Sulfadimidine

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

NOEL fertily on mice for Sulfadimidine from subchronic study = 625 mg/kg/bw/day

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Study duration:

subchronic

Species:

mouse

Quality of whole database:

Study mentioned in IARC Monographs, Vol.79, 2001, p.349-350.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Some studies regarding the effect on fertility of Sulfadimidine are available.

The studies are reported in this summary considering the different species.

 

Rats:

Fischer 344 rats, derived from specific pathogen free rats, were dosed with Sulfadimidine in the feed for three generations, with two litters per generation, at dose levels of 600, 1200, or 2400 ppm. Each group initially contained 45 animals/sex. A separate control group of 90 animals/sex was fed untreated feed and served as controls. There were no significant dose-related changes in litter size, sex ratios, fertility, or stillbornes (ref. Littlefield, Three-generation reproduction and toxicity study of sulfamethazine in Fischer 344 rats, unpublished reports Nos.419, 421, 422 from the National Center for Toxicological Research,Food and Drug Administration, Jefferson, Arkansas.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., 1988 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)

 

Mice:

The effect of Sulfamethazine (synonym of Sulfadimidine) on fertility was assessed in three groups of 20 male and 20 female Swiss CD-1 mice given diets containing the drug at 0.25, 0.5 or 1.0% (equivalent to 0, 313, 625 and 1250 mg/kg bw per day) and compared with a control group of 38 males and 38 females. The mice were exposed to sulfamethazine continuously during the 7-day pre-mating and 98-day co-habitation periods. The effects observed in the F0 group receiving 1% Sulfamethazine included significant decreases in the number of litters produced and in the number of live pups per litter and a significant increase in the proportion of live male pups per total live pups per litter. Despite of decrease in number of litters at dose of 1% no treatment-related histopathological effects (no effect on sperm mobility and no effect on female reproductive tract) were observed in the pituitary or reproductive organs of male or female mice in the group fed 1% sulfamethazine. Exposure of mice to 0.25 or 0.5% sulfamethazine in the diet during the continuous breeding phase of the study had no effect on fertility or reproductive performance. NOEL Sulfadimidine mice fertility = 625 mg/kg/bw/day (ref. Reel et all, Fundam. appl. Toxicol., 18, 609–615, 1992 mentioned in IARC Monographs, Vol.79, 2001, p.349-350.Note: the same study is mentioned also 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 with reference to Reed et all, Sulfamethazine: reproduction and fertility assessment in CD-1 mice when administered via the diet,unpublished report No. NTP-84-092 from the National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.Submitted to WHO by the US Coordinator of the Codex Alimentarius, US Department of Agriculture, Washington, D.C., 1984)

 

Based on studies reported above on rats and mice there is no particular concern regarding effect on fertility of Sulfadimidine. The decreases of number of litters was observed in mice but not in rats and only at high dose (1250 mg/kg/bw/day) but no treatment-related histopathological effects were observed (no effect on sperm mobility and no effect on female reproductive tract)

 

Effects on developmental toxicity

Description of key information

NOEL developmental toxicity on rat from Sulfadimidine = 540 mg/kg/bw/day but no effect observed in the offspring of women treated with Sulfadimidine.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Species:

rat

Quality of whole database:

Data reported by WHO,Toxicological evaluation of Certain Veterinary Drug Residues in Food (WHO Food additives Series 33), 1994 free available on website http://www.inchem.org/documents/jecfa/jecmono/v33je07. with reference to Wolkowski-Tyl unpublished study of 1982 submitted to WHO

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Some studies regarding teratogenicity of Sulfadimidine are available.

The studies are reported in this summary considering the different species.

 

Rats:

