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EC number: 202-705-0
CAS number: 98-83-9
Alpha-methylstyrene was tested in a guideline study for carcinogenicity in rats and mice (NTP, 2007).
Based on the available data classification for carcinogenicity is not
warranted according to EC regulation 1272/2008.
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.
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.
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