Carcinogenesis studies of benzophenone in rats and mice
Introduction
Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer (NTP, 2000). It is also used in the manufacturing of insecticides, agricultural chemicals, and hypnotics, antihistamines, and other pharmaceuticals, as an ultraviolet curing agent in sunglasses and ink, as an additive in plastics, coatings, and adhesive formulations, and, as a flavor ingredient (NTP, 2000). Concentrations of benzophenone in food products range from 0.57 ppm in nonalcoholic beverages to 3.27 ppm in frozen dairy products; it may also be an ingredient in baked goods, soft candy, gelatins, and puddings.
Benzophenone was selected for toxicity and carcinogenicity testing based on the potential for occupational and consumer exposure and a lack of chronic toxicity data. Incorporated in a sunscreen, benzophenone produced an allergic skin reaction in one patient, as assessed by photo patch testing (Cook and Freeman, 2001). Derivatives of benzophenone, particularly 2-hydroxy-4-methoxybenzophenone (benzophenone-3) and 2-hydroxy-4-methoxybenzophenone-5-sulfonic acid (benzophenone-4), are skin irritants that cause photoallergy and have been associated with allergic contact dermatitis (Alanko et al., 2001) and facial erythema (Nedorost, 2003).
The National Toxicology Program previously performed 14-week toxicity studies on benzophenone and published the results in a separate report (NTP, 2000). In the 14-week exposure to benzophenone at concentrations of 1250, 2500, 5000, 10,000 or 20,000 ppm in rats and mice, the liver and kidney were identified as the primary target organs of benzophenone toxicity in rats (NTP, 2000). In mice, the liver was the major target of toxicity. In rats, liver changes were observed at exposure concentrations greater than or equal to 5000 ppm, while in mice, microscopic changes in the liver were observed in all exposed groups.
The present studies were performed to characterize the chronic toxicity and carcinogenicity of benzophenone when administered in the diet to F344/N rats and B6C3F1 mice.
Section snippets
Chemical
Benzophenone (CAS# 119-61-9, ∼99.5% pure) was obtained from Aldrich Chemical Company (Milwaukee, WI). The dose formulations were prepared at least once a month by mixing benzophenone with feed and were found to be stable for at least 35 days. Periodic analyses of the dose formulations were conducted using HPLC; all formulations were within 10% of the target concentrations. The formulations were stored at 5 °C for up to 35 days following preparation.
Experimental animals and housing conditions
All rodent studies were conducted at Battelle
Rats
Survival of 1250 ppm males was significantly less than that of the control group (4% compared to 44% in controls), while survival of exposed female groups was similar to that of the controls. Final body weights of high dose groups were 13–14% lower than controls for both males and females. Also, feed consumption was slightly lower both in high dose males and females. Dietary concentrations of 312, 625, and 1250 ppm resulted in average daily doses of approximately 15, 30, and 60 mg benzophenone/kg
Discussion
In the current 2-year benzophenone studies, the target organs of toxicity were liver, kidney, nose, and testes. Neoplastic responses occurred in the kidney, liver, and hematopoietic system.
Rats exposed to benzophenone exhibited a positive trend in the incidences of renal tubule adenoma. The NTP has shown that examination of the entire kidney, by step sectioning of residual tissues, enables a more precise evaluation of the potential chemical-related induction of renal proliferative lesions than
Acknowledgement
This work was supported by the Division of Intramural Research, NIEHS, NIH.
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