Artificially-inseminated New Zealand White rabbits (30 per group) were exposed to 0, 62.5, 125, or 250 mg/kg/day boric acid. Aqueous solutions were delivered by gavage in a volume of 5 ml/kg on gestational days 6-19. At study termination (gd 30), the uterus was examined to determine pregnancy status (18-23 pregnancies/group), and to evaluate the number of resorptions, and dead or live fetuses. Dead or live fetuses were weighed, and live fetuses examined for external, visceral and skeletal defects.
Pregnant does exhibited no overt symptoms attributable to boric acid toxicity, except that vaginal bleeding was noted at 250 mg/kg/day (2-11 does/day on gd 19-30). All high-dose does with this symptom had no live fetuses on gd 30. Vaginal bleeding was not observed in any control females, and in only one female/group at 62.5 or 125 mg/kg/day (day 20 or 22, respectively; each female had 5-7 live fetuses at term). Maternal deaths (one each in the 62.5 or 125 mg/kg/day groups on gd 25 and 22, respectively) were not clearly related to boric acid treatment. Maternal food consumption was decreased during most of the treatment period (gd 6-15) at 250 mg/kg/day , and was increased at 125 and 250 mg/kg/day after treatment (gd 25-30). Maternal body weight (gd 9-30), weight gain during treatment (gd 6-19), gravid uterine weight and number of corpora lutea per dam were each decreased at 250 mg/kg/day . Corrected maternal weight gain was increased at both 125 and 250 mg/kg/day . Maternal liver weight (absolute or relative) was not affected by boric acid exposure. Relative maternal kidney weight was increased at 250 mg/kg/day , but absolute kidney weight was not affected. Microscopic evaluation of maternal kidney sections did not indicate any pathology associated with boric acid exposure. Thus, 250 mg/kg/day was the "Lowest Observed Adverse Effect Level" for pregnant does, and 125 mg/kg/day was the maternal "No Observed Adverse Effect Leve1".
No definitive evidence of developmental toxicity was observed following exposure of pregnant does to either 62.5 or 125 mg/kg/day boric acid during the period of major organogenesis (gd 6-19). At 250 mg/kg/day , developmental toxicity included a high rate of prenatal mortality (90% of implants/litter were resorbed vs. 6% for controls). Prenatal mortality was also expressed as an increased proportion of pregnant females with no live fetuses (73% vs 0% of controls) and as a reduction in the number of live fetuses/live litter on gd 30 (2.3/litter vs. 8.8 for controls). The incidence of malformed live fetuses/litter was also increased at 250 mg/kg/day (81% vs. 26% for controls), primarily due to the incidence of fetuses with cardiovascular defects (72% vs. 3% for controls). The most prevalent cardiovascular malformation was interventricular septal defect which was observed in 57% (8/14) of high dose fetuses as compared to 0.6% (1/159) of fetuses in the control group. At 250 mg/kg/day , the average fetal body weight/litter was 92% of the average control weight, but this difference did not reach statistical significance. Thus, 250 mg/kg/day was the LOAEL for developmental toxicity and 125 mg/kg/day was the no observed adverse effect level.
In summary, decreased food intake and vaginal bleeding associated with pregnancy loss were the only clear manifestations of toxicity in does exposed to 250 mg/kg/day boric acid on gd 6-19. The same dose was associated with severe developmental toxicity, i.e., 90% prenatal mortality/litter and 81% malformed fetuses/litter. No definitive maternal or developmental effects were observed at 62.5 or 125 mg/kg/day .