Developmental toxicity of bropirimine in rats after oral administration.
Timed-pregnant Upj:TUC(SD)spf (Sprague-Dawley) rats were orally (gastric intubation) dosed with bropirimine (an immunomodulator and inducer of interferon with antiviral and antitumor activities against experimental models) at 100, 200 or 400 mg/kg/day (first experiment), or at 25, 50, or 100 mg/kg/day (second experiment), on days 7-15 of gestation. In the first experiment, maternal toxicity occurred in all bropirimine-treated groups as evidenced primarily by significant decreases in weight gain, as compared to the vehicle control group. Embryotoxicity also occurred as evidenced by a dose-related increase in the number of dams with early implantation sites only. This pronounced effect on early embryonic development led to an insufficient number of offspring to access the developmental toxicity of bropirimine. This effect and the fact that all three doses were toxic to the dams dictated that a second experiment be carried out at lower doses. Significant effects on maternal weight gain also were observed in the second experiment, at least in the first 4 days of dosing, although only one dam in the 100 mg/kg/day group had early implantation sites only, in contrast to 11 such dams at this dosage in the first experiment. However, the fact that there were significant dose-related increases in the incidence of several variations in fetuses in this group indicated that there also was embryotoxicity at 100 mg/kg/day in the second experiment. Thus, although no biologically significant increases in the incidence of any malformation or major variation were found in this study, the results did indicate that bropirimine was embryotoxic at dosages which also produced significant maternal toxicity.
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Reproductive and Developmental Toxicology, Upjohn Company, Kalamazoo, Michigan 49001.
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D000014:Abnormalities, Drug-Induced / Q000196:embryology*; D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D020964:Embryo Loss / Q000139:chemically induced*; D005260:Female; D005313:Fetal Death / Q000139:chemically induced*; D009152:Mutagenicity Tests; D011247:Pregnancy; D051381:Rats; D011919:Rats, Inbred Strains
D000970:Antineoplastic Agents; D003596:Cytosine; C033560:bropirimine