Groups of pregnant CD rats were dosed by gavage with 0, 540, 680, or 860 mg Sulfadimidine/kg bw/day on days 6-15 of gestation. Dams were killed on day 20 of gestation. Observations included clinical signs, mortality, maternal body and liver weight, the number of resorptions, live and dead fetuses, litter size, and fetal weight. All fetuses were subjected to gross, skeletal, and visceral examinations. One dam from the low-dose group died during the study. In all treated dams the incidences of alopecia, rough coat, light-coloured faeces, and urine stains were increased. Maternal body-weight gain was decreased and relative liver weight was increased in all treated dams. In the high-dose group, fetuses had decreased body weights and the number of malformed fetuses/litter was increased. The incidence of gross or visceral malformations of fetuses/litter was increased at 860 mg/kg bw/day with the predominant malformations being cleft palate, hydroureter, and hydronephrosis. The incidence of hydroureter and hydronephrosis was also elevated in the mid-dosegroup.The NOEL for embryo- and fetotoxicity was 540 mg/kg bw/day. NOEL Sulfadimidine teratogenicity rat = 540 mg/kg/bw/day (ref. Wolkowski-Tyl et all,Teratological evaluation of sulfamethazine (CAS no. 57-68-1) in New Zealand white rabbits. Unpublished report project no.31U-2077 from RTI, Research Triangle Park, NC, USA. Submitted to WHO by the National Institute of Environmental Health Sciences, ResearchTriangle Park, NC, USA, 1982 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. Note: the same or a similar study - teratogenicity study on rats during gestional days 6-15 by gavage with 0, 545, 685 and 865 mg/kg/day of Sulfamethazine- is reported with analogous result in HSDB report of Sulfamethazine-synonym of Sulfadimidine - with reference to NTP, Teratologic Evaluation of Sulfamethazine (CAS No. 57-68-1) in CD Rats,NTP Study No. TER9?108 (June 28, 1985))

In a recent study reported in Toxnet with reference to a chinese publication (Wang et all,Wei Sheng Yan Jiu. , Jan; 39(1):83-5, 2010) some effects of Sulfadimidine on thyroid gland of rats were observed during perinatal exposure. This study is of no concern based on different effect of Sulfadimidine on rats/ mice thyroid gland (negative effects) if compared with effect on monkeys (no alteration)- see section 7.7 "Carcinogenicity" of this IUCLID dossier.

 

Rabbit:

Groups of pregnant female New Zealand white rabbits were orally administered Sulfadimidine (by gavage) at 0, 600, 1200, 1500, or 1800 mg/kg bw/day on days 6 to 19 of gestation. Dams were killed on day 30 of gestation. No effects were observed on the number of corpora lutea, implantation sites or implantation loss, number of live fetuses sex distribution/litter, or fetal body weight. The incidences of gross, visceral, or skeletal malformations were not increased. No treatment-related effects were observed on the weight or gross appearance of the kidneys. A dose-related occurrence of clinical signs such as alopecia, pink or red ears, and weepy eyes was observed in treated dams. Maternal mortality was 3.0, 6.0, 4.0,20, and 19% in the 0, 600, 1200, 1500, and 1800 mg/kg bw/day treatment groups, respectively. Maternal body-weight gain was significantly decreased at 1200, 1500, and 1800 mg/kg bw/day. A dose-related increase in the percent resorptions and fetal deaths/litter was observed. The NOEL for embryotoxicity was 1200mg/kg bw/day. NOEL Sulfadimidine teratogenecy rabbit= 1200 mg/kg/bw (ref.Wolkowski-Tyl et all,Teratological evaluation of sulfamethazine (CAS no. 57-68-1) in New Zealand white rabbits. Unpublished report project no.31U-2077 from RTI, Research Triangle Park, NC, USA. Submitted to WHO by the National Institute of Environmental Health Sciences, ResearchTriangle Park, NC, USA, 1982 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.Note: the same study is reported in HSDB report of Sulfamethazine-synonym of Sulfadimidine - with reference toNTP, Teratologic Evaluation of Sulfamethazine (CAS No. 57-68-1) in CD Rats,NTP Study No. TER9?108 (June 28, 1985))

 

Humans:

As reported in IARC Monographs, Vol.79, 2001, p.349 with reference to Heinonen et all, Birth Defects and Drugs in Pregnancy, Littleton, MA, Publishing Sciences Group, pp. 298-301,1977 no increase in malformation rates in the offspring of 47 women treated with Sulfamethazine (synonym of Sulfadimidine) was observed during the first four lunar months of pregnancy.

 

Based on studies available on rats and rabbits and above all based on the evidence from human study there is no particular concern regarding teratogenicity of Sulfadimidine.

Justification for classification or non-classification

From the data available related to reproductive toxicity for Sulfadimidine, there is no reason of concern and no classification is proposed for reproductive and developmental toxicity of Sulfadimidine in accordance with the CLP Regulation (EC n.1272/2008).