1、n-Butyl Acetate 01/03 n-BUTYL ACETATE CAS # 123-86-4 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI January 2003 Copyright 2003 NSF International n-Butyl Acetate 01/03 i TABLE OF CONTENTS 1.0 INTRODUCTION .1 2.0 PHYSICAL AND CHEMICAL PROPERTIES .3 2.1 Organoleptic Properties 4 3.0 PRO
2、DUCTION AND USE4 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 Exposure6 6.0 COMPARATIVE KINETICS AND METABOLISM IN HUMA
3、NS AND LABORATORY ANIMALS6 6.1 Absorption 6 6.1.1 Humans.6 6.1.2 Laboratory Animals 7 6.2 Distribution.7 6.2.1 Humans.7 6.2.2 Laboratory Animals 7 6.3 Metabolism .7 6.3.1 Humans.7 6.3.2 Laboratory Animals 7 6.4 Excretion.9 6.4.1 Humans.9 6.4.2 Laboratory Animals 9 7.0 EFFECTS ON HUMANS10 7.1 Case Re
4、ports.10 7.2 Epidemiological Studies.10 7.3 Irritation and Sensitization Studies10 7.3.1 Irritation10 7.3.2 Sensitization 10 8.0 EFFECTS ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS 11 n-Butyl Acetate 01/03 ii 8.1 Limited-Exposure Effects11 8.1.1 Irritation and Sensitization Studies11 8.1.2 Ocula
5、r Exposure Studies 11 8.2 Single-Exposure Studies 11 8.3 Short-Term Exposure Studies 12 8.4 Long-Term and Chronic Exposure Studies.14 8.4.1 Subchronic Exposure Studies.14 8.4.2 Chronic Exposure Studies 21 8.5 Studies of Genotoxicity and Related End-Points 22 8.5.1 Mutagenicity Assays23 8.5.2 Assays
6、of Chromosomal Damage.23 8.5.3 Other Assays of Genetic Damage .24 8.6 Reproductive and Developmental Toxicity Studies 24 8.6.1 Reproductive Toxicity .24 8.6.2 Developmental Toxicity in Rabbits.25 8.6.3 Developmental Toxicity in Rats26 8.7 Studies of Immunological and Neurological Effects .27 8.7.1 I
7、mmunological Effects27 8.7.2 Neurological Effects .28 9.0 RISK CHARACTERIZATION29 9.1 Hazard Assessment 29 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action 29 9.1.2 Weight-of-Evidence Evaluation and Cancer Characterization.33 9.1.3 Selection of Key Study and Critical Effect.33 9.1.4 I
8、dentification of Susceptible Populations 34 9.2 Dose-Response Assessment .34 9.2.1 Calculation of the oral RfD from 13-week gavage study in rats (General Foods, 1978) .35 9.3 Exposure Characterization .36 9.4 TAC Derivation37 9.5 STEL Derivation 37 10.0 RISK MANAGEMENT.38 10.1 SPAC Derivation 38 11.
9、0 RISK COMPARISONS AND CONCLUSIONS.38 12.0 REFERENCES.40 13.0 APPENDICES46 13.1 Inhalation to Oral Dose Conversions46 n-Butyl Acetate 01/03 iii 13.1.1 Bernard and David (1996) 46 13.1.2 Hackett et al. (1982)46 13.1.3 Nelson et al. (1989) .47 14.0 PEER REVIEW HISTORY47 2003 NSF n-Butyl Acetate 01/03
10、iv AUTHORS, 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 contacted
11、 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: Lori Bestervelt, Ph.D. Gwendolyn Ball, Ph.
