1、 2006 NSF Adipic Acid 11/06 ADIPIC ACID CAS # 124-04-9 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI November 2006 Copyright 2006 NSF International NSF 2006 Adipic Acid 11/06 iTABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organoleptic Properties4 3.0
2、 PRODUCTION AND USE .4 3.1 Production4 3.2 Use.5 4.0 ANALYTICAL METHODS.5 4.1 General Methods of Analysis5 4.2 Analysis in Biological Matrices 7 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE .7 5.1 Sources of Human Exposure 8 5.2 Sources of Environmental Exposure .8 5.2.1 Air.8 5.2.2 Water 9 5.2.3
3、 Dust and Soil10 5.2.4 Natural Sources .10 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS10 6.1 Absorption11 6.2 Distribution 11 6.3 Metabolism.11 6.3.1 Studies in Humans.11 6.3.2 Studies in Laboratory Animals12 6.4 Elimination/Excretion .15 6.5 Conclusions Regarding Compar
4、ative Kinetics and Metabolism 16 7.0 EFFECTS ON HUMANS .18 7.1 Irritation and Sensitization.18 7.2 Ocular Exposure Studies 18 7.3 Case Reports 18 7.4 Epidemiological Studies20 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS20 8.1 Limited-Exposure Effects .20 8.1.1 Irritation and Sensitiz
5、ation Studies.20 NSF 2006 Adipic Acid 11/06 ii8.1.2 Ocular Exposure Studies.20 8.2 Single-Exposure Studies21 8.3 Short-Term Exposure Studies23 8.4 Long-Term and Chronic Exposure Studies 24 8.4.1 Subchronic Studies 24 8.4.2 Chronic Studies28 8.4.3 In Vitro Studies29 8.5 Studies of Genotoxicity and Re
6、lated End-Points29 8.5.1 Mutagenicity Assays 29 8.5.2 Assays of Chromosomal Damage30 8.5.3 Other Assays of Genetic Damage32 8.6 Reproduction and Developmental Toxicity Studies .33 8.6.1 Two-Generation Reproduction Study33 8.6.2 In Vitro Study.33 8.6.3 Developmental Toxicity Studies 33 8.7 Studies of
7、 Immunological and Neurological Effects.34 9.0 RISK CHARACTERIZATION .35 9.1 Hazard Assessment35 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .35 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization37 9.1.3 Selection of Key Study and Critical Effect37 9.1.4 Identificati
8、on of Susceptible Populations .38 9.2 Dose-Response Assessment.38 9.2.1 Oral RfD Calculation 42 9.3 Exposure Assessment 42 9.4 TAC Derivation .42 9.5 STEL Derivation43 10.0 RISK MANAGEMENT 46 10.1 SPAC Derivation.46 11.0 RISK COMPARISONS AND CONCLUSIONS 47 12.0 REFERENCES 48 13.0 PEER REVIEW HISTORY
9、 .58 NSF 2006 Adipic Acid 11/06 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 remains solely with NSF International, and the author
10、 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 suitable. Internal NSF Peer Reviewers: Clif McLel
11、lan, M.S. Jackie Russell, M.P.H. 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 o
12、rganizations 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 Adv
13、isory 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 University Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product S
14、afety Noveon, Inc. NSF 2006 Adipic Acid 11/06 ivJennifer Orme-Zavaleta, Ph.D. Director, Research Planning and Coordination Staff National Health and Environmental Effects Laboratory U.S. Environmental Protection Agency Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California
15、 NSF 2006 Adipic Acid 11/06 vEXECUTIVE SUMMARY Adipic Acid Oral Risk Assessment CAS # 124-04-9 PARAMETER LEVEL UNITS DERIVED NOAEL (no-observed-adverse-effect level) 400 mg/kg-day From 33-week and chronic repeated dose studies in rats Oral RfD (oral reference dose) 4 mg/kg-day From 33-week and chron
16、ic repeated dose studies in rats with a 100x total uncertainty factor TAC (total allowable concentration) 30 mg/L For a 70 kg adult drinking 2 L/day using a 20% relative source contribution for drinking water SPAC (single product allowable concentration) 3 mg/L From the TAC, using the default 10 sou
17、rces of adipic acid in drinking water STEL (short term exposure level) 100 mg/L From a 19-week repeated dose study, for a 10 kg child drinking 1 L/day KEY STUDY Lang, K., and Bartsch, A-R. 1953. ber den stoffwechsel und die vertrglichkeit der adipinsure. Biochem Zeitschrift 323:462-468; with support
18、 from Horn, H.L., E.G. Holland, and L.W. Hazelton. 1957. Safety of adipic acid as compared with citric and tartaric acid. Agric Food Chem 5(10):759-762. CRITICAL EFFECT A weight of evidence NOAEL was established based on effects including reduced survival, diarrhea, decreased body weight during grow
19、th, and intestinal and liver pathology. UNCERTAINTY FACTORS Factors applied in calculating the oral RfD include: 10x for interspecies extrapolation 10x for intraspecies extrapolation 1x for subchronic to chronic extrapolation 1x for LOAEL to NOAEL 1x for database deficiencies The total uncertainty f
