Cumene is produced in a modified Friedel-Crafts reaction process that uses acidic catalysts to alkylate benzene with propylene. Cumene is the principal chemical used in the production of phenol and acetone. Cumene is used to produce acetophenone, α-methylstyrene, diisopropylbenzene, and dicumylperoxide; as a thinner; as a constituent of some petroleum-based solvents; in gasoline blending, diesel fuel, and high-octane aviation fuel; and as a raw material for peroxides and oxidation catalysts. Because cumene is a good solvent for fats and resins, it has been suggested as a replacement for benzene in many industrial applications. Cumene occurs naturally in petroleum and in a variety of foodstuffs. Cumene was nominated for study by the NIEHS because of its high production volume, presence in gasoline and other fuels, potential for human exposure, and lack of existing carcinogenicity test data. Male and female F344/N rats and B6C3F1 mice were exposed to cumene (greater than 99.9% pure) by inhalation for 2 weeks, 3 months, or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, rat bone marrow, and mouse peripheral blood.
Two-week study in rats
Groups of five male and five female rats were exposed to cumene vapor at concentrations of 0, 250, 500, 1,000, 2,000, or 4,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 16 days. All rats exposed to 4,000 ppm died on day 1, and two male and three female rats exposed to 2,000 ppm died by day 4. Mean body weights of 2,000 ppm rats were significantly less than those of the chamber controls. Rats exposed to 2,000 ppm that died early were severely lethargic following daily exposure. Liver and kidney weights of all exposed groups were increased. Accumulation of minimal to mild hyaline droplets was observed in the renal tubular cortex of males exposed to concentrations of 250 to 2,000 ppm.
Two-week study in mice
Groups of five male and five female mice were exposed to cumene vapor at concentrations of 0, 250, 500, 1,000, 2,000, or 4,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 17 days. All mice exposed to 4,000 ppm died on day 1; all mice exposed to 2,000 ppm died on day 2, and four female mice exposed to 1,000 ppm died by day 4. Mean body weights of all exposed groups were similar to those of the chamber controls. Mice exposed to 2,000 ppm were severely lethargic after the first exposure. The four female mice exposed to 1,000 ppm that died early exhibited signs of lethargy and ataxia. Liver weights, both relative and absolute, were increased in all groups of surviving males and in 250 and 500 ppm female groups.
Three-month study in rats
Groups of 10 male and 10 female rats were exposed to cumene vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. Additional clinical pathology groups of 10 male and 10 female rats were exposed to the same concentrations for 23 days. All rats survived to the end of the study, and mean body weights of all exposed groups were similar to those of the chamber controls. Kidney and liver weights of 250 ppm or greater males and liver weights of 1,000 ppm females were significantly greater than those of the chamber controls. There were significant differences between exposed and chamber control females in the relative length of time spent in the estrous stages. The amount of α2u-globulin in the right kidneys was significantly increased in male rats exposed to 125 ppm or greater. The incidences of medullary granular casts in males exposed to 250 ppm or greater were significantly increased. The severities of renal tubule cortex hyaline droplet accumulation and regeneration increased with increasing exposure concentration in male rats.
Three-month study in mice
Groups of 10 male and 10 female mice were exposed to cumene vapor at concentrations of 0, 62.5, 125, 250, 500, or 1,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 14 weeks. Eight 1,000 ppm females died during week 1 of the study. Mean body weights of males exposed to 500 or 1,000 ppm were significantly less than those of the chamber controls. The eight 1,000 ppm female mice that died during the first week of the study exhibited clinical signs of acute toxicity, including lethargy or ataxia. Liver weights of mice exposed to 500 or 1,000 ppm were significantly increased. The weight of the cauda epididymis and the spermatid count were significantly decreased in 1,000 ppm males.
Two-year study in rats
Groups of 50 male and 50 female rats were exposed to cumene vapor at concentrations of 0, 250, 500, or 1,000 ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. Survival of all exposed groups of rats was similar to that of the chamber controls. Mean body weights of 1,000 ppm females were slightly less than those of the chamber controls during the second year of the study but were similar to the chamber controls at the end of the study.
Incidences of adenoma of the respiratory epithelium in the nose occurred with a positive trend in males and were significantly increased in all exposed groups of males and in 250 ppm females. Incidences of hyperplasia of basal cells in the olfactory epithelium in the nose of all exposed groups and hyperplasia of the respiratory epithelium in the nose of all exposed groups of males and 1,000 ppm females were significantly increased.
