Comparative inhalation teratogenicity of four glycol ether solvents and an amino derivative in rats.

Previous research demonstrated the inhalation teratogenicity of the solvent 2-ethoxyethanol in rats and rabbits. As this is one of a class of widely used industrial solvents, we investigated the teratogenicity of five structurally related compounds. Each chemical was vaporized and administered to approximately 15 pregnant rats in one to three concentrations for 7 hr/day on gestation days 7 to 15, and dams were sacrificed on day 20. Fetuses were individually weighed, and two-thirds of them were fixed in Bouin's solution and examined for soft-tissue anomalies. The other one-third were fixed in alcohol, stained with Alizarin Red and examined for skeletal defects. Data were analyzed on a litter basis; three solvents were compared with a pooled group (N = 34) of sham-exposed controls, and the remaining two were compared with a group of 15 controls. At concentrations which were apparently not maternally toxic, 2-methoxyethanol was highly embryotoxic, producing complete resorptions at 200 ppm; increased resorptions, reduced fetal weights and skeletal and cardiovascular defects occurred at both 100 and 50 ppm. 2-ethoxyethyl acetate at 600 ppm induced complete resorption of litters; 390 ppm reduced fetal weights and induced skeletal and cardiovascular defects, but only a single defect was observed at 130 ppm. 2-Butoxyethanol evidenced slight maternal toxicity at 200 ppm but produced no increase in congenital defects at that concentration. Neither 2-(2-ethoxyethoxy)ethanol (100 ppm) nor 2-methylaminoethanol (150 ppm) was maternally toxic or embryotoxic. In summary, shorter alkyl chained glycol ethers produced greater embryotoxicity than those having longer chains, and the ester produced effects equivalent to the ether, both patterns predictable from the biochemical literature.

Potentiative interactions between caffeine and various teratogenic agents.

Acetazolamide and inhibitors of DNA synthesis (hydroxyurea, 5-fluoro-2'-deoxyuridine), RNA synthesis (actinomycin D), and protein synthesis (cycloheximide, emetine) were each administered to pregnant rats together with caffeine at doses where each agent alone caused minimal embryotoxicity. Caffeine co-administered with any of the other agents induced a powerful potentiative response. It is not clear from the present experiments whether much lower caffeine dosage, as normally encountered in humans, would potentiate embryotoxicity due to other agents.

Teratogenicity of 2-ethoxyethanol by dermal application.

Undiluted 2-ethoxyethanol or water (control) was applied to the skin of pregnant Sprague-Dawley rats on days 7--16 of gestation (sperm = day 1). Applications were made 4 times daily in volumes of 0.25 or 0.50 ml 2-ethoxyethanol. Females exhibited ataxia following treatment of the high-dose group, and weight gain was significantly (p less than u. 0.001) reduced in the last half of gestation. Litters were collected by caesarian section on day 21 of gestation, and fetuses were examined for external defects. Half of the fetuses were cleared and stained in alizarin red S for skeletal examinations, and half were examined for visceral defects by the Wilson technique. Intrauterine death was 100% in the high-dose group. In the lower dosage group, there was a significant increase in the number of pregnant females with 100% dead implants (p less than 0.001), a significant reduction in the number of live fetuses per litter (p less than 0.001), a significant reduction in fetal body weight (p less than 0.001), and a significant increase in the incidence of skeletal variations (p less than 0.05) and cardiovascular malformations (p less than 0.05).