1、 MIAK 01/04 METHYL ISOAMYL KETONE CAS # 110-12-3 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI January 2004 Copyright 2004 NSF International MIAK 01/04 iTABLE OF CONTENTS 1.0 INTRODUCTION .1 2.0 PHYSICAL AND CHEMICAL PROPERTIES .3 2.1 Organoleptic Properties 3 3.0 PRODUCTION AND USE4
2、 3.1 Production 4 3.2 Use .4 4.0 ANALYTICAL METHODS .4 4.1 Analysis in Water.4 4.2 Analysis in Biological Matrices.5 5.0 SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE5 5.1 Sources of Human Exposure.5 5.2 Sources of Environmental Exposure5 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMANS AND LABORATOR
3、Y ANIMALS5 6.1 Absorption 5 6.1.1 Oral5 6.1.2 Inhalation6 6.1.3 Dermal.6 6.2 Distribution.6 6.3 Metabolism .6 6.4 Elimination/Excretion7 6.4.1 Oral7 6.4.2 Inhalation7 6.4.3 Intravenous .7 6.4.4 Dermal.7 7.0 EFFECTS ON HUMANS8 7.1 Case Reports.8 7.2 Epidemiological Studies.8 8.0 EFFECTS ON LABORATORY
4、 ANIMALS AND IN VITRO TEST SYSTEMS 8 8.1 Limited-Exposure Effects8 8.1.1 Irritation and Sensitization Studies8 8.1.2 Ocular Exposure Studies 9 8.2 Single-Exposure Studies 9 8.3 Short-Term Exposure Studies 9 MIAK 01/04 ii8.3.1 Three-week Gavage Studies9 8.3.2 Two-week Inhalation Study11 8.4 Long-Term
5、 and Chronic Exposure Studies.13 8.4.1 Gavage.14 8.4.2 Inhalation15 8.5 Studies of Genotoxicity and Related End Points.17 8.5.1 Mutagenicity Assays17 8.5.2 Assays of Chromosomal Damage.18 8.5.3 Other Assays of Genetic Damage .18 8.6 Reproductive and Developmental Toxicity Studies 18 8.7 Studies of I
6、mmunological and Neurological Effects .18 9.0 RISK CHARACTERIZATION19 9.1 Hazard Assessment 19 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action 19 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization.20 9.1.3 Selection of Key Study and Critical Effect.21 9.1.4 Identificatio
7、n of Susceptible Populations 22 9.2 Dose-Response Assessment .23 9.2.1 Dose Conversion .23 9.3 Exposure Characterization .25 9.4 TAC Derivation26 9.5 STEL Derivation 26 10.0 RISK MANAGEMENT.27 10.1 SPAC Derivation .27 11.0 RISK COMPARISONS AND CONCLUSIONS.28 12.0 REFERENCES.29 13.0 APPENDICES33 13.1
8、 Odor and Recognition Threshold.33 13.2 Single Exposure Inhalation Absorption Study in Rats (Katz et al., 1986) .34 13.3 Single Exposure Study in Rats (Eastman Kodak, 1995) 34 13.4 Single Exposure Study in Mice (De Ceaurriz et al., 1984).34 13.5 Two-week Inhalation Study (Katz et al., 1986; Katz, 19
9、83) 34 13.6 Thirteen-week Inhalation Study (Katz et al., 1986; Katz, 1983) .35 13.7 Chromosomal Aberration Assay (Eastman Kodak, 1986b).35 13.8 Mouse BALB/3T3 Cell Transformation Assay (Eastman Kodak, 1980)36 MIAK 01/04 iii13.9 Neurobehavioral Inhalation Study (De Ceaurriz et al., 1984).36 13.10 13-
10、week Diisobutyl Ketone Inhalation Study (Dodd et al., 1987)37 13.11 14-week Methyl Isobutyl Ketone Inhalation Study (Phillips et al., 1987) 37 13.12 Reproduction and Developmental Study of Methyl Ethyl Ketone (Deacon et al., 1981) 38 14.0 PEER REVIEW HISTORY38 MIAK 01/04 iv AUTHORS, PEER REVIEWERS,
11、AND ACKNOWLEDGEMENTS Author: Toxicology Services Department 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 contacted with comments or for
12、 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: Lori Bestervelt, Ph.D. Gwendolyn Ball, Ph.D. Clif McLellan, M.S
13、. Maryann Sanders, 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 organizati
14、ons 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 Boa
15、rd) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Director, Environmental Health Science Safe Environments Programme Health Canada Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industries, Inc. MIAK 12/02 vRobert Hinderer, Ph
16、.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/WED Adi Pour, Ph.D. Director, Douglas County Health Department Omaha, Nebraska Calvin Willhite, Ph.D. Department of Toxic Substances Control State of Californ
