1、2007 NSF Ethylenediamine 05/07 ETHYLENEDIAMINE CAS # 107-15-3 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI May 2007 Copyright 2007 NSF International2007 NSF Ethylenediamine 05/07 TABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organoleptic Properties3
2、 3.0 PRODUCTION AND USE .4 3.1 Production4 3.2 Use.4 3.2.1 Industrial Use.4 3.2.2 Food Additive Use5 3.2.3 Pharmaceutical Use.6 4.0 ANALYTICAL METHODS.6 4.1 Analysis in Water 6 4.2 Analysis in Biological Matrices 6 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .7 5.1 Sources of Human Exposure 7 5.
3、2 Sources of Environmental Exposure.7 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS7 6.1 Absorption9 6.1.1 Humans9 6.1.2 Laboratory Animals.9 6.2 Distribution 11 6.2.1 Humans11 6.2.2 Laboratory Animals.12 6.3 Metabolism.14 6.3.1 Humans14 6.3.2 Laboratory Animals.14 6.4 Eli
4、mination/Excretion .16 6.4.1 Humans16 6.4.2 Laboratory Animals.16 6.4.3 Summary of Comparative Kinetics between Humans and Laboratory Animals .18 7.0 EFFECTS ON HUMANS .19 7.1 Case Reports 19 7.1.1 Asthma .19 i2007 NSF Ethylenediamine 05/07 7.1.2 Contact Dermatitis and Skin Sensitization .20 7.2 Con
5、trolled Exposure Studies21 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS21 8.1 Limited-Exposure Effects .22 8.1.1 Irritation and Sensitization Studies.22 8.1.2 Ocular Exposure Studies.22 8.2 Single-Exposure Studies23 8.3 Short-Term Exposure Studies23 8.3.1 Dietary Exposure Study in F34
6、4 Rats.23 8.3.2 Gavage Study in F344 Rats .24 8.3.3 Gavage Study in B6C3F1 Mice .25 8.3.4 Dietary Exposure Study in B6C3F1Mice .25 8.3.5 Vapor Inhalation Study in Rats.26 8.4 Long-Term and Chronic Exposure Studies 27 8.4.1 Subchronic Studies 27 8.4.2 Chronic Oral (Dietary Administration) Study 31 8.
7、4.3 Chronic Dermal Study in Mice33 8.4.4 In vitro assays 34 8.5 Studies of Genotoxicity and Related End-Points34 8.5.1 Mutagenicity Assays 34 8.5.2 Assays of Chromosomal Damage36 8.5.3 Other Assays of Genetic Damage36 8.6 Reproduction and Developmental Toxicity Studies .38 8.6.1 Two-Generation Repro
8、duction Assay .38 8.6.2 Developmental Toxicity .39 8.7 Studies of Immunological and Neurological Effects.42 9.0 RISK CHARACTERIZATION .44 9.1 Hazard Assessment44 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .44 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization49 9.1.
9、3 Selection of Key Study and Critical Effect50 9.1.4 Identification of Susceptible Populations .51 9.2 Dose-Response Assessment.51 9.2.1 Uncertainty Factor Selection.51 9.2.2 Calculation of the Oral RfD 54 9.3 Exposure Characterization.54 ii2007 NSF Ethylenediamine 05/07 9.4 TAC Derivation .55 9.5 S
10、TEL Derivation55 9.5.1 Selection of Key Study and Critical Effect for the STEL Derivation.55 9.5.2 Selection of Uncertainty Factors for the STEL Derivation57 9.5.3 STEL Derivation59 10.0 RISK MANAGEMENT 60 10.1 SPAC Derivation 60 11.0 RISK COMPARISONS AND CONCLUSIONS 60 12.0 REFERENCES 62 12.1 REFER
11、ENCES CITED .62 12.2 REFERENCES NOT CITED (Cited/Reviewed by WHO/IPCS, 1999 and/or BUA, 1997)70 13.0 APPENDICES .78 13.1 Appendix A: Selected Data Tables .78 13.2 Appendix B: Dose Conversions.80 13.2.1 Single-Dose Vapor Inhalation Study with Human Volunteers .80 13.2.2 30-Day Vapor Inhalation Study
12、in Rats80 13.3 Appendix C: Benchmark Dose Results 81 14.0 PEER REVIEW HISTORY .94 iii2007 NSF Ethylenediamine 05/07 AUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS Author: NSF Toxicology Services NSF International 789 Disbar Road Ann Arbor, MI 48105 Disclaimer: The responsibility for the content of th
13、is 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 may
14、 not be equally suitable. Internal NSF Peer Reviewers: Gwendolyn Ball, Ph.D. Clif McLellan, M.S. Angela Ewing, 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 vol
15、untary 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. Environm
16、ental 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 Michigan St
17、ate University Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. iv2007 NSF Ethylenediamine 05/07 Jennifer Orme-Zavaleta, Ph.D. Director, Research Planning and Coordination Staff National Health and Environmental Effects Laboratory U.S. Environmental Protection A
18、gency Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California v2007 NSF Ethylenediamine 05/07 EXECUTIVE SUMMARY ETHYLENEDIAMINE Oral Risk Assessment CAS # 107-15-3 PARAMETER LEVEL UNITS DERIVED: NOAEL (no observed adverse effect level) 45 mg/kg-day From a chronic feeding st
19、udy in rats. Oral RfD (oral reference dose) 2 mg/kg-day From a chronic feeding study in rats with a 30x uncertainty factor. TAC (total allowable concentration) 10 mg/L From the oral RfD, for a 70 kg adult drinking 2 L/day with a default 20% Relative Source Contribution for drinking water. SPAC (sing
20、le product allowable concentration) 2 mg/L From the TAC, assuming the default 10 sources of ethylenediamine in the drinking water distrubution system. STEL (short term exposure level) 40 mg/L From a subchronic feeding study in rats, for a 10 kg child drinking 1 L/day. KEY STUDY Hermansky, S.J., R.S.
