© 1995 Oxford University Press
research-article |
The Evaluation of the Developmental Toxicity of Hydrochlorothiazide in Mice and Rats1
Chemistry and Life Sciences, Center for Life Sciences and Toxicology, Research Triangle Institute P.O. Box 12194, Research Triangle Park, North Carolina 27709-2194 *National Center for Toxicological Research, Division of Teratogenesis Jefferson, Arkansas 72079
Received April 4, 1994; accepted December 22, 1994
Timed-pregnant CD-1 outbred albino Swiss mice and CD Sprague-Dawley rats were administered hydrochlorothiazide (HCTZ, USP) in corn oil by gavage during major organogenesis, Gestational Days (GD) 6 through 15. The doses administered were 0, 300, 1000, or 3000 mg/kg/day for mice and 0, 100, 300, or 1000 mg/kg/day for rats. Maternal clinical status was monitored daily during treatment. At termination (GD 17, mice; GD 20, rats), confirmed pregnant females (20–27 per group, mice; 36–39 per group, rats) were evaluated for clinical status and gestational outcome; each live fetus was examined for external, visceral, and skeletal malformations. In mice, no maternal mortality was observed. However, clinical signs including dehydration, pioerection, lethargy, and single-day weight loss appeared to be doserelated. HCTZ had no effect on maternal weight gain or water consumption, gravid uterine weight, relative maternal liver weight, or relative maternal kidney weight. There was no definitive evidence of embryotoxicity or fetal toxicity for mice on GD 17. Thus, the no observed adverse effect level (NOAEL) for both maternal and developmental toxicity was 3000 mg/kg/day. In rats, HCTZ had no effect on maternal survival, clinical signs, or water consumption. Clinical signs were not dose-related. Maternal weight gain during treatment was depressed at 1000 mg/kg/day. Gravid uterine weight and relative maternal liver weight were unaffected. Relative maternal kidney weight was slightly (7–8%) increased at all dose levels, but there was no evidence of a dose response. Thus, the maternal NOAEL for rats was 300 mg/kg/day, based on decreased maternal weight gain during treatment at 1000 mg/kg/ day. HCTZ had no effect on prenatal mortality, fetal growth, or morphological development in rats. The developmental NOAEL was 
l000 mg/kg/day. In summary, oral administration of HCTZ to mice at doses up to 3000 mg/kg/day and rats at doses up to 1000 mg/kg/day during organogenesis produced no evidence of developmental toxicity in either species, in spite of mild maternal toxicity in rats at 1000 mg/kg/day.