Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity: inhalation
Effect level (male rat) LOAEC = 100 ppm
Target organ: kidney
Effect level (female rat) NOAEC = 400 ppm
Target organ: liver, adrenal gland

Key value for chemical safety assessment

Additional information

The potential for tertiary butyl acetate to cause target organ toxicity following repeated exposure is well understood. In key repeat-exposure studies conducted according to EPA OPPTS Guideline 870.3465, groups of male and female rats and mice were exposed 6 hours/day, 7 days/week for 13 weeks by the inhalation route to 0, 100, 400 or 1600 ppm tertiary butyl acetate. The NOAEC was 400 ppm based on higher liver and adrenal gland weights were observed in 1600 ppm females. Significant target organ effects in male rats were limited to alpha-2u-globulin nephropathy, a common spontaneous lesion in certain strains of male rat that is frequently exacerbated by chemical exposure but is not relevant to human health risk assessment. The NOAEC for non-acute systemic toxicity in mice was considered to be 400 ppm based on slight liver enlargement in both sexes at 1600 ppm with minimal centrilobular hypertrophy in a single female, lower T4 levels (but no effects on TSH, T3, or microscopic evaluation of the thyroid) in 1600 ppm males, and a marginally higher PCNA labeling index in 1600 ppm females only. The NOAEC for transient acute clinical findings in the mouse 13 week study was 100 ppm with sporadic hyperactivity noted in the 400 and 1600 ppm animals. Both of these studies have been discussed and expertly reviewed in a publication by Faber et al (2014), with the citation appearing in the relevant repeated dose endpoint study records.

 

No chronic toxicity studies conducted with tertiary butyl acetate were identified. Since absorbed tertiary butyl acetate is rapidly metabolized and the primary metabolite of tertiary butyl acetate is tertiary butyl alcohol, 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. In rodents, repeated exposure to tertiary butyl alcohol appears to target the kidney for toxicity. In 13-week and 2-year oral studies conducted with tertiary butyl alcohol, there was an increase in chronic progressive nephropathy. In an expert evaluation by Hard (2001; found in this IUCLID dossier under “Additional toxicological information”), the author examined the renal effects of tertiary butyl alcohol in rats and mice following subchronic and chronic exposure and the progression to neoplasia in male rats only. He suggests the observed effects may involve the induction of alpha-2u-globulin nephropathy (a condition unique to male rats), a dose-related enhancement of chronic progressive nephropathy (CPN), or possibly a combination of both. In a review published by Hard et al. (2009; found in this IUCLID dossier under “Additional toxicological information”), the authors analyzed the available published literature on the nature of rat CPN and human renal disease and along with their personal experiences, concluded that based on differences in biology and pathology, there is no counterpart of chronic progressive nephropathy in humans. The authors further recommended “that chemically-induced exacerbation of CPN not be acknowledged as an indicator of human toxic hazard.”

 

The only statistically significant non-neoplastic effects observed in mice exposed to tertiary butyl alcohol by the oral route for a lifetime (males received a maximum of 1868-2896 mg/kg bw/day; females received 1786-3488 mg/kg bw/day) were an increase in the incidence of thyroid follicular cell hyperplasia (at all dose levels in males and higher dose levels in females) and chronic inflammation and transitional epithelial hyperplasia of the urinary bladder (high-dose animals of both sexes). In a review by McClain (2001; found in this IUCLID dossier under “Additional toxicological information”), the author evaluated possible causes for the thyroid gland changes observed only in mice in the 2-year chronic studies. The author postulates that the thyroid gland hyperplasia seen in this study is a consequence of microsomal enzyme induction of thyroid hormone metabolism. This in turn causes a compensatory increase in pituitary TSH which after long term, low level stimulation of the thyroid gland results in follicular cell hypertrophy and hyperplasia. There are important species differences between rodents and humans in thyroid gland physiology. As a result, rodents appear to be much more susceptible than humans to the development of adverse thyroid effects such as hyperplasia and ultimately neoplasia which occurs secondary to altered thyroid gland function.

Justification for classification or non-classification

When groups of male and female rats and mice were exposed to tertiary butyl acetate by the inhalation route at concentrations up to 1600 ppm for 6 hours/day, 7 days/week for 13 weeks, the only significant target organ effect was alpha-2u-globulin nephropathy observed in male rats at all exposure concentrations. Alpha-2u-globulin nephropathy is present as a spontaneous lesion in certain strains of rat and is usually less prominent in females than males. This type of nephropathy has not been reported in humans and it was not reported in male or female mice exposed to the same airborne concentrations of tertiary butyl acetate as rats. Systemic toxicity in female rats was limited to higher liver and adrenal gland weights in the 1600 ppm exposure group with no corresponding gross- or histopathology. Transient acute clinical signs were observed in mice only and resolved before the next exposure period. Non-acute systemic effects in mice were minor and limited to slight liver enlargement in both sexes at 1600 ppm with minimal centrilobular hypertrophy in a single female, lower T4 levels in 1600 ppm males, and a marginally higher PCNA labelling index in 1600 ppm females. No other dose-related acute or target organ effects were reported for rats or mice exposed to tertiary butyl acetate by the inhalation route for up to 13 weeks.

 

The only significant non-neoplastic lesions observed in rodents exposed to tertiary butyl alcohol by the oral route for up to two years were chronic progressive nephropathy and an increased incidence of thyroid follicular cell hyperplasia in mice. Chronic progressive nephropathy is present as a spontaneous lesion in the strain of rat used in the 2-year studies and is usually less prominent in females than males. Chronic progressive nephropathy has not been reported in humans and was not reported in male or female mice exposed to dose levels of approximately 2000 mg/kg bw/day for a lifetime. A number of chemicals, when tested for prolonged periods at high concentrations, have caused thyroid follicular cell hyperplasia in rodents with no corresponding effect reported in humans exposed to lower concentrations. Thyroid effects were not observed in rats following lifetime exposure by the oral route. By comparison to rodents, the human thyroid appears to be much less sensitive to adverse effects on thyroid hormone production/secretion and the proposed mechanism leading to thyroid hyperplasia in rodents.

 

Based on a weight-of-the-evidence assessment of data for both tertiary butyl acetate and its primary metabolite tertiary butyl alcohol, tertiary butyl acetate is not classified for “Specific Target Organ Toxicity – Repeated Exposure” according to EU CLP (Regulation (EC) No. 1272/2008), and UN GHS.