1、Hazard Narrative for Tertiary-Butyl Alcohol (TBA) CAS Number 75650Regulatory Analysis and Scientific Affairs PUBLICATION NUMBER 4743 OCTOBER 2005Hazard Narrative for Tertiary-Butyl Alcohol (TBA) CAS Number 75-65-0 Regulatory and Scientific Affairs API PUBLICATION 4743 OCTOBER 2005 PREPARED BY: Annet
2、te Shipp, Ph.D. Tracy McDonald Cynthia Vanlandingham, MS ENVIRON International Corporation 602 East Georgia Ruston, Louisiana 71270 SPECIAL NOTES API publications necessarily address problems of a general nature. With respect to particular circumstances, local, state, and federal laws and regulation
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15、 Harley Hopkins, Regulatory Analysis and Scientific Affairs Department (RASA) Bruce Jarnot, Regulatory Analysis and Scientific Affairs Department (RASA) MEMBERS OF THE SOIL AND GROUNDWATER TECHNICAL TASK FORCE (S/GTTF) Curtis Stanley, Shell Global Solutions (US), Inc., S/GTTF Chairman MEMBERS OF THE
16、 TOXICOLOGY TASK FORCE (TTF) David Steup, Shell Oil Products (US), Inc., TTF Chairman WORK GROUP MEMBERS Wayne Daughtrey, Exxon Mobil Biomedical Sciences Michael Firth, Exxon Mobil Biomedical Sciences John (Rick) Greiner, ConocoPhillips Kirk OReilly, formerly, Chevron Corporation Energy Technology C
17、ompany Fred Reitman, Shell Oil Products (US), Inc Mark Saperstein, BP Eric Stine, Chevron Corporation Energy Technology Company Stacey Waterman, Atlantic Richfield Company (A BP affiliated Company) REVIEWERS Marcy Banton, Lyondell Chemical Company George Cruzan, ToxWorks, Inc. Lorraine Twerdok, Amer
18、ican Petroleum Institute Table of Contents Executive Summary. i 1.0 Introduction. 1 2.0 Hazard Narrative. 2 2.1 Overview. 2 2.2 Carcinogenicity Studies 3 2.2.1 Human Data 3 2.2.2 Animal Data 3 2.3 Analysis of Other Key Data 6 2.3.1 Pharmacokinetics 6 2.3.2 Animal Toxicity Studies . 8 2.3.2.1 Acute a
19、nd Subacute. 8 2.3.2.2 Subchronic 8 2.3.2.3 Reproductive and Developmental Studies 13 2.3.3 Mutagenicity and Genotoxicity Studies 14 2.4 Potential Modes of Action 17 2.4.1 Mode of Action for Kidney Tumors in Rats. 17 2.4.1.1 Overview of 2u-globulin-induced Renal Tumors 17 2.4.1.2 Evidence that TBA i
20、s a CIGA chemical. 18 2.4.2 Mode of Action for Thyroid Tumors in Mice. 28 2.5 Weight of Evidence. 33 3.0 Dose-Response Assessment 35 3.1 Selection of Data for Dose-Response Modeling. 35 3.2 Estimation of the Human Equivalent Dose. 35 3.3 Estimation of Point of Departure 37 3.4 Evaluation of the Appr
21、oach for Low-dose Extrapolation. 39 3.5 Extrapolation to Low Doses 40 4.0 Discussions and Conclusions 42 5.0 References. 58 Appendix A. 64 Appendix B. 71 Tables Table 1: Incidences of Neoplastic and Nonneoplastic Lesions in Male Rats at 15-Month Interim Sacrifice 44 Table 2: Incidences of Neoplastic
22、 and Nonneoplastic Lesions in Female Rats at 15-Month Interim Sacrifice. 45 Table 3: Incidences of Neoplastic and Nonneoplastic Lesions in Female Rats at Final Sacrifice 46 Table 4: Incidences of Neoplastic and Nonneoplastic Lesions in Male Rats at Final Sacrifice 47 Table 5: Incidences of Neoplasti
23、c and Nonneoplastic Lesions in Male Mice at Final Sacrifice. 48 Table 6: Incidences of Neoplastic and Nonneoplastic Lesions in Female Mice at Final Sacrifice . 49 Table 7: Comparison of Nephropathy and Carcinogenicity in Male and Female Rats exposed to Chemicals Inducing 2u -Globulin Accumulation (C
24、IGA) and TBA . 50 Table 8: Genotoxicity of Chemicals Inducing 2u-Globulin Accumulation (CIGA) and TBA 52 Table 9: Chemicals That Interfere with Thyroid Hormostatis . 53 Table 10: Mouse Thyroid Tumor Dose-Response Modeling Results 54 Table 11: Results of the Benchmark Modeling for Follicular Cell Hyp
