The potential toxicity of bromochloroacetic acid was evaluated using a short-term reproductive and developmental toxicity screen. This study design was selected to identify the physiologic process (development; female reproduction; male reproduction; various somatic organs/processes) that is the most sensitive to bromochloroacetic acid exposure.
The dose range-finding study was conducted at concentrations of 0, 30, 100, 300, and 500 ppm of bromochloroacetic acid in the drinking water for two weeks. Since no changes in body weight, feed or water consumption occurred, a higher top dose was selected for the main study, which used dose levels of 0, 60, 200, and 600 ppm (Groups 1, 2, 3, and 4, respectively). The main study utilized two groups of male rats designated as male Group A (non-BrdU treated animals, 10 per group in Groups 1-4) and male Group B (BrdU treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4, and three groups of female rats designated as female Group A (peri-conception exposure, 10 per group in Groups 1-4), female Group B (gestational exposure, 13 per group in Groups 1-4), and female Group C (peri-conception exposure, BrdU-treated, 5 animals in Groups 1, 2, and 3, and 8 animals in Group 4). BrdU exposure was included to help assess cell turnover. Control animals received deionized water, the vehicle.
During the treatment period, all animals except one survived to the scheduled necropsy and there were no clinical signs of general toxicity noted at any dose level. There were no treatment-related effects on body weights or feed consumption. Water consumption was decreased by 21-34% at many of the intervals for the 600 ppm rats. The overall calculated consumption of BCA for Groups 2-4 was 7, 20, and 50 mg/kg/day, respectively.
Clinical chemistry and hematology endpoints at necropsy were unaffected by BCA treatment except for a 16% increase in the albumin to globulin ratio in the 600 ppm A males; decreases of 15 and 20% in the alanine aminotransferase parameter in the 200 and 600 ppm A males, respectively; and increases of 5 and 9% in albumin in the 60 and 600 ppm A males, respectively. The increases in albumin to globulin ratio and albumin represent a small but possible biologically significant indicator of dehydration, probably attributable to decreased fluid consumption. The decreases in alanine aminotransferase are of little toxicological significance.
Organ weights and organ-to-body weight ratios were comparable except for an increase of 13% and 10% in liver-to-body weight ratios in the 600 ppm A and B males, respectively. Gross findings were comparable across all groups. An increase in cytoplasmic vacuolization of hepatocytes was seen in all treated Group A males but was not observed in the corresponding Group B males examined for Labeling Index. The Group C females had an apparent treatment-related increase in renal tubular dilatation/degeneration. The LI for the liver, kidney, and urinary bladder from the B males and C females showed small changes between treated and control groups, although these changes have no or questionable biological significance.
Treatment-related findings noted in the male and female reproductive parameters were: a 16% decrease in total implants per litter in the 600 ppm A females and a 50% decrease in the number of live fetuses per litter in the 600 ppm C females. Other changes that occurred but were not statistically significant were: increases in % post-implantation loss in the 600 ppm C females and in the 60, 200, and 600 ppm B females; increases in % pre-implantation loss in the 600 ppm A females and in the 60, 200, and 600 ppm C females; an increase in total resorptions in the 600 ppm C females; and decreases in total implants in the 60, 200, and 600 ppm C females. Combining the data for the Group A and C females revealed decreases of 29% in live fetuses per litter and 25% in total implants per litter. The visceral evaluation of the heart and brain of the B female pups using Wilson's soft tissue free hand slicing technique did not reveal any treatment-related effects.
Results of this study indicate that BCA at doses of 600 ppm produced a consistent decrease in water consumption in both sexes and affected reproductive function in females at a dose of 600 ppm. From these data, BCA is taste-aversive and a general toxicant in both sexes at 600 ppm and also a female reproductive toxicant at 600 ppm.