Effect of oral dosing vehicles on the developmental toxicity of flubendazole in rats.
Flubendazole was suspended in deionized water or olive oil and administered by gavage once daily to pregnant rats on Days 8-15 of pregnancy to examine if the embryolethal and teratogenic doses were affected by the vehicles used. Flubendazole in olive oil caused a statistically significant increase in embryolethality at doses of 7.83 mg/kg per day and higher, with complete resorption in all dams at 31.33 mg/kg per day. When flubendazole was suspended in deionized water, a significant increase in embryolethality occurred only at a maternal dose of 125.32 mg/kg per day. The proportion of litters with anomalous fetuses was significantly increased at doses of 31.33 mg/kg per day and above when flubendazole was administered in deionized water, but increased at doses at four times lower when flubendazole was administered as in olive oil. Administered as a single dose in olive oil on any one of Days 6-12 of pregnancy, a flubendazole dose of 31.33 mg/kg caused significant increases in embryolethality and decreased fetal body weights on Days 7-9, with an 82.7% incidence of embryolethality on Day 8, with complete resorption in 5 of the 8 dams. The critical periods for teratogenic effects were between Days 8 and 11 of pregnancy, with Day 9 being the most critical. Fetuses with gross, skeletal, or internal anomalies were seen in dams given a single dose of as low as 7.83 mg/kg.
Yoshimura
Haruo
H
National Veterinary Assay Laboratory, Ministry of Agriculture, Forestry and Fisheries, 1-15-1 Tokura, Kokubunji, 185-8511 Tokyo, Japan. yosimuh@nval.go.jp
D000014:Abnormalities, Drug-Induced / Q000473:pathology; D000015:Abnormalities, Multiple / Q000139:chemically induced*; D000284:Administration, Oral; D000818:Animals; D000871:Anthelmintics / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005327:Fetal Resorption / Q000139:chemically induced; D020567:Fetal Weight / Q000187:drug effects; D005865:Gestational Age; D008098:Litter Size / Q000187:drug effects; D008431:Maternal-Fetal Exchange; D008463:Mebendazole / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity*; D000069463:Olive Oil; D014677:Pharmaceutical Vehicles / Q000008:administration & dosage*; D010938:Plant Oils / Q000008:administration & dosage; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013723:Teratogens / Q000633:toxicity*; D014867:Water / Q000008:administration & dosage / Q000737:chemistry
D000871:Anthelmintics; D000069463:Olive Oil; D014677:Pharmaceutical Vehicles; D010938:Plant Oils; D013723:Teratogens; D014867:Water; D008463:Mebendazole; C018945:flubendazole