1、 2007 NSF Methyl Isobutyl Ketone - 05/07 METHYL ISOBUTYL KETONE CAS # 108-10-1 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI May 2007 Copyright 2007 NSF International 2007 NSF Methyl Isobutyl Ketone -05/07 TABLE OF CONTENTS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
2、24 25 26 27 28 29 30 31 32 33 34 35 1.0 INTRODUCTION.1 2.0 PHYSICAL AND CHEMICAL PROPERTIES.3 2.1 Organoleptic Properties3 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
3、 EXPOSURE .5 5.1 Sources of Human Exposure 5 5.2 Sources of Environmental Exposure .5 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATORY ANIMALS6 6.1 Absorption6 6.1.1 Humans6 6.1.2 Laboratory Animals.6 6.2 Distribution 7 6.2.1 Humans7 6.2.2 Laboratory Animals.8 6.3 Metabolism.8 6.3.1
4、Humans8 6.3.2 Laboratory Animals.2 6.4 Elimination/Excretion .3 6.4.1 Humans3 6.4.2 Laboratory Animals.4 6.5 Physiologically-Based Pharmacokinetic Models 4 6.6 Conclusions Regarding Comparative Kinetics and Metabolism 4 7.0 EFFECTS ON HUMANS .4 7.1 Case Reports 4 7.2 Epidemiological Studies4 7.2.1 C
5、ontrolled Exposure Studies.5 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS5 i 2007 NSF Methyl Isobutyl Ketone -05/07 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 8.1 Limited-Exposure Effects .5 8.1.1 Irritation and Sensitization Stu
6、dies.5 8.1.2 Ocular Exposure Studies.6 8.2 Single-Exposure Studies6 8.2.1 Oral Exposure6 8.2.2 Other Exposure Routes6 8.3 Short-Term Exposure Studies7 8.3.1 Oral Exposure7 8.3.2 Inhalation Exposure7 8.3.3 Dermal Exposure.10 8.4 Long-Term and Chronic Exposure Studies 10 8.4.1 Subchronic Studies 10 8.
7、4.2 Chronic Studies16 8.5 Studies of Genotoxicity and Related End-Points18 8.5.1 Mutagenicity Assays 18 8.5.2 Assays of Chromosomal Damage19 8.5.3 Other Assays of Genetic Damage20 8.6 Reproduction and Developmental Toxicity Studies .20 8.6.1 Reproduction Studies.20 8.6.2 Developmental Toxicity Studi
8、es 22 8.7 Studies of Immunological and Neurological Effects.24 8.7.1 Immunological Effects 24 8.7.2 Neurological Effects 24 9.0 RISK CHARACTERIZATION .27 9.1 Hazard Assessment27 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action .27 9.1.2 Weight-of-Evidence Evaluation and Cancer Charact
9、erization32 9.1.3 Selection of Key Study and Critical Effect37 9.1.4 Identification of Susceptible Populations .41 9.2 Dose-Response Assessment.41 9.2.1 Uncertainty Factor Selection.41 9.2.2 Oral RfD Calculation 45 9.3 Exposure Assessment 45 9.4 TAC Derivation .46 9.5 STEL Derivation46 9.5.1 Selecti
10、on of Key Study and Critical Effect for the STEL Derivation.46 ii 2007 NSF Methyl Isobutyl Ketone -05/07 1 2 3 4 5 6 7 8 9 10 11 12 13 9.5.2 Uncertainty Factor Selection.46 9.5.3 STEL Calculation 49 10.0 RISK MANAGEMENT 50 10.1 SPAC Derivation.50 11.0 RISK COMPARISONS AND CONCLUSIONS 50 12.0 REFEREN
11、CES 54 13.0 APPENDIX A: Reference Tables.66 14.0 APPENDIX B Alternate Calculations 69 14.1 Tyl et al. (1987) Alternate RfD Calculation69 14.2 Benchmark Dose and Drinking Water Unit Risk Determination.71 14.3 Margin of Exposure Calculation .75 15.0 PEER REVIEW HISTORY .76 iii 2007 NSF Methyl Isobutyl
12、 Ketone - 05/07 AUTHORS, PEER REVIEWERS, AND ACKNOWLEDGEMENTS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 Author: NSF Toxicology Services 1.800.NSF.MARK NSF International 789 Dixboro Road Ann Arbor, MI 48105 D
13、isclaimer: 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 trade names, proprietary products, or specific equipment does not constitute an endorsement by NSF Inter
14、national, nor does it imply that other products may not be equally suitable. Internal NSF Peer Reviewers: Gwendolyn Ball, Ph.D. Clif McLellan, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on the NSF Health Advisory Board in providing peer review. The
15、se peer reviewers serve on a voluntary 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 Technolo
16、gy/Office of Water U.S. Environmental 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 Burs
17、ian, Ph.D. Professor Michigan State University Craig Farr, Ph.D., DABT Director, Product Stewardship and Toxicology Health, Environment and Safety Arkema, Inc. iv 2007 NSF Methyl Isobutyl Ketone - 05/07 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 Robert Hinderer, Ph.D. Director of Health, Toxicology, and
18、 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. Department of Toxic Substances Control State of California v 2007 NSF Methyl Isobutyl Ketone - 05/07 EXECUTIVE SUMMARY 1 2 Methyl
19、 Isobutyl Ketone Oral Risk Assessment CAS # 108-10-1 PARAMETER LEVEL UNITS DERIVED NOAEL (no-observed-adverse-effect level) 1,000 mg/kg-day From a subchronic gavage study in rats. Oral RfD (oral reference dose) 1 mg/kg-day From a subchronic gavage study in rats with a 1,000x uncertainty factor. TAC
20、(total allowable concentration) 7 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 (single product allowable concentration) 0.7 mg/L From the TAC, assuming 10 drinking water sources of methyl isobutyl ketone. STEL (sh
21、ort term exposure level) 100 mg/L From a subchronic gavage study in rats adjusted for a 10 kg child drinking 1 L/day. KEY STUDY MAI (Microbiological Associates, Inc.). 1986. Subchronic toxicity of methyl isobutyl ketone in Sprague Dawley rats. Final Report. Study No. 5221.04. Performed by Microbiolo
22、gical Associates, Inc. for Research Triangle Institute. Unpublished report dated July 15, 1986. CRITICAL EFFECT No effects considered adverse were observed after subchronic gavage exposure to methyl isobutyl ketone in rats. UNCERTAINTY FACTORS 10x for interspecies extrapolation 10x for intraspecies
