National Toxicology Program

National Toxicology Program
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Abstract for TR-515 - Propylene Glycol Mono-t-Butyl Ether (Cas No. 57018-52-7)

Toxicology and Carcinogenesis Studies of Propylene Glycol Mono-t-Butyl Ether (CAS No. 57018-52-7) In F344/N Rats and B6C3F1 Mice and a Toxicology Study of Propylene Glycol Mono-t-Butyl Ether In Male NBR Rats (Inhalation Studies)

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Chemical Formula:  C7H16O2

Propylene glycol mono-t-butyl ether is used as a solvent for all-purpose cleaners, electronic chemicals, inks, adhesives, nail polish lacquers, and other waterreducible coatings. Propylene glycol mono-t-butyl ether was nominated for study by the United States Consumer Product Safety Commission because of its widespread use, potential for human exposure, and the lack of adequate toxicological, chronic toxicity, and carcinogenicity information. Male and female F344/N rats and B6C3F1 mice were exposed to propylene glycol mono-tbutyl ether (at least 99% pure) by inhalation for 2 weeks, 3 months, or 2 years. The chemical structure of propylene glycol mono-t-butyl ether indicated a potential to induce a2u-globulin nephropathy, a male-specific renal syndrome characterized by the accumulation of hyaline droplets in the proximal tubule epithelium of F344/N rats. Thus, male NBR rats, which do not develop this condition, were exposed to propylene glycol mono-t-butyl ether concurrently with F344/N rats for 2 weeks for comparison of renal lesion development. Genetic toxicology studies were conducted in Salmonella typhimurium, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes.

2-WEEK STUDY IN RATS

Groups of five male and five female F344/N rats and five male NBR rats were exposed to 0, 75, 150, 300, 600, or 1,200 ppm propylene glycol mono-t-butyl ether vapor 6 hours per day, 5 days per week for 16 days. All rats survived to the end of the study, and mean body weights of exposed groups were similar to those of the chamber controls. Renal toxicity studies were performed in male F344/N and NBR rats. The number of cells labeled with proliferating cell nuclear antigen and the labeling index (number of labeled nuclei/total nuclei) in the left kidney of 1,200 ppm male F344/N rats were significantly greater than those in the chamber controls. No significant differences in labeling indices were noted in NBR rats. Kidney weights of 600 ppm male F344/N rats were significantly increased. Liver weights of male and female F344/N rats exposed to 600 and 1,200 ppm and male NBR rats exposed to 1,200 ppm were significantly increased.

2-WEEK STUDY IN MICE

Groups of five male and five female B6C3F1 mice were exposed to 0, 75, 150, 300, 600, or 1,200 ppm propylene glycol mono-t-butyl ether 6 hours per day, 5 days per week for 17 days. All mice survived to the end of the study. Mean body weights of 1,200 ppm female mice were significantly greater than those of the chamber control group. Liver weights of 600 and 1,200 ppm males and of 300 ppm or greater females were significantly increased.

3-MONTH STUDY IN RATS

Groups of 25 male and 20 female F344/N rats were exposed to 0, 75, 150, 300, 600, or 1,200 ppm propylene glycol mono-t-butyl ether vapor 6 hours per day, 5 days per week for 2 (five male renal toxicity rats), 4 or 6 (10 male and 10 female clinical pathology rats), or 14 (10 core study rats) weeks. All core study rats survived to the end of the study. Mean body weight gains of 1,200 ppm males and 600 and 1,200 ppm females were significantly increased.

At week 12, urinalysis results indicated that exposure of rats to propylene glycol mono-t-butyl ether caused increases in urine volume, glucose and protein concentrations, and the activities of aspartate aminotransferase in males and increases in the activities of lactate dehydrogenase and N-acetyl-b-D-glucosaminidase in males and females. Renal toxicity studies were performed on male rats sacrificed at 2 and 6 weeks and at the end of the study. In kidney tissue examined for cell proliferation, the numbers of PCNA-labeled cells and labeling indices in exposed groups of rats were generally significantly greater than those of the chamber controls at all three time points. Exposure-related increases in a2u-globulin concentrations in males occurred throughout the study.

Kidney weights of all exposed groups of males and of 300 ppm or greater females and liver weights of all exposed groups of males and 600 ppm or greater females were increased. Incidences of renal tubule regeneration and granular casts in the medulla of the kidney in exposed rats were increased, and the severities of hyaline droplets generally increased with increasing exposure concentration.

