Ethylene glycol is a major constituent of motor vehicle antifreeze-coolant fluids and is also found in other commercial products including hydraulic brake fluids, adhesives, printer's inks, and wood stains. It is used in the manufacture of polyester films and fibers, polyethylene terephthalate (PET) solid state resins, plasticizers, elastomers, cellophane, and other products. Previous 13-week and 2-year studies of ethylene glycol in F344 rats were considered adequate to evaluate the toxicology and carcinogenicity of ethylene glycol in this species and strain; therefore, the present studies were conducted in mice only. Toxicology and carcinogenesis studies were conducted by administering ethylene glycol (greater than 99% pure) in feed to male and female B6C3F1 mice for 13 weeks and 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse lymphoma L5178Y cells, and Chinese hamster ovary cells.
Groups of 10 male and 10 female mice received feed containing 0, 3, 200, 6,300, 12,500, 25,000 or 50,000 ppm ethylene glycol. All mice survived to the end of the studies. Final mean body weights of dosed male and female mice and feed consumption of dosed males were similar to those of the controls. Feed consumption of dosed females was significantly greater than that of controls. Absolute and relative organ weights of mice administered ethylene glycol were generally similar to those of controls throughout the study. No chemical-related clinical findings were observed.
Chemical-related kidney and liver lesions, seen only in 25,000 and 50,000 ppm male mice, consisted of nephropathy and centrilobular hepatocellular hyaline degeneration (cytoplasmic accumulation of non-birefringent, eosinophilic, globular, or crystalline material resembling erythrocyte fragments).
Groups of 60 mice received diets containing ethylene glycol for up to 103 weeks (males: 0, 6, 250, 12,500, or 25,000 ppm; females: 0, 12,500, 25,000, or 50,000 ppm). These concentrations correspond to daily doses of approximately 1,500, 3,000, or 6,000 mg/kg body weight for male mice and 3,000, 6,000, or 12,000 mg/kg for females. Dietary concentrations greater than 50,000 ppm have the potential to affect the nutritional value of the feed. Interim evaluations were performed on six males and nine or ten females from each dose group at 15 months.
Survival, body weights, feed consumption, and clinical findings in the two-year studies
At the end of the 2-year studies, survival rates of male and female mice exposed to ethylene glycol were similar to those of controls. Mean body weights and feed consumption of exposed male and female groups were also similar to those of controls.
No clinical findings associated with the administration of ethylene glycol were observed.
No chemical-related neoplasms were observed in male or female mice in these studies. Hepatocellular hyaline degeneration was seen in mid- and high-dose male and high-dose female mice. Pulmonary arterial medial hyperplasia was observed at an increased incidence in exposed females but not in exposed males. Incidence and severity of nephropathy were not affected by treatment in either sex. Small numbers of oxalate-like crystals, calculi, or both were noted in renal tubules, urethrae, and/or urinary bladders in a few high-dose male mice.
Ethylene glycol did not induce gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537, trifluorothymidine resistance in mouse L5178Y lymphoma cells, or sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells. All tests were conducted with and without exogenous metabolic activation (S9).
Under the conditions of these 2-year feed studies, there was no evidence of carcinogenic activity of ethylene glycol in male B6C3F1 mice receiving 6, 250, 12,500, or 25,000 ppm, or in female B6C3F1 mice receiving 12,500, 25,000, or 50,000 ppm. Administration of ethylene glycol resulted in hepatocellular hyaline degeneration in male mice fed diets containing 12,500 or 25,000 ppm and in female mice fed diets containing 50,000 ppm. An increased incidence of medial hyperplasia of small pulmonary arteries and arterioles occurred in female mice fed diets containing 12,500, 25,000, or 50,000 ppm ethylene glycol.