23、extrapolation 10x for extrapolation from a less-than-lifetime study to a lifetime exposure duration 1x for extrapolation from a LOAEL to a NOAEL 1x for database deficiencies. Therefore, the total uncertainty factor was 1,000x. TOXICITY SUMMARY Limited data in humans were identified. Short-term, subc
24、hronic, reproduction, and developmental toxicity data via oral or inhalation exposure in laboratory animals were identified, along with a chronic inhalation bioassay in rats and mice. Subchronic gavage exposure in rats caused transient narcosis, liver and kidney weight increases, altered blood param
25、eters, and renal nephropathy. Increased narcosis, liver and kidney weights and altered blood parameters were observed after subchronic inhalation of methyl isobutyl ketone. Maternal and fetotoxicity were observed in developmental inhalation studies. Two subchronic oral studies in rats were available
26、, but a drinking water study evaluated an insufficient number of animals, used only one concentration, and included only females. Increased liver and kidney weights and nephropathy were observed without hepatic histopathology in a standardized subchronic gavage study in rats. The increased liver wei
27、ght was likely an adaptive response to metabolizing high bolus doses of methyl isobutyl ketone. The renal effects after subchronic gavage were attributed to spontaneous nephropathy and/or alpha-2-globulin nephropathy, since they were limited to male rats. The transient narcosis observed after gavage
28、 but not after drinking water exposure at the same dose was attributed to bolus dosing. Further, narcosis was inconsistently observed after inhalation exposure and most observations of narcosis after subchronic oral, intraperitoneal or inhalation exposures were present only during the first few to s
29、everal weeks of exposure, but not at study termination. Gestational inhalation exposure resulted in reduced fetal body weight in rats and mice, reduced ossification in rats, and increased fetal death in mice. The non-neoplastic and neoplastic lesions observed in male and female F344 rats and B6C3F1
30、mice chronically inhaling methyl isobutyl ketone were attributed to spontaneous nephropathy and/or alpha-2-globulin nephropathy, thus not considered relevant to humans and/or were within historical control ranges, thus not considered toxicologically significant. However, interpretation of the effect
31、s in male rats chronically inhaling methyl isobutyl ketone was confounded by reduced survival. The subchronic gavage study was selected as the key since it was a standardized study, and the oral route was preferred for derivation of an RfD, since there were no kinetic or metabolism data in humans wh
32、ich could be used to reduce route to route or interspecies extrapolation. The weight of genotoxicity evidence suggests that methyl isobutyl ketone is not genotoxic. Since no epidemiological studies in humans or chronic oral data in animals were identified, the data are inadequate for an assessment o
33、f human carcinogenic potential of methyl isobutyl ketone after oral exposure. CONCLUSIONS Based on the concurrence of oral and inhalation data in laboratory animals, and on the uncertainty factors selected to account for interspecies extrapolation, intraspecies variability, and database deficiencies
34、, the drinking water action levels developed in this risk assessment are protective of public health. 3 vi 2007 NSF Methyl Isobutyl Ketone - 05/07 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 1.0 INTRODUCTION This document has been prepared to allow
35、 toxicological evaluation of the unregulated contaminant methyl isobutyl ketone in drinking water, as 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). Bot
36、h 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 reference dose (RfD) approach (Barnes and Dourson, 1988; Dourson, 1994; U.S. EPA, 1993;
37、 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) are applied to the highest dose showing no significant effects. This highest dose is derived from human exposure data when
38、 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% confidence limit on the dose resulting in an estimated 10% increase in response (the LED10or BMDL10fro
39、m 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 preferred in this case. The RfD is expressed in mg/kg-day. It is defined by the U.S. EPA as “an
40、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 deleterious effects during a lifetime” (Barnes and Dourson, 1988; U.S. EPA, 1993; U.S. EPA, 2005a). NSF u
41、ses 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 at-the-tap conditions, is defined as the RfD multiplied by the 70 kg weight of an average adult
42、 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, is also applied in calculating the TAC. The relative source contribution should be data derive
43、d, 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 sources (mg/day) 36 37 38 39 40 2 L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 41 42
44、43 44 45 46 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 sources of the substance in the drinking water treatment and 1 20
45、07 NSF Methyl Isobutyl Ketone - 05/07 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 distribution system. In the absence of source data, a default multiple source factor of 10 is used. This accounts for the possibility
46、 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 solvents expected to extract at higher level
47、s 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 level must decay to a level at or below the TAC under
48、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 appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999; U.S. EPA, 2003b; U.S. EPA, 2005b). If there is sufficient evidence to use a non-linear model, the LED10or BMDL10, divided by the anticipated exposure, is calc
