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Carcinogenicity

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Styrene oxide was tested for carcinogenicity in one experiment in mice and in two experiments in rats by oral gavage. It produced benign and malignant tumours of the forestomach in animals of each species and sex and induced hepatocellular tumours in male mice. It was also tested in one strain of rats by prenatal exposure followed by postnatal gastric intubation, producing benign and malignant tumours of the forestomach.

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Carcinogenicity in mice after oral administration

 

Groups of 52 male and 52 female B6C3F1mice, seven weeks old, were administered styrene oxide at doses of 0, 375, or 750 mg/kg by gavage in corn oil (Lijinsky 1986).The test material was 96.6 % pure, with unspecified amounts of benzaldehyde, benzene, and an unidentified chemical as impurities. Styrene oxide was administered three times per week for 104 weeks; three to four weeks after the final dose, all surviving animals were sacrificed. There was a marked reduction in the survival of high-dose male and female mice, and the body weights were reduced in both groups (50 % died by week 60), in the high-dose groups. Styrene oxide administration was associated with increased incidences of proliferative changes in the forestomach of male and female mice. Both dose levels caused significantly increased incidences of squamous cell papillomas of the forestomach in males and females and squamous cell carcinomas in males and lowdose females. The incidences of papillomas and carcinomas combined were increased in both sexes at both dose levels. In males, tumors of the liver were significantly increased at the low dose; poor survival of the high-dose animals may have been responsible for the observation of no significant increase in liver tumors in the high-dose group.

 

Carcinogenicity in rats after oral administration

 

Groups of 40 male and 40 female Sprague-Dawley rats, 13 weeks old, were administered styrene oxide at doses of 0, 50, or 250 mg/kg by gavage in olive oil (Maltoni et al. 1979; Contiet al. 1988). Styrene oxide was administered 4 to 5 days per week for 52 weeks; animals were then observed until death. The last animal died 156 weeks after the initial dose of styrene oxide. The styrene oxide dosage regimen had no effect on body weight gain or survival in either sex. Administration of styrene oxide to male and female rats was associated with dose-related increased incidences of neoplasms of the forestomach. No significant increases in the incidences of tumours at other sites were reported. The incidences of squamous cell papillomas/acanthomas and carcinomas of the forestomach were increased in dose-related manners in rats of both sexes.

 

Groups of 52 male and 52 female F344/N rats (nine weeks old) were administered styrene oxide at doses of 0, 275, or 550 mg/kg by gavage in corn oil (Lijinsky 1986). The styrene oxide study material was 96.6 % pure, with unspecified amounts of benzaldehyde, benzene, and an unidentified impurity. Styrene oxide was administered three times per week for 104 weeks. All surviving animals were sacrificed three to four weeks after the final dose. Body weights and survival of the high-dose animals of both sexes were reduced. Styrene oxide administration resulted in dose-related increased incidences of tumours of the forestomach in both sexes at both doses. No evidence of increased tumour incidences at other sites was reported. In a few (< 10 %) animals, the carcinomas metastasized to the liver and other organs.

 

A group of 14 pregnant BDIV inbred rats (age not specified) received 200 mg/kg body weight styrene oxide (97 % pure) by gavage in olive oil on day 17 of gestation (Ponomarkov et al. 1984).Beginning at four weeks of age, their offspring (43 males and 62 females) received styrene oxide once a week by gavage in olive oil at doses of 100 to 150 mg/kg for 96 weeks. Total dosages were estimated to be 2.5 g for females and 5.0 g for males. The concurrent control group included 49 male and 55 female rats with no prenatal or postnatal exposure to styrene oxide. The control group received olive oil by gavage. The study was terminated at 120 weeks. When the first tumour appeared (time not specified), 42 male and 60 female Styrene oxide -dosed progeny were alive. The incidences of forestomach tumours were increased in styrene oxide-dosed male and female rats. Hyperplasia, dysplasia, and hyperkeratosis of the forestomach also were reported in treated rats. No evidence of increased tumour incidences at other sites was reported.

 

Carcinogenicity in mice after dermal administration

A group of 40 C3H mice (13 weeks old) of unspecified sex received three weekly applications of a 5 % solution of styrene oxide in acetone to the shaved dorsal skin for up to two years. Dose volumes were not specified. No skin tumours were observed in the 17 mice that survived for at least 24 months. Another group of 40 C3H mice received similar treatment with a 10 % solution of styrene oxide in acetone. Survival clearly was affected; only 18 mice survived for as long as 12 months, and only two mice survived for 17 months. No skin tumours were observed (Weil et al.1963).

 

A group of 30 male Swiss ICR/Ha mice (eight weeks old) received three weekly dermal applications of 100 mg of a 10 % solution of styrene oxide in benzene. Median survival time of dosed animals was 431 days. Three mice (10 %) had skin tumours, one of which was a squamous cell carcinoma. Eleven of 150 controls (7 %) developed skin tumours, one of which was a squamous cell carcinoma. In this study, the vehicle might contribute to the tumorigenic effect (Van Duuren et al.1963).

 

 

Cell proliferation:

In a cell proliferation study, Fischer 344 rats, were treated with 800, 1000 and 1500 mg/kg 3 times a week or single doses of 20, 50, 125, 200, 500, and 800 mg/kg styrene oxide. Doses above 50 mg/kg caused increased integration of tritiated thymidine (which was used as a pulse label) in the forestomach, which is a marker for cell proliferation. (Dalbey et al, 1996).

 

In another study, Male F344 rats were treated for 4 weeks with 0, 137, 275, and 550 mg/kg styrene oxide by p.o. gavage 3 times/week. Cell proliferation in the forestomach was observed by the means of immunohistochemistry for BrdU incorporated into DNA. The labelling index for cell proliferation increased from 49.1 (control group) to 70.3 % (550 mg/kg), in the midregion, from 42.6 to 59.2 %, and in the prefundic region from 41.6 to 54.3 %. No clear dose-response relationship was seen (Cantoreggi et al, 1993).

 

Justification for classification or non-classification

It can be concluded that orally administered styrene oxide is carcinogenic to laboratory animals, causing increased incidences of squamous cell neoplasms in the forestomachs of male and female mice and of male and female rats. In the single study in mice, styrene oxide administration also was associated with an increased incidence of hepatocellular neoplasms in male mice.

IARC concluded that there was sufficient evidence of carcinogenicity of styrene oxide in experimental animals. In addition to the consistent induction of proliferative changes and benign and malignant tumors of the forestomach in mice and rats, IARC’s conclusion regarding the carcinogenicity of Styrene oxide and its classification as probably carcinogenic in humans was based on the following information:

 

  • Styrene oxide forms covalent adducts with DNA in humans, mice, and rats.
  • Styrene oxide induces gene mutations in bacterial and rodent cells in vitro.
  • Styrene oxide induces chromosomal aberrations, micronuclei, and sister chromatid exchanges in human cells in vitro.
  • Styrene oxide induces chromosomal aberrations and sister chromatid exchanges in mice in vivo.

 

Styrene oxide is listed in REACH VO Annex XVII, appendix 2 and has to be classified as carcinogen Cat. 2 according directive to 67/548 EEC and carcinogen Cat. 1B according toCLP (EU-GHS) Regulation (EC) No 1272/2008.