The incidences of renal tubule adenoma in all exposed groups of males, renal tubule carcinoma in 500 and 1,000 ppm males, and renal tubule adenoma or carcinoma (combined) in all exposed groups of males were increased; the difference from chamber controls for the combined incidence was significant at 500 ppm. The incidences of hyperplasia of the renal tubule and transitional epithelium of the renal pelvis in 500 and 1,000 ppm males and mineralization of the renal papilla in all exposed groups of males were significantly greater than those of the chamber controls.
The incidence of interstitial cell adenoma (including bilateral) of the testis was significantly increased in 1,000 ppm male rats, and there was a positive trend in the incidences across all groups.
Two-year study in mice
Groups of 50 male and 50 female mice were exposed to cumene vapor at concentrations of 0, 125 (female mice only), 250, 500, or 1,000 (male mice only) ppm, 6 hours plus T90 (12 minutes) per day, 5 days per week for 105 weeks. An exposure concentration-related decrease in survival occurred in male mice, and the survival of 1,000 ppm males was significantly less than that of the chamber controls. Mean body weights of 1,000 ppm males were generally less than those of the chamber controls after week 8 of the study, and those of 500 ppm females were less from week 28 until week 76 of the study.
The incidences of alveolar/bronchiolar adenoma, alveolar/bronchiolar carcinoma, and alveolar/bronchiolar adenoma or carcinoma (combined) in all exposed groups of mice occurred with positive trends and were significantly greater than those in the chamber controls. The incidences of alveolar epithelial bronchiole metaplasia and bronchiole hyperplasia were significantly increased in all exposed groups of mice. p53 and K-ras mutations were found in 52% and 87% of lung neoplasms in exposed mice compared to 0% and 14% in the chamber controls, respectively.
In female mice, the incidences of hepatocellular adenoma and hepatocellular adenoma or carcinoma (combined) occurred with positive trends and were significantly increased in the 500 ppm group. In male mice, there were significant increases in the incidences of eosinophilic foci of the liver.
The incidences of hemangiosarcoma in the spleen and of follicular cell adenoma in the thyroid gland were significantly increased in 1,000 ppm male mice.
In the nose, the incidences of olfactory epithelium atrophy, basal cell hyperplasia of the olfactory epithelium, atypical hyperplasia of the olfactory epithelium, hyperplasia of olfactory epithelium glands, and suppurative inflammation were generally significantly increased in 500 and 1,000 ppm males and 500 ppm females. The incidence of squamous metaplasia of the respiratory epithelium was significantly increased in 500 ppm females. The incidence of basal cell hyperplasia was also significantly increased in 250 ppm females.
The incidences of epithelial hyperplasia of the forestomach in the 500 and 1,000 ppm groups of males and the incidences of ulceration and inflammation of the forestomach in 1,000 ppm males were significantly increased.
Genetic toxicology
Cumene was not mutagenic in S. typhimurium strain TA97, TA98, TA100, or TA1535, when tested with and without liver S9 activation enzymes. Cumene induced small, but significant, increases in micronucleated polychromatic erythrocytes in bone marrow of male rats treated by intraperitoneal injection. In contrast, no increase in micronucleated erythrocytes was observed in peripheral blood of male or female mice exposed to cumene by inhalation for 3 months.
Conclusions
Under the conditions of these 2-year inhalation studies, there was clear evidence of carcinogenic activity of cumene in male F344/N rats based on increased incidences of respiratory epithelial adenoma in the nose and renal tubule adenoma or carcinoma (combined). Increased incidences of interstitial cell adenoma of the testis may have been related to exposure to cumene. There was some evidence of carcinogenic activity of cumene in female F344/N rats based on the incidences of respiratory epithelium adenoma in the nose. There was clear evidence of carcinogenic activity of cumene in male B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. The increased incidences of hemangiosarcoma in the spleen and follicular cell adenoma in the thyroid gland in male mice may have been related to cumene exposure. There was clear evidence of carcinogenic activity of cumene in female B6C3F1 mice based on increased incidences of alveolar/bronchiolar neoplasms. Increased incidences of hepatocellular adenoma or carcinoma (combined) in female mice were also considered to be related to exposure to cumene.
Exposure of male rats to cumene resulted in nonneoplastic lesions of the kidney characteristic of α2u-globulin accumulation. Exposure to cumene resulted in nonneoplastic lesions in the nose of male and female rats; the lung, nose, liver, and forestomach of male mice; and the lung and nose of female mice.