1、 2006 NSF Hexamethylenediamine 07/06 HEXAMETHYLENEDIAMINE CAS # 124-09-4 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI June 2006 Copyright 2006 NSF International 2006 NSF Hexamethylenediamine 07/06 iTABLE OF CONTENTS 1.0 INTRODUCTION .1 2.0 PHYSICAL AND CHEMICAL PROPERTIES .3 2.1 Org
2、anoleptic Properties 4 3.0 PRODUCTION AND USE5 3.1 Production 5 3.2 Use .5 4.0 ANALYTICAL METHODS .5 4.1 Analysis in Water.5 4.2 Analysis in Biological Matrices.6 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE6 5.1 Sources of Human Exposure.6 5.2 Sources of Environmental Exposure6 6.0 COMPARATIVE K
3、INETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS6 6.1 Absorption 7 6.2 Distribution.7 6.3 Metabolism .8 6.3.1 Study in Humans 8 6.3.2 In Vitro Conversion to Metabolites 8 6.4 Elimination/Excretion10 6.4.1 Humans.10 6.4.2 Laboratory Animals 10 6.5 Conclusions Regarding Comparative Kinetics and
4、 Metabolism.11 7.0 EFFECTS ON HUMANS11 7.1 Case Reports.11 7.2 Epidemiological Studies.11 7.3 Inhibition of Antitrypsin .11 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS 12 8.1 Limited-Exposure Effects12 8.1.1 Irritation and Sensitization Studies12 8.1.2 Ocular Exposure Studies 13 8.2
5、Single-Exposure Studies 13 8.2.1 LD50 Studies.13 2006 NSF Hexamethylenediamine 07/06 ii8.2.2 Approximate Lethal Dose Studies 15 8.2.3 Effects on Ornithine Decarboxylase Activity .16 8.3 Short-Term Exposure Studies 16 8.3.1 Oral Studies.16 8.3.2 Inhalation Studies.18 8.4 Long-Term and Chronic Exposur
6、e Studies.20 8.4.1 Subchronic Studies, Oral20 8.4.2 Subchronic Studies, Inhalation21 8.4.3 Subchronic Studies, Dermal.25 8.4.4 Chronic Studies.25 8.5 In vitro Studies .26 8.6 Studies of Genotoxicity and Related End-Points 26 8.6.1 Mutagenicity Assays26 8.6.2 Assays of Chromosomal Damage.27 8.6.3 Oth
7、er Assays of Genetic Damage .28 8.7 Reproduction and Developmental Toxicity Studies28 8.7.1 Two-Generation Reproduction Study.28 8.7.2 Other Reproduction Assays 30 8.7.3 Developmental Toxicity Studies30 8.8 Studies of Immunological and Neurological Effects .34 8.8.1 Immunological Effects34 8.8.2 Neu
8、rological Effects .36 9.0 RISK CHARACTERIZATION37 9.1 Hazard Assessment 37 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action 37 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization.40 9.1.3 Selection of Key Study and Critical Effect.40 9.1.4 Identification of Susceptible Pop
9、ulations 42 9.2 Dose-Response Assessment .42 9.2.1 Uncertainty Factor Selection42 9.2.2 Oral RfD Calculation44 9.3 Exposure Assessment.45 9.4 TAC Derivation45 9.5 STEL Derivation 45 9.5.1 Uncertainty Factor Selection for STEL Derivation.46 9.5.2 STEL Calculation .48 2006 NSF Hexamethylenediamine 07/
10、06 iii10.0 RISK MANAGEMENT.48 10.1 SPAC Derivation .48 11.0 RISK COMPARISONS AND CONCLUSIONS.48 12.0 REFERENCES.49 13.0 APPENDICES55 13.1 Appendix A: Selected Data Tables55 13.2 Appendix B: Dose Conversions .58 13.2.1 2-Week Inhalation in Rats and Mice (Hebert et al., 1993; NTP, 1993)58 13.2.2 Subch
11、ronic Study Inhalation (Johannsen et al., 1987).58 13.2.3 Subchronic Study Inhalation (Hebert et al., 1993; NTP, 1993)59 13.2.4 Mutagenicity Assays (NTP, 1993, Witt et al., 2000).59 13.2.5 Immunological Reactivity (Shubik et al., 1978).60 14.0 PEER REVIEW HISTORY60 2006 NSF Hexamethylenediamine 07/0
12、6 ivAUTHORS, 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 remains solely with NSF International, and the author noted above should be contacte
13、d 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 suitable. Internal NSF Peer Reviewers: Gwendolyn Ball, Ph.D. Clif McLellan, M.S.
