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.
Carbon disulfide, a widely used industrial chemical, was evaluated for toxic and teratogenic effects in artificially inseminated New Zealand White rabbits. CS (0, 25, 75 and 150 mg/kg/day, po) in corn oil was administered in a volume of 1 ml/kg body weight on gestational days 6 through 19. Females were weighed and observed during daily treatment and at 4 hours post-dosing for clinical signs of toxicity. At sacrifice on gd 30, a total of 23-28 confirmed-pregnant females per treatment group were evaluated. The gravid uterus for each dam was weighed and the number of implantation sites, and live, dead, or resorbed fetuses were recorded. All live fetuses were weighed and examined for external, visceral and skeletal malformations.
The mortality rate for treated females was 3.5% (1/29), 0% (0/26), 3.3% (1/30), and 7.1% (2/28) for the vehicle control through high dose, respectively. Maternal body weight on gd 0, gd 6 (i.e., prior to the initiation of treatment), gd 12 (i.e., midway through the treatment period) and gd 30 (i.e., immediately prior to sacrifice) did not differ significantly among treatment groups. On gd 19 (i.e., the final day of treatment) maternal body weight was decreased across treatment groups in a dose-related manner with 150 mg/kg/day CS dams exhibiting body weights significantly below vehicle controls. Maternal weight gain during treatment, maternal weight gain during gestation and gravid uterine weight were each decreased in a dose-related manner. Maternal weight gain during the treatment period was significantly below controls for dams treated with 75 or 150 mg/kg/day CS. Gestational weight gain was below controls only for the high-dose group. Absolute weight gain (i.e. maternal gestational weight gain minus gravid uterine weight) did not differ significantly among treatment groups. Both absolute and relative maternal liver weight were increased in a dose-related manner with statistically significant increases above vehicle control observed in the 75 and 150 mg/kg/day CS groups. Since maternal body weight at sacrifice did not differ among treatment groups, the increase in absolute and relative maternal liver weight appears to reflect a treatment related hepatic response, but the data collected did not allow further characterization of this response.
The percentage per litter of resorbed, nonlive (i.e., dead plus resorbed) or affected (i.e., nonlive plus malformed) fetuses was increased in a dose-related manner, and all CS-treated groups were significantly above vehicle controls on these measures. The proportion of litters with one or more resorbed, nonlive or affected fetuses also increased in a dose-related manner, but only the high-dose group (150 mg/kg/day, CS) was significantly above vehicle controls on these measures. No statistically significant differences among treatment groups were observed in the percentage of dead fetuses (i.e., fetuses weighing „10 g with discernible digits, but showing no vital signs at uterine dissection) per litter or in the proportion of litters with one or more dead fetuses.
Among those litters containing live fetuses, there were no differences among dose groups in the proportion of males per live litter. The number of live fetuses per litter, as well as average fetal body weight per live litter, were reduced in a dose-related manner, with CS 150 litters significantly smaller than controls on both measures. The percentage of fetuses malformed per litter, but not the proportion of litters with one or more malformed fetuses, differed significantly among treatment groups and a clear dose-effect relationship was observed. In conclusion, CS (25, 75 or 150 mg/kg/day, po) administered on gd 6 through 19, produced dose-related maternal and fetal toxicity, and increased the incidence of malformed fetuses in New Zealand White rabbits relative to the vehicle control group. The incidence of resorptions was significantly increased at all doses tested (i.e., 12.30%, 32.47%, 41.60% and 61.16% resorbed in the vehicle through high-dose, respectively), but the incidence of malformations in the control group (5.72%) was significantly exceeded only in the high dose group (19.51% malformed fetuses per litter).