New Study Examines Connection Between Formulation and Benzene Levels in BPO Products

Image credit: © balsamic - stock.adobe.com

A recent research letter published in JAMA Dermatology reviewed the connection between the formulation of benzoyl peroxide (BPO)-containing products related to benzene levels.¹ The new letter follows the ongoing research into benzene found in BPO products. On March 6, 2024, Valisure, an independent testing laboratory, found elevated levels of benzene when 111 BPO products were incubated at 37°C (98.6°F: standard body temperature), 50°C (122°F: accepted pharmaceutical stability/shelf-life testing temperature), and 70°C (158°F: transportation or passenger vehicle temperature).²

As BPO is a commonly used over-the-counter and prescription treatment for acne, clinicians and consumers alike seek clarity on the risks associated with BPO’s ability to degrade into benzene at various temperatures.

“Any product that has been exposed to high temperatures or is expired should be discarded due to the risk of it breaking down into benzene. However, for products that have been stored appropriately, I do not think this issue is likely to pose a clinically meaningful risk,” John Barbieri, MD, MBA, research author, board-certified dermatologist, and director of the Advanced Acne Therapeutics Clinic at Brigham and Women’s Hospital in Boston, Massachusetts, told Dermatology Times.

He added, “Observational studies have not found that those who use benzoyl peroxide-containing products have higher levels of benzene in their blood or increased risk of cancer. In addition, the absolute exposure to benzene, even from some of the most concerning products tested by Valisure, does not appear likely to be a clinically meaningful exposure compared to other sources of benzene in our daily environment.”

Barbieri et al’s research letter addressed the need to find ways to minimize the formation of benzene in BPO products, as BPO is a key acne treatment. The letter authors noted that given the differences in benzene levels in various brands and BPO products, the formulation, production, and distribution may affect benzene levels, as noted in previous research.³

"The results of the products sampled in this study suggest that formulation is likely the strongest contributor to benzene concentrations in BPO drug products that are commercially available because the magnitude of benzene detected correlates most closely with specific brands or product types within certain brands,” wrote Kucera et al in a study published in the Journal of Investigative Dermatology in October 2024.³

Research Methods

Barbieri et al evaluated the vehicles of the 111 BPO products tested by Valisure in 2024. Products were categorized according to use (leave-on or wash), BPO concentration, days until expiration, whether the products had formulations that could indicate BPO experienced higher temperatures during formulation such as hot processing, encounters with antioxidants such as butylated hydroxytoluene (BHT), and more acidity of the product (final formulation), which could “quench benzoate free radicals before they can decarboxylate into benzene(ie, benzoic acid).” The authors used multivariable linear regression to evaluate the association between product characteristics and benzene levels.

Hot processing was defined as “cream cleansers that only include a high melting point emulsifier or surfactant (eg, glyceryl stearate) and lotions or creams with a high melting point emulsifier near the top of the ingredient list, or as the sole emulsifier.”

Results

Among the 111 BPO-containing products that were re-evaluated (median benzene concentration of 0.89 parts per million), leave-on products demonstrated significantly lower concentrations of benzene. According to Barbieri et al, there was no significant association between BPO concentration and benzene concentrations.

The FDA specifies that no drug products should contain benzene due to its toxicity, but that 2 parts per million is acceptable only for products that absolutely require benzene for manufacturing.⁴

“There was a weak, although statistically significant association between days to expiration date and benzene concentration,” wrote Barbieri et al.

In multivariable regression models that were adjusted for BPO concentration, product type, and days until expiration date, conditions related to hot processing were associated with increased benzene concentrations and BHT was associated with decrease benzene concentrations. Additionally, benzoic acid was associated with “numerically lower” benzene concentrations, however, it did not reach statistical significance. The results were similar when testing was adjusted for brands.

Clinical Implications

According to Barbieri et al, the results of their research suggest that formulation characteristics may explain the variation in detected benzene levels between products and brands.

“The presence of excipients (ie, inactive ingredients) suggestive of higher temperature formulation (ie, high melting point emulsifiers) were associated with higher benzene concentrations, whereas the presence of antioxidants (ie, BHT) and benzoic acid (which could reflect greater acidity of the product that might quench benzoate free radicals before they can decarboxylate) were associated with lower benzene concentrations,” the authors wrote.

Valisure also addressed the use of antioxidants by investigating common antioxidants in a model system of therapeutically relevant 10% BPO in glycerol. “The results show that simply the addition of an antioxidant can substantially reduce the formation of benzene by over 98%. These and other techniques that Valisure has investigated could help address the BPO degradation problem and fix it for future drug formulations,” wrote Valisure in the March 6th annoucement.²

Barbieri et al noted that leave-on products are typically formulated in smaller batches than washes and may be quicker to cool, and therefore suggesting their association with lower benzene concentrations. Overall, the authors stated that formulation, production, and distribution play a large role in the formation of benzene in BPO.

“These results raise important hypotheses for potential strategies to reduce benzene in benzoyl peroxide-containing products, including excipient selection and stricter temperature controls during formulation and distribution,” Barbieri et al wrote.

The authors recognized that the research was limited by its observational design and that further prospective studies are needed to confirm their findings.

“We did not find any evidence to support meaningful formation of benzene at room temperature. The lack of an association between expiration date and meaningful benzene formation over time is reassuring that products are likely relatively stable at room temperature. In addition, we found much of the variation in benzene levels between products could be explained by a few formulation factors. These findings provide important hypotheses for manufacturers to explore to reduce the likelihood that benzene forms during formulation and distribution of benzoyl peroxide-containing products,” Barbieri told Dermatology Times.

References

1. Barbieri JS, Rubin CB, Pham JP, Wong M. The role of formulation in benzene formation in benzoyl peroxide products. JAMA Dermatol. 2025 Feb 12. doi: 10.1001/jamadermatol.2024.6443
2. Valisure detects benzene in benzoyl peroxide. News release. Valisure. March 6, 2024. Accessed February 12, 2025. https://www.valisure.com/valisure-newsroom/valisure-detects-benzene-in-benzoyl-peroxide
3. Kucera K, Zenzola N, Hudspeth A, et al. Evaluation of benzene presence and formation in benzoyl peroxide drug products. J Invest Dermatol. October 7, 2024. https://www.jidonline.org/article/S0022-202X(24)02155-9/fulltext
4. FDA alerts drug manufacturers to the risk of benzene contamination in certain drugs. US Food and Drug Administration. December 27, 2023. Accessed February 12, 2025. https://www.fda.gov/drugs/pharmaceutical-quality-resources/fda-alerts-drug-manufacturers-risk-benzene-contamination-certain-drugs