Hydrochlorothiazide, a widely used thiazide diuretic, was evaluated for toxic and teratogenic effects in timed-pregnant CD-1 mice. HCTZ (0, 300, 1000, and 3000 mg/kg/day) suspended in corn oil was administered by gavage in a volume of 10 ml per kilogram of body weight daily on gestational days 6 through 15. Females were weighed and observed during daily treatment and at 4 hours post-dosing for clinical signs of toxicity. At sacrifice on gd 17, a total of 20-27 dams (i.e., confirmed-pregnant females) per treatment group were evaluated. The gravid uterus for each dam was weighed, and the number of implantation sites, and live, dead, or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral, and skeletal malformations.
During HCTZ treatment, dams exhibited clinical signs of toxicity including weight loss, piloerection, lethargy, and rough coat. The maternal mortality rate was 0% for all dose groups. Maternal body weight on gd 0 (i.e., day of assignment to dose groups) did not differ among dose groups but did exhibit a statistically significant increase across successive replicates. No difference among dose groups or across replicates was observed on gd 6 (i.e., prior to initiation of dosing), 11, 15, or 17. Significant replicate-related differences were observed for maternal liver weight (absolute and relative) and fetal body weight (average, male, and female), which were most likely influenced by the replicate effects observed in the gd 0 maternal body weight. Maternal water consumption also exhibited replicate-related differences.
There were no dose-related effects of HCTZ on any measure of maternal toxicity throughout the treatment period (gd 6 through 15), including maternal kidney weight. Maternal water consumption exhibited a significant upward trend in dams assigned to increasing dose groups on gd 0-6 and 15-17. The number of corpora lutea/dam exhibited differences among treatment groups which were inconsistent across replicates. These differences in the number of corpora lutea are not considered to be biologically significant with respect to the teratologic evaluation of HCTZ since the corpora lutea are formed prior to initiation of dosing on gd 6. The effect of replicate on the number of corpora lutea/dam is due primarily to the replicate effect on percent preimplantation loss since there were no significant differences in the number of implantation sites/litter among replicates. There were no dose-related differences in the number or proportion per litter of resorbed, dead, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive plus malformed) fetuses. Likewise, the number or proportion of litters with resorbed, dead, nonlive, or affected fetuses was not significantly altered from control in any dose group.
Among those litters containing live fetuses, there were no differences among dose groups in the number of live fetuses per live litter, the proportion of males per live litter, or average fetal body weight per litter. There was a significant dose-response trend for absolute number of litters with malformed fetuses, proportion of malformed fetuses per litter, and proportion of females malformed per litter. These trends were based solely on the occurrence of 2 malformed female fetuses (out of a total 1041 male and female fetuses examined) in the high dose group, with a malformation incidence of 0% for control through 1000 mg/kg/day for female fetuses, and control through high dose group for male fetuses. In conclusion, HCTZ (0, 300, 1000, or 3000 mg/kg/day) administered on gd 6 through 15, produced no dose-related maternal or fetal toxicity, and failed to significantly increase the incidence of malformations in CD-1 mice.