21、 Yang, R.H. Garman, and H.W. Leung. 1999. Chronic toxicity and carcinogenicity studies of ethylenediamine dihydrochloride by dietary incorporation in Fischer 344 rats. Food Chem Toxicol 37(7):765-76. CRITICAL EFFECT General toxicity, such as decreased mean terminal body weight gain, organ weights an
22、d altered clinical parameters, observed in male and female rats fed ethylenediamine dihydrochloride for two years. UNCERTAINTY FACTORS 3x for interspecies extrapolation 10x for intraspecies extrapolation 1x for extrapolation from a less-than-lifetime study to a lifetime exposure duration 1x for extr
23、apolation from a LOAEL to a NOAEL 1x for database deficiencies. Therefore, the total uncertainty factor was 30x. TOXICITY SUMMARY No oral toxicity data for ethylenediamine in humans were located. A number of case reports and controlled studies in humans described the potential for occupational expos
24、ure to ethylenediamine to cause contact dermatitis and skin sensitization. Inhalation of ethylenediamine vapors in humans has provoked asthmatic attacks in asthmatics. Oral short-term, subchronic, chronic, reproduction, and developmental toxicity studies in laboratory rodents have been published for
25、 ethylenediamine. Short-term to subchronic oral exposure resulted in statistically reduced mean body and organ weights and altered clinical parameters in rats and mice. In the liver, hepatocellular pleomorphism was observed in rats after subchronic and chronic dietary administration, as well as in t
26、he F1generation rats of a two-generation reproduction feeding study. Since the effect did not progress to liver tumors and was not accompanied by consistent changes in liver weight or enzymes, it was not considered adverse. The critical effect was considered reduced terminal mean body weight gain in
27、 male (23%) and female (17%) rats in the chronic feeding study, which occurred at 162 mg/kg-day, with a NOAEL of 45 mg/kg-day. The concurrent reduced organ weights and altered clinical parameters were considered to be secondary to the reduced body weight. The NOAEL approach was selected over the ben
28、chmark dose approach to determine the RfD since the reduced body weight gain exceeded 10% and was statistically significant only at the highest dose. Mixed results were obtained in Salmonella typhimurium reverse mutation assays. Ethylenediamine failed to induce forward mutations or sister chromatid
29、exchange in Chinese hamster ovary cells in vitro, and did not affect unscheduled DNA synthesis in cultured rat hepatocytes. Ethylenediamine produced negative results in a rat dominant lethal mutation assay in vivo. The weight of evidence suggests that ethylenediamine has some mutagenic potential in
30、bacterial cells in vitro, but there are insufficient data to evaluate the mutagenic potential of ethylenediamine in vivo. Ethylenediamine was not carcinogenic via the oral or dermal exposure route in rodents. Due to the lack of human epidemiology data or a carcinogenicity bioassay in a second animal
31、 species, data are inadequate for an assessment of human carcinogenic potential. CONCLUSIONS Chronic oral exposure to ethylenediamine caused general toxicity, such as reduced mean body weight gain and organ weights, but did not cause cancer in male or female rats. No human epidemiological data were
32、located. Uncertainty factors were used to account for interspecies and intraspecies differences, and drinking water action levels developed in this risk assessment are protective of public health. vi2007 NSF Ethylenediamine 05/07 1.0 INTRODUCTION This document has been prepared to allow toxicologica
33、l evaluation of the unregulated contaminant ethylenediamine in drinking water, as an extractant from one or more drinking water system components tested 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
34、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, 2002), which
35、assumes the threshold for these endpoints 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 fr
36、om 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 BMDL10from benchmark dose programs) can be used (
37、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 “an estimate (with uncertainty spanning perh
38、aps 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, 2005a). NSF uses the RfD to derive three product eval
39、uation 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 adult assumed to drink two liters of water pe
40、r 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 derived, if possible. Alternately, a 20% defau
41、lt 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) 2L/day The single product allowable concentration (SPAC), used
42、 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 12007 NSF Ethylenediamine 05/07 distribution system. In the absence of source d
43、ata, 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 in drinking water. Finally, a short-term-exposure level (STEL)-at a higher level than the TAC-may
44、 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 duration
45、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 cancer are
46、evaluated using modeling to fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999; U.S. EPA, 2003b; 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 of expo
47、sure. 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. EPA to b
48、e 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 generally require documentation of a benefit 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 determi
