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.
Tetrahydrofuran, a four-carbon cyclic ether, is widely used as an industrial solvent. Although it has been used in large quantities for many years, few long-term toxicology studies, and no reproductive or developmental studies, have been conducted on THF. This study addresses the potential for THF to cause developmental toxicity in rodents by exposing Sprague-Dawley rats and Swiss (CD-1) mice to 0, 600, 1800, or 5000 ppm tetrahydrofuran vapors, 6 hours per day, 7 days per week. Each treatment group consisted of 10 virgin females (for comparison), and 33 positively mated rats or mice. Positively mated mice were exposed on days 6-17 of gestation, and rats on 6-19 dg. The day of plug or sperm detection was designated as 0 dg. Body weights were obtained throughout the study period, and uterine and fetal body weights were obtained at sacrifice (rats, 20 dg; mice, 18 dg). Implants were enumerated and their status recorded and live fetuses were examined for gross, visceral, skeletal, and soft-tissue craniofacial defects.
The only overt symptom exhibited by pregnant rats was a reduction in body weight gain for the 5000-ppm group and there were no maternal deaths. However, mean body weights of virgin females were not affected, thus indicating that pregnancy was a factor in the toxicological response. The pregnancy rate was 93%. The mean gravid uterine weight and the extragestational weight gain (EGWG; sacrifice body weight minus gravid uterine weight minus 0 dg weight) were reduced for the 5000-ppm group relative to the control, but the difference was not significant. There were no treatment-related effects on the number of implantations, the mean percent of live pups/litter and resorptions/litter, or on the fetal sex ratio. Fetal weights were significantly reduced for the 5000-ppm exposure group relative to controls. The mean percent affected fetuses per litter was not significantly different among treatment groups for any individual malformation or variation or for combined totals.
Mice exhibited overt symptoms of toxicity at the 1800- and 5000-ppm THF concentrations. Approximately 30% of the animals in the 1800-ppm group, and all in the 5000-ppm group, were subject to narcosis. Approximately 27% of the pregnant animals and 30% virgins in the 5000-ppm group died during the first six days of exposure; consequently, this group was removed from exposure to prevent further mortality. There were no maternal deaths in either the 600 or 1800-ppm exposure groups. As in rats, the mean body weights of virgin mice at sacrifice were not significantly affected by exposure to THF. Mean body weights of pregnant mice and uterine weights were significantly less than controls for the 5000- and 1800-ppm groups at sacrifice. The EGWG was also significantly reduced for the 5000-ppm group.
There was no effect on the number of implantations per dam, and the mean pregnancy rate for all mated mice was 86%. There was a significant reduction in the mean percent of live pups/litter for the 1800- and 5000-ppm groups and a corresponding increase in the percent of resorptions/litter. Pregnant females in the 5000-ppm exposure group that survived to the scheduled sacrifice had litters with a 95% incidence of resorption. Neither fetal weight nor the sex ratio was affected in the 600- or 1800-ppm groups. The mean percent affected fetuses per litter was not significantly different among treatment groups for any individual malformation or for combined totals. There was an exposure-correlated increase in the incidence of reduced sternebral ossifications; however differences between groups were not significant.
Swiss (CD-1) mice appeared to be much more susceptible to the toxic effects of THF, manifested as narcosis, mortality, and intrauterine death, than were the rats. The rats appeared unaffected by THF exposure except for a slight, but significant, decrease in maternal and fetal weight at the 5000-ppm level. Interestingly, in mice the reduction in maternal weight gain and the increase in intrauterine death at the 1800-ppm level were not accompanied by a treatment-associated decline in live fetal weight, nor by an increase in the incidence of fetal malformations. These facts suggest that in mice, if the conceptus survives, development as assessed by this experimental design, continues in a normal fashion.