Glycidol is used as a chemical intermediate in the pharmaceutical industry, as a stabilizer in the manufacture of vinyl
polymers, and as an intermediate in the synthesis of
glycerol,
glycidyl ethers, and
amines.
Glycidol was nominated for carcinogenicity study by the United States Environmental Protection Agency.
Glycidol was selected for study in the haploinsufficient
p16(Ink4a)/p19(Arf) mouse because it was found to be carcinogenic in rats and mice in conventional 2-year rodent studies (NTP, 1990), but was negative in a study in p53+/- mice (Tennant et al., 1999). Male and female haploinsufficient
p16(Ink4a)/p19(Arf) mice received
glycidol (greater than 95% pure) by gavage for 40 weeks. Genetic toxicology studies were conducted in mouse peripheral blood erythrocytes. 40-WEEK STUDY IN MICE: Groups of 15 male and 15 female haploinsufficient
p16(Ink4a)/p19(Arf) mice were administered 0, 25, 50, 100, or 200 mg
glycidol/kg
body weight in deionized water by gavage, 5 days per week for 40 weeks. Survival of 200 mg/kg male and female mice was less than that of the vehicle control groups, but the differences were not significant. Mean
body weights of 200 mg/kg male mice and 50, 100, and 200 mg/kg female mice were less than those of the vehicle controls. The left testis, left epididymis, and left cauda epididymis weights were significantly decreased in 200 mg/kg males; the number of sperm heads per cauda epididymis were also significantly decreased in this group.
Enlarged spleen and foci of discolored liver were observed in 200 mg/kg male mice at necropsy. These findings corresponded to infiltration by histocytic
sarcoma or extramedullary hematopoiesis. The incidences of
histiocytic sarcoma were increased in dosed groups of males and in females administered 50 mg/kg or greater, and the incidences in 50 and 200 mg/kg males were significantly greater than that in the vehicle control group. In the lung, incidences of alveolar/bronchiolar
adenoma were significantly increased in 100 mg/kg males and 200 mg/kg females; multiple
adenomas were seen in some dosed males.
Squamous cell papillomas of the forestomach were seen in one 200 mg/kg male, one 100 mg/kg female, and three 200 mg/kg females. Significantly increased incidences of epithelial
hyperplasia occurred in the forestomach of 200 mg/kg males and females. Neuronopathy,
gliosis, and
hemorrhage of the brain were observed at various sites in a few 200 mg/kg males and 100 and/or 200 mg/kg females.
GENETIC TOXICOLOGY: Under the conditions of this 40-week gavage study, there was clear evidence of carcinogenic activity of
glycidol in male haploinsufficient
p16(Ink4a)/p19(Arf) mice based on the occurrence of
histiocytic sarcomas. The increased incidences of alveolar/bronchiolar
adenomas in male mice were also considered to be related to
glycidol administration. There was some evidence of carcinogenic activity of
glycidol in haploinsufficient
p16(Ink4a)/p19(Arf) female mice based on the occurrence of alveolar/bronchiolar
adenoma. The occurrence of forestomach
papillomas in female mice may also have been related to
glycidol administration. Treatment of male and female haploinsufficient
p16(Ink4a)/p19(Arf) mice with
glycidol was associated with forestomach
hyperplasia and neuronopathy in the and brain.