Carcinogenesis studies of benzophenone in rats and mice

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Abstract

Benzophenone, an aryl ketone, is used primarily as a photoinitiator and fragrance enhancer. Groups of 50 male and 50 female F344 rats and B6C3 F1 mice were fed diets containing 0, 312, 625, and 1250 ppm benzophenone for 105 weeks. Survival of males exposed to 1250 ppm benzophenone was significantly less than that of controls. There was a positive trend in the incidence of renal tubule adenoma in male rats; these neoplasms were accompanied by significantly increased incidences of renal tubule hyperplasia. Increased incidences of mononuclear cell leukemia were observed in male rats exposed to 312 or 625 ppm benzophenone and in female rats exposed to 625 ppm benzophenone. Liver lesions observed included significantly increased incidences of hepatocytic centrilobular hypertrophy in all exposed groups of rats. In mice, survival of all exposed groups was generally similar to that of the control groups. In male mice, there were significantly increased incidences of hepatocellular adenoma in the 625 and 1250 ppm groups. In female mice, the incidences of hepatocellular adenoma in the 625 and 1250 ppm groups were higher than expected after adjusting for the lower body weights in these groups. The incidences of kidney nephropathy in exposed groups of female mice, as well as the severity of nephropathy in exposed groups of males, were significantly increased. The incidences of metaplasia of the olfactory epithelium were significantly increased in 1250 ppm mice. Rare histiocytic sarcomas were observed in female rats and mice in the 625 and 1250 ppm groups.

Under the conditions of these 2-year studies, there was some evidence of carcinogenic activity of benzophenone in male F344/N rats based on increased incidences of renal tubule adenoma. There was equivocal evidence of carcinogenic activity of benzophenone in female F344/N rats based on the marginal increased incidences of mononuclear cell leukemia and histiocytic sarcoma. There was some evidence of carcinogenic activity of benzophenone in male B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenoma. There was some evidence of carcinogenic activity of benzophenone in female B6C3F1 mice based on increased incidences of histiocytic sarcoma; the incidences of hepatocellular adenoma in female B6C3F1 mice may have been related to benzophenone exposure.

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.

References (26)

  • H.A. Hejaz et al.

    Synthesis, in vitro and in vivo activity of benzophenone-based inhibitors of steroid sulfatase

    Bioorg. Med. Chem.

    (2004)
  • C.J. Portier et al.

    Testing for increased carcinogenicity using a survival-adjusted quantal response test

    Fundam. Appl. Toxicol.

    (1989)
  • K. Alanko et al.

    Occupational allergic contact dermatitis from benzophenone-4 in hair-care products

    Contact Dermatitis

    (2001)
  • A.J. Bailer et al.

    Effects of treatment-induced mortality and tumor-induced mortality on tests for carcinogenicity in small samples

    Biometrics

    (1988)
  • J.C. Barrett et al.

    Cellular and molecular mechanisms of chemically induced renal carcinogenesis

    Renal Failure

    (1991)
  • N. Cook et al.

    Report of 19 cases of photoallergic contact dermatitis to sunscreens seen at the skin and Cancer Foundation

    Australas. J. Dermatol.

    (2001)
  • C.W. Dunnett

    A multiple comparison procedure for comparing several treatments with a control

    J. Am. Stat. Assoc.

    (1955)
  • S.L. Eustis et al.

    The utility of multiple-section sampling in the histopathological evaluation of the kidney for carcinogenicity studies

    Toxicol. Pathol.

    (1994)
  • C.H. Frith et al.

    The morphology, immunohistochemistry, and incidence of hematopoietic neoplasms in mice and rats

    Toxicol. Pathol.

    (1993)
  • G.C. Hard

    Mechanisms of chemically induced renal carcinogenesis in the laboratory rodent

    Toxicol. Pathol.

    (1998)
  • J.K. Haseman et al.

    Body weight-tumor incidence correlations in long-term rodent carcinogenicity studies

    Toxicol. Pathol.

    (1997)
  • M. Hollander et al.

    Nonparametric Statistical Methods

    (1973)
  • National Research Council

    Guide for the Care and Use of Laboratory Animals

    (1985)
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