17、ia NSF 2004 MIAK 01/04 vi EXECUTIVE SUMMARY Methyl Isoamyl Ketone Oral Risk Assessment CAS # 110-12-3 PARAMETER LEVEL UNITS CALCULATED: NOAEL (no-observed-adverse-effect level) 25 mg/kg-day From a 13-week rat inhalation study. Oral RfD (oral reference dose) 0.008 mg/kg-day From a 13-week rat inhalat
18、ion study. TAC (total allowable concentration) 0.06 mg/L For a 70 kg adult drinking 2 L/day with a 20% Relative Source Contribution for drinking water. SPAC (single product allowable concentration) 0.006 mg/L For a 70 kg adult drinking 2 L/day. STEL (short term exposure level) 0.8 mg/L For a 10 kg c
19、hild drinking 1 L/day. KEY STUDIES Katz, G.V., E.R. Renner Jr., and C.J. Terhaar. 1986. Subchronic inhalation toxicity of methyl isoamyl ketone in rats. Fund. Appl. Toxicol. 6:498-505. Katz, G.V. 1983. Two week and 90-day inhalation studies of methyl isoamyl ketone in rats. Health and Environment La
20、boratories, Eastman Kodak Company. CRITICAL EFFECT Hepatocyte hypertrophy in both sexes and minimal necrosis of the liver in males. UNCERTAINTY FACTORS Factors applied in calculating the oral RfD: 3x for interspecies extrapolation 10x for intraspecies extrapolation 10x for subchronic to chronic extr
21、apolation 1x for extrapolation from LOAEL to NOAEL 10x for database deficiencies The total uncertainty factor is therefore 3,000x. TOXICITY SUMMARY Toxicology evaluations of methyl isoamyl ketone include acute, subacute, subchronic, and genotoxicity studies. Developmental and neurotoxicity studies a
22、re available for structurally related ketones. The gavage studies located for methyl isoamyl ketone contained deficiencies considered to impact the risk assessment. A 13-week study evaluated only one dose level in male rats only, and a three-week study evaluated only male rats and did not include co
23、mplete clinical chemistry or histological evaluation. The critical study was a 13-week rat inhalation study, which identified a NOAEL of 212 ppm (human equivalent oral dose of 25 mg/kg-day) based on increased mean absolute and relative liver weight and hepatocyte hypertrophy in both sexes. The chang
24、es in liver weight and liver pathology were also observed in the subchronic gavage study. Histopathological changes noted in the kidneys of males were associated with alpha-2-globulin nephropathy, thus were not relevant to human health. Based on a rat hepatic peroxisome proliferation study, the live
25、r changes are not likely attributable to hepatic peroxisome proliferation, thus were considered relevant for this risk assessment. A human equivalent oral RfD of 0.01 mg/kg-day was derived from the 13-week rat NOAEL, using appropriate dose conversion factors and an inhalation absorption factor of 50
26、%, based on absorption data for methyl ethyl ketone, since oral or inhalation kinetic, dynamic, or metabolic data for methyl isoamyl ketone were unavailable. Methyl isoamyl ketone was not mutagenic in Salmonella typhimurium over a range of doses in the presence and absence of metabolic activation, a
27、nd was negative in a 3T3 cell transformation assay. The evidence of chromosomal aberrations observed at high concentrations was discounted since these concentrations were greater than 10 mM and cytotoxicity was observed. CONCLUSIONS Subacute and subchronic toxicity data exist to characterize the mag
28、nitude and duration of methyl isoamyl ketone exposure required to induce hepatotoxicity in rats. Although the weight of evidence of genotoxicity data suggests that methyl isoamyl ketone is not genotoxic, no chronic animal or human epidemiological studies were identified for methyl isoamyl ketone. Th
29、us the cancer risk to humans from exposure to methyl isoamyl ketone cannot be determined. Taking into account the uncertainty factors used, the drinking water action levels established for methyl isoamyl ketone are considered to be protective of public health. NSF 2004 MIAK 01/04 11.0 INTRODUCTION T