25、erplasia in Male and Female Mice in the 2-year Chronic Bioassay (in mg/kg/day). . 55 Figures Figure 1: Incidence of Thyroid Neoplastic and Non-Neoplastic Lesions versus Dose in Male Mice 56 Figure 2: Incidence of Thyroid Neoplastic and Non-Neoplastic Lesions versus Dose in Female Mice. 57 i Executiv
26、e Summary Tertiary Butyl Alcohol (TBA) has many industrial and chemical uses (NTP 1995). TBA is used in the manufacture of perfumes and cosmetics, as an additive in gasoline to improve the oxygen content, and is a metabolite of the fuel oxygenate, methyl-tert-butylether (MTBE) (NTP 1995). The Nation
27、al Toxicology Program (NTP 1995) has conducted a two-year drinking water bioassay with TBA in male and female rats and mice. Results of these studies showed increases in the incidence of renal tubule hyperplasia and renal tubule adenomas in male rats; however, the incidence of renal tubule hyperplas
28、ia or adenoma was not significantly increased in female rats. In male and female mice, incidence of thyroid follicular cell hyperplasia was increased, and the incidence of thyroid follicular cell adenoma was increased in female mice. Based on these findings, the NTP (1995) concluded there was some e
29、vidence of carcinogenic activity in male rats and female mice, there was equivocal evidence of carcinogenicity in male mice and no evidence of carcinogenicity in female rats. The purpose of this investigation was to conduct a quantitative risk assessment according to USEPA guidelines (USEPA 2005) in
30、 which data on the mode of action by which TBA induced renal tumors in rats and thyroid tumors in mice was considered. When data from animal studies, such as the TBA bioassays, are extrapolated to humans to provide estimates of lifetime cancer risks, then potential differences in pharmacokinetics (m
31、etabolism) and pharmacodynamics (sensitivity and mode of action) between the animal species and humans is considered in the estimation of human equivalent doses and in extrapolation from high doses typically used in the animal bioassays to low doses to which humans may be potentially exposed. Pharma
32、cokinetic, toxicity, and mode of action data for TBA were reviewed and data selected for quantitative dose-response modeling. The major findings of the review of pharmacokinetic and toxicity data that influenced the dose-response assessment included: Pharmacokinetic data indicate that TBA is poorly
33、metabolized in vivo (Baker et al. 1982; Thurman et al. 1980) and slowly eliminated from the blood of rats and mice (McComb and Goldstein 1979), likely as a conjugate with glucuronide (Aarstad et al. 1985; Thurman et al. 1980). However, pharmacokinetic data were insufficient at this time to develop a
34、 pharmacokinetic model for TBA or to make a chemical-specific adjustment for pharmacokinetic differences between rats and humans. ii TBA was not mutagenic in Salmonella typhimurium strains TA98, TA100, TA1535 and TA1537 at doses up to 10,000 g/plate, with or without induced rat or hamster liver S9 f
35、ractions (Zeiger et al. 1987). Tertiary-butyl acetate (TBAc), a metabolic precursor for TBA was also not mutagenic in the same strains, with or without microsomal induction at doses up to 5000 g/plate (McGregor et al. 2005). TBA was positive in S. typhimurium strain TA102 (Williams-Hill et al. 1999)
36、; however, this result was not replicated in two other studies in which TBA was dissolved in either dimethylsulfoxide or water at doses up to 5000 g/plate; TBAc was also non-mutagenic in studies in which both TA102 and Escherichia coli WP2uvrA/pKM101 were evaluated (McGregor et al. 2004; McGregor et
37、 al. 2005). Both TA102 and E. coli WPs strains are sensitive to oxidative damage to DNA. TBA undergoes limited metabolism and is a free radical scavenger rather than a generator of reactive oxygen species; therefore, production of oxidative damage to DNA is highly unlikely. TBA should be considered
