review of the Reference Dose and