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1、 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 2-CHLORO-1,4-BENZENEDIAMINE CAS # 615-66-7 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI May 2005 Copyright 2005 NSF International 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 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 8.1.1 Irritation and Sensitization Studies.7 8.1.2 Ocular

4、 Exposure Studies.7 8.2 Single-Exposure Studies7 8.3 Short-Term Exposure Studies7 8.4 Long-Term and Chronic Exposure Studies 8 8.4.1 Subchronic Studies 8 8.4.2 Chronic Studies9 8.5 Studies of Genotoxicity and Related End-Points12 8.5.1 Mutagenicity Assays 12 8.5.2 Assays of Chromosomal Damage12 8.5.

5、3 Other Assays of Genetic Damage12 8.6 Reproduction and Developmental Toxicity Studies .13 8.6.1 Two-Generation Reproduction Study13 8.6.2 Developmental Toxicity Studies 13 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 ii8.7 Studies of Immunological and Neurological Effects.14 9.0 RISK CHARACTERIZATION

6、 .14 9.1 Hazard Assessment14 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .14 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization15 9.1.3 Selection of Key Study and Critical Effect18 9.1.4 Identification of Susceptible Populations .18 9.2 Dose-Response Assessment.18 9.

7、2.1 Benchmark Dose Modeling.18 9.2.2 Uncertainty Factor Selection.20 9.2.3 Oral RfD Calculation 21 9.3 Exposure Assessment 21 9.4 TAC Derivation .22 9.5 STEL Derivation22 9.5.1 Uncertainty Factor Selection.22 9.5.2 STEL Calculation 24 10.0 RISK MANAGEMENT 24 10.1 SPAC Derivation.24 11.0 RISK COMPARI

8、SONS AND CONCLUSIONS 24 12.0 REFERENCES 25 13.0 APPENDICES .29 13.1 Dose conversions .29 13.2 Salmonella typhimurium Reverse Mutation Assay Results34 13.3 Benchmark Dose Results 35 14.0 PEER REVIEW HISTORY .37 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 iiiAUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENT

9、S 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 remains solely with NSF International, and the author noted above should be contacted with comments or for clarification. Mention of

10、 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 suitable. Internal NSF Peer Reviewers: Gwendolyn Ball, Ph.D. Clif McLellan, M.S. Jackie Russell, M.P.H. Carolyn Gillilland, M.S.

11、 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 basis, and their opinions do not necessarily represent the opinions of the organizations with which they are

12、 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 Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairman, NSF Health Advisory Board) Director TERA (Toxi

13、cology Excellence for Risk Assessment) David Blakey, D.Phil. Director, Environmental Health Science Safe Environments Programme Health Canada Steven Bursian, Ph.D. Professor Michigan State University 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 ivRandy Deskin, Ph.D., DABT Director, Toxicology and Prod

14、uct Regulatory Compliance Cytec Industries Inc. Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/WED Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California 2005

15、NSF 2-Chloro-1,4-benzenediamine 05/05 vEXECUTIVE SUMMARY 2-CHLORO-1,4-BENZENEDIAMINE Oral Risk Assessment CAS # 615-66-7 PARAMETER LEVEL UNITS DERIVED BMDL10(95% confidence limit at 10% response level) 15 mg/kg-day From a chronic feeding study in rats Oral RfD (oral reference dose) 0.05 mg/kg-day Fr

16、om the BMDL10with a 300x total uncertainty factor TAC (total allowable concentration) 0.3 mg/L For a 70 kg adult drinking 2 L/day, with a 20% relative source contribution for drinking water SPAC (single product allowable concentration) 0.03 mg/L From the TAC, assuming 10 potential sources of 2-chlor

17、o-1,4-benzenediamine in drinking water STEL (short term exposure level) 0.5 mg/L From a chronic rat feeding study and based on a 10 kg child drinking 1 L/day. KEY STUDY NTP/NCI (National Toxicology Program/National Cancer Institute). 1978a. Bioassay of 2-Chlorophenylenediamine Sulfate for Possible C

18、arcinogenicity. Technical Report Series No. 113 DHEW Publication No. (NIH) 78-1368, U.S. Department of Health Education and Welfare, National Cancer Institute, Bethesda, MD 20014. CRITICAL EFFECT Transitional cell hyperplasia of the kidney and renal pelvis in male rats. UNCERTAINTY FACTORS Uncertain

