Registration Dossier

Administrative data

Description of key information

Sub-chronic data are available from a study in rats and mice. The most dominant effect in both species was the basal cell hyperplasia and hyperkeratosis of the forestomach and/or hyperplasia of the liver cells. A NOAEL of 300 mg/kg bw/3 days/week  (corrected 128 mg/kg bw/day) could only be determined for male mice.  

Key value for chemical safety assessment

Mode of Action Analysis / Human Relevance Framework

Additional information

In a sub-chronic study, groups of 10 male and 10 female F344 rats were given doses of styrene oxide (in corn oil) corresponding to 3000, 1500, 750, 360 and 180 mg/kg bw three times a week. A control group was given only corn oil. These groups were treated for 24 weeks. In addition 12 rats of each sex were given 1500 or 360 mg/kg bw for interim sacrifice of 4 rats at 5, 10, and 15 weeks of the study; 12 additional controls given vehicle were also used for interim sacrifice.

 

Decrease survival was seen in the rats given the highest dose of styrene oxide. Of the rats given 3000 mg/kg bw 30 % of the males died in the first 5 weeks and 40 % of the females died in the first 5 weeks; all were dead at 10 weeks. Of the rats given 1500 mg/kg bw 20 % of the females and 30 % of the males died at 24 weeks. Histopathologic examination of the animals revealed basal cell hyperplasia and hyperkeratosis of the forestomach and lesions in the liver, including hemorrhagic necrosis in those that died; several rats also had renal tubular epithelial degeneration or necrosis. Among the rats given lower doses, all of which survived, the changes observed histologically were some degree of liver cell hyperplasia, which varied from mild to moderate, and renal tubular degeneration in a few cases. There was no significant depression of weight gain among the animals receiving the three lowest doses of styrene oxide, but there was some decrease (> 10 %) at the two highest doses. The diffuse liver cell hyperplasia was somewhat greater in the group of rats given 750 mg/kg bw styrene oxide than in the group given 360 mg/kg bw styrene oxide in which it was only mild at most.

 

In the sub-chronic study in mice, groups of 10 male and 10 females were given 900, 600, 300, 90 or 60 mg/kg bw styrene oxide, three time a week. A group of controls received only corn oil. An interim sacrifice group of 12 animals received 600 or 900 mg/kg bw styrene oxide or the vehicle only. Treatment of the mice lasted 20 weeks. All animals were weighted once a week and were examined histopathologically for signs of toxicity at death or when sacrificed following the last treatment.

 

No death, no impairment of weight gain, and no pathologic findings other than basal cell hyperplasia and hyperkeratosis of the forestomach at the highest dose and hyperplasia of the liver in which it was mild or absent at the lower doses and moderate at the highest dose. There was no weight gain depression at 900 mg/kg bw styrene oxide.

A NOAEL of 300 mg/kg bw/3 days/week (corrected 128 mg/kg bw/day) could only be determined for male mice. There are no detailed data available for liver cell hyperplasia, however these findings does not affect the termimation of NOAEL, because they are specific for this strain of mice. For male/female rats and female mice only a LOEL can be determined, due to the absence of historical control data.

Justification for classification or non-classification

Based on a repeated dose toxicity study in mice and rats there is no evidence for specific target organ toxicity comply with the classification requirements regarding specific target organ toxicity — repeated exposure outlined in regulation (EC) 1272/2008 or the former Directive on classification and labelling 67/548/EEC.