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Abstract for TR-511

Toxicology and Carcinogenesis Studies of Dipropylene Glycol in F344/N Rats and B6C3F1 Mice (Drinking Water Studies)

CASRN: 25265-71-8
Chemical Formula: C6H14O3
Molecular Weight: 134.18
Synonyms/Common Names: Bis(2-hydroxypropyl) ether; 2,2N-dihydroxydipropyl ether; 2,2N-dihydroxyisopropyl ether; di-1,2-propylene glycol; dipropylene glycol (6CI); dipropyl glycol; oxybis-propanol; oxydipropanol; 1,1N-oxydi-2-propanol; 2-(2-Hydroxypropoxy)-1-propanol 1,1N-Oxybis(2-propanol) 2,2N-Oxybis(1-propanol)
Report Date: June 2004

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Abstract

Dipropylene glycol is a component of many widely used commercial products such as antifreeze, air fresheners, cosmetic products, solvents, and plastic. The National Cancer Institute nominated dipropylene glycol for carcinogenicity studies based on its high production volume and suspected widespread consumer and occupational exposure. Male and female F344/N rats and B6C3F1 mice were exposed to dipropylene glycol (greater than 99% pure) in drinking water for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium.

2-Week Studies in Rats

Groups of five male and five female F344/N rats were exposed to 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm dipropylene glycol (equivalent to average daily doses of approximately 635, 1,450, 2,650, 5,850, or 13,000 mg dipropylene glycol/kg body weight to males and 850, 1,670, 2,860, 5,420, or 11,100 mg/kg to females) in drinking water for 2 weeks. All rats survived to the end of the study. Mean body weights of 80,000 ppm males and females were significantly less than those of the controls. Water consumption by exposed and control groups was generally similar. Liver and kidney weights of males and females generally increased with increasing exposure concentration. Focal fatty change occurred in the livers of all 80,000 ppm males.

2-Week Studies in Mice

Groups of five male and five female B6C3F1 mice were exposed to 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm dipropylene glycol in drinking water for 2 weeks. Due to leaking water bottles, water consumption measurements were unreliable; therefore, the average daily dose of dipropylene glycol achieved for each exposure group was not calculated. All mice survived to the end of the study. The mean body weight gain of 80,000 ppm males was significantly less than that of the controls. Thinness, hypoactivity, and abnormal gait were observed in 80,000 ppm females. Liver weights of 80,000 ppm mice were significantly increased. There were no lesions attributed to dipropylene glycol exposure.

3-Month Study in Rats

Groups of 10 male and 10 female F344/N rats were exposed to 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm dipropylene glycol (equivalent to average daily doses of approximately 425, 890, 1,840, 3,890, or 12,800 mg/kg to males and 460, 920, 1,690, 3,340, or 8,950 mg/kg to females) in drinking water for 3 months. All rats survived to the end of the study. Mean body weights of all exposed groups of males and 20,000 ppm or greater females were significantly less than those of the control groups. Water consumption by 80,000 ppm males and females increased during the second week of the study and was greater than that by controls for the remainder of the study. Hypoactivity and poor hair coats were observed in all 80,000 ppm males.

Hematology results indicated that exposure of rats to dipropylene glycol induced a minimal erythron decrease at week 14 in males and increases in serum alanine aminotransferase and sorbitol dehydrogenase activities and/or total bile acid concentrations that suggest a hepatic effect in males and females. Liver weights of rats receiving 10,000 ppm or greater and kidney weights of rats receiving 40,000 and 80,000 ppm were greater than those of the controls. Minimal to mild hypertrophy of the adrenal cortex occurred in all exposed groups of rats. The incidences of liver and kidney lesions were significantly increased in 20,000 ppm or greater males and 80,000 ppm females. Focal olfactory epithelial degeneration was present in all 80,000 ppm rats. Male rats in the 80,000 ppm group had small testes, preputial glands, seminal vesicles, and prostate glands. The left testis, cauda epididymis, and epididymis weights of 80,000 ppm males were significantly decreased. The incidences of testicular atrophy, epididymal hypospermia, preputial gland atrophy, and seminal vesicle depletion were generally increased in the 80,000 ppm group. Epididymal hypospermia consisted of decreases in epididymal sperm counts per cauda and spermatid heads per gram testis.

3-Month Study in Mice

Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 5,000, 10,000, 20,000, 40,000, or 80,000 ppm dipropylene glycol (equivalent to average daily doses of approximately 715, 1,350, 2,620, 4,790, or 11,000 mg/kg to males and 1,230, 2,140, 4,020, 7,430, or 14,700 mg/kg to females) in drinking water for 3 months. Three males and one female exposed to 80,000 ppm and one 20,000 ppm female died during the study. Body weights of 10,000 ppm females were significantly greater than those of the controls. Water consumption by exposed males and females was generally less than that by the controls. Hypoactivity and dehydration were observed in 80,000 ppm males and females. Liver weights of 40,000 ppm males and 80,000 ppm males and females were significantly greater than those of the controls. The estrous cycle of 80,000 ppm females was significantly longer than that of the controls. Centrilobular hypertrophy of the liver occurred in 40,000 ppm males and 80,000 ppm males and females.

