Dermal Exposure to Cumene Hydroperoxide: Assessing Its Toxic Relevance and Oxidant Potential

Abstract

Cumene hydroperoxide (CHP) is a high production volume chemical that is used to generate phenol and acetone. Dermal exposure to CHP was hypothesized to result in systemic tissue toxicity, production of free radicals, and consequent decrease in plasma antioxidant levels. To evaluate the hypothesis and characterize the toxicity of CHP, male and female B6C3F1/N mice and F344/N rats were exposed to varying doses of CHP applied topically for 14 or 90 days. No significant changes in survival or body weight of mice and rats were observed following 14 days of exposure. However, 90 days of CHP exposure at the high dose (12 mg/kg) triggered a significant decrease (-15%) in the body weight of the male rat group only. Irritation of the skin was observed at the site of application and was characterized by inflammation and epidermal hyperplasia. In treated animals, histology of liver tissue, free radical generation, and antioxidant levels in blood plasma were not significantly changed as compared to the corresponding controls. Consistent with the lack of systemic damage, no increase in micronucleated erythrocytes was seen in peripheral blood. In conclusion, topical CHP application caused skin damage only at the application site and did not cause systemic tissue impairment.

Keywords: Ames assay; industrial chemical; oxidizing agent; skin irritant.

Figure 1

Histopathology of skin lesions at the Site of Application from the 14-day studies of cumene hydroperoxide in rats and mice. 1A. Normal skin from a control rat. Epidermis (long arrows), hair follicles (short arrows), sebaceous glands (curved arrows), dermis (asterisk). 1B. Epidermal hyperplasia in a male rat characterized by moderate thickening of the epidermis (long arrows) that extends into the hair follicles (short arrows). Note the hyperplastic sebaceous glands (curved arrows). 1C. Exudate in a female mouse characterized by accumulation of a layer of eosinophilic proteinaceous fluid, keratin and degenerate neutrophils on the surface of the epidermis (arrows). Note inflammatory cells within the dermis (asterisk). 1D. Exudate in a male rat characterized by marked accumulation of successive layers of proteinaceous fluid, keratin and degenerate neutrophils on the surface of the hyperplastic epidermis (arrows). 1E. Hair follicle hyperplasia in a female mouse characterized by increased number of follicles within the dermis extending into the subcutis (arrows). 1F. Aberrant hair follicle growth (arrows) in a male rat. Note deformed hair follicles growing perpendicular to the orientation of hair follicles (arrows). 1G. Necrosis of the superficial epidermis characterized by hypereosinophilia and loss of cellular detail (arrows). Note inflammatory cells throughout the dermis. 1H. Fibrosis (arrows) in the papillary dermis of a male rat.

Figure 2

Histopathology of skin lesions at the Site of Application from the 90-day studies of cumene hydroperoxide in rats and mice exposed to 12 mg/kg cumene hydroperoxide. Lesions in male and female rats are generally similar to those observed in the 14-day studies. 2A. Normal skin from a control rat. Epidermis (long arrows), hair follicles (short arrows), sebaceous glands (curved arrows), dermis (asterisk). 2B. Epidermal hyperplasia (long arrows) and sebaceous gland hyperplasia (short arrows) in a male rat. Note inflammatory cells throughout the dermis. 2C. Epidermal hyperplasia (long arrows) and chronic active inflammation in the dermis of a female mouse. 2D. Exudate (arrows) on the epidermal surface in a female rat. Note complete loss of the underlying epidermis (ulcer). 2E. Marked exudate (arrows) on the epidermis surface of a female. 2F. Follicular hyperplasia (arrows) in a female rat. Note epidermal hyperplasia and sebaceous gland hyperplasia. 2G. Aberrant follicular hyperplasia (arrows) in a female rat. 2H. Necrosis of the superficial epidermis (arrows) in a male rat.