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Description of key information

Sulfamethazine (synonym of Sulfadimidine) is not classifiable as to its carcinogenicity to humans (IARC category: Group 3). Thyroid tumours were observed in mice and rats but no in monkeys and there is no alert regarding carcinogenicity in humans.

Key value for chemical safety assessment

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Mode of Action Analysis / Human Relevance Framework

As reported in IARC Monographs, Vol.79, 2001, p.354 Sulfamethazine (synonym of Sulfadimidine) produces thyroid tumours in mice and rats by a non-genotoxic mechanism, which involves inhibition of thyroid peroxidase resulting in alterations in thyroid hormone concentrations and increased secretion of thyroid-stimulating hormone. No effects on thyroid gland function were found in dogs and in cynomolgus monkeys treated with sulfamethazine. Consequently, sulfamethazine would be expected not to be carcinogenic to humans.

Justification for classification or non-classification

As reported in IARC Monographs, Vol.79, 2001, p.354 Sulfamethazine (synonym of Sulfadimidine) is not classifiable as to its carcinogenicity to humans (Group 3). Sulfamethazine produces thyroid tumours in mice and rats by a non-genotoxic mechanism, which involves inhibition of thyroid peroxidase resulting in alterations in thyroid hormone concentrations and increased secretion of thyroid-stimulating hormone. No effects on thyroid gland function were found in dogs and in cynomolgus monkeys treated with sulfamethazine. Consequently, sulfamethazine would be expected not to be carcinogenic to humans and no classification is proposed for carcinogenicity of Sulfadimidide according to the CLP Regulation (EC n. 1272/2008).

Additional information

As reported in IARC Monographs, Vol.79, 2001, p.354 Sulfamethazine (synonym of Sulfadimidine) is not classifiable as to its carcinogenicity to humans (Group 3). Sulfamethazine produces thyroid tumours in mice and rats by a non-genotoxic mechanism, which involves inhibition of thyroid peroxidase resulting in alterations in thyroid hormone concentrations and increased secretion of thyroid-stimulating hormone. No effects on thyroid gland function were found in dogs and in cynomolgus monkeys treated with sulfamethazine. Consequently, sulfamethazine would be expected not to be carcinogenic to humans .

To support this statement in addition to evidence reported in section 7.5 "Repeated dose toxicity" of this IUCLID dossier other 2 chronic studies (the first on rats and the second on mice) and one subcronic study on monkeys are reported in IARC Monographs, Vol.79, 2001, p.345-349:

- chronic study on rats: Groups of 90 male and 90 female Fischer 344 rats were fed diets containing Sulfamethazine (purity > 99%) at a concentration of 10, 40, 600, 1200 or 2400 mg/kg from weaning for 24 months. The incidences of combined thyroid gland follicular-cell adenomas and adenocarcinomas at 24 months were 0, 2, 0, 5, 5 and 11% (0/180, 2/87, 0/90, 4/88, 4/83 and 10/87) in males and 4, 0, 1, 5, 10 and 9% (6/170, 0/90, 1/85, 4/84, 9/87 and 8/88) in females in controls and at the five dietary concentrations, respectively. The corresponding incidences of follicular-cell adenocarcinomas were 0/180, 2/87, 0/90, 2/88, 2/83 and 7/87 for males and 1/170, 0/90, 0/85, 0/84, 6/87 and 6/88 for females. The differences in the incidence of thyroid neoplasia were statistically significant at the two higher doses in both males and females when compared with controls (p < 0.05). There were no other treatment-related neoplasms. Thyroid follicular-cell hyperplasia, described as focal, multifocal or diffuse, was observed at the three higher doses. (ref. Littlefield et all, Food chem. Toxicol., 28, 157–167, 1990 mentioned inIARC Monographs, Vol.79, 2001, p.346)

- chronic study on mice: Groups of 96 male and 96 female B6C3F1 mice, 3–4 weeks of age, were fed diets containing Sulfamethazine (purity, 97–99%) at 300, 600, 1200, 2400 or 4800 mg/kg for 24 months, while 192 males and 192 female controls received basal diet. Additional groups of 24 male and 24 female mice were included for necropsy at 12 and 18 months. No deaths occurred. A statistically significant (p < 0.001) increase in the incidence of follicular-cell adenomas of the thyroid gland was observed in mice at the highest dietary concentration killed after 24 months. The incidences were 2/184, 0/95, 1/92, 4/88, 4/94 and 31/93 for males, and 5/180, 1/91, 1/93, 0/95, 2/94 and 23/89 for females in the controls and at the five concentrations, respectively. One male at 2400 mg/kg of diet and one female each at 600 and 4800 mg/kg had one follicular-cell carcinoma. Diffuse and focal thyroid follicular-cell hyperplasia was also observed at the three highest concentrations in males and at the two highest concentrations in females. Marginally significant but inconsistent, non-dose-related increases in the incidence of hepatocellular tumours were also reported in female mice. (ref.Littlefiled et all, Food chem. Toxicol., 27, 455–463, 1989 mentioned in IARC Monographs, Vol.79, 2001, p.345)

- subcronic study on monkeys: No effect on thyroid gland function was observed in cynomolgus monkeys (Macaca fascicularis) at doses of up to 300 mg/kg bw per day for 13 weeks (ref. McClain, Mutat. Res., 333, 131–142, 1995 mentioned in IARC Monographs, Vol.79, 2001, p.349. Note: the conditions of the study seem the same of the study Markiewicz, 1991 reported in section 7.5 "Repeated dose toxicity" of this IUCLID dossier).

 

 Sulfamethazine (synonym of Sulfadimidine) is not classifiable as to its carcinogenicity to humans (IARC category: Group 3). Thyroid tumours were observed in mice and rats but no in monkeys and there is no alert regarding carcinogenicity in humans.