Sulfadimidine

Endpoint summary

Description of key information

NOEL oral 90 days rat = 2mg/kg/bw (Note: inhibition of thyroid peroxidase resulting in alterations in thyroid hormone concentrations and increased secretion of thyroid-stimulating hormone; mechanisms observed in rat and mice but not in monkey and it would not be expected for humans). No data regarding repeated dose toxicity for inhaltion and dermal routes.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Data reported by WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 25), 1990 free available on web http://www.inchem.org/documents/jecfa/jecmono/v25je06.htm . The primary source (Littlefield unpublished study of 1985 submitted to WHO) is reported in WHO Food additives Series 25, 1990.

System:

endocrine system

Organ:

thyroid gland

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

As reported also in IARC Monographs, Vol.79, 2001, p.354-355 Sulfametidine (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. Some effects on T4/THS quantity were observed also in pigs but no effects on thyroid gland function were found in dogs and in cynomolgus monkeys treated with sulfamethazine. Consequently, sulfamethazine would be expected not to have effect and not to be cancerogenic to humans.

Additional information

Some repeated oral toxicity studies for different species are available regarding Sulfadimidine.

The studies are reported in this summary considering the different species and inside each group the studies are reported from longer till shorter.

 

Rats

- 24 months study on rat fed with 10, 40, 600,1200 and 2400 ppm of Sulfadimidine: a decrease in total thyroid hormone was observed starting from 600 ppm.NOEL rat Sulfadimidine= 40 ppm (ref.Fullerton et all, J.Toxicol.Env. Health, 22,175-185, 1987 mentioned in Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 25), 1990 available on website http://www.inchem.org/documents/jecfa/jecmono/v25je06.htm)

 

- 90 day study conducted on rats at dose of 2,6 or 20 mg/kg/bw/day. Definitive changes were seen at 20 mg/kg bw/day, slight changes were seen at 6 mg/kg bw/day, and no effects were seen at 2 mg/kg bw/day. NOEL rat Sulfadimidine = 2 mg/kg/bw/day (ref. Littlefield, 90-day study on sulfamethazine in Fischer 344 rats, unpublished report No. 334 from the National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas. Submitted to WHO by the US Coordinator of the Codex Alimentarius, US Department of Agriculture, Washington, D.C. mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 25), 1990 available on website http://www.inchem.org/documents/jecfa/jecmono/v25je06.htm)

 

- 13 weeks study (about 90 days) conducted on rat fed with sulfadimidine sodium salt at concentrations of 0, 40,150, 600, 2400, or 4800 mg/kg (equal to 0, 2.2, 8.5, 34, 136 or 261 mg/kg bw/day): increase in thyroid weight at two higher doses; hyperplasia and limited hypertrophy at 600 mg/kg equal to 34 mg/kg/bw. NOEL rat for Sulfadimidine sodium salt= 8.5 mg/kg/bw (Braverman et all, A three-month study in rats to investigate the effects of sulfamethazine on thyroid function:effect on serum TSH, T3, T4 and reverse T3 concentrations.Unpublished report no. UM-90-201-013 from the University ofMassachusetts Medical School, Division of Endocrinology Laboratory,Worcester, MA, USA. Submitted to WHO by the Animal Health Institute,USA,1991 mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07.htm)

 

- 4 weeks study (28 days) on rats: TSH levels were significantly elevated in rats consuming the 2400, and 4800 mg/kg sulfadimidine diets. At 600 and 1200 mg/kg feed a slight increase in TSH levels was seen.(ref. Cullison et all,Evaluation of the dose-dependent effects of sulfamethazine on rat thyroid stimulating hormone (TSH) levels. Unpublished report from the Division of Veterinary Medical Research Center for Veterinary Medicine, US Food and Drug Administration. Final report for DVMR study 312.04. Submitted to the WHO by the US FDA, Rockville, MD, USA, 1990 mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07.htm)

 

-4 weeks study (28 days) on rats: orally administration at 0, 1, 2.5, 5, 10, 25, 50, 100, 200, 400 and 600 mg/kg/bw/day: no death related to treatment at any dose but at doses ≥ 200 mg/kg/bw decrease of T3 and T4 and increase of THS. Hyperplasia and hypertropia of thyroid folliular are observed starting from dose 10 mg/kg/bw.NOEL rat Sulfadimidine = 5 mg/kg/bw/day (ref.McClain et all, A four-week exploratory study of dose-response characteristics for the effects of sulfamethazine on thyroid function in rats. Study no.05421. Unpublished report (no 127736) of Toxicology and Pathology of Hoffman-La Roche Inc., Nutley, NJ, USA.Submitted to WHO by the Animal Health Institute, Alexandria, VA, USA., 1993 mentionedin WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07).

 

Mechanism of action

Negative effects caused by Sulfadimidine are due to its ability to increase the level of THS. This mechanism was demonstrated by McClain in 13 weeks study on rats fed with 0 or 2400 mg sulfadimidine/kg (equivalent to 120 mg/kg bw/day) and supplemental thyroid hormone (T4/T3:molar ratio 9:1, concentration10, 20, 30, or 40 µg/kg of feed).Treatment with a combination of thyroid hormone and Sulfadimidine reduced the diffuse hypertrophy and diffuse hyperplasia observed with Sulfadimidine alone in a dose-related manner. (Ref. McClain et all, A three-month study in rats to investigate the reversibility of the effects of sulfamethazine on thyroid finction by treatment with thyroid hormone (study no. 05724). Unpublished report no. 127737 from Toxicology and Pathology, Hoffmann-La Roche Inc., Nutley, NJ,USA. Submitted to WHO by the Animal Health Institute, Alexandria,VA, USA,1993 mentioned inmentionedin WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07).

