The Non-Clinical Evaluation Subcommittee of the Drug Evaluation Committee, Japan Pharmaceutical Manufacturers Association (JPMA) collected historical control data from developmental and reproductive toxicity studies, which were conducted by the member companies and associated contract laboratories between 1986 and 1993. The data include spontaneous incidences of fetal morphological alterations and other observations made at terminal cesarean sections in rats, rabbits and mice. In addition, mating and natural delivery data in rats are also provided. There were strain differences as well as inter-laboratory variations in the incidences of fetal visceral and skeletal alterations for both rats and rabbits. These inter-laboratory variations were attributed to differences in the selection of observation parameters, observation criteria and classification of the findings.Key words: historical data, reproduction, cesarean section data, fetal anomalies Adequate historical control data are of fundamental importance in the interpretation of the observation made in developmental and reproductive toxicity studies. The incidences of spontaneous fetal morphological T. Nakatsuka et al. 48 alterations in laboratory animals have been reported in Japan by several investigators [Kameyama et al., 1980 (data from 13 facilities); Morita et al., 1987 (Japan Pharmaceutical Manufacturers Association (JPMA) survey, data from 52 facilities)]. These data including the terminology used have provided a most useful information base to individuals conducting developmental and reproductive toxicity studies in Japan. In general, these kinds of database should be regularly updated and improved.The primary purpose of the present survey was to compile a historical control database on developmental and reproductive toxicity studies conducted in Japan between 1986 and 1993. This data set was compiled from information provided by JPMA member companies and associated contract laboratories and included the spontaneous incidences of fetal external, visceral and skeletal alterations as well as the reproductive data from terminal cesarean sections in rats, rabbits and mice. In addition, data from mating trials and pup survival following natural delivery in rats, both of which were not included in the previous survey (Morita et al., 1987), were compiled here. The second purpose was to determine if differences in observation procedures correlate with any inter-laboratory variations observed in the incidences of visceral and skeletal alterations among the participating laboratories. MATERIALS AND METHODS QuestionnaireIn March 1993, a questionnaire was sent to 103 member companies of JPMA and 31 contract laboratories in Japan. The questionnaire form was designed to obtain information on data from terminal cesarean sections and fetal external, visceral and skeletal examinations in rats, rabbits and mice. Also, data from mating trials and natural delivery in rats were requested. Participants were asked to include only those data from development...

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L-691,121 is a class III antiarrhythmic agent which blocks potassium currents, leading to prolongation of cardiac potential and prevention of cardiac arrhythmia. In a developmental toxicity study in rats, there was a dose-dependent decrease in embryonic/fetal survival, and death of the entire litter was seen at an oral dose of 0.8 mg/kg per day. The critical period for embryolethality was determined as gestational days (GD) 10-13. In a study where females received 1 mg/kg on a critical day (GD 10 or 12) and were killed at 24-h intervals, a high embryonic mortality was seen at 72 h (GD 10 treatment) or 48 h (GD 12 treatment) after dosing. The surviving embryos had morphological abnormalities such as enlarged cardiac tube and pericardium, generalized edema, and hematoma. In order to investigate a possible mechanism for the embryolethality, GD 11 embryos were dissected from females at 4 h after dosing of 1 mg/kg and incubated for 5 h in vitro. The embryonic heart rates were decreased for the first 2 h after incubation but tended to recover to control levels thereafter. When GD 11 embryos were incubated for 4 h with the drug, there were decreases in the heart rates during the entire observation period. In a washout study where the embryos were transferred to drug-free medium after 1-h exposure, decreased heart rates recovered to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)