Cumene

Carcinogenicity

Description of key information

In the recent NTP evaluation (NTP 2009), cumene was tested in guideline studies for carcinogenicity in rats and mice. These studies were presented as robust study summaries in IUCLID Section 7.7.

Justification for classification or non-classification

Based on the mode of action considerations (alpha-2u globulin and CYP2F2, CYP2F4 mediated cytotoxicity) there is no need for classification of cumene as carcinogenic Cat 1 or 2 in terms of EU classification. In addition, genotoxicity in vitro and in vivo was negative.

Additional information

CARCINOGENICITY IN EXPERIMENTAL ANIMALS

 

In the EU RAR (2001) no results were listed.

In the recent NTP evaluation (NTP 2009), cumene was tested in guideline studies for carcinogenicity in rats and mice. These studies were presented as robust study summaries in IUCLID Section 7.7.

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.

Based on criteria set by NTP it was concluded by the authors that cumene showed clear evidence of carcinogenicity based on adenoma of nose and adenoma or carcinoma of the kidney (male rats only).

The male rat kidney toxicity and resulting tumors fit the alpha-2u-globulin mode of action (MOA). This MOA does not occur in humans and, therefore, these tumors are not relevant for human risk assessment.

The effects observed in the respiratory epithelium are mediated by cytotoxicity and regenerative hyperplasia. The cytotoxicity is derived from species specific metabolic activation via CYP2F4 in rats.

Species differences observed between mouse and rat are likely contributed to different enzymatic metabolism by CYP2F2 in mouse and CYP2F4 in rat. The human CYP2F1 is much less prevalent in these tissues and is much less effective at metabolizing these compounds than either 2F2 or 2F4.

Therefore, this mode of action is of low relevance for humans and the relevance for human health risk assessment should be considered with care.

 

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 1000 (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 1000 ppm males was significantly less than that of the chamber controls. Mean body weights of 1000 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.

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.

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 incidences of squamous metaplasia of the respiratory epithelium were significantly increased in 500 ppm females. The incidence of basal cell hyperplasia was also significantly increased in 250 ppm females.

Based on criteria set by NTP it was concluded by the authors that cumene showed clear evidence of carcinogenicity based on alveolar/bronchiolar adenoma and carcinoma of the lung.

The effects observed in the lungs are mediated by cytotoxicity and regenerative hyperplasia. The cytotoxicity is derived from species specific metabolic activation via CYP2F2 in mice.

Species differences observed between mouse and rat are likely contributed to different enzymatic metabolism by CYP2F2 in mouse and CYP2F4 in rat. The human CYP2F1 is much less prevalent in these tissues and is much less effective at metabolizing these compounds than either 2F2 or 2F4.

Therefore, this mode of action is of low relevance for humans and the relevance for human health risk assessment should be considered with care.