19、ty 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 LOAEL to a NOAEL 3x for database deficiencies. The total uncertai

20、nty factor is, therefore, 300x. TOXICITY SUMMARY No oral data in humans were available. 2-Chloro-1,4-benzenediamine sulfate did not cause a statistical increase in any tumor type in rats or mice after chronic dietary administration. However, transitional cell hyperplasia of the kidney and renal pelv

21、is was observed in male and female rats at increased incidence compared to controls. The incidence of renal epithelial hyperplasia was dose related in males, but a NOAEL could not be identified. Hepatic focal necrosis was observed in male mice at an increased incidence compared to controls, but the

22、incidence was not dose-related. No kinetic and limited metabolism studies in humans and laboratory animals were identified for 2-chloro-1,4-benzenediamine. In the Salmonella typhimurium reverse mutation assay, 2-chloro-1,4-benzenediamine sulfate produced dose-related increases in revertant colonies

23、of more than twice the background level at higher doses but in the absence of cytotoxicity. 2-Chloro-1,4-benzenediamine was negative in the in vivo alkaline single cell assay (Comet assay) and in the alkaline elution assay for the detection of hepatic DNA damage. The limited genotoxicity data identi

24、fied for 2-chloro-1,4-benzenediamine or its sulfate salt precluded definitive conclusions regarding its genotoxic potential. However, structure-activity relationship studies suggest that the genotoxic or carcinogenic potential of 2-chloro-1,4-benzenediamine is less than that of 4-chloro-1,2-benzened

25、iamine or 4-chloro-1,3-benzenediamine. Further, no statistical increases in tumors were observed after chronic feeding. The data are inadequate for an assessment of human carcinogenic potential of 2-chloro-1,4-benzenediamine or its sulfate salt. For the purposes of this risk assessment, 2-chloro-1,4

26、-benzenediamine was considered a non-carcinogen. A NOAEL could not be identified for the critical effect of transitional cell hyperplasia of the kidney and renal pelvis in male rats. A BMDL10of 15 mg/kg-day was determined, since the incidence was dose-related. This effect was considered non-neoplast

27、ic, since the rats were treated for at least 24 months, as recommended by current U.S. EPA health effects testing guidelines, and the effect did not progress into renal tumors. CONCLUSIONS The drinking water action levels developed in this risk assessment are protective of public health since they w

28、ere developed based on chronic oral data for 2-chloro-1,4-benzenediamine sulfate from the most sensitive endpoint and laboratory animal species. 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contamina

29、nt 2-chloro-1,4-benzenediamine in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/ANSI 61 (2004), or as a contaminant in a drinking water treatment chemical evaluated under NSF/ANSI 60 (2004). Both non-cancer and cancer endpoints have been consi

30、dered, 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, 2002), which assumes that there is a t

31、hreshold for these endpoints that will not be exceeded if appropriate uncertainty factors (Dourson et al., 1996; U.S. EPA, 2002) 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 studie

32、s 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 BMDL10from benchmark dose programs) can be used (U.S. EPA,

33、 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 “an estimate (with uncertainty spanning perhaps an or

34、der 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 uses the RfD to derive three product evaluation cr

35、iteria 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 adult assumed to drink two liters of water per day. A

36、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 derived, if possible. Alternately, a 20% default contri

37、bution 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 product allowable concentration (SPAC), used for wa

38、ter 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 system. In the absence of source data, a default multiple source factor o

39、f 10 is used. 2005 NSF 2-Chloro-1,4-benzenediamine 05/05 2This 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-exposure level (STEL), at a higher level than the T

40、AC, 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 duration, with uncertainty factors appropriate to the du

41、ration 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 laboratory extraction data. Endpoints related to can

42、cer 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, 2005). 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

43、 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 target risk range of 10-6to 10-4is considered by the U.S.

44、 EPA to be safe and protective of public health (U.S. EPA, 1991a). For the purposes of NSF/ANSI 60 (2004) and 61 (2004), 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 benefi

45、t to counteract 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 (2004) and 61 (2004). Application of these values to other

46、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 industry or government studies prio

47、r 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 the Presidential/Congressional Co

48、mmission 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. EPA, 1996a), draft revised Guide

49、lines 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, 2005), 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 th