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Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day

Additional information

For repeated dose toxicity, studies were performed by Perstorp AB using NesterolTM and by Eastman using TexanolTM, both trade names for isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol. The Eastman 51 -day study in rats was selected as the key study, as it represented the longest duration and greatest exposure.

The potential for TexanolTM to cause target organ toxicity following repeated exposure is well understood. One guideline repeat-exposure study and a shorter lesser study were available for review. In a combined repeat dose and reproductive/developmental toxicity screening study conducted according to OECD Guideline 422, male rats were exposed to up to 1000 mg/kg bw/day by oral gavage for 51 consecutive days while females were exposed for 40 to 51 days. For males, there were no significant treatment-related effects on mortality, clinical signs, body weight and body weight gain, feed consumption, or hematology. Although there was an increase in absolute and relative liver weights in all male dose groups, no treatment-related changes were observed during the macroscopic examination. Microscopically, centrilobular hepatomegaly was observed in the livers of male rats in the mid- and high-dose groups but this was considered an adaptive metabolic response rather than a toxic response due to the absence of degenerative changes to the liver. Certain clinical chemistry parameters, i.e., mean aspartate aminotransferase and/or alanine aminotransferase levels, which would be expected to rise when liver damage occurs, were both significantly lower in all male dose groups when compared to the controls. The only other significant effect noted in male rats was an increase in absolute and relative kidney weights in the high-dose group and the presence of hyaline droplet formation, increased incidence of regenerative tubular epithelium, increased incidence of dilated tubules, and the presence of granular casts at the corticomedullary junction in the kidneys of mid- and high-dose animals. Mean creatinine levels, which would be expected to rise when kidney function is impaired, were significantly lower in the mid- and high-dose groups. For females, there were no significant treatment-related effects on mortality, clinical signs, body weight and body weight gain, or feed consumption. Hematology and clinical chemistry evaluations were not conducted on the females. Although there was an increase in absolute and relative liver weights in the high-dose female group, no treatment-related changes were observed during the macroscopic examination. Microscopically, centrilobular hepatomegaly was observed in the livers of female rats in the mid- and high-dose groups but this was considered an adaptive metabolic response rather than a toxic response due to the absence of degenerative changes to the liver. Kidney lesions were not observed in female rats. 

In a supporting subacute toxicity study in which groupsof 5 rats/sex were administered up to 1000 mg/kg bw/day of TexanolTM by oral gavage for a total of 11 doses over a 15-day period, there were no significant treatment-related effects on mortality, clinical signs, body weight or body weight gain, food consumption, hematology, clinical chemistry, organ weights, or gross or microscopic effects in either sex. Minor increases in liver weights in animals receiving 1000 mg/kg bw/day occurred in the absence of clinical chemistry changes or gross or microscopic liver changes. The presence of minimal to minor hyaline droplet degeneration in the kidneys of all males occurred in the absence of gross lesions or significant clinical chemistry changes which might be indicative of impaired kidney function.

In a subchronic toxicity study, NesterolTM was administered per os via oral gavage to groups of male and female Sprague-Dawley rats at dose levels of 0, 15, 150, and 1000 mg/kg bw/day (5 rats/sex/group) for 28 days. No test substance related effects were observed in clinical observations, body weights, food consumption, hematology parameters, clinical chemistry parameters and in blood smear analysises. Statistically significant increased liver weights were observed in female animals treated with 1000 mg/kg bw/day with minimal centrilobular hepatocyte enlargement in 2 of 5 animals and this effect was considered to be related to test substance exposure. Cortical tubular eosinophilic inclusions in the kidneys of 150 (trace 3 of 5 animals) and 1000 (minimal 2 of 5 animals and moderate 3 of 5 animals) mg/kg bw/day was observed and considered related to test substance exposure. Under the conditions of this study, the NOEL following oral gavage exposure to Nesterol for 28 days was 15 (male) and 150 (female) mg/kg bw/day in rats.

Justification for classification or non-classification

Target organ effects in rats following repeated exposure to up to 1000 mg/kg bw/day of the test material by oral gavage for 51 days in males and 40-51 days in females were limited to the liver in both sexes and the kidneys in the male dose groups. Although there was an increase in absolute and relative liver weights in all male dose groups and the high-dose group females, no treatment-related changes were observed in either sex during the macroscopic examination. Microscopically, centrilobular hepatomegaly was observed in the livers of mid- and high-dose groups of both sexes but this was considered an adaptive metabolic response due to the absence of degenerative changes to the liver. There were no adverse effects on clinical chemistry parameters which would be suggestive of liver damage. Kidney changes in males included increases in kidney weights in the high-dose group and the presence of hyaline droplet formation, increased incidence of regenerative tubular epithelium, increased incidence of dilated tubules and the presence of granular casts at the corticomedullary junction in the kidneys of mid- and high-dose animals. Clinical chemistry changes which are indicative of impaired kidney function were not observed. The kidney lesions were typical of alpha 2-μ globulin nephropathy, a common spontaneous lesion in male rats and frequently exacerbated by chemical exposure. The increased incidence of chronic progressive nephropathy in male rats was most likely due to epithelial damage from the presence of hyaline droplets in cortical tubules and not to test substance-related toxicity. The significance of increased hyaline droplet degeneration and lesions suggestive of alpha 2-μ globulin nephropathy is unclear since these effects have not been observed in humans or other species. The NOAEL for systemic effects in both sexes was considered to be 1000 mg/kg bw/day. Based on a weight-of-the-evidence assessment, isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol is not classified for “Specific Target Organ Toxicity – Repeated Exposure” according to EU CLP.