Dibenzoyl peroxide

Endpoint summary

Description of key information

No case of skin cancer was observed in human despite the wide use of dibenzoyl peroxide especially in acne treatment.
Many human cases of skin sensitisation have been observed with dibenzoyl peroxide.

Additional information

Benzoyl peroxide is the most widely used active ingredient in topical acne preparations in the US (FDA, 2010) and EU (EMA, 2015; SCCNPF, 2002). It is available in creams, solutions, soaps, cleansers, shaving creams, and pledgets both by prescription and over the counter. Its use as an acne treatment is based on its keratolytic and antibacterial properties. It is used in concentrations usually ranging from 2.5% to 10%, but it has also been utilized at higher concentrations to treat stasis ulcers.

Skin cancer

Reviews of epidemiological studies did not show any significant association between the prescribed use (for several decades) of benzoyl peroxide to treatment of acne and malignant melanoma, or between the occurrence of acne and malignant melanoma (Binder et al, 1995; Kraus et al., 1995):

Two case-control studies have been conducted with the specific aim of assessing the risks of skin cancer associated with the use of benzoyl peroxide (Cartwright et al., 1988; Hogan et al., 1991). The first of these involved 152 melanoma cases aged 45 and under who were diagnosed between 1984 and 1986 in Yorkshire, England and 262 age- and sex-matched controls (Cartwright et al., 1987). No interviews were conducted with patients or their relatives, with medical records serving as the basis for characterization of benzoyl peroxide use. The medical records showed that four cases and 15 controls had used benzoyl peroxide, indicating that a significantly (P= 0.049) smaller number of skin cancer cases than controls had used benzoyl peroxide. The sole use of medical records in obtaining information regarding benzoyl peroxide use may have resulted in an underestimate of the total incidence of use, since the use of nonprescription products may not have been recorded. The authors conclude that the "... study indicates there is no evidence that acne sufferers or individuals prescribed benzoyl per­ oxide have an increased risk of malignant melanoma."

In the second and more definitive study of skin cancer and benzoyl peroxide use, two different approaches were taken. One approach involved the use of data on the prescription use of benzoyl peroxide obtained through the Saskatchewan drug plan (Hogan, 1989), while the other involved the use of data on general nonprescription use of benzoyl peroxide obtained through questionnaires completed by cases and controls (Hogan et al., 1991). In both parts of the study, cases and controls were matched according to age and sex. The cases were identified through the Saskatchewan Cancer Registry and represented over 90% of the skin cancer cases who might have used benzoyl peroxide between 1966 and 1988 (prescription use 1975-1988; nonprescription use 1966-1988). Cases included patients with any type of skin cancer and were not restricted to melanoma, as was the situation with the previously conducted studies discussed above (Cartwright et al., 1987). In the prescription and nonprescription segments of the Hogan et al., (1991) study, the cases included 41 squamous cell tumors and 25 malignant melanomas, with the remainder and majority being basal cell carcinomas.

In the study of the prescription use of benzoyl peroxide there were 931 cases and 7630 controls (Hogan et al., 1989). As noted above, data on prescription benzoyl per­ oxide use came from the Saskatchewan drug plan, where availability to patients began in 1975. This plan is uni­versally available across the province without charge to subscribers and therefore would be expected to provide complete data on the prescription use of benzoyl peroxide. Among the skin cancer cases, 13(1.4% of cases) had used benzoyl peroxide by prescription compared to 66 (0.9%) control subjects. The odds ratio for skin cancer in subjects using benzoyl peroxide was 1.27, with a95% confidence interval of 0.69-2.35, which was not statisti­cally significant. While the power of this study was stronger than the previously discussed case-control study by Cartwright, pursuit of even greater statistical power led to phase II discussed below. In a second phase of this work, 872 skin cancer cases and 2798 age- and sex-matched controls responded to a questionnaire (Hogan et al., 1991). This represented a90.9% response rate for cases and a 79.9% response rate for controls. The emphasis of the questionnaire was on acne and acne treatment, particularly benzoyl peroxide treatment. An attempt to limit recall bias was made by supplying all subjects with a comprehensive list of brand names of all products containing benzoyl peroxide available since 1966. Subjects were between the ages of 10 and56, and the cases represented at least 90% of facial skin cancer cases who may have used benzoyl peroxide since the time of its introduction in Canada in 1966. There were no significant differences between cases and controls in the severity of the acne, the number of different acne treatments tried, or the duration of benzoyl peroxide use. There were 168subjects who reported benzoyl peroxide use, 33 were cases and 135 were controls. No significant difference was found in the relative number of cases and controls who had used benzoyl peroxide, although a slightly greater percentage of controls than cases had used benzoyl peroxide. The univariate odds ratio for skin cancer of the face and neck for benzoyl peroxide use was 0.84 with 95% confidence limits of 0.51 to 1.38. Multivariate logistic regression analysis gave an odds ratio of 0.80 (95% confidence interval, 0.48-1.33). The small difference between the univariate and multi­variate odds ratios for benzoyl peroxide indicates that the use of benzoyl peroxide did not exacerbate the risk associated with the presence of other identified skin cancer risk factors such as X-ray irradiation, fair skin, light hair color, and/or family history. Statistical analyses were conducted to assess the effects ofduration of use and time since last use of benzoyl peroxide (Dr. Anthony Miller, unpublished communication). These analyses showed no relationships between duration or time of use and cancer risk, although this cannot be considered a conclusive finding due to the small number of cases in each subgroup defined by specific exposure parameters. By epidemiological standards, this study was substantial because the overall power of the study was approximately 85% to detect an odds ratio of 1.33 at an alpha risk of 0.05. This study was sufficiently sensitive to detect all known nondrug risk factors for skin cancer, including light skin and hair, X-ray irradiation, Celtic origin, family history of skin cancer, and susceptibility to sunburn.

The findings of Hogan et al. (1991) are consistent with those of other studies investigating risk factors for skin cancer. The lack of associations between acne or benzoyl peroxide use and skin cancer has been previously re­ ported, as have the positive associations between skin cancer and light skin, exposure to X-ray irradiation, and other known risk factors. The observed association of skin cancer with sunburn, tanning, and skin color indicates the adverse influence of ultraviolet (UV) light in this population. Given the high degree of power of the study, the exceptionally high response rate, and the consistency of the findings with other published reports, the results of the study by Hogan et al. (1991) provide convincing evidence of the lack of association between ben­ zoyl peroxide use and melanoma or nonmelanoma skin cancer development in humans. The results of this study also provide evidence of a lack of influence of benzoyl peroxide on UV light-induced skin carcinogenesis, since UV light-induced carcinogenesis was clearly in operation in the population studied.

Skin sensitisation

An early study indicated that benzoyl peroxide was a potent cutaneous sensitizer. Further studies and clinical experience have demonstrated that benzoyl peroxide used to treat acne is a rare sensitizer (Hogan, 1991).