38、to be non-mutagenic. Studies that assessed the potential genotoxicity of TBA with and without metabolic activation were all negative. A L5178Y mouse lymphoma mutagenicity test was negative at TBA doses up to 5,000 g/mL (Zeiger et al. 1987). Neither sister chromatid exchanges nor chromosomal aberrati
39、ons were noted in Chinese Hamster Ovary (CHO) cell cytogenetics tests (NTP 1995). A mouse peripheral blood micronucleus test performed on blood samples from male and female B6C3F1mice following a 13-week exposure to TBA in drinking water at concentrations up to 40,000 g/mL did not show an increase i
40、n the frequency of micronucleated normochromic erythrocytes (NCEs) or the percentage of polychromatic erythrocytes (PCEs) (NTP 1995, 1997). No increase in percentage of PCEs was noted in rats receiving intraperioneal injections of TBA at doses up to 625 mg/kg (NTP 1997). Evidence of unspecified DNA
41、damage was noted in human leukemia HL-60 cells using a Comet Assay at concentrations up to 2224 g/mL (Tang et al. 1997) only the English abstract of this Chinese study was available at this time. Based on the weight of the evidence, TBA should be considered non-genotoxic. Data support the hypothesis
42、 that renal tumors in male rats formed in response to a cascade of biological events associated with 2u-globulin nephropathy, a condition unique to male rats (USEPA 1991). Nephropathy leading to tumor development results when 2u-globulin accumulates in the proximal tubule resulting in the characteri
43、stic protein droplet and lysosome accumulation in the proximal tubule. This leads to cellular necrosis and sustained cellular proliferation and the subsequent promotion of initiated cells, resulting in the formation of neoplasms (McGregor and Hard 2001; USEPA 1991). The available toxicity and other
44、mode of action data satisfy the criteria outlined by the International Agency for Research on Cancer (IARC) (1999) and USEPA (1991) needed to conclude that renal tumors in male rats occur by a 2u-globulin-mediated mode of action. Further, the pattern of observed kidney effects in male rats exposed t
45、o TBA is the same as 9 other chemicals classified by the USEPA (1991) as “chemicals inducing 2u -globulin accumulation” (CIGA). These findings provide convincing evidence that the renal tumors are 2u-globulin-mediated. In addition, there is in vivo evidence that no proteins in human kidney can funct
46、ion in a manner analogous to 2u-globulin (Meek et iii al. 2003). Consequently, compounds that produce renal tumors in male rats via the 2u-globulin-mediated pathway are not relevant to humans and the use of these renal tumors in human health risk assessment is not appropriate (USEPA 1991). The patte
47、rn of thyroid follicular cell hyperplasia and follicular adenoma, viewed in light of benign tumors only and in only one sex and species and the negative mutagenicity data, strongly suggests an epigenetic mode of action for TBA in the production of thyroid tumors in female mice. USEPA (1998) guidelin
48、es for the evaluation of thyroid tumors in rodents recommend the data needed to provide the evidentiary basis for a non-linear, threshold approach. While not all of the recommended data were available at this time, the overall weight of evidence strongly suggests that TBA is acting by indirectly dis
49、rupting thyroid hormone balance through enzyme induction (possibly by increased glucuronidation and biliary elimination of thyroid hormones). The possible ways in which the thyroid-pituitary axis can be disturbed are all likely to be processes that have thresholds, that is, a certain amount of disruption would be required before feedback loops result in sustained thyroid stimulating hormone (TSH) stimulation of follicular cells which then results in the biological cascade of cell proliferation, hyperplasia, and neoplasia (USEPA 1998). While expec
