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No studies are available for sodium tert-butanolate. Therefore, read-across to the reaction product tert-butyl alcohol was performed. Here, 2 GLP-studies performed by NTP are available, also published by Cirvello et al. (1995).

60 F344 rats/group/gender received tert-butyl alcohol in concentrations of 1.25, 2.5 or 5 mg/mL (males) and 2.5, 5 or 10 mg/mL (females) with the drinking water for 2 years. After 15 month, an interim killing showed increased relative kidney weights in male animals of the 2.5 and 5 mg/mL groups and absolute and relative kidney weights in females of all treatment groups. In addition, spontaneaus nephropathy in both sexes was more pronounced compared to the control group. One male rat receiving 5 mg/mL had a tubule adenoma in the kidney.

At the end of the study, the mortality in the high-dose group for both sexes was significantly higher compared to the controls and was suggested to be based on nephrotoxicity. The body weights were reduced in male (15% to 24%) and female rats (21% at 10 mg/mL). Symptoms of intoxication could not be detected. In histological examination, the severity of age-related spontaneaus nephropathy was significantly increased in the male animals receiving 5 mg/mL, and in the females of all doses shown by e.g. regeneration processes in the tubule epithelium, protein crystallization, hyperplasia in the transitional epithelium but without necrosis. Male rats showed a dose-dependent increase in the incidence of mineralization which is typical for a2u-globulin nephropathy. Neoplastic damage could not be detected in females. For males, an increased incidence of tubule cell adenomas or carcinomas was found which failed to be dose-dependent due to increased mortality and nephrotoxicity in the high dose group but was significantly increased in the 2.5 mg/mL group.The incidence of tubule cell adenomas or carcinomas in the controls was very high so that it is diffucult to use it as evidence of carcinogenic effects of tert-butyl alcohol.

The occurring chronic progressive nephropathy (CPN) is both, a degenerative and regenerative disease which is characterized by a highly proliferative population of epithelial cells as a possible compensatory regenerative response to tubule atrophy. As described in the publication of Hard et al., 2009, a significant correlation between CPN and the development of renal tubule tumors could be found which can be explained by the high proliferation rate. This is expected to amplify in chemical-induced exacerbations of CPN resulting in slightly increased risk of renal tumor development. Since chemical-induced exacerbations can not be regarded as higher expression of nephrotoxicty, it concludingly can be argued that it is not relevant for inter species extrapolation from rats to humans.

This 2-year study was also carried out using B6C3F1 mice which received tert-butyl alcohol with their drinking water with following doses: 5, 10 or 20 mg/mL. At the end of the study, survival at 20 mg/mL was lower compared to controls. Body weights of the female mice in the 20 mg/mL group were lower (10 -15 %) compared to the control group. No clinical signs of intoxication were seen in any group. In histological examination, findings were detected for the thyroid gland and bladder. Chronic inflammation and hyperplasia could be observed in the bladder of the 20 mg/mL groups. In the thyroid gland, the incidence for adenoma was significantly increased in females receiving 20 mg/mL. With regard to the data for body weight gain and mortality, this dose seemed to be above the MTD (maximum tolerated dose). The incidence in male mice was increased at 10 mg/mL but failed to be dose-dependent or significant. Nevertheless, it has to be mentioned that the data of tert butanol are under current CoRAP-evaluation by the Member States Competent Authorities.

As in these studies in rats and male mice non-neoplastic effects were found even at the lowest dose tested in each case, the NOEL for systemic-toxic effects is below 1.25 mg/mL (for males below 90 mg/kg and for female rats below 180 mg/kg). The NOAEL for mice lies below 5 mg/mL (female: 540 mg/kg; male: 510 mg/kg).

Justification for classification or non-classification

The neoplastic effects that were found in mice occurred at doses that exceeded the maximum tolerated dose. In rats, neoplastic effects only occurred in male animals but without dose-dependency due to high mortality. Additionally, control group also had a high incidence of nephrocarcinogenicity.

Based on the available data, no classification is proposed according to EU directive 67/548/EEC and EU regulation (EC) NO. 1272/2008 (CLP).