12、D. Clif McLellan, M.S. 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 opini
13、ons of the organizations with which they are affiliated. Edward Ohanian, Ph.D. (Chairperson, NSF Health Advisory Board) Acting 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 Ch
14、airperson, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Acting Director, Environmental Health Science Safe Environments Programme Health Canada Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industr
15、ies, Inc. 2003 NSF n-Butyl Acetate 01/03 v Robert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, M.S. Associate Director for Science USEPA/NHEERL/WED Adi Pour, Ph.D. Director, Douglas County Health Department Omaha, Nebraska Calvin Willhite, P
16、h.D. Department of Toxic Substances Control State of California 2003 NSF n-Butyl Acetate 01/03 vi EXECUTIVE SUMMARY n-Butyl Acetate Oral Risk Assessment CAS # 123-86-4 PARAMETER LEVEL UNITS CALCULATED NOAEL (no observed-adverse-effect level) 600 mg/kg-day From a 13-week gavage study in rats Oral RfD
17、 (oral reference dose) 0.2 mg/kg-day From a 13-week gavage study in rats TAC (total allowable concentration) 1 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) 0.1 mg/L For a 70 kg adult drinking 2 L/day
18、. STEL (short term exposure level) 20 mg/L From a 13-week gavage study in rats, for a 10 kg child drinking 1 L/day. KEY STUDY General Foods Corporation. 1978. Butyl Acetate. Ninety-Day Oral Toxicity Study in Rats. Report Number 377-004. Prepared by General Food Corporation. October 2. CRITICAL EFFEC
19、T(S) In both sexes, dose-related stomach lesions and reduced motor activity. UNCERTAINTY FACTORS Factors applied in calculating the oral RfD: 10x for interspecies extrapolation 10x for intraspecies extrapolation 10x for subchronic to chronic extrapolation 1x for extrapolation from a LOAEL to a NOAEL
20、 3x for database deficiencies The total uncertainty factor is therefore 3,000x. TOXICITY SUMMARY The critical study chosen to derive the oral RfD was a 13-week gavage study in which rats were administered 0, 600, 2,000, or 6,000 mg/kg-day of n-butyl acetate in corn oil. The low dose was considered t
21、he NOAEL. At the mid dose, which was considered the LOAEL, histopathological examination revealed slight to moderate stomach lesions, described as inflammatory infiltrates, edema, degeneration, and/or necrosis of the non-glandular and/or glandular mucosa and submucosa, and/or epithelial hyperkeratos
22、is and acanthosis. The stomach lesions were observed in 3/20 male rats and 3/20 female rats. Reduced motor activity was also observed, but quantitative data were not provided. At the high dose, the incidence of stomach lesions and reduced motor activity increased, such that the stomach lesions were
23、observed in 11/20 males and 10/20 females. Quantitative data for reduced motor activity were again not provided. Sedation and hypoactivity were also observed in a subchronic gavage study in mice and two subchronic inhalation studies in rats. The gavage study was chosen as the key study, since an ora
24、l study is more appropriate for calculation of the RfD. In developmental studies in rabbits and rats, statistically significant increases in retinal folds, misaligned sternebrae, and clear gallbladders were observed in the offspring of rabbit dams inhaling human equivalent doses of 2,030 mg/kg n-but
25、yl acetate for seven hours/day during GD 1-19. In rats, a statistically significant reduction in fetal size and increased incidences of hydroureters, rib dysmorphology, and reduced pelvic ossification were observed in offspring from dams inhaling human equivalent doses of 2,030 mg/kg n-butyl acetate
26、 for seven hours/day during various gestational and non-gestational exposure paradigms. Reduced food consumption and body and/or organ weight changes were observed in both rabbit and rat dams. The mode of action of the stomach lesions is unknown. Since n-butyl acetate is rapidly metabolized to n-but
27、anol in the blood and brain, the likely mediator of the sedation and hypoactivity caused by n-butyl acetate is n-butanol. n-Butyl acetate was not genotoxic in Salmonella, E. coli, S. cerevisiae, or Chinese hamster ovary cell assays. CONCLUSIONS The critical effects of oral exposures to n-butyl aceta
28、te in rats are stomach lesions and reduced motor activity. Due to the lack of chronic data in humans and laboratory animals, the carcinogenic potential of n-butyl acetate cannot be determined. The weight of genotoxicity evidence suggests that n-butyl acetate is not genotoxic. The uncertainty factors
29、 used to account for the database deficiencies, such as the lack of adequate oral studies, and two-generation reproduction or immunological data, should ensure that the drinking water action levels are protective of human health. 2003 NSF n-Butyl Acetate 01/03 1 1.0 INTRODUCTION This document has be
30、en prepared to allow toxicological evaluation of the unregulated contaminant n-butyl acetate 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 evaluated under NSF/ANSI 6
31、0 (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, 1988; Dourson, 1994; U.
32、S. EPA, 1993), 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 data when available, but mor
33、e 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 BMDL from benchmark dose pro
34、grams) 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 “an estimate (with uncert
35、ainty 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, 1999a). NSF uses the RfD to derive
36、 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 assumed to drink two
37、 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 derived, if possible. Alter
38、nately, 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 single product allowable concent
39、ration (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 absence of source data, a defaul
40、t multiple source factor of 10 is used. 2003 NSF n-Butyl Acetate 01/03 2 This 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 l
41、evel 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 factors approp
42、riate 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 related to cancer are
43、 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 insufficient ev
44、idence 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 protective of public h
45、ealth (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 additional risk. The Rf
46、D, 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 done with care
47、, 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 introduce uncert
48、ainty 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 Management (
49、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 Assessmen