3-MONTH STUDY IN MICE

Groups of 10 male and 10 female B6C3F1 mice were exposed to 0, 75, 150, 300, 600, or 1,200 ppm propylene glycol mono-t-butyl ether 6 hours per day, 5 days per week for 14 weeks. All mice survived to the end of the study. Final mean body weights of 300 and 1,200 ppm males and mean body weight gains for 150, 300, and 1,200 ppm males were significantly less than those of the chamber control group. Liver weights of 600 and 1,200 ppm males and females were significantly increased. The estrous cycle length of 1,200 ppm females was significantly increased. The incidences of minimal to mild centrilobular hypertrophy of the liver were significantly increased in 600 ppm males and 1,200 ppm males and females. The incidence of minimal squamous metaplasia of the respiratory epithelium of the nose was significantly increased in 1,200 ppm males.

2-YEAR STUDY IN RATS

Groups of 50 male and 50 female F344/N rats were exposed to 0, 75, 300, or 1,200 ppm propylene glycol mono-t-butyl ether vapor 6 hours per day, 5 days per week for 104 weeks. Survival of 300 ppm males was less than that of the chamber controls. Mean body weights of 1,200 ppm males and females were less than those of the chamber controls during the second year of the study. In 1,200 ppm males and females the excretion of propylene glycol mono-t-butyl ether glucuronide in urine, expressed as the metabolite to creatinine ratios, were generally significantly less than those in the groups exposed to 75 or 300 ppm.

Incidences of renal tubule hyperplasia, renal tubule hyaline droplet accumulation, papilla mineralization, and transitional epithelial hyperplasia were increased in most exposed groups of males. Marginally increased incidences of renal tubule adenoma and adenoma or carcinoma (combined) occurred in 300 and 1,200 ppm males. The severities of chronic nephropathy increased with increasing exposure concentration in males and females and were significantly increased in all exposed groups of males and in 1,200 ppm females. The incidences of hepatocellular adenoma occurred with a positive trend in male rats. The incidences of basophilic foci of the liver were significantly increased in all exposed groups of males; the incidence of clear foci of the liver was significantly increased in 1,200 ppm females. The incidences of hyaline degeneration of the olfactory epithelium in all exposed groups of males and females and the incidence of corneal mineralization in 1,200 ppm females were significantly increased.

2-YEAR STUDY IN MICE

Groups of 50 male and 50 female B6C3F1 mice were exposed to 0, 75, 300, or 1,200 ppm propylene glycol mono-t-butyl ether vapor 6 hours per day, 5 days per week for 104 weeks. Survival of exposed groups of mice was similar to that of the chamber control groups throughout the study. Mean body weights of 1,200 ppm females were slightly less than those of the chamber control group at the end of the study. Clinical findings included ataxia, shallow breathing, and lethargy in 1,200 ppm mice during the first 6 months of the study and pale foci of the eyes in 1,200 ppm females in the last month of the study.

The incidences of hepatocellular adenoma, hepatocellular adenoma or carcinoma (combined), and hepatoblastoma occurred with positive trends in males and females, and the incidences in the 1,200 ppm groups were increased. The incidences of eosinophilic foci and multinucleated hepatocytes in 1,200 ppm males and eosinophilic foci in 1,200 ppm females were significantly increased. The incidence of mild corneal mineralization was significantly increased in 1,200 ppm females.

GENETIC TOXICOLOGY

Propylene glycol mono-t-butyl ether was mutagenic in S. typhimurium strain TA97 in the absence of liver S9 activation enzymes; negative results were obtained with strain TA97 in the presence of rat or hamster liver S9 enzymes, in strains TA98, TA100, and TA1535 with and without S9, and in strain TA1537 without S9. Propylene glycol mono-t-butyl ether did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells, with or without S9. Propylene glycol mono-t-butyl ether induced a small but significant increase in the frequency of micronucleated normochromatic erythrocytes in peripheral blood of female mice in the 3-month study; no significant increase in micronucleated normochromatic erythrocytes was seen in male mice, and percentages of polychromatic erythrocytes were similar in the exposed and chamber control groups.

CONCLUSIONS

Under the conditions of this 2-year inhalation study, there was equivocal evidence of carcinogenic activity of propylene glycol mono-t-butyl ether in male F344/N rats based on marginally increased incidences of renal tubule and liver neoplasms. There was no evidence of carcinogenic activity of propylene glycol mono-t-butyl ether in female F344/N rats exposed to 75, 300, or 1,200 ppm. There was clear evidence of carcinogenic activity of propylene glycol mono-t-butyl ether in male and female B6C3F1 mice based on increased incidences of liver neoplasms.

Exposure of male rats to propylene glycol mono-t-butyl ether resulted in nonneoplastic lesions of the kidney characteristic of a2u-globulin accumulation. Exposure to propylene glycol mono-t-butyl ether resulted in nonneoplastic lesions of the liver and nose in male and female rats, the liver in male and female mice, and the eyes in female rats and mice. Kinetic and biomarker studies indicated that clearance was saturated at the 1,200 ppm exposure for both rats and mice.