30、his document has been prepared to allow toxicological evaluation of the unregulated contaminant methyl isoamyl ketone in drinking water, as an extractant from one or more drinking water system components evaluated under NSF/ANSI 61 (2002), or as a contaminant in a drinking water treatment chemical e
31、valuated under NSF/ANSI 60 (2002). 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 reference dose (RfD) approach (Barnes and Dourson
32、, 1988; Dourson, 1994; U.S. EPA, 1993a), which assumes that there is a threshold for these endpoints that will not be exceeded if appropriate uncertainty factors (Dourson et al., 1996) are applied to the highest dose showing no significant effects. This highest dose is derived from human exposure da
33、ta 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% confidence limit on the dose resulting in an estimated 10% increase in response (the LED10or BM
34、DL from benchmark dose programs) can be used (U.S. EPA, 2001). 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
35、 “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 deleterious effects during a lifetime” (Barnes and Dourson, 1988; U.S. EPA, 1993a; U.S. EPA, 1999a).
36、 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 at-the-tap conditions, is defined as the RfD multiplied by the 70 kg weight of an average
37、 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, is also applied in calculating the TAC. The relative source contribution should be data
38、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 sources (mg/day) 2L/day or TAC (mg/L) = RfD (mg/kg-day) x 70 kg x 0.2 (RSC) 2L/day The singl
39、e 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 distribution system. In the absen
40、ce of source data, a default multiple source factor of 10 is used. NSF 2004 MIAK 01/04 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)
41、, 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 STEL is calculated from the NOAEL or the LED10of an animal study of 14- to 90-days duration, with uncertainty
42、 factors appropriate to the duration of the study. The contaminant level must decay to the TAC or below under static conditions, or to the SPAC or below under flowing conditions within 90 days, based on the contaminant decay curve generated from over-time laboratory extraction data. Endpoints relate
43、d to cancer are evaluated using modeling to fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S. EPA, 1999b). If there is sufficient evidence to use a non-linear model, the LED10or BMDL, divided by the anticipated exposure, is calculated to give a margin of exposure. If there is
44、insufficient evidence to document non-linearity, a linear model drawing a straight line from the LED10or BMDL to 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 protecti
45、ve of public health (U.S. EPA, 1991a). For the purposes of NSF/ANSI 60 (2002) and 61 (2002), 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 additiona
46、l 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 determining compliance of products with the requirements of NSF/ANSI 60 (2002) and 61 (2002). Application of these values to other exposure scenarios should be
47、done with care and with a full 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 int
48、roduce uncertainty into an evaluation 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 (1983) and from The Presidential/Congressional Commission on Risk Assessment and Risk
49、 Management (1997a, 1997b). Other guidelines used in the development of this assessment may include the following: Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1986a), Proposed Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1996a), draft revised Guidelines for Carcinogen Risk Assessment (U.S. EPA, 1999b), Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991b), Guidelines for Reproductive Toxicity Risk Assessment (U.S. EPA, 1996b), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998), Recommend
