1、t-Butanol 06/03 t-BUTANOL CAS # 75-65-0 ORAL RISK ASSESSMENT DOCUMENT NSF International Ann Arbor, MI June 2003 Copyright 2003 NSF Internationalt-Butanol 06/03 iTABLE OF CONTENTS 1.0 INTRODUCTION .1 2.0 PHYSICAL AND CHEMICAL PROPERTIES .3 2.1 Organoleptic Properties 3 3.0 PRODUCTION AND USE4 3.1 Pro
2、duction 4 3.2 Use .4 4.0 ANALYTICAL METHODS .5 4.1 Analysis in a Water Matrix.5 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 HUMANS AND LABORATO
3、RY ANIMALS6 6.1 Absorption 7 6.1.1 Absorption in Humans7 6.1.2 Absorption in Laboratory Animals.7 6.2 Distribution.7 6.2.1 Distribution in Humans7 6.2.2 Distribution in Laboratory Animals.8 6.3 Metabolism .10 6.3.1 Metabolism in Humans.10 6.3.2 Metabolism in Laboratory Animals11 6.3.3 In Vitro Metab
4、olism Studies.13 6.4 Elimination/Excretion14 6.4.1 Elimination/Excretion in Humans.14 6.4.2 Elimination/Excretion in Laboratory Animals 15 6.5 Pharmacokinetic Modeling .15 6.6 Comparative Metabolism and Kinetics16 7.0 EFFECTS ON HUMANS17 7.1 Case Reports.17 7.2 Epidemiological Studies.18 8.0 EFFECTS
5、 ON LABORATORY ANIMALS AND IN VITRO TEST SYSTEMS 18 t-Butanol 06/03 ii8.1 Limited-Exposure Effects18 8.1.1 Irritation and Sensitization Studies18 8.1.2 Ocular Exposure Studies 18 8.2 Single-Exposure Studies 18 8.3 Short-Term Exposure Studies 19 8.4 Long-Term and Chronic Exposure Studies.19 8.4.1 Sub
6、chronic Studies .19 8.4.2 Chronic Studies.24 8.5 Studies of Genotoxicity and Related End-Points 28 8.5.1 Mutagenicity Assays28 8.5.2 Assays of Chromosomal Damage.29 8.5.3 Other Assays of Genetic Damage .30 8.6 Reproductive and Developmental Toxicity Studies 31 8.6.1 Reproductive Toxicity .31 8.6.2 D
7、evelopmental Toxicity Studies33 8.7 Studies of Immunological and Neurological Effects .34 8.7.1 Immunological Effects34 8.7.2 Neurological Effects .35 9.0 RISK CHARACTERIZATION41 9.1 Hazard Assessment 41 9.1.1 Evaluation of Major Non-Cancer Effects and Mode of Action 41 9.1.2 Weight-of-Evidence Eval
8、uation and Cancer Characterization.43 9.1.3 Selection of Key Study and Critical Effect.45 9.1.4 Identification of Susceptible Populations 46 9.2 Dose-Response Assessment .46 9.2.1 Kidney Effects in Female Rats .46 9.2.2 Thyroid Follicular Cell Hyperplasia in Mice.48 9.3 Exposure Characterization .51
9、 9.4 TAC Derivation52 9.5 STEL Derivation 52 10.0 RISK MANAGEMENT.53 10.1 SPAC Derivation .53 11.0 RISK COMPARISONS AND CONCLUSIONS.53 12.0 REFERENCES.55 12.1 References Cited 55 12.2 References Not Cited.64 t-Butanol 06/03 iii13.0 ANNEX A BENCHMARK DOSE RESULTS66 13.1 Model Selected for the TAC Cal
10、culation.66 13.2 Model Selected for the STEL Calculation.70 14.0 PEER REVIEW HISTORY73 2003 NSF t-Butanol 06/03 ivAUTHORS, 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
11、 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 International, nor does it imply that othe
12、r products may not be equally suitable. Internal NSF Peer Reviewers: Lori Bestervelt, Ph.D. Clif McLellan, M.S. Maryann Sanders, M.S. Amanda Phelka, M.S. External Peer Reviewers: NSF gratefully acknowledges the efforts of the following experts on the NSF Health Advisory Board in providing peer revie
13、w. These 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. (Chairperson, NSF Health Advisory Board) Director, Health and Ecological Criteria Division Office of Science and
14、 Technology/Office of Water U.S. Environmental Protection Agency Michael Dourson, Ph.D., DABT (Vice Chairperson, NSF Health Advisory Board) Director TERA (Toxicology Excellence for Risk Assessment) David Blakey, D.Phil. Acting Director, Environmental Health Science Safe Environments Programme Health
15、 Canada Randy Deskin, Ph.D., DABT Director, Toxicology and Product Regulatory Compliance Cytec Industries, Inc. 2003 NSF t-Butanol 06/03 vRobert Hinderer, Ph.D. Director of Health, Toxicology, and Product Safety Noveon, Inc. Jennifer Orme-Zavaleta, Ph.D. Associate Director for Science USEPA/NHEERL/W
16、ED Adi Pour, Ph.D. Director, Douglas County Health Department Omaha, Nebraska Calvin Willhite, Ph.D. Department of Toxic Substances Control State of California 2003 NSF t-Butanol 06/03 viEXECUTIVE SUMMARY t-Butanol Oral Risk Assessment CAS # 75-65-0 PARAMETER LEVEL UNITS DERIVED BMDL10(benchmark dos
17、e level) 133 mg/kg-day From a chronic rat study Oral RfD (oral reference dose) 1 mg/kg-day From a chronic rat study TAC (total allowable concentration) 9 mg/L For a 70 kg adult drinking 2 L/day, with a 20% relative source contribution for water SPAC (single product allowable concentration) 0.9 mg/L
18、For a 70 kg adult drinking 2 L/day STEL (short term exposure level) 40 mg/L From a subchronic study, for a 10 kg child drinking 1 L/day KEY STUDY National Toxicology Program (NTP). 1995. Toxicology and Carcingoenesis Studies of t-Butyl Alcohol (CAS No. 75-65-0) in F344/N Rats and B6C3F1 Mice (Drinki
19、ng Water Studies). Technical Report Series No. 436. CRITICAL EFFECT Absolute and relative kidney weight increases in female rats. UNCERTAINTY FACTORS 10x for interspecies extrapolation because there are differences in rate of elimination and identity and quantity of metabolites between rats and huma
20、ns 10x for intraspecies extrapolation 1x for study duration, as a chronic study was used 1x for LOAEL-to-NOAEL conversion, as benchmark dose modeling was used 1x for database deficiency, as the required studies are all available, although the two-generation reproduction study on t-butanol is as a me
