Oxytetracycline hydrochloride, a commonly used antibiotic, was evaluated for teratogenicity following maternal exposure. Timed-pregnant CD rats were dosed by gavage (po) on gestational days 6 through 15 with oxytetracycline hydrochloride (0, 1200, 1350, 1500 mg/kg/day) in corn oil. These dose groups are referred to as OX-0, OX-1200, OX-1350 or OX-1500, respectively. Dams were weighed on gd 0, 6 through 15 (prior to daily dosing) and 20 (immediately after sacrifice) and were also observed for clinical signs of toxicity. At sacrifice on gd 20, dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e., sites, resorptions, dead fetuses, live fetuses). Live fetuses were dissected from the uterus and evaluated for live litter size, body weight, sex and gross morphological abnormalities. All live fetuses were examined for visceral malformations employing the Staples' fresh tissue dissection method. Half of the fetuses were decapitated prior to 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 was 0% (0/37 dams) in OX-0, 5.6% (2/32) in OX-1200, 15.2% (5/33) in OX-1350 and 24.2% (8/33) in OX-1500 dose groups. A significant downward trend for reduction in maternal body weight was seen on gd 11, 15 and 20, with values from the OX-1200 and OX-1500 groups significantly lower than controls for all three time points; OX-1350 values were also significantly lower than controls for gd 11 and 15. Maternal weight gain during gestation and treatment exhibited a significant downward trend with values from OX-1200 and OX-1500 significantly lower than controls for both parameters; OX-1350 values were lower for weight gain during treatment. Maternal liver weight exhibited a significant downward trend with values from all three dose groups significantly lower than controls. Clinical signs during treatment which exhibited a dose-related incidence included weight loss of more than 5 grams/24 hours, respiratory difficulties and rough coat. There were no statistically significant dose-related differences in number or percent of implantation sites/dam, resorptions, deaths, nonlives, affected or live fetuses per litter. Fetal body weight (all live fetuses, live male or live female fetuses) per litter at gd 20 exhibited a significant downward trend with values from all three dose groups significantly lower than control values for all three parameters. There were no significant differences among treated and control groups in the number or percentage of males, females or live fetuses malformed per litter nor in the number of litters with malformed fetuses. Examination of malformation incidence by category produced no evidence of dose-response trends, no significant pairwise comparisons, nor any evidence for any malformation unique to or with a higher incidence in any of the treated groups relative to controls.
In conclusion, no evidence of teratogenicity of oxytetracycline hydrochloride was seen in pregnant CD rats when administered by gavage during the time of organogenesis (gd 6-15) at doses which produced evidence of maternal and fetal toxicity.