API PUBL 4743-2005

$44.20

Hazard Narrative for Tertiary-Butyl Alcohol (TBA)

Published By	Publication Date	Number of Pages
API	2005	88

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Description

Tertiary Butyl Alcohol (TBA) has multiple industrial and chemical uses. 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 National Toxicology Program (1995) has conducted a 2-year drinking water bioassay with TBA in rats and mice. Results of this study showed increases in the incidence of renal tubule hyperplasia and renal adenomas in male rats; however, the incidence of renal tubule hyperplasia or adenoma was not significantly increased in female rats. In male and female mice, the incidence of thyroid follicular cell hyperplasia was increased, and in female mice, the incidence of thyroid follicular cell adenoma was also increased. Based on these findings, the NTP (1995) concluded that there was: 1) some evidence of carcinogenic activity in male rats and female mice; 2) equivocal evidence of carcinogenicity in male mice; and 3) no evidence of carcinogenicity in female rats. The results of genotoxicity tests (Salmonella reverse mutation assay, mouse lymphoma cell mutation test, sister chromatid exchange assay, chromosomal aberration assay in Chinese hamster ovary (CHO) cells and micronucleus assay) conducted by NTP (1995) with TBA were negative.

The California Office of Environmental Health Hazard Assessment (OEHHA) (CALEPA 1999) developed an interim drinking water level of 12 µg/L based on the incidence of kidney tumors reported in male rats in the NTP (1995) study. In this calculation, OEHHA estimated a cancer slope factor using linear extrapolation and body weight3/4 scaling to extrapolate to the human equivalent concentration at a 1 x 10-6 extra lifetime cancer risk level. Default assumptions were used for body weight (70 kg) and water consumption (2 L/day). In the period since OEHHA developed their interim water level, additional data has been published that suggests the kidney tumors observed in male rats form as a result of TBA binding to a2u-globulin (Borghoff et al. 2001; Williams and Borghoff 2001), the protein that also plays a key role in the development of protein droplet (a2u) nephropathy in male rats. Protein droplet nephropathy occurs when a2u-globulin, a protein synthesized in the liver of male rats, accumulates in tubular cells in the kidney (CIIT 1996). This condition is unique to male rats and an analogous condition does not occur in humans (CIIT 1996). Therefore, kidney tumors that form in male rats via a a2u-globulin-mediated pathway should not be used in human health risk assessment (USEPA 1991). After reviewing these data and while agreeing with the concept that there are chemical agents that produce renal tumors in some species of rats that are not relevant to humans and acknowledging that TBA does induce a2u-globulin in male rats, Budroe et al. (2004) maintained that the kidney tumors in male rats could be used for human cancer risk assessment.

The purpose of this investigation was to conduct a quantitative risk assessment according to USEPA guidelines (2005) in 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 (metabolism) and pharmacodynamics (sensitivity and mode of action) between animal species and humans are considered in: 1) the estimation of human equivalent doses, and 2) the extrapolation from high doses typically used in the animal bioassays and low doses to which humans may be potentially exposed. Pharmacokinetic, toxicity, and mode of action data for TBA were reviewed and data selected for quantitative dose-response modeling.

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