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.
Diphenhydramine hydrochloride, a widely used antihistamine, was evaluated for toxic and teratogenic effects in timed-pregnant CD rats. DPH (0, 25, 50 or 100 mg/kg/day) in distilled water was administered by oral gavage on gestational days 6 through 15 to 25-27 females per treatment group; these treatment groups are referred to as DPH-0, DPH-25, DPH-50 and DPH-100, respectively. Dams were weighed on gestational days 0, 6-15 (prior to daily dosing) and 20 (immediately following sacrifice), and were also observed daily during treatment for clinical signs of toxicity. At sacrifice on gestational day 20, dams were evaluated for body weight, liver weight, gravid uterine weight and status of uterine implantation sites (i.e. , implantation sites, resorptions, dead fetuses, live fetuses). Individual live fetuses were dissected from the uterus, weighed, sexed and examined for gross, visceral and skeletal malformations.
All dams in all treatment groups survived to sacrifice on gestational day 20. Statistically significant dose-response trends were seen for maternal body weight (gestational day 11, 15, and 20), maternal weight gain during gestation, maternal weight gain during treatment and absolute maternal weight gain (i.e., weight gain during gestation minus gravid uterine weight) with significantly lower body weights and smaller weight gains in the high dose group. No significant differences among dose groups were observed for gravid uterine weight or relative maternal liver weight (i.e., % body weight), although a dose-related trend toward decreased absolute maternal liver weight was observed. Weight loss of more than 5 grams/day was observed in 35% (9/26) of DPH-100 dams as early as the second day of treatment. Other clinical signs included sedation, ataxia , respiratory distress and pica (i. e., excessive consumption of woodchip bedding).
Examination of uterine implantation sites revealed no statistically significant differences on the following measures: number of implantation sites per dam; number or percent of resorptions, fetal deaths, nonlive fetuses (dead plus resorbed) or affected fetuses (nonlive plus malformed) per litter; proportion of litters with one or more resorptions, fetal deaths, nonlive or affected. There was no difference among treatment groups in the number of live fetuses per live litter (i.e., litters with one or more live fetuses) or in the proportion of males per live litter. Average fetal body weight per litter for live fetuses in live litters was significantly lower than controls only in the DPH-100 dose group with males and females being equally affected on this measure. A small, but statistically nonsignificant increase in the percentage of malformed fetuses per litter was observed with an incidence of 0.83%, 1.07%, 0.65% and 3.43% for the control through high-dose groups, respectively. The proportion of litters with one or more malformed fetuses also failed to show a statistically significant difference among dose groups. Since the majority of malformed fetuses (11/12) in the DPH-100 group exhibited either hydroureter and/or hydronephrosis, the proportion of litters containing one or more fetuses with renal malformation(s) was compared for the control (1/26) vs. the high-dose (4/24) groups, but this comparison also failed to reach statistical significance.
In conclusion, when diphenhydramine hydrochloride was administered to pregnant CD rats during organogenesis at oral doses up to 100 mg/kg/day, no clear evidence of a teratogenic effect was observed even at the highest dose, which produced clear signs of maternal and fetal toxicity.