Developmental toxicity of orally administered thiabendazole in ICR mice.
Thiabendazole (TBZ) is a potent anthelmintic and fungicide used in the treatment of parasitic infections in humans and domestic animals and post-harvest protection of agricultural commodities. TBZ is not teratogenic or selectively foetotoxic in rats or rabbits, in contrast to several other benzimidazole derivatives. However, when administered orally to pregnant (Jcl:ICR) mice at lethal dosages, malformations were observed in treated fetuses. To assess whether the effects found in this previous study were attributable to maternal toxicity or TBZ the present study was conducted. TBZ doses of 25, 100 or 200 mg/kg/day were selected based on a preliminary range-finding study in which maternotoxicity was evident at doses of 200 mg/kg/day or above. The compound was administered during gestation days 6-15 as a solution in olive oil. Caesarean sections were completed on gestation day 18 and complete fetal examinations conducted. Decreases in maternal weight gain relative to controls were found at doses of 100 mg/kg/day or above, which paralleled decreases in foetal weights in these same dose groups. However, there were no treatment-related external, visceral or skeletal anomalies in any treatment group. Therefore, TBZ was not teratogenic or selectively foetotoxic in mice, with no-observed-effect levels (NOEL) of 25 and greater than 200 mg/kg/day for maternal and fetal weight effects and teratogenicity, respectively. These results indicate that foetal effects noted in previous studies in mice were probably secondary to severe maternal toxicity.
Lankas
G R
GR
Merck Research Laboratories Department of Safety Assessment, West Point, PA 19486, USA. george_lankas@merck.com
Nakatsuka
T
T
Ban
Y
Y
Komatsu
T
T
Matsumoto
H
H
D000014:Abnormalities, Drug-Induced; D000284:Administration, Oral; D000818:Animals; D000969:Antinematodal Agents / Q000008:administration & dosage / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005314:Embryonic and Fetal Development / Q000187:drug effects*; D005260:Female; D051379:Mice; D008813:Mice, Inbred ICR; D019055:No-Observed-Adverse-Effect Level; D011247:Pregnancy; D013045:Species Specificity; D013827:Thiabendazole / Q000008:administration & dosage / Q000633:toxicity*; D013997:Time Factors; D015430:Weight Gain
D000969:Antinematodal Agents; D013827:Thiabendazole