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.
Formamide is a widely used industrial solvent, and its developmental toxicity in laboratory species has been reported previously. This study was performed due to the lack of data from pregnant rats exposed during the entire embryo/fetal period.
Dose selection was based on a screening study in which CD rats were treated by gavage with 0, 62, 125, 250, 500, or 1000 millgrams FORM per kilogram body weight per day on gestational days 6-19 (NTP, 1998). Maternal toxicity was noted at greater than or equal to 250 mg/kg/day, including morbidity, and reductions in water/food intake, body weight, and weight gain. Fetal body weight was reduced at greater than or equal to 125 mg/kg/day (NTP, 1998).
In this study, female Sprague-Dawley-derived (CD ) rats were dosed by gavage with FORM (50, 100, or 200 mg/kg/day) or its vehicle (deionized/distilled water) on gd 6-19. The dose volume was 5 ml/kg. Twenty-five timed-mated rats were assigned to each group. Dams were monitored at regular intervals throughout gestation for clinical signs, food and water intake, and body weight. At necropsy on gd 20, the following were recorded: maternal clinical condition; body, liver, and gravid uterine weights; pregnancy status; and number of corpora lutea. In the gravid uterus, the numbers of resorbed, dead, or live fetuses were recorded. All live fetuses were weighed, sexed, and examined for external morphological anomalies. Approximately, one-half of the fetuses were examined for visceral anomalies, including internal head structures, and the remaining fetuses were examined for skeletal anomalies.
Pregnancy was confirmed in 88-92% of females/group. No maternal deaths occurred, and there were no dose-related clinical signs. Maternal body weight exhibited significant decreasing trends (gd 15-20), with significant reductions at 200 mg/ kg/day on gd 18, 19, and 20. Maternal body weight gain was also reduced at 200 mg/kg/day from gd 6 to 9, from gd 15 to 18, for the treatment period as a whole (gd 6 to 20), and for the gestational period as a whole (gd 0 to 20). However, maternal gestational weight gain, corrected for gravid uterine weight, was not affected. Maternal food and water intake were also unaffected
Maternal liver weight (absolute or relative) was not affected by FORM exposure. Gravid uterine weight exhibited a significant decreasing trend (100, 94, and 87% of control weight), and the reduction was significant at 200 mg/kg/day.
Prenatal mortality (resorptions and late fetal deaths), live litter size, and percent males/litter were not affected by FORM exposure. Average fetal body weight/litter exhibited a decreasing trend (98, 97, and 85% of average control weight), with significant reductions at greater than or equal to 100 mg/kg/day. No statistically significant differences were observed in the incidences of fetal morphological anomalies (malformations or variations).
In summary, CD rats were dosed by gavage with FORM (0, 50, 100, or 200 mg/ kg/day) on gd 6-19. Minimal evidence of maternal toxicity was found at 200 mg/kg/day. Gravid uterine weight was reduced at 200 mg/kg/day, and fetal body weight was reduced at greater than or equal to 100 mg/ kg/day. Thus, the maternal toxicity no observed adverse effect level was 100 mg/kg/day, and the lowest observed adverse effect level was 200 mg/kg/day. The developmental toxicity NOAEL was 50 mg/kg/day, and the LOAEL was 100 mg/kg/day.