Narita, H; Sakauchi, N; Ohashi, M; Murakami, Y; Hamada, S; Ogasawara, H; Tanaka, N; Noguchi, O; Misawa, N; Inomata, N
Tocoretinate was administered orally to Crj:CD(SD) female rats daily from day 6 to day 17 of pregnancy at dosages of 100, 300 and 1,000 mg/kg; the purpose was to evaluate the possible effect of tocoretinate on fetal development and the growth, morphological development, behavior and reproductive ability of the first generation offspring (F1). For study of the possible drug effect on fetal development, an additional group of female rats were treated with 2,000 mg/kg of tocoretinate. No dams were found dead in any groups, and no marked toxic signs due to tocoretinate could be detected on daily observations. The body weights of pregnant females receiving 2,000 mg/kg of tocoretinate were significantly lower on days 15 and 20 of pregnancy than those of control dams. The food consumption of dams receiving 300, 1,000 or 2,000 mg/kg was also significantly smaller than that of control dams from the start of administration to the end of pregnant period. The maintenance of pregnancy, length of pregnancy, parturition and lactational performance were not affected in any treatment group. In the first F1 generation fetuses, no marked changes were observed in the viability, body weights, sex ratio or the classification of intrauterine deaths, such as implantation sites, resorptions or macerated fetuses, of any tocoretinate-treated groups compared with those of the controls. And the incidence of malformations of the F1 fetuses in the tocoretinate-treated dams was not meaningfully different from that of the controls on external, skeletal or visceral examination. No abnormalities were noted in the postnatal development of the F1 pups born to tocoretinate-treated mothers. No adverse effects of tocoretinate were observed in the functional test, learning behavior test, emotionality test or reproductive capability test of F1 offspring. The results suggest that the toxicological no-effect dose of tocoretinate on the dams is 100 mg/kg. The no-effect dose of tocoretinate regarding embryolethal and developmental toxicity of F1 fetuses seems to be more than 2,000 mg/kg; and the no-effect dose for neonatal behavior, viability, growth and reproductive capability of F1 generation offspring seems to be more than 1,000 mg/kg.
