tert-butyl acetate

Endpoint summary

Additional information

In the key study (Huntingdon Life Sciences Ltd., 2000), the absorption, distribution, metabolism and excretion of tertiary butyl acetate in the rat was investigated in an inhalation study conducted according to US EPA Guideline OPPTS 870.7485 in which groups of male rats were exposed to 100 or 1000 ppm radiolabelled test material for 6 hours followed by the separate collection of urine, feces and expired air for 7 days. At both concentrations, the absorbed radioactivity was rapidly excreted after termination of the exposure period. At the low exposure level, most of the inhaled dose was eliminated in the urine (89% during the first 24 hours). Means of 2.69, 4.76 and 0.69% of the dose were found in feces, expired air and tissues, respectively. At the high exposure level, excretion in expired air was considerably greater (27% of the dose) with 69% excreted in urine. Means of 0.97 and 0.22% were found in feces and tissues, respectively. At both exposure levels, most of the excreted radioactivity was recovered during the first 24 hours and greater than 99% of the absorbed dose was eliminated in excreta by 7 days after exposure. At the 1000 ppm exposure level, a lower proportion of available radioactivity was absorbed (ca 0.16% vs. 0.30%) and an increased proportion was excreted in expired air suggesting some saturation of absorption and metabolism. 

Four major metabolites were identified in urine and one in expired air. Of the urinary metabolites, two of the major metabolites were glucuronides of tertiary butyl alcohol and 2-hydroxymethylisopropyl acetate. A third major metabolite in urine was the aglycone of 2-hydroxymethylisopropylacetate glucuronide. The fourth major metabolite was identified as 2-hydroxyisobutyric acid which accounted for 57-58% of the urinary metabolites at 100 and 1000 ppm. One of the minor urinary metabolites was identified as the glucuronide of t-butyl-2-hydroxyacetate. A large proportion of radioactivity in expired air of animals receiving the high dose was the parent tertiary butyl acetate. The metabolism of tertiary butyl acetate appears to follow two major routes: hydroxylation of the tert-butyl moiety to form 2-hydroxymethylisopropyl acetate and hydrolysis of the ester linkage to form tertiary butyl alcohol. In both cases, the available hydroxyl groups were conjugated with glucuronic acid. Free tertiary butyl alcohol was not detected. A major metabolite of tertiary butyl alcohol in rats, 2-hydroxyisobutyric acid, was detected. A minor route of metabolism was the hydroxylation of the acetate moiety in the parent molecule (t-butyl-2-hydroxyacetate), followed by glucuronide conjugation. Based on the proportion of metabolites that can clearly be assigned to one or the other major pathways, there also appears to be a dose-dependency to the metabolic pathways with the hydrolysis of the ester linkage favored at 1000 ppm while hydroxylation of the tert-butyl moiety predominates at the 100 ppm exposure level.  

 

Based on this study, inhaled tertiary butyl acetate is rapidly eliminated via exhaled air and the urine. Saturation of metabolism occurs at higher concentrations. Very little tertiary butyl acetate was retained in tissues after 7 days, suggesting efficient metabolism and excretion, and a low potential to bioaccumulate.

 

A supporting study by Groth and Freundt (1994) also demonstrated the rapid absorption and metabolism of tertiary butyl acetate. In this study, groups of anaesthetized female rats were continuously exposed to 440 ppm tertiary butyl acetate via a tracheal cannula for five hours or 900 ppm tertiary butyl acetate for 255 min. Blood samples were analyzed for tertiary butyl acetate and tertiary butyl alcohol during exposure and for 45 minutes following termination of exposure. During exposure to tertiary butyl acetate, concentrations of tertiary butyl acetate and the metabolite, tertiary butyl alcohol, increased continuously in the blood during the exposure period. There was no evidence of partial saturation of tertiary butyl acetate absorption at either exposure concentration. Concentrations of tertiary butyl acetate were approximately twice as high in rats exposed to 900 ppm of the test material. Following cessation of exposure, blood levels of tertiary butyl acetate rapidly declined. Forty-five minutes after cessation of exposure, blood levels of tertiary butyl acetate and tertiary butyl alcohol were approximately 50% and 100% of peak, respectively. 

 

An overarching review was conducted by Bus et al (2015)* which examined its primary use as a solvent in industrial and consumer products. Derivations of acute and chronic reference (RfC) values were made to develop hazard quotients (HQ) for various exposure scenarios in the US EPA risk assessment of tertiary butyl acetate; most HQ values less than 1, confirming low risks to human health. The publication also discusses the use of metabolic surrogate read-across in reducing animal testing.

 

The assessment found that tertiary butyl acetate has a low order of toxicity following subchronic inhalation exposure, and neurobehavioral changes (hyperactivity) in mice observed immediately after termination of exposure were the effects used as conservative endpoints for derivation of the acute and chronic RfC values. Tertiary butyl acetate was concluded to not be genotoxic and, although this substance has not been tested for carcinogenicity, it is unlikely to be a human carcinogen in that its non-genotoxic metabolic surrogates tertiary butyl alcohol and methyl tertiary butyl ether (MTBE) produced only male rat α -2u-globulin-mediated kidney cancer and high-dose specific mouse thyroid tumors, both of which have little qualitative or quantitative relevance to humans.

* Bus JS, Banton MI, Faber WD, Kirman CR, McGregor DB & Pourreau DB (2015) Human health screening level risk assessments of tertiary-butyl acetate (TBAC): Calculated acute and chronic reference concentration (RfC) and Hazard Quotient (HQ) values based on toxicity and exposure scenario evaluations, Critical Reviews in Toxicology, 45:2, 142-171

These studies indicate that following inhalation exposure, tertiary butyl acetate that is absorbed undergoes rapid metabolism primarily to tertiary butyl alcohol with further oxidation to 2-hydroxyisbutyric acid and excretion in the urine. Based on all available data, tertiary butyl acetate is expected to have a low potential to bioaccumulate. Since the primary metabolite of tertiary butyl acetate is tertiary butyl alcohol, it can be argued that inclusion of data from several long term studies conducted with tertiary butyl alcohol are relevant to the overall evaluation of target organ toxicity from exposure to tertiary butyl acetate and have therefore been included in this submission.