Hydroxyurea as a reference standard in teratological screening. Comparison of the embryotoxic and teratogenic effects following single intraperitoneal or repeated oral administrations to pregnant rats.
The antimitotic drug hydroxyurea (HU) has been evaluated as a positive standard for teratological screening in rats. Single intraperitoneal administration of HU to pregnant Sprague Dawley rats at the dose level of 750 mg/kg induced embryolethality or specific anomalies depending on the day of treatment: HU administration on days 7, 8, 9, 10 or 11 produced lethal effects in a high percentage of embryos; cardiovascular malformations were specifically induced by a single dose on day 10, ocular anomalies on day 10 or 11, palatoschisis or diaphragmatic hernia on day 12, limb or paw deformities on day 10, 11, 12 or 13. This experiment demonstrated the high susceptibility of the genotype of our colony of rats to the embryotoxic potential of HU. Repeated oral administration of HU during the organogenetic period (from day 6 to day 15 of gestation), at dose levels ranging from 50 to 450 mg/kg, led to a dose dependent embryolethal and teratogenic effect. Live foetuses at term generally showed severe ocular and craniofacial anomalies; hydrocephalus, cardiovascular anomalies, vertebral and costal defects were also registered. Limb malformations were not frequent and paw abnormalities were totally absent. In our experimental conditions, the dose level of 300 mg/kg is regarded as a suitable positive control dosage in teratological testing of new molecules by oral route.
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000284:Administration, Oral; D000818:Animals; D004622:Embryo, Mammalian / Q000187:drug effects*; D005260:Female; D005865:Gestational Age; D006918:Hydroxyurea / Q000008:administration & dosage / Q000633:toxicity*; D007274:Injections, Intraperitoneal; D011247:Pregnancy; D051381:Rats; D013723:Teratogens
D013723:Teratogens; D006918:Hydroxyurea