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1、 2006 NSF 4-Chloro-1,3-benzenediamine 07/06 4-CHLORO-1,3-BENZENEDIAMINE CAS # 5131-60-2 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI July 2006 2006 NSF International 2006 NSF 4-Chloro-1,3-benzenediamine 07/06 iTABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES

2、.3 2.1 Organoleptic Properties3 3.0 PRODUCTION AND USE .4 3.1 Production4 3.2 Use.4 4.0 ANALYTICAL METHODS.4 4.1 Analysis in Water 4 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 .5 6.0 C

3、OMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS5 7.0 EFFECTS ON HUMANS .5 7.1 Case Reports 5 7.2 Epidemiological Studies6 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS6 8.1 Limited-Exposure Effects .6 8.2 Single-Exposure Studies6 8.3 Short-Term Exposure Studies6 8.4

4、 Long-Term and Chronic Exposure Studies 7 8.4.1 Subchronic Studies 7 8.4.2 Chronic Studies7 8.5 Studies of Genotoxicity and Related End-Points11 8.5.1 Mutagenicity Assays 11 8.5.2 Assays of Chromosomal Damage12 8.6 Reproduction and Developmental Toxicity Studies .13 8.7 Studies of Immunological and

5、Neurological Effects.13 9.0 RISK CHARACTERIZATION .14 9.1 Hazard Identification14 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .14 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization16 2006 NSF 4-Chloro-1,3-benzenediamine 07/06 ii9.1.3 Selection of Key Study and Critic

6、al Effect20 9.1.4 Identification of Susceptible Populations .22 9.2 Dose-Response Assessment.22 9.2.1 Uncertainty Factor Selection.22 9.2.2 Oral RfD Derivation 24 9.3 Exposure Assessment 24 9.4 TAC Derivation .24 9.5 STEL Derivation25 10.0 RISK MANAGEMENT 25 10.1 SPAC Derivation.25 11.0 RISK COMPARI

7、SONS AND CONCLUSIONS 26 12.0 REFERENCES 28 13.0 APPENDICES .33 13.1 Dose Conversions 33 13.2 Benchmark Dose Results 35 13.2.1 Benchmark Dose Modeling.35 13.2.2 Slope Factor Calculation.37 13.2.3 Unit Risk Calculation 38 13.2.4 Alternate TAC Derivation Based on Cancer Risk 38 13.2.5 Benchmark Dose Re

8、sults.39 14.0 PEER REVIEW HISTORY .41 2006 NSF 4-Chloro-1,3-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 this document rema

9、ins 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 may not be equally

10、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 on a voluntary bas

11、is, 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. Environmental Prot

12、ection 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 Michigan State Univer

13、sity Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. 2006 NSF 4-Chloro-1,3-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 of California 200

14、6 NSF 4-Chloro-1,3-benzenediamine 07/06 vEXECUTIVE SUMMARY 4-CHLORO-1,3-BENZENEDIAMINE Oral Risk Assessment CAS # 5131-60-2 PARAMETER LEVEL UNITS DERIVED NOAEL (no observable adverse effect level) 140 mg/kg-day From a chronic feeding study in rats Oral RfD (oral reference dose) 0.5 mg/kg-day From th

15、e chronic feeding study NOAEL in female rats TAC (total allowable concentration) 0.3 mg/L For a 70 kg adult drinking 2 L water/day with a 300x uncertainty factor and a 10x safety factor SPAC (single product allowable concentration) 0.03 mg/L From the TAC, assuming 10 potential sources of 4-chloro-1,

16、3-benzenediamine in drinking water STEL (short term exposure level) 0.3 mg/L Set equal to the TAC due to inadequate information to establish a higher action level. KEY STUDY National Toxicology Program (NTP)/National Cancer Institute (NCI). 1978. Bioassay of 4-Chloro-m-phenylenediamine For Possible

17、Carcinogenicity. Technical Report Series No. 85 DHEW Publication No. (NIH) 78-1335, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014. CRITICAL EFFECT The critical effect was reduced mean body weight in male and female rats administered 4-chloro-1,3-benze

18、nediamine in feed for two years. UNCERTAINTY FACTORS Uncertainty factors applied in calculating the oral RfD are as follows: 10x for interspecies extrapolation 10x for intraspecies extrapolation 1x for extrapolation from a less-than-lifetime study to lifetime duration 1x for extrapolation from a LOA

