The following abstract presents results of a study conducted by a contract laboratory for the National Toxicology Program. The findings may not have been peer reviewed and were not evaluated in accordance with the levels of evidence criteria established by NTP in March 2009. For more information, see the Explanation of Levels of Evidence for Developmental Toxicity. The findings and conclusions for this study should not be construed to represent the views of NTP or the U.S. Government.
Hydrochlorothiazide (HCTZ), a widely used thiazide diuretic, was evaluated for toxic and teratogenic effects in timed-pregnant CD® rats. HCTZ (0, 100, 300, and 1000 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 (gd) 6 through 15. Females were weighed and observed during daily treatment and at 4 hours post-dosing for clinical signs of toxicity. At sacrifice, a total of 36-39 dams (i.e., confirmed-pregnant females) per treatment group were evaluated. The gravid uterus of 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 piloerection, weight loss, alopecia, diarrhea, pinworms, chromodacryorrhea (bloody tears), light-colored feces, and bloody uro-genital area. The maternal mortality rate was 0% for all dose groups. Maternal body weight on gd 0 (i.e., day of assignment to dose groups) and gd 6 (i.e., day of initiation of dosing) did not differ among dose groups. Maternal body weight exhibited a significant dose-related decrease on gd 11, 15, and 20, with significant dose effects in the high dose group versus control on gd 11 and 15. Measures of maternal weight gain (gestation, treatment, and absolute) also exhibited significant dose-related downward trends, with a significant treatment effect on maternal weight gain during treatment in the 1000 mg/kg/day dose group. Maternal liver weight and relative maternal kidney weight displayed significant dose-related downward trends. Significant dose effects were observed for absolute and relative maternal kidney weight at all dose levels.
HCTZ had no effect on gravid uterine weight, maternal water consumption, number of corpora lutea per dam, implantation sites per litter, percent preimplantation loss, number or proportion of resorbed, dead, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive plus malformed) fetuses. Likewise, neither the number nor the proportion of litters with resorbed, dead, nonlive, or affected fetuses was significantly different 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 proportions of males per live litter, or average fetal body weight per litter. In addition, HCTZ had no effect on the number or proportion of litters with malformed fetuses, or number or proportion of males or females malformed per litter.
In conclusion, HCTZ (0, 100, 300, or 1000 mg/kg/day) administered on gd 6 through 15, produced no dose-related fetal toxicity, and failed to significantly increase the incidence of malformations in CD® rats, even in the presence of significant maternal toxicity.