Formulation factors may explain benzene levels in acne products stored at room temperature
Key takeaways:
- Formulations suggestive of higher temperature processing were associated with greater benzene concentrations.
- This included those with higher melting point emulsifiers or surfactants.
Formulation may be the primary factor responsible for the presence of high benzene levels in benzoyl peroxide-containing acne products stored at room temperature, according to published results.
In a recent JAMA Dermatology research letter, John Barbieri, MD, MBA, assistant professor at Harvard Medical School and director of the advanced acne therapeutics clinic at Brigham and Women’s Hospital, and colleagues found that the variation in benzene levels among benzoyl peroxide (BPO) products and brands are best explained by formulation characteristics.
“Our findings highlight that while room temperature storage is unlikely to result in clinically meaningful benzene formation in benzoyl peroxide-containing products, formulation choices are associated with differences in benzene level,” Barbieri told Healio.
Barbieri’s research comes on the heels of a recently published study in The Journal of Investigative Dermatology, which found that 111 BPO products stored at room temperature in retail stores were substantially contaminated with benzene and also suggested formulation could be to blame.
Factors associated with low benzene levels
In Barbieri’s study, he and his colleagues evaluated the vehicles for the same 111 products analyzed in the Journal of Investigative Dermatology study to examine whether formulation discrepancies were linked with high benzene levels.
The products were categorized according to use (such as leave-on wash), BPO concentration, days until expiration date and whether they had formulations that could indicate higher temperatures encountered by BPO formulation.
The researchers found that significantly decreased benzene concentrations, measured as parts per million (ppm), in BPO products were associated with leave-on formulations (coefficient, –5.83; 95% CI, –8.15 to –3.51) and formulations containing the antioxidant butylated hydroxytoluene (coefficient, –8.15; 95% CI, –13.03 to –3.26).
Although not a significant finding, formulations containing benzoic acid were also associated with numerically lower benzene concentrations (coefficient, –5.16; 95% CI, –10.54 to 0.23).
These findings may be explained by the fact that leave-on products are formulated in smaller batches than washes and may cool more quickly, resulting in lower benzene concentrations, according to Barbieri. Similarly, antioxidants, such as butylated hydroxytoluene, or acidifying agents, such as benzoic acid, may be able to reduce benzene formation by quenching benzoate-free radicals before they can degrade into benzene.
The study reported no significant association between benzoyl peroxide concentration and benzene concentrations.
Factors associated with high benzene levels
In contrast, increased benzene concentrations were significantly associated with conditions consistent with hot processing (coefficient, 7.34; 95% CI, 5.04-9.64).
Hot processing may occur when certain formulations, depending on the ingredient list, may be exposed to high temperatures, meaning the BPO in that product was also exposed to high temperatures. The most likely products to undergo hot processing are cream cleansers, lotions and creams that include a high melting point emulsifier or surfactant.
“Since these are necessary components of a formulation, they cannot be eliminated. However, manufacturers should critically evaluate their formulations,” Barbieri said. “Choosing excipients that require less heating during formulation and ensuring batches are kept cool once benzoyl peroxide is introduced are potential strategies to reduce benzene formation in these products.”
Christopher G. Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine and one of the investigators in the Journal of Investigative Dermatology study, told Healio it is “reassuring to see” that Barbieri’s study “aligns with our perspective that reformulation could help address benzoyl peroxide instability.”
“More experimental research is needed to learn how to reformulate safer BPO products,” he said when asked how companies should respond to this mounting evidence. “We also await regulatory clarification and guidance from the FDA, which is conducting their own investigations.”
Is room temperature storage a concern?
According to the researchers’ analysis of expiration dates, the data suggest that each 100 days of BPO product storage at room temperature is associated with an increase of less than 1 ppm of benzene.
“This is relatively low compared to the impact of formulation and production methods,” Barbieri said. “This suggests that benzene formation during room temperature storage is likely a relatively minor factor.”
Bunick stated that whether the formation of benzene stored at room temperature over time is “‘clinically meaningful’ remains a topic of debate, but “avoiding benzene exposure is clearly preferable.”
“Benzene is highly likely to form from benzoyl peroxide over time at room temperature, with strong evidence supporting this,” he said. “Multiple products have been shown to form benzene in concentrations of dozens of ppm at body temperature, which is lower than the FDA’s stability study temperature. Notably, numerous products, including sunscreens, hand sanitizers and body sprays, have been recalled for containing as little as 2 ppm of benzene.”
Solutions
While formulation, production and distribution may play roles in the formation of benzene in BPO products, Barbieri said, this ingredient is still an essential, safe part of acne care.
“It is important to keep in mind that benzoyl peroxide is a cornerstone of acne treatment with no clear alternative,” he said. “Fortunately, clinical studies to date have not identified any association between the use of benzoyl peroxide-containing products with blood benzene level or risk of cancer.”
Nevertheless, he encourages manufacturers to reconsider their processes.
“Manufacturers should avoid high-temperature processing methods and consider using antioxidants, like butylated hydroxytoluene, or acidifying agents, such as benzoic acid, to reduce benzene formation,” he said. “Implementing stricter temperature controls during manufacturing may also help limit benzene formation.”
In addition to alterations in formulation and production, the researchers suggest changing distribution methods may also be beneficial with Bunick stating that “cold chain distribution may reduce benzene formation rates.”
While Barbieri said storage conditions “appear to have minimal impact,” ensuring proper handling, including an avoidance of high temperatures during transportation, “may still be beneficial.”
“These findings provide hypotheses for manufacturers to test as strategies to minimize benzene formation during formulation, production and distribution,” Barbieri said. “While formulation characteristics were associated with benzene levels, other unassessed factors may contribute. Further prospective studies are needed to confirm these findings and refine recommendations.”
As studies continue to evaluate the risks of benzene formation in BPO products, Bunick stresses a need for action.
“Most importantly,” he said, “the focus should remain on effectively addressing this issue for the benefit of consumers and patients.”
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For more information:
John Barbieri, MD, MBA, can be reached at jbarbieri@bwh.harvard.edu.