2-Year Study in Rats

Groups of 50 male and 50 female F344/N rats were exposed to 0, 2,500, 10,000, or 40,000 ppm dipropylene glycol (equivalent to average daily doses of approx-imately 115, 470, or 3,040 mg/kg to males and 140, 530, or 2,330 mg/kg to females) in drinking water for 2 years. Survival of 40,000 ppm males was significantly less than that of the control group. Mean body weights of 40,000 ppm males and females were less than those of the controls throughout the study. Water consumption by 40,000 ppm males was greater than that by the controls.

The incidences of nephropathy were significantly increased in 10,000 and 40,000 ppm males, and the severities were greater than that in the controls. Increased incidences of focal histiocytic and focal granulomatous inflammation of the liver in males, bile duct hyperplasia of the liver in males and females, olfactory epithelium degeneration of the nose in males and females, and olfactory epithelium atrophy and thrombosis of the nose in males were considered related to dipropylene glycol exposure. The incidence of minimal to mild suppurative inflammation of the salivary gland was significantly increased in 40,000 ppm males. There were no increased incidences of neoplasms that were attributed to exposure to dipropylene glycol.

2-Year Study in Mice

Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 10,000, 20,000, or 40,000 ppm dipropylene glycol (equivalent to average daily doses of approximately 735, 1,220, or 2,390 mg/kg to males and 575, 1,040, or 1,950 mg/kg to females) in drinking water for 2 years. Survival of males and females was similar to that of the controls. Mean body weights of 40,000 ppm males were less than those of the controls throughout the study, and mean body weights of 40,000 ppm females were less during the second year of the study. Water con-sumption by 40,000 ppm males was less than that by the controls. There were no increased incidences of neoplasms or nonneoplastic lesions that were attributed to exposure to dipropylene glycol.

Genetic Toxicology

Dipropylene glycol was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535 with or without induced rat or hamster liver S9 enzymes.

Conclusions

Under the conditions of this 2-year drinking water study, there was no evidence of carcinogenic activity of dipropylene glycol in male or female F344/N rats exposed to 2,500, 10,000, or 40,000 ppm. There was no evidence of carcinogenic activity of dipropylene glycol in male or female B6C3F1 mice exposed to 10,000, 20,000,or 40,000 ppm.

Exposure to dipropylene glycol in drinking water resulted in increased incidences and severities of nephropathy in male rats, increased incidences of focal histiocytic and focal granulomatous inflammation of the liver in male rats, increased incidences of suppurative inflammation of the salivary gland in male rats, increased incidences of bile duct hyperplasia in male and female rats, increased incidences of olfactory epithelial atrophy and thrombosis of the nose in male rats, and increased incidences of olfactory epithelial degeneration of the nose in male and female rats.

Studies

Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Dipropylene Glycol
 

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1 Mice

Female
B6C3F1 Mice

Concentrations in drinking water

0, 2,500, 10,000, or 40,000 ppm

0, 2,500, 10,000, or 40,000 ppm

0, 10,000, 20,000, or 40,000 ppm

0, 10,000, 20,000, or 40,000 ppm

Body weights

40,000 ppm group less than the control group

40,000 ppm group less than the control group

40,000 ppm group less than the control group

40,000 ppm group less than the control group

Survival rates

23/50, 27/50, 27/50, 0/50

30/50, 31/50, 38/50, 31/50

40/50, 39/50, 35/50, 34/49

37/50, 38/50, 38/50, 33/50

Nonneoplastic effects

Kidney: nephropathy (41/47, 47/50, 50/50, 48/48); severity of nephropathy (2.1, 2.2, 2.8, 3.9)
Liver: inflammation, focal, histiocytic (18/50, 27/50, 46/49, 48/48); inflammation, focal, granulomatous (22/50, 26/50, 42/49, 27/48); bile duct hyperplasia (34/50, 38/50, 43/49, 44/48)
Nose: olfactory epithelium, atrophy (4/46, 3/50, 3/50, 34/49); olfactory epithelium, degeneration (0/46, 0/50, 0/50, 7/49); thrombosis (2/46, 5/50, 4/50, 9/49)
Salivary Gland: suppurative inflammation (0/49, 1/49, 0/55, 22/50)

Liver: bile duct hyperplasia (2/50, 3/50, 7/50, 18/49)
Nose: olfactory epithelium, degeneration (0/48, 0/48, 0/46, 9/49)

None

None

Neoplastic effects

None

None

None

None

Level of evidence of carcinogenic activity

No evidence

No evidence

No evidence

No evidence

Genetic Toxicology
Assay Results
Salmonella typhimurium gene mutations: Negative in strains TA97, TA98, TA100, and TA1535 with and without S9