The hypophysis is the target organ in rats for Sulfadimidine: in 7 days study on rats hypophysectomised and on normal rats a decrease in T3 and T4 in plasma was observed in both animals but histological change in thyroid was present only in normal rats.(ref.Dowing et all, A seven-day exploratory study to assess thyroid function in normal and hypophysectomized rats treated with sulfamethazine. Study no. 05992.Unpublished report (no 132014) of Toxicology and Pathology ofHoffmann-La Roche, Nutley, NJ, USA.Submitted to WHO by the Animal Health Institute, Alexandria, VA, USA mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available at website http://www.inchem.org/documents/jecfa/jecmono/v33je07).

 

Other repeated oral toxicity studies for Sulfadimidine were performed on other species different from rat.

  

Mice

Sulfadimidine was administered in the feed for 90 days to five groups of 12 male and 12 female weanling (3-4 weeks old) B6C3F1 SPF mice at dosages of 300, 600, 1200, 2400, or 3600 ppm. The primary objective of the study was to establish appropriate doses for a carcinogenicity study.There was a significant increase in the brain to body weight ratio at the 300, 1200, and 2400 ppm in male mice. (ref. Littlefield, 90-day study on sulfamethazine in B6C3F1 mice, unpublished report No. 333 from the National Center for Toxicological Research, Food and Drug Administration, Jefferson,Arkansas. Submitted to WHO by the US Coordinator of the Codex Alimentarius, US Department of Agriculture, Washington, D.C., 1985 mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 25), 1990 available on website http://www.inchem.org/documents/jecfa/jecmono/v25je06.htm)

 

Pigs

Groups of 5 male weanling pigs received diets containing 0,125, 250, 500, or 1000 mg Sulfadimidine/kg feed (equivalent to 0, 5, 10, 20, or 40 mg/kg bw/day) for 4 weeks. A good correlation between decreases in T4 and increases in TSH was observed. NOEL pig Sulfadimidine= 125 mg/kg equivalent to 5 mg/kg/bw/day(ref . Cullison et all, Estimation of the sensitivity of the swine model for the goitrogenic effects of drugs. Unpublished report from the Division of Veterinary Medical Research Center for Veterinary Medicine, US Food and Drug Administration. Final report for DVMR study 312.03. Submitted to WHO by the US FDA, Rockville, MD, USA, 1990 mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07.htm)

Dogs

 Sulfadimidine was administered orally in gelatin capsules once daily, seven days a week, for 96 days to three groups of three male and three female beagle dogs at dosages of 2, 6, and 20 mg/kg bw/day. An additional group of three male and three female dogs served as controls and received empty gelatin capsules on a similar regimen.There were no dose related findings in symptomology, body weight, food consumption, ophthalmology, hematology, urinalysis, organ weight, organ to body weight ratio, or pathology. All dogs survived for the duration of the test. (ref. Smith, A three month oral toxicity study of sulfamethazine in beagle dogs, unpublished report No. 72R-780 from BioDynamics Inc., East Millstone, New Jersey, to SmithKline and French, Westchester, Pennsylvania. Submitted to WHO by the US Coordinator of the Codex Alimentarius, US Department of Agriculture,Washington, D.C., 1973 mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 25), 1990 available on website http://www.inchem.org/documents/jecfa/jecmono/v25je06.htm)

Monkeys

Groups of Cynomolgus monkeys (4/sex/group) were orally administered doses of 0, 30, 100, or 300 mg sulfadimidine sodium/kg/bw/day for 13 weeks. No effects were observed (no depression of T3 or T4 and no increase in TSH).NOEL monkey Sulfadimidine sodium = 300 mg/kg/bw/day (ref.Markiewicz, 13-Week subchronic study with sulfamethazine in Cynomolgus monkeys with a special evaluation of thyroid function and morphology. Unpublished final report no.2609-100 from Hazleton, Washington Inc., Vienna, VA, USA. Submitted to WHO by the Animal Health Institute, Alexandria, VA, USA,1991 mentioned in WHO, Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07.htm)

 

As conclusion, reported also in IARC Monographs, Vol.79, 2001, p.354-355 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. Some effects on T4/THS quantity were observed also in pigs but no effects on thyroid gland function were found in dogs and in cynomolgus monkeys treated with sulfamethazine. Consequently, Sulfamethazine would be expected not to have effect and not to be cancerogenic to humans.

Justification for classification or non-classification

As reported also in IARC Monographs, Vol.79, 2001, p.354-355 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. Some effects on T4/THS quantity were observed also in pigs but no effects on thyroid gland function were found in dogs and in cynomolgus monkeys treated with sulfamethazine. Consequently, Sulfadimidine would be expected not to have effect and not to be cancerogenic to humans and no classification is proposed regarding specific target organ toxicity after repeated exposure for this substance according to the CLP Regulation (EC n. 1272/2008).