19、EL to a NOAEL 3x for database deficiencies The total uncertainty factor is, therefore, 300x. TOXICITY SUMMARY No human epidemiological, kinetic, or metabolic data were available for 4-chloro-1,3-benzenediamine. Reduced mean body weight, renal nephropathy, and hepatic basophilic cytoplasmic changes w

20、ere observed in male and female F344 rats at an increased incidence compared to concurrent controls after dietary administration of 4-chloro-1,3-benzenediamine for 78 weeks. Renal nephropathy was also observed in control rats. The kidney and liver changes are common findings among control F344 rats

21、from chronic studies, thus were not considered treatment-related. Tumors observed at increased incidences compared to controls included adrenal pheochromocytomas and testicular interstitial-cell tumors in male rats. Both tumor types in rat adrenal glands and testes occurred at incidences within hist

22、orical control ranges. Thus, those findings were not considered treatment-related. Dose-related reductions in mean body weight in male and female mice and renal glomerulonephritis in male mice were observed compared to concurrent controls after dietary administration of 4-chloro-1,3-benzenediamine f

23、or 78 weeks. The combined incidence of hepatocellular carcinomas and adenomas was increased compared to controls in female mice. The biological significance of the hepatocellular tumors in mice is unclear, since the incidence was within some published historical control ranges but outside others. Fu

24、rther, there is a high spontaneous incidence of hepatocellular tumors in B6C3F1 mice. The weight of evidence suggests that 4-chloro-1,3-benzenediamine is genotoxic in vitro. In the absence of cytotoxicity, 4-chloro-1,3-benzenediamine was mutagenic in S. typhimurium with and without metabolic activat

25、ion. It also induced chromosomal aberrations and sister chromatid exchanges in vitro. No in vivo genetic toxicity data were available. Since 4-chloro-1,3-benzenediamine was considered negative for carcinogenicity in the rat but equivocal in the mouse, and due to the positive in vitro but lack of in

26、vivo genotoxicity data, the weight of evidence supports the conclusion that there is inadequate information to assess carcinogenic potential (U.S. EPA, 2005) resulting from oral exposure to 4-chloro-1,3-benzenediamine. CONCLUSIONS Reduced mean body weight in rats was considered the critical effect.

27、Rats were considered to be more sensitive than mice since the administered doses were a magnitude lower in rats. The drinking water action levels derived in this risk assessment are protective of public health, since they were based on chronic oral data from the most sensitive laboratory animal spec

28、ies. Further, a safety factor of 10x was applied to the TAC to address the positive in vitro genotoxic data and carcinogenic potential demonstrated by 4-chloro-1,3-benzenediamine. 2006 NSF 4-Chloro-1,3-benzenediamine 07/06 11.0 INTRODUCTION This document has been prepared to allow toxicological eval

29、uation of the unregulated contaminant 4-chloro-1,3-benzenediamine in drinking water, as an extractant from one or more 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 a

30、nd 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 (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993; U.S. EPA, 200

31、2), which assumes that there is a threshold for these endpoints that will not be exceeded if appropriate uncertainty 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 wh

32、en 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 (the LED10or BMDL10f

33、rom benchmark dose programs) can be used (U.S. EPA, 2003a). 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 the U.S. EPA as “a

34、n 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.S. EPA, 2003b). NSF

35、 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 weight of an average adu

36、lt 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 should be data deri

37、ved, 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) 2 L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2 L/day The single

38、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 2006 NSF 4-Chloro-1,3-benzenediamin

39、e 07/06 2distribution system. In the absence of source data, a default multiple source factor of 10 is used. 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, a short-term-

40、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 90-days durat

41、ion, with uncertainty factors appropriate to the duration of the study. The contaminant level must decay to a level at 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 l

42、aboratory 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, 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

43、anticipated exposure, is calculated to give a margin of exposure. If there is insufficient evidence to document non-linearity, 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 targe

44、t risk range of 10-6to 10-4is considered to be safe and protective of public health. (U.S. EPA, 1991a). 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 genera

45、lly require documentation of a benefit to balance the additional risk. The RfD, TAC, SPAC, and STEL 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). App

46、lication 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 comparative magnitude and duration of the exposures. These values do not have the rigor of regulatory values, as data gaps are generally filled by i

47、ndustry or government studies prior to regulation. Data gaps introduce uncertainty into an evaluation, 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

48、 The Presidential/Congressional Commission on Risk Assessment and Risk Management (1997a, 1997b). Other 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

49、. EPA, 1996a), draft revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), draft final 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), Guid