NSF DODECANEDIOIC ACID-2006 DODECANEDIOIC ACID CAS # 693-23-2 ORAL RISK ASSESSMENT DOCUMENT《十二烷二酸 CAS号》.pdf

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1、 2006 NSF Dodecanedioic Acid 11/06 DODECANEDIOIC ACID CAS # 693-23-2 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI November 2006 Copyright 2006 NSF International 2006 NSF Dodecanedioic Acid 11/06 iTABLE OF CONTENTS 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organol

2、eptic 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 .6 5.1 Sources of Human Exposure 6 5.2 Sources of Environmental Exposure .6 6.0 COMPARATIVE KIN

3、ETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS6 6.1 Absorption6 6.2 Distribution 7 6.2.1 Studies in Humans.7 6.2.2 Studies in Rats8 6.3 Metabolism.10 6.3.1 Studies in Humans.10 6.3.2 Studies in Rats11 6.4 Elimination/Excretion .17 6.4.1 Studies in Humans.17 6.4.2 Studies in Rats18 6.5 Integra

4、ted Kinetics and Metabolism Studies 19 6.5.1 Studies in Humans.19 6.5.2 Studies in Rats22 7.0 EFFECTS ON HUMANS .23 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS23 8.1 Limited-Exposure Effects .23 8.1.1 Irritation and Sensitization Studies.23 8.1.2 Ocular Exposure Studies.24 8.2 Single

5、-Exposure Studies24 2006 NSF Dodecanedioic Acid 11/06 ii8.3 Short-Term Exposure Studies24 8.4 Long-Term and Chronic Exposure Studies 24 8.4.1 Subchronic Studies 24 8.4.2 Chronic Studies24 8.4.3 In Vitro Studies25 8.5 Studies of Genotoxicity and Related End-Points25 8.5.1 Mutagenicity Assays 25 8.5.2

6、 Assays of Chromosomal Damage25 8.5.3 Other Assays of Genetic Damage25 8.6 Reproduction and Developmental Toxicity Studies .25 8.7 Studies of Immunological and Neurological Effects.26 9.0 RISK CHARACTERIZATION .26 9.1 Hazard Assessment26 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Actio

7、n .27 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization28 9.1.3 Selection of Key Study and Critical Effect28 9.1.4 Identification of Susceptible Populations .28 9.2 Dose-Response Assessment.28 9.2.1 Uncertainty Factor Selection.28 9.2.2 Oral RfD Calculation 30 9.3 Exposure Assessment 3

8、0 9.4 TAC Derivation .31 9.5 STEL Derivation31 9.5.1 Uncertainty Factor Selection.31 9.5.2 STEL Calculation 33 10.0 RISK MANAGEMENT 33 10.1 SPAC Derivation.33 11.0 RISK COMPARISONS AND CONCLUSIONS 33 12.0 REFERENCES 34 13.0 PEER REVIEW HISTORY .39 14.0 REFERENCES NOT REVIEWED .42 2006 NSF Dodecanedi

9、oic 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 noted above shou

10、ld 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 McLellan, M.S. Externa

11、l 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 affilia

12、ted. 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 (Toxicology E

13、xcellence 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 Safety Noveon, Inc. 2006 NSF Dodecanedi

14、oic Acid 11/06 ivErnest E. McConnell, D.V.M., M.S. (Path) ToxPath, Inc. Raleigh, NC Jennifer 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 Su

15、bstances Control State of California 2006 NSF Dodecanedioic Acid 11/06 vEXECUTIVE SUMMARY Dodecanedioic Acid Oral Risk Assessment CAS # 693-23-2 PARAMETER LEVEL1UNITS DERIVED NOAEL (no-observed-adverse-effect level) 74 mg/kg-day From a human oral bolus dose study supported by studies using intraveno

16、us infusion. Oral RfD (oral reference dose) 70 mg/kg-day From the NOAEL with a 1x total uncertainty factor. TAC (total allowable concentration) 30 mg/L A TAC of 500 mg/L was calculated from the oral RfD, the default 70 kg body weight and 2 L/day water consumption of an adult, and a 20% relative sour

17、ce contribution for drinking water. The TAC was limited by the 30 mg/L water solubility of dodecanedioic acid. SPAC (single product allowable concentration) 30 mg/L A SPAC of 50 mg/L was calculated from the TAC based on the default 10 sources of dodecanedioic acid in drinking water. The SPAC was lim

18、ited by the 30 mg/L water solubility of dodecanedioic acid. STEL (short term exposure level) 30 mg/L A STEL of 700 mg/L was calculated from the NOAEL using the default 10 kg body weight and 1 L/day water consumption of a child. The STEL was limited by the 30 mg/L water solubility of dodecanedioic ac

