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Carcinogenicity

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Description of key information

Alpha-methylstyrene was tested in a guideline study for carcinogenicity in rats and mice (NTP, 2007).

Key value for chemical safety assessment

Additional information

Rats

In this study (design comparable to OECD Guideline 451 without clinical pathology), groups of 50 male and 50 female F344/N rats were exposed by whole body inhalation to alpha-methylstyrene at concentrations of 0, 100, 300 or 1000 ppm for 6 hrs per day and 5 days per week (except holidays) for 105 weeks. Survival rates of exposed male and female rats were similar to those of the chamber controls. The mean body weights of 1000 ppm males and females were less than those of the chamber control groups during year 2 of the study. Two 1000 ppm males and one 300 ppm male had renal tubule carcinomas, and one 300 ppm male had a renal tubule adenoma. Because of the neoplasms observed in >= 300 ppm males at the end of the study and the finding of alpha2u-globulin accumulation in the kidneys at 3 months, which is often associated with kidney neoplasms, additional step sections of kidney were prepared; additional males with focal hyperplasia or adenoma were identified. The incidences of renal tubule adenoma and carcinoma (combined) in the 1000 ppm males were significantly greater than those in the chamber controls when the single and step sections were combined. The incidence of mineralization of the renal papilla was significantly increased in 1000 ppm males. Although the incidence of mononuclear cell leukaemia in 1000 ppm males was significantly increased compared to the chamber controls (overall rates: 58.7, 67.7, 61.9 or 80.2 %; terminal rates: 63, 72, 52 or 64 %; historical incidences: 47.1 +/- 10.3 % with a range of 32 - 66 %), this finding is equivocal due to the high incidences in historical controls. In the nose, the incidences of basal cell hyperplasia were significantly increased in all exposed groups of males and females, and the incidences of degeneration of the olfactory epithelium were increased in 1000 ppm males and females and 300 ppm females.

The exposure related kidney toxicity in males exhibited some features of alpha2u-globulin nephropathy. This finding is supported by the results of a 14 week study (see section 7.5.3), where groups of 10 male and 10 female rats were exposed by whole-body inhalation to alpha-methylstyrene at concentrations of 0, 75, 150, 300, 600 or 1000 ppm for 6 hrs per day and 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. In this study, kidney weights were significantly increased in 1000 ppm males and at >= 600 ppm females. The incidences of renal hyaline droplet accumulation were similar between exposed groups and chamber control groups, but the severity of hyaline droplet accumulation in >= 600 ppm males was greater than in chamber controls. Consistent with the hyaline droplet accumulation, an exposure related increase in alpha2u-globulin was detected in the kidneys of males exposed to alpha-methylstyrene.

NTP stated that alpha-methylstyrene showed some evidence of carcinogenicity based on the increased incidences of renal tubule adenomas and carcinomas (combined) in male rats, while there was no evidence of carcinogenicity in female rats. The male rat kidney toxicity and resulting tumours fit the alpha2u-globulin mode of action, which is not occurring in humans. Therefore, these tumours are not relevant for human risk assessment.

Mice

In this study (design comparable to OECD Guideline 451 without clinical pathology), groups of 50 male and 50 female B6C3F1 mice were exposed by whole body inhalation to alpha-methylstyrene at concentrations of 0, 100, 300 or 600 ppm for 6 hrs per day and 5 days per week (except holidays) for 105 weeks. Survival of all exposed male and female mice was similar to that of the chamber control groups. Mean body weights of 600 ppm males were less than those of the chamber control group throughout the study, and those of 600 ppm females were less after week 13. The mean body weights of 300 ppm males and females were less than those of the chamber controls during much of the study, but these groups recovered by the end of the study. The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in the 100 and 600 ppm males and in all exposed groups of females. The incidences of hepatocellular adenoma were significantly increased in all exposed groups of females, and the incidences in all exposed groups of males and females exceeded the historical range for chamber controls. The incidences of hepatocellular carcinoma and eosinophilic foci of the liver were significantly increased in 600 ppm females. The incidences of olfactory epithelial metaplasia and hyperplasia of the glands overlying the olfactory epithelium were significantly increased in all exposed groups of males and females. In addition, atrophy of the olfactory epithelium was significantly increased in >= 300 ppm males. The incidence and severity of nephropathy were increased in 600 ppm females compared to chamber controls. Epithelial hyperplasia of the forestomach also was present in male mice.

NTP stated that alpha-methylstyrene showed equivocal evidence of carcinogenicity based on marginally increased incidences of hepatocellular adenomas and carcinomas (combined) in male mice, while there was clear evidence of carcinogenicity in female mice based on increased incidences of hepatocellular adenomas and carcinomas. However, these tumours have a high background rate, are probably an epigenetic phenomenon related to an increase in hepatocellular turnover and there are doubts about whether quantitative transferability exists, particularly if the substance is not genotoxic (such in the case of alpha-methylstyrene) and this type of tumour is the only one that occurs to an increased incidence. Therefore, these tumours are not relevant for human risk assessment.

Justification for classification or non-classification

Based on the available data classification for carcinogenicity is not warranted according to EC regulation 1272/2008.