Abstract for TER81109

Teratologic Evaluation of Sulfamethazine in New Zealand White Rabbits

CASRN: 57-68-1
Chemical Formula: C12H14N4O2S
Molecular Weight: 278.3346
Report Date: May 7, 1984


The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.

Sulfamethazine, a widely used antibacterial agent, was evaluated for teratogenicity following maternal exposure. Artificially inseminated New Zealand White rabbits were dosed by gavage on gestational days 6 through 19 with sulfamethazine (0, 600, 1200, 1500 or 1800 mg/kg/day) with distilled water as vehicle. These dose groups are referred to as SM-0, SM-600, SM-1200, SM-1500 and SM-1800 respectively. Does were weighed on gestational days 0, 6-19 (prior to daily dosing) and 30 (immediately prior to sacrifice), and were also observed for clinical signs of toxicity. At sacrifice on gestational day 30, does were evaluated for body weight, liver weight, kidney weights, gravid uterine weight and status of uterine implantation sites (i.e., implantation sites, resorptions, dead fetuses, live fetuses). Live fetuses were dissected from the uterus and live litter size, as well as individual fetal body weight and gross morphological abnormalities were recorded. All live fetuses were sexed and examined for visceral malformations employing the Staples' fresh tissue dissection method. Half of the fetuses were decapitated immediately after dissection and the heads were fixed in Bouin's solution for free hand sectioning and examination (Wilson's Technique). All fetal carcasses were cleared and stained with Alizarin Red S and examined for skeletal malformations.

The maternal mortality in the present study was 3.12% (1/32 does) at SM-0, 6.25% (2/32) at SM-600, 3.57% (1/28) at SM-1200, 20.00% (7/35) at SM-1500 and 18.75% (6/32) at SM-1800. A significant dose-related downward trend was seen for maternal body weight on gd 12 and 19 and for weight gain (treatment period) with values for gd 12 weight significantly lower than controls for SM-1200 and SM-1500, and with values for gd 19 weight and weight gain during treatment significantly lower than controls for SM-1200, SM-1500 and SM-1800. Relative maternal liver weight exhibited a significant upward trend but no significant pairwise comparisons. Maternal kidney weights were unaffected by treatment. Clinical signs, seen in a dose-related manner, included alopecia, pink or red ears, weepy eyes, absence of feeding and congestion.

Percentage of resorptions, nonlive (dead plus resorbed) and affected (nonlive plus malformed) per litter all exhibited a significant upward trend with values from these parameters from SM-1800 elevated relative to controls. In addition, the percent affected was elevated at SM-1500 relative to controls. There were no treatment-related effects on number or mean body weight of live fetuses (male and/or female) per litter, nor on the incidence of gross, visceral or skeletal malformations per litter, nor in the number or percent of fetuses malformed per litter. Examination of malformation incidence by category indicated no malformations unique to or with a higher incidence in any of the SM-exposed groups relative to controls.

In conclusion, no evidence of teratogenicity of sulfamethazine was seen when administered by gavage to pregnant NZW rabbits during organogenesis at doses which produced maternal and fetal mortality and toxicity (1200-1800 mg/kg/day).