1,2,3,4-Butanetetracarboxylic acid is a widely used industrial chemical that has potential new applications in the finishing of permanent press fabrics. Developmental toxicity assessments of this chemical have not been previously reported.
In a screening study, Sprague-Dawley-derived (CD) rats were dosed by gavage with BTCA (0, 62.5, 125, 250, 500 or 1000 mg/kg body weight/day) on gestational days 6 through 19 (NTP, 1998). At 1000 mg/kg/day, maternal toxicity included morbidity (1 out of 15 females) and minor alterations in food and water intake. Evidence of developmental toxicity was limited to a decreasing trend for male fetal body weight.
In this study, timed-mated Sprague-Dawley-derived (CD) rats were dosed by gavage with BTCA (250, 500, or 1000 mg/kg/day) or its vehicle (deionized/distilled water) on gd 6 through 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/water intake, and body weight. At necropsy (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, numbers of resorbed, dead, or live fetuses were recorded. Live fetuses were weighed, sexed, and examined for external (100%), visceral (50%) and skeletal (50%) anomalies.
In the high-dose group, one female was removed from the study due to a gavage accident, and one maternal death occurred on gd 17 (1/24 females). Clinical signs included weight loss (increasing severity with increasing dose) and piloerection (less than or equal to 4 females/day at the high dose). Rooting in the cage bedding after dosing suggested an aversion to the sensory properties of the dose formulations (less than or equal to 3 females/day at the mid dose and less than or equal to 5 females/day at the high dose). Maternal relative feed intake was transiently reduced at 1000 mg/kg/day (gd 6 to 9) and at 500 mg/kg/day (gd 12 to 15). Maternal relative water intake was increased at 1000 mg/kg/day (gd 12 to 15, 18 to 19, 19 to 20, and the treatment period as a whole).
At 1000 mg/kg/day, maternal body weight was significantly reduced on gd 12, 15, 18, 19, and 20. Maternal body weight gain during treatment (gd 6 to 20) and gestation (gd 0 to 20) and corrected weight gain also showed significant reductions at the high dose. Gravid uterine weight and maternal relative liver weight were not affected. Absolute maternal liver weight exhibited a decreasing trend but showed no significant differences between control and BTCA-treated groups.
At scheduled necropsy, confirmed pregnancy rates were high for all groups (84-100%). Prenatal mortality and average live litter size did not differ among groups. Average fetal body weight per litter in BTCA-treated groups was 97-103% of the control weight, and no significant trends were found. No statistically significant differences were observed in the incidences of fetal malformations or variations.
In summary, CD rats were dosed by gavage with BTCA (0, 250, 500, or 1000 mg/kg/day) on gd 6 through 19. One maternal death, reduced body weight, and reduced weight gain were noted at the high dose. Thus, the maternal toxicity no observed adverse effect level was 500 mg/kg/day and the lowest observed adverse effect level was 1000 mg/kg/day. No definitive evidence of developmental toxicity was found at any dose, and the high dose satisfies the U.S. EPA limit rule for developmental toxicity studies (U.S. EPA, 1997, 1998). Thus, the developmental toxicity NOAEL is greater than or equal to 1000 mg/kg/day.