Reproductive and developmental toxicity study of a new antineoplastic agent, S-1 (II) - Teratological study in rats by oral administration

Abstract

S-1 is a newly developed antineoplastic agent consisting of the mixture of tegafur (FT), 5-chloro-2, 4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo) in a molar ratio of 1: 0.4: 1. The teratogenic potential of S- 1 was studied in rats given S-1 at the daily oral doses of 0, 1, 3, 5 and 7 mg/kg/day (as a dose of FT). S-1 was given from day 7 to day 17 of pregnancy. The study included postnatal evaluation of the growth, development, and reproductive performance of the F1 generation. In rats receiving 7 mg/kg of S-1, maternal body weight gain and food consumptions were reduced, stillbirths increased, livebirths decreased slightly and F1 viability decreased. Fetal body weights decreased significantly in rats receiving 5 mg/kg or more of S-1. External and skeletal anomalies did not increase, but hydrocephaly increased slightly and total number of visceral anomalies increased significantly in the fetuses of rats receiving 7 mg/kg of S-1. Hydrocephaly was observed also in F1 offspring from the rats receiving 7 mg/kg of S-1 during lactation period. Body weight gains of F1 offspring from the rats receiving 7 mg/kg of S-1 during lactation period was reduced. Functional development, emotional tests, learning texts, reproductive performance of the F1 generation and development of the F2 generation were not affected by the S-1 administration. In conclusion, under the condition of this study, the non-observed effect dose levels (NOELs) of S-1 for general toxicity for dams was 5 mg/kg/day, however, NOELs of S-1 was determined to be 7 mg/kg/day or more for reproductive ability. The NOELs of S-1 for the offspring was established to be 3 mg/kg/day.