19、id. 1 The specified levels are based on the only available controlled human study by the oral route, supported by studies at higher levels using intravenous infusion. The existence of large food sources of dodecanedioic acid or its precursor dodecanoic acid and human tolerance of higher levels by in

20、fusion suggest these levels are likely conservative. Further, the TAC, SPAC, and STEL are limited by the water solubility of the chemical and are not based on any observed health effect. KEY STUDY Passi, S., M. Nazzaro-Porro, M. Picardo, G. Mingrone, and P. Fasella. 1983. Metabolism of straight satu

21、rated medium chain length (C9 to C12) dicarboxylic acids. J Lipid Res 24:1140-1147. CRITICAL EFFECT No critical effect was identified in humans or laboratory animals over the tested dose ranges. UNCERTAINTY FACTORS Factors applied in calculating the oral RfD include: 1x for interspecies extrapolatio

22、n 1x for intraspecies extrapolation 1x for subchronic to chronic extrapolation 1x for LOAEL to NOAEL extrapolation 1x for database deficiencies The total uncertainty factor is therefore 1x. TOXICITY SUMMARY Oral and parenteral studies in humans provided more direct representation of human response t

23、o dodecanedioic acid than animal studies. No signs of toxicity were seen in any of the volunteer subjects tested. Mild reductions in leukocyte (lymphocyte) counts were not considered adverse in the only repeated dose oral rat study. The single and repeated dose human and animal studies are in agreem

24、ent regarding the lack of any health hazard from oral or parenteral exposure to this chemical. The mode of action of dodecanedioic acid is well understood. The chemical can be metabolized in the liver by the fatty acid -oxidation pathway, and it can also be produced in the liver from dodecanoic acid

25、, a common food oil component, by -oxidation. A Salmonella typhimurium reverse mutation assay produced negative results, as did a mouse bone marrow micronucleus assay. The only repeated dose oral study in laboratory animals was not adequate to address the carcinogenic potential of this compound. How

26、ever, there is considerable human exposure to dodecanoic acid from food sources, and the human body is capable of producing dodecanedioic acid in the liver from dodecanoic acid by -oxidation. Based on negative findings for mutagenicity and clastogenicity, and on the extent of human exposure over tim

27、e, dodecanedioic acid is not likely to be carcinogenic to humans based on U.S. EPA guidelines. CONCLUSIONS The existence of naturally occurring dodecanedioic acid or its precursor (dodecanoic acid) in edible plant and animal products as well as the existence of normal metabolic pathways for handling

28、 dietary dicarboxylic acids, which dodecanedioic acid has been shown to follow, suggest the potential for human toxicity is low. Based on the results of controlled human studies of the use of this chemical for parenteral nutrition, the drinking water action levels established in this document are pr

29、otective of human health. 2006 NSF Dodecanedioic Acid 11/06 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant dodecanedioic acid in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/

30、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 the U.S. Environmental Protection Agency (U.S. EPA) has been used. Non-cancer endpoin

31、ts 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 exceeded if appropriate uncertainty factors (Dourson et al., 1996; U.S. EPA, 2002; WHO/IPCS

32、, 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 no-observed-adverse-effect level (NOAEL) taken directly from the dose-response data,

33、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-effect level (LOAEL) can also be used, with an additional uncertainty factor, althou

34、gh 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 exposure to the human population (including sensitive subgroups) that is likely to be withou

35、t 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 total allowable concentration (TAC), generally used to evaluate the results of extra

36、ction 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), to ensure that the RfD is not exceeded when food and other non-water sources of expos

37、ure 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. EPA, 1991a). The TAC calculation is then as follows: TAC (mg/L) = RfD (mg/kg-day) x 70

38、 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 water treatment chemicals and for water contact materials normalized to flowing at-the-tap conditions, is the TAC divided b

39、y 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. 2006 NSF Dodecanedioic Acid 11/06 2This accounts for the possibility that more than one product in the wate

40、r 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 solvents expected to extract at higher levels from new product, but also expected t

41、o 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 level must decay to a level at or below the TAC under static conditions, or to a level at or

42、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 appropriate dose-response data (U.S. EPA, 1996a, U.S. EPA, 1999; U.S. EPA,

43、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 non-linearity, a linear model drawing a straight line from the LED10o

44、r 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, 1991a). For the purposes of NSF/ANSI 60 (2005) and 61 (2005), the TAC

45、 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

46、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 full understanding of the derivation of the values and of the comparativ

47、e 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 evaluation, and require the use of additional uncertainty factors to pr

48、otect 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; 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 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999), dra