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Administrative data

Description of key information

Reliable studies are available for oral application as well as for exposure via inhalation.
Oral (MHW Japan, 1997):
Study design according to OECD Guideline No. 422
NOEL: 40 mg/kg bw
LOAEL: 200 mg/kg bw (based on histological changes in liver and kidneys of both sexes and in thymus of female rats; increase in GPT in male rats)
Inhalation (rats & mice; NTP, 2007)
Study design comparable to OECD Guideline No. 413
NOAEL: 150 ppm for males (based on kidney & liver weights)
Inhalation (several species; Wolf et al., 1956)
6 months, 7h/d, 5d/week
NOAEL: 200 ppm (based on kidney & liver, reduction in growth)
Dermal:
For the dermal route there are no data available. However, as inhalation is the most important route of exposure and for this endpoint a recent NTP study in rats and mice is available, no dermal repeated dose toxicity study is considered to be needed or scientifically justified.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
LOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
984 mg/m³
Study duration:
subchronic
Species:
monkey

Additional information

Oral:

In this study performed according to OECD Guideline 422, alpha-methylstyrene was given to SD (Crj:CD) rats of both sexes at dose levels of 0, 40, 200 or 1000 mg/kg/day by oral administration for 43 days from 14 days prior to mating to days after mating in males and for the periods including 14 days prior to mating and from gestation period, followed by delivery until post-partum day 3 in females.

At 1000 mg/kg, male rats showed a suppression of body weight gain, and a decrease in food consumption, and one animal died due to ischuria with urinary calculi. Female rats showed slight suppression of body weight gain in the late gestation period. Histopathological examination demonstrated increases of liver and kidney sizes, acidophilic change of hepatocytes and increase of fatty droplets in the fascicular zone of the adrenals in both sexes, increase of hyaline droplets and basophilic change in the renal tubular epithelium, formation of urinary calculi and hyperplasia of the mucosal epithelium in the urinary bladder in male rats, and vacuolation and infiltration of lymphocytes in the renal tubular epithelium and atrophy of the thymus in female rats. Blood chemical examination in male rats showed increases in GPT, urea nitrogen and potassium, and a decrease in triglyceride.

At 200 mg/kg, similar histological changes were found in the liver and kidneys of both sexes, and the thymus of female rats, and an increase in GPT was observed in male rats. Haematological examination showed that the test substance had no effects in males.

The LOAEL for repeated dose toxicity was 200 mg/kg/day. The NOEL was given with 40 mg/kg/day for both sexes.

Inhalation (rats):

In this study (design comparable to OECD Guideline 413), 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. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Kidney weights were significantly increased in 1000 ppm males and at >= 600 ppm females. Statistically significant increases in liver weights occurred at >= 150 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. Morphologic changes were not detected in the liver.

From this study a NOAEL of 300 ppm for male rats was derived, based on effects relevant for human health risk assessment.

Inhalation (mice):

In this study (design comparable to OECD Guideline 413), groups of 10 male and 10 female B6C3F1 mice 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.

Two females in the 1000 ppm group died before exposure on day 3. Final mean body weights of >= 600 ppm males and 75, 300, and 1000 ppm females were significantly less than those of the chamber controls; final mean body weight gains of mice exposed to >= 300 ppm were also significantly less. Moderate to severe sedation (males only) and ataxia were observed at 1000 ppm. The absolute liver weights of >= 600 ppm females and the relative liver weights of >= 300 males and females were significantly increased. The oestrous cycle lengths of >= 600 ppm females were significantly longer than that of the chamber controls. Minimal to mild centrilobular hypertrophy was present in the livers of males and females at >= 600 ppm. The incidences of exposure-related nasal lesions, including atrophy and hyperplasia of Bowman’s glands and atrophy and metaplasia of the olfactory epithelium, were significantly increased in all exposed groups of males and females. The incidences of hyaline degeneration, characterized by the accumulation of eosinophilic globules in the cytoplasm of the respiratory epithelium, were significantly increased in females at >= 150 ppm.

The findings in mice at the respiratory epithelium was not considered to be relevant for human health risk assessment. The effects observed in liver weight at 300ppm did not lead to effects in histopathology or clinical chemistry. Therefore, a NOAEL of 300 ppm has been derived.

In further inhalation studies several species were exposed for approx. 6 months to vapour 7h/d, 5d/week).

At 200 ppm no toxic effects were noted, while effects such as changes in organ weights or slight growth depression were noted at >= 600 ppm. A concentration of 3000 ppm caused severely increased mortality. The NOAEL was reported to be 200 ppm (984 mg/m3). This study was used by SCOEL to derive an OEL.

Justification for classification or non-classification

Based on the current findings there is no indication of a specific target organ with relevance to human health.