21、tabolite of methyl t-butyl ether The total uncertainty factor is therefore 100x. TOXICITY SUMMARY t-Butanol is a relatively nontoxic compound with acute effects similar to ethanol. Subchronic and chronic studies in rats identified the kidney as the target organ in both males and females, based on or
22、gan weight increases and pathology. However, male rat kidney effects were discounted as due to -2-globulin accumulation, an effect that is not relevant to human health. Mice showed hypoactivity due to the high dose levels used, and mild kidney effects in a subchronic study, but showed thyroid follic
23、ular cell hyperplasia, adenoma, and a single high-dose carcinoma in a chronic study. The kidney effects in rats resulted in a lower oral RfD than the oral RfD in mice, considering the thyroid effects to have a threshold. Relative female rat kidney weights were used for the risk assessment calculatio
24、ns of both the TAC and the STEL. Studies in rats and mice suggest that t-butanol is not a developmental toxicant. A two-generation reproduction study of methyl t-butyl ether, which is metabolized to t-butanol and formaldehyde, showed no effects that could be attributed to t-butanol. Evidence suggest
25、s that t-butanol is not a genotoxic chemical, based on a number of in vitro genetic toxicity studies. However, based on the chronic studies in rats and mice, the “data are inadequate for an assessment of human carcinogenic potential” of t-butanol. No adequate or reliable human epidemiological study
26、exists. Long-term animal studies in rats produced carcinogenic responses in male rats due to an -2-globulin effect that is of no relevance to human health. Relevant kidney weight and histopathology effects were seen in female rats. Long-term animal studies in mice produced hyperplasia, adenoma, and
27、one high-dose carcinoma of the thyroid, of questionable relevance to human health because rodents are significantly more sensitive than humans to thyroid effects. CONCLUSIONS The uncertainty factors for interspecies and intraspecies extrapolation, used in conjunction with the female relative kidney
28、weight BMDL10 values, should ensure that the drinking water action levels established in this document are adequately protective of public health. 2003 NSF t-Butanol 06/03 11.0 INTRODUCTION This document has been prepared to allow toxicological evaluation of the unregulated contaminant t-butanol in
29、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 60 (2002). Both non-cancer and cancer endpoints have been considered, and risk assessment methodo
30、logy 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), which assumes that there is a threshold for these endpoints that will not be exce
31、eded 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 more often is derived from studies in laboratory animals. Either the no-observed-adverse-effect lev
32、el (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 programs) can be used (U.S. EPA, 2001a). The lowest-observed-adverse-effect level (LOAEL) can also
33、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 exposure to the human population (incl
34、uding 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 three product evaluation criteria for non-cancer endpoints. The total allowable concentration
35、(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), to ensure that the RfD is not e
36、xceeded 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. EPA, 1991a). The TAC calculation
37、 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 contact materials normalized to
38、 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. 2003 NSF t-Butanol 06/03 2This accounts for the possibi
39、lity 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 l
40、evels 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 the TAC or below under static
41、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 evaluated using modeling to fit a curve to the appropriate dose-response data (U.S. EPA, 1996a; U.S.
42、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 evidence to document non-linearity, a linear model drawing a straight line from the LED10or BMDL to zero
43、, 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 (2002) and 61 (2002), the TAC is set at the
44、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 effects data an
45、d 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, and with a full understanding of the derivation of the values and of the comparative magnitude and
46、 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 protect public he
47、alth. 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 (1997a, 1997b). Other guidelines used in the development of this assessment may include the followin
48、g: 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 1999b), Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991b), Guidelines for Repro
49、ductive Toxicity Risk Assessment (U.S. EPA, 1996b), Guidelines for Neurotoxicity Risk Assessment (U.S. EPA, 1998a), Recommendations for and Documentation of Biological Values for Use in Risk Assessment (U.S. EPA, 1988), and Health Effects Testing Guidelines (U.S. EPA 1996c; U.S. EPA, 2002a). The literature search strategy employed for this compound was based on the Chemical Abstract Service Registry Number (CASRN) and at least one common name. As a minimum, the following data banks were searched: 2003 NSF t-Butanol
