Updates on Benzene in Benzoyl Peroxide Products at AAD

Christopher Bunick, MD, PhD

Benzoyl peroxide (BPO) has been a popular topic in both dermatology and consumer headlines within the past week, specifically from news of high levels of benzene found in BPO-containing acne products such as cleansers and lotions. Valisure, an independent testing laboratory in Connecticut, tested 66 BPO products and found high levels of benzene when BPO products were incubated at 37°C (98.6°F: body temperature), 50°C (122°F: accepted pharmaceutical stability testing temperature) and 70°C (158°F: hot car temperature).

Valisure’s findings have been criticized by some, as questions were raised about testing products at such high temperatures. Valisure has been transparent about the reason for the temperatures in their stability testing, writing, “The purpose of stability studies is not to copy the conditions of an average consumer, rather, the purpose is to ensure the product is safe to use for the entire products lifecycle, from manufacturing through distribution to its expiration date, often a total of 3 years for pharmaceutical products. Products must be stable during this entire time and through all the possible ‘bumps’ along the road. It is common to condense the total stability of a product intended for multiple years of use by performing ‘accelerated’ stability studies that elevate the temperature for a few months. For example, according to publicly available calculators, 3 years of room temperature stability is equal to about 169 days at 50°C (122°F). Valisure broadly observed dramatically high levels of benzene in only 18 days at 50°C.”¹

Valisure also noted that the FDA specifically prefers this testing approach, which is outlined in its regulations on storage conditions.

Christopher Bunick, MD, PhD, FAAD, associate professor of dermatology and physician-scientist at the Yale School of Medicine, has closely followed benzene contamination news in dermatology since the first detection of benzene contamination in sunscreen. At the 2024 American Academy of Dermatology (AAD) Annual Meeting in San Diego, California, Bunick presented updates on benzene in BPO to an overflowing room of attendees looking for more information and data. Bunick has no financial disclosures related to Valisure, and is passionate about providing dermatologists with up-to-date information to help better inform their patients.²

Bunick began with a history of benzene through academic papers, starting with a German paper from 1936 that evaluated the thermal decomposition of diacyl peroxides, which BPO is a diacyl peroxide. In 1997, Akzo Nobel filed for a patent for the “Reduction of benzene formation in dibenzoyl peroxide formulations.”

“Recently, however, it has been discovered that BPO formulations such as pastes, emulsions, and suspensions based on organic plasticizers, whether in the presence or absence of water, show continuously increasing levels of free benzene throughout their useful lifetime. This free benzene is formed due to the slow decomposition of the BPO over time,” wrote Akzo Nobel.

From their patent application, Akzo also wrote that the minimization of benzene’s formulation is highly desirable due to its known carcinogenic properties.

“Almost 20 to 30 years ago, a company was trying to solve the benzoyl peroxide decomposition problem,” said Bunick.

As a result of these studies, the FDA did complete an investigation, but they did not fully deem BPO safe. After animal testing, it was found that “Benzoyl peroxide is a tumor promoter in several animal species. The significance of this finding in humans is unknown,” a statement that is now added to the nonclinical toxicology section of BPO-containing product’s package label.

The USP released a statement on March 8, 2024, related to the benzene testing from Valisure, stating that benzene contamination should be taken seriously, but that if changes are made to a USP method, complete validation data is needed to prove a product meets USP standards.

“Perhaps the most important line in this entire statement is the next one: ‘It is important to note that USP standards are applicable during the entire shelf life of the product, not just at the time of release,’” said Bunick. “The problem with the USP statement is that the FDA already rejected their methods as not being good enough, and you wouldn’t know that unless you read the FDA’s statement."

In 2020, the FDA rejected USP’s method of gas chromatography- flame ionization detection (GC-FID) for benzene analysis, which is a method that has less precision and accuracy.

The FDA industry standard of gas chromatography-mass spectrometry (GC-MS), which is more accurate, is the method Valisure chose to use in its recent petition.

Validating Valisure’s Findings

The findings of benzene in BPO products were validated by 3 different labs using 4 different technology platforms, including GC-MS, GC-HRMS, HPLC, and SIFT-MS. Bunick shared updates that CBS News followed up with the labs, and 2 of the 3 confirmed Valisure’s results when contacted.

“There’s been concerns that superficially when you look at the petition, that it’s all about elevated temperatures. That’s not true. Benzene was also found extensively at room temperature on the shelf/off the shelf. The focus of the petition is stability studies,” said Bunick.

Of the 66 products tested at day 0 at room temperature, 10 of the products had more than 10 parts per million of benzene, and 19 products had more than 2 parts per million of benzene. According to Bunick, the problem with BPO is degradation, not contamination. He also reminded attendees that while the FDA “allows” up to 2 parts per million of benzene, that is only if it is absolutely necessary to manufacture said product. Bunick added that with so many other acne treatments available, it is not absolutely necessary to manufacture BPO with such unsafe levels of benzene, even at 2 parts per million.

Stability testing is not meant to replicate consumer use or “real-world” use, it’s intended to evaluate the full, 3-year product “life cycle.” 3-year stability at room temperature is equal to 169 days at 50°C or 122°F which is based on industry standards. It is a regulatory requirement to perform stability testing on products and should be conducted on products under normal storage conditions, or, preferably, under exaggerated conditions, according to the FDA.

However, in some cases, stability testing does overlap with real-world outcomes. Bunick shared new data for the first time today that demonstrated that of 5 BPO products tested at 37°C (98.6°F), or human skin temperature, 1 product had more than 10 parts per million of benzene, and all 5 had over 2 parts per million of benzene.

When considering Valisure’s testing, Bunick pointed out that every time Valisure detected a carcinogen in consumer products, some form of a recall followed.

Bunick noted that many people have questioned who is Valisure. Valisure is a company hired by the United States Department of Defense to check the quality of drugs for the United States military. Their number one funder is drug purchasers, according to Bunick, because these companies want to know what they are buying is safe.

Bunick wrapped up his session by reviewing recent benzene studies and news items, all of which called out benzene’s associated risk with various cancers such as leukemia. Regulatory agencies such as the CDC, WHO, EPA, and NOSH have all made similar statements that benzene is a known human carcinogen.

In December 2023, the FDA released new guidance for industry for the reformulation of drug products containing carbomers manufactured with benzene. The FDA has also proposed a ban on hair-straightening products containing formaldehyde, another carcinogen, with the proposed ban expected in April 2024.

“So, what does this all mean and what am I going to advise for patients? I will say we as a community have to see what is validated. I do not necessarily think at this moment that no one should use benzoyl peroxide. I think there has to be a proportional response until more data comes out,” said Bunick.

He concluded, "With Valisure’s agreement, that for those providers and patients who wish to continue benzoyl peroxide-containing products, that a proportional response at this time would be to keep the product refrigerated at all times, renew the medicine every 3 to 6 months, and avoid heated storage. This will not necessarily eliminate all benzene, but should slow its decomposition. This measure gives the medical community a chance to await further investigation and recommendations.”

References

1. The importance of stability testing. News release. Valisure. March 6, 2024. Accessed March 11, 2024. https://www.valisure.com/valisure-newsroom/the-importance-of-stability-testing
2. Bunick C. Discussion of new findings in benzene in BPO-containing products. Presented at: 2024 American Academy of Dermatology Annual Meeting; March 8-12, 2024; San Diego, CA.