The timing of implantation was investigated in Kbl:NZW rabbits to assess the appropriate period of administration of test compounds recommended in the ICH Guideline for reproductive and developmental toxicity studies. After copulating in the morning (day 0 of gestation), pregnant rabbits were euthanized in the morning daily on days 6–9 of gestation. Their uteri were morphologically examined and the process of implantation was investigated. On day 6 of gestation, blastocysts had fixed their position in the uterine lumen for implantation, but they had not yet attached to the uterine mucosa. On day 7 of gestation, implantation sites were macroscopically recognized as protrusions of the uterine wall. Histological examination revealed that ob‐placental implantation occurs in the antimesometrial region on days 7 and 8, while placental implantation occurs in the mesometrial region on days 8 and 9 of gestation. It was also found that organogenesis progresses in parallel with implantation.

No abstract

Sm 857 SE is an antiallergic drug chemically described as 11-Oxo-11H-pyrido(2,1-b)quinazoline-2-carboxylic acid that has activity against allergic bronchoconstriction in animal models. The purpose of this study was to investigate the teratogenic potential in pregnant rats and rabbits when administered during the critical period of organogenesis. The drug was suspended in aqueous 0.25% carboxymethylcellulose (CMC) solution. Daily doses of 20, 90, or 400 mg/kg were given orally by gavage to rats on days 7 through 17 of gestation and to rabbits on days 6 through 18. Two additional studies were done in rats dosed with 400 mg/kg, and with 90, 200, or 400 mg/kg, respectively. Doses of 20, 90, and 200 mg/kg had no meaningful effects on maternal animals of either species or on their offspring. A dose of 400 mg/kg was maternally toxic in rats as shown by the effects on body weight and food consumption. Among pregnant rabbits, two deaths and three miscarriages occurred at this dose. In rats, 400 mg/kg caused embryonic death, retarded fetal development, and two specific malformations, namely microphthalmia and vertebral-costal defects. A mild teratogenic action of 400 mg/kg also occurred in the first additional study but not in the second one. There was, however, one anophthalmia in a rat fetus of the 90 mg/kg group. In rabbits, no embryotoxic or teratogenic effects were observed. These species differences were explained by the concentration and protein binding in maternal serum as well as by the relatively high concentration of 14C-Sm 857 SE in the rat fetus.