Synonyms: 1-(1,1-Dimethylethoxy)-2-propanol; 1-methyl-2-tert-butoxyethanol; propylene glycol mono-tert-butyl ether; tert-butoxypropanol; 1-tert-butoxy-2-propanol; 1-tertiary-butoxypropan-2-ol

Trade names: Arcosolv PTB

 


Summary of the 2-Year Carcinogenesis and Genetic Toxicology Studies of Propylene Glycol Mono-t-butyl Ether

 

Male
F344/N Rats

Female
F344/N Rats

Male
B6C3F1 Mice

Female
B6C3F1 Mice

Concentrations in air

Chamber control, 75, 300, or 1,200 ppm

Chamber control, 75, 300, or 1,200 ppm

Chamber control, 75, 300, or 1,200 ppm

Chamber control, 75, 300, or 1,200 ppm

Body weights

1,200 ppm group less than the chamber control group

1,200 ppm group less than the chamber control group

Exposed groups similar to the chamber control group

1,200 ppm groups slightly less than the chamber control group

Survival rates

27/50, 29/50, 16/50, 22/50

33/50, 34/50, 28/50, 36/50

35/50, 40/50, 40/50, 37/50

39/50, 36/50, 42/50, 39/50

Nonneoplastic effects

Kidney: renal tubule hyperplasia (standard evaluation - 0/50, 3/50, 7/49, 19/50; standard and extended evaluations - 10/50, 20/50, 23/49, 30/50); hyaline droplet accumulation (1/50, 2/50, 9/49, 17/50); renal papilla mineralization 0/50, 8/50, 28/49, 41/50); transitional epithelium hyperplasia (2/50, 1/50, 6/49, 15/50); severity of chronic nephropathy (1.9, 2.3, 2.9, 3.5)

Liver: basophilic foci (6/50, 18/50, 15/49, 17/50)

Nose: olfactory epithelium hyaline degeneration (0/50, 25/49, 45/49, 50/50)

Kidney: severity of chronic nephropathy (1.5, 1.6, 1.7, 2.1)

Liver: clear cell foci (12/49, 13/50, 11/50, 27/50)

Nose: olfactory epithelium hyaline degeneration (10/49, 22/49, 48/50, 50/50)

Eye: corneal mineralization (0/49, 0/50, 0/50, 10/50)

Liver: eosinophilic foci (9/50, 14/49, 11/50, 29/50); multinucleated hepatocytes (27/50, 23/49, 24/50, 46/50)

Liver: eosinophilic foci (11/49, 10/50, 9/50, 27/49)

Eye: corneal mineralization (1/50, 2/50, 0/50, 20/48)

Neoplastic effects

None

None

Liver: hepatocellular adenoma (18/50, 23/49, 26/50, 36/50); hepatocellular carcinoma (9/50, 8/49, 13/50, 11/50); hepatocellular adenoma or carcinoma (25/50, 26/49, 33/50, 41/50); hepatoblastoma (0/50, 0/49, 1/50, 5/50)

Liver: hepatocellular adenoma (14/49, 8/50, 10/50, 37/49); hepatocellular carcinoma (4/49, 8/50, 7/50, 10/49); hepatocellular adenoma or carcinoma (18/49, 14/50, 16/50, 41/49); hepatoblastoma (0/49, 0/50, 0/50, 2/49)

Equivocal Findings

Kidney: renal tubule adenoma (standard evaluation - 1/50, 1/50, 3/49, 2/50; standard and extended evaluations combined - 1/50, 2/50, 5/49, 4/50); renal tubule adenoma or carcinoma (standard evaluation - 1/50, 1/50, 3/49, 3/50; standard and extended evaluations combined - 1/50, 2/50, 5/49, 5/50)

Liver: hepatocellular adenoma (3/50, 0/50, 2/49, 6/50)

None

None

None

Level of evidence of carcinogenic activity

Eqivocal evidence

No evidence

Clear evidence

Clear evidence

Genetic Toxicology
Assay Results

Salmonella typhimurium gene mutations:

Positive in strain TA97 without S9; negative in strains TA98, TA100, and TA1535 with and without S9; negative in strain TA1537 without S9

Sister chromatid exchanges
      Cultured Chinese hamster ovary cells in vitro:

Negative with and without S9

Chromosomal aberrations
      Cultured Chinese hamster ovary cells in vitro:

Negative with and without S9

Micronucleated erythrocytes
      Mouse peripheral blood in vivo:

Negative in males; weak positive in females


Report Date: March 2004

Pathology Tables, Survival and Growth Curves from NTP 2-year Studies

Target Organs & Incidences from 2-year Studies


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