14、 Virunya Bhat, 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 basis, and their opinions do not necessarily represent the opinions of the organizations
15、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 Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairman, NSF Health Advisory Board)
16、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 University 2006 NSF Hexamethylenediamine 07/06 vCraig Farr, Ph.D., DABT Director, Product St
17、ewardship and Toxicology Health, Environment and Safety Arkema, Inc. Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Gene McConnell, Ph.D. Consultant ToxPath Jennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/WED Calvin Willhite, Ph.D. De
18、partment of Toxic Substances Control State of California 2006 NSF Hexamethylenediamine 07/06 viEXECUTIVE SUMMARY Hexamethylenediamine Oral Risk Assessment CAS # 124-09-4 PARAMETER LEVEL UNITS DERIVED NOAEL (no-observed-adverse-effect level) 150 mg/kg-day From a 2-generation reproduction study in rat
19、s. Oral RfD (oral reference dose) 2 mg/kg-day From a 2-generation reproduction study in rats with a 100x uncertainty factor. TAC (total allowable concentration) 10 mg/L From the oral RfD, for a 70 kg adult drinking 2L/day with a default 20% Relative Source Contribution for drinking water. SPAC (sing
20、le product allowable concentration) 1 mg/L From the TAC, assuming the default 10 sources of hexamethylenediamine in drinking water. STEL (short term exposure level) 20 mg/L From a developmental study in rats, for a 10 kg child drinking 1L/day KEY STUDY Short, R.D, F.R. Johannsen, and J.L. Scharden.
21、1991. A two-generation reproduction study in rats receiving diets containing hexamethylenediamine. Fundamental and Applied Toxicology. 16 : 490-494. CRITICAL EFFECT Decreased parental body weight, decreased pup weight, decreased absolute testicular weight and decreased litter size. UNCERTAINTY FACTO
22、RS Uncertainty factors applied in calculating the oral RfD are as follows: 10x for interspecies extrapolation 10x for intraspecies variability 1x for extrapolation from a less-than-lifetime study to lifetime duration 1x for extrapolation from a LOAEL to a NOAEL 1x for database deficiencies. Therefor
23、e, the total uncertainty factor is 100x. TOXICITY SUMMARY The only human toxicity data were from a metabolism study in which the excretion of hexamethylenediamine was determined to be a rapid process. A possible pathway for the metabolism of hexamethylenediamine to mono-acetylated hexamethylenediami
24、ne and 6-aminohexanoic acid was proposed. In vitro metabolism data using mouse fibroblasts suggested that hexamethylenediamine inhibited the activity of ornithine decarboxylase, an enzyme involved in the biosynthesis of polyamines. Toxicological data available for hexamethylenediamine in laboratory
25、animals included short-term, subchronic, two-generation reproduction, developmental and genetic toxicity studies. The critical study chosen to derive the oral RfD was a two-generation reproduction study in which rats were administered hexamethylenediamine in the diet at 0, 50, 150, or 500 mg/kg-day.
26、 The NOAEL identified was 150 mg/kg-day, based on decreased parental body weight, decreased pup weight, decreased absolute testicular weight and decreased litter size. Hexamethylenediamine administration did not affect reproductive success. Salmonella typhimurium reverse mutation and in vivo and in
27、vitro chromosomal aberration assays showed hexamethylenediamine was not genotoxic. An in vivo micronucleus assay showed an increase in polychromatic erythrocytes in the total erythrocyte population with no increase in micronucleated normochromatic or polychromatic erythrocytes. CONCLUSIONS Due to th
28、e lack of epidemiological data in humans or chronic data in laboratory animals, there is inadequate information to assess the carcinogenic potential of hexamethylenediamine. Decreased parental body weight, decreased pup weight, decreased absolute testicular weight and decreased litter size in the tw
29、o-generation reproduction study were the most sensitive endpoints of toxicity observed in the available studies. Based on the identified critical effects and the uncertainty factors applied, the drinking water action levels derived in this risk assessment are protective of human health. 2006 NSF Hex
30、amethylenediamine 07/06 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant hexamethylenediamine in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/ANSI 61 (2005), or as a contaminan
31、t 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 Protection Agency (U.S. EPA) has been used. Non-cancer endpoints are evaluated using the referen
32、ce 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 factors (Dourson et al., 1996; U.S. EPA, 2002; WHO/IPCS, 2005) are applied to the highest
33、 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 level (NOAEL) taken directly from the dose-response data, or the calculated lower 95% confid
34、ence 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 be used, with an additional uncertainty factor, although the benchmark dose approach is
35、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 (including sensitive subgroups) that is likely to be without an appreciable risk of deleterio
36、us 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 (TAC), generally used to evaluate the results of extraction testing normalized to static
37、 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 exceeded when food and other non-water sources of exposure to the chemical are considered
38、, 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 calculation is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70 kg total contribution of other so
39、urces (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 to flowing at-the-tap conditions, is the TAC divided by the estimated total number of so
40、urces 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 Hexamethylenediamine 07/06 2This accounts for the possibility that more than one product in the water and/or its distribution system
41、 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 to extract at higher levels from new product, but also expected to decay rapidly over time. The S
42、TEL 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 must decay to a level at or below the TAC under static conditions, or to a level at or below the SPAC under flowing condition
43、s 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 dose-response data (U.S. EPA, 1996a, U.S. EPA, 1999; U.S. EPA, 2003c; U.S. EPA, 2005a). If there is s
44、ufficient 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-linearity, a linear model drawing a straight line from the LED10or BMDL10to zero, is used as a default.
45、 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). For the purposes of NSF/ANSI 60 (2005) and 61 (2005), the TAC is set at the 10-5risk level, and the
46、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 i
47、n 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 understanding of the derivation of the values and of the comparative magnitude and duration of the exposur
48、es. 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 protect public health. The general guidelin