20、actor is therefore 100x. TOXICITY SUMMARY Adipic acid has been used as a direct food additive for several decades. The JECFA Acceptable Daily Intake (ADI) is 0-5 mg/kg. Bolus oral doses of up to 10 g (140 mg/kg for a 70 kg adult) adipic acid were tolerated by humans. Several repeated dose oral studi
21、es in rats, from five weeks to lifetime duration, have been conducted on adipic acid resulting in NOAEL values in the range of 400-3,000 mg/kg-day. Decreased body weight was observed in most studies with survival, diarrhea, chronic intestinal inflammation, regeneration activity in the principal part
22、 of the kidney, and enlargement of liver cell nuclei and occasionally whole cell volume observed in some instances at high doses. Some of these effects may have been related to administration of adipic acid in a wheat/milk diet, or to acidity of the chemical. Although the feeding studies were old an
23、d did not include all the endpoints required under current guidelines, few adverse effects were noted in the examined hematology and clinical parameters, or in the macroscopic and microscopic examination of many organs and tissues after lifetime exposure. The limited correlation of toxicity with exp
24、osure duration likely resulted from the rapid (within a few hours) and extensive ( 70%) metabolism of adipic acid to carbon dioxide. Adipic acid is normally metabolized by the mammalian fatty acid -oxidation pathway. Developmental toxicity studies in rats, mice, hamsters, and rabbits have been perfo
25、rmed with adipic acid. No adverse effects were noted in dams or fetuses at maternal doses approaching 300 mg/kg-day given during the period of organogenesis. Adipic acid was not mutagenic in Salmonella typhimurium reverse mutation assays. Chromosomal aberration assays, although uniformly negative, h
26、ad sufficient protocol deficiencies based on current guidelines to preclude a conclusion regarding clastogenicity. A chronic study in rats did not detect any treatment-related tumors, but used an inadequate number of animals and assessed too few endpoints to meet current guidelines. Due to deficienc
27、ies in the only available chronic study as well as in the genetic toxicity studies, the data are inadequate for an assessment of human carcinogenic potential under current regulatory guidelines. CONCLUSIONS Based on the studies reviewed, the metabolic pathway for adipic acid, and the uncertainty fac
28、tors applied, the TAC, SPAC, and STEL drinking water action levels derived in this document are protective of public health. NSF 2006 Adipic Acid 11/06 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant adipic acid in drinking water, as
29、 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 and cancer endpoints have been considered, and risk assessment methodology developed by
30、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 threshold for these endpoints that will not be exceed
31、ed 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 when available, but more often is derived from studies in laboratory animals. Either the
32、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, 2003a). The lowest-observed-adverse
33、-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 order of magnitude) of a daily exposur
34、e 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 criteria for non-cancer endpoints. The
35、 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 relative source contribution (RSC),
36、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 contribution for water can be used (U.S. E
37、PA, 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 for water treatment chemicals and for water
38、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 of 10 is used. NSF 2006 Adipic Acid 11/
39、06 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 TAC, may be calculated for contaminants such as solvent
40、s 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 of the study. The contaminant must decay to a l
41、evel 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 evaluated using modeling to fit a curve to the appro
42、priate 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
43、 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 be safe and protective of public health. (U.S. EPA,
44、 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, a
45、nd 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). Application of these values to other exposure scenarios should be done with care, and with a fu
46、ll 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 prior to regulation. Data gaps introduce uncertainty into an e
47、valuation, 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, 19
48、97b). 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 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), draft final Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2003c), final Guidelines For Carcinogen Risk Assessment (U.S. EPA, 2005a), Guidelines for Developmen
