Is Hydroquinone Safe

Currently, the short answer seems to be that it depends on how you use it. Despite the controversy over hydroquinone's safety, there have apparently been no reports of anyone developing cancer from hydroquinone—in over 50 years of cosmetic use as a skin whitener and many more decades of human exposure via industrial and photography development.¹

In fact, we consume many foods that naturally contain arbutin, which readily converts to hydroquinone in our stomachs. Oral ingestion of hydroquinone is absorbed in the body far easier than through dermal application, and in both types of exposure is quickly eliminated from the body through urination. The U.S. Food and Drug Administration (FDA) cited a study demonstrating that only 0.04 μg-equivalents/ml of hydroquinone was measurable as the peak level after application of 2% hydroquinone cream.¹ Based on this, the equivalent of a daily dose of legally prescribed (4%) or marketed over-the-counter (OTC) topical 2% hydroquinone cream could realistically be as safe as a day of ingesting typical amounts of food items such as coffee, pears, berries, tea, and wheat bread.^2,3

Historical Review—The International Community

Hydroquinone’s safety has been a question asked by the international community for over 30 years. In 1994, following up on inconclusive evaluations completed by the International Agency for Research on Cancer (IARC) and the Nordic Expert Group for Documentation of Occupational Exposure Limits, the International Programme on Chemical Safety (IPCS) essentially advised that additional studies needed to be conducted to assess hydroquinone’s toxicity to humans. This report also recommended restricting OTC sales of hydroquinone preparations because of evidence of abusive over-use as a skin lightener. Despite some deaths from ingestion of photography chemicals that contained hydroquinone (but not necessarily due to hydroquinone), one in vivo study on men and women who ingested 300-500 mg of hydroquinone daily for 3-5 months noted no measurable effects in both blood and urine tests. Other effects on humans were specified in 1994 as:⁴

• An in vivo study which demonstrated negligible effects of up to 3% hydroquinone concentration cream on the skin of human volunteers of all races.
• Case reports of redness and contact dermatitis from exposure to concentrations of 1% or less liquid solution to up to 5% in a base cream.
• Rare reports of ochronosis and leukoderma with creams containing up to 2% hydroquinone.
• Reports of eye irritation and serious eye injury after long-term exposure to airborne substances containing hydroquinone.

Although in vivo animal studies demonstrated toxicity and/or mutagenic effects to the kidneys, immune systems, and bone marrow cells, these were not demonstrated in humans—possibly because the routes of exposure were different than those typically occurring with humans.⁴

Two years later IPCS published a companion report reiterating the 1994 recommendations restricting the use of OTC hydroquinone creams, and noted that current OTC guidelines were in place in both the United States and Europe restricting the concentration to 2% or below.⁵ Since then, however, OTC hydroquinone has been banned in Japan and in Europe (in 2001) due to its link with occurrences of leukoderma and ochronosis.¹

The FDA Weighs In

On August 29, 2006, the FDA rescinded its 1982 proposed GRASE hydroquinone, and proposed that all new products containing hydroquinone would have to undergo a new drug review.⁶ What does this mean in terms of availability of hydroquinone creams? If the FDA issues a final ruling reclassifying these OTC creams from non-GRASE to new drug, topical hydroquinone creams will only be available by prescription and only after review and approval of a new drug application by the manufacturers of these formerly OTC products.⁷

The FDA based its decision on studies that demonstrated “some evidence” that hydroquinone caused kidney tumors in rats (when orally ingested) and years of case reports of ochronosis caused by hydroquinone creams. Although particularly unsightly and apparently irreversible, this bluish-black discoloration and thickening of the skin has mostly occurred in people living in African countries after years of using hydroquinone formulations of much higher concentrations than available here. Over the years, there have been a handful of ochronosis cases reported as a result of using low-concentration hydroquinone cream, but even these may be due to other contributing factors—like the concurrent use of other products with ingredients known to cause ochronosis.⁶

As of 2009, the FDA has not issued any final ruling on the status of OTC hydroquinone, and many doctors consider the ban as unnecessary given the lack of convincing evidence of carcinogenic risk to humans and the rarity of ochronosis occurrence.^3,8 Presumably the FDA deemed earlier human studies, including one that showed no increased mortality rates from kidney cancer for 879 men and woman who worked for some 48 years manufacturing hydroquinone, were insufficient evidence of safety to counteract the animal studies.⁹

Recent Evidence

In 2007, Dr. Jacob Levitt, a dermatologist from the Mount Sinai Medical Center Department of Dermatology (who also owns or owned at the time of publication significant shares in a company that manufactures OTC hydroquinone creams) published a lengthy article in response to the FDA’s 2006 proposed rule to ban the OTC sale of these creams. He pointed out that the animal studies regarding the carcinogen risk to humans were both contradicted by results of other equally valid animal studies (which he cited—including a long term study commissioned by the U.S. government’s National Toxicology Program) and by evidence that the renal and blood cancers that did occur in these rats arose from different mechanisms and organs than in humans.³

Although any such rebuttal from a party that has a financial stake in the outcome of an action must be carefully considered in light of a potential conflict of interest, even subsequent studies than those cited by Dr. Levitt support or enhance his position. This includes a recent recommendation that human toxicity decisions not be based on a chemical’s effect on chronic progressive nephropathy (the precursor to kidney tumors in the FDA-cited studies) in rats, since there is no evidence of a corresponding condition in humans.¹⁰

A 2007 review of hydroquinone’s toxicity by a respected and well-known toxicology expert, Dr. Douglas McGregor,¹¹ involving the carcinogenic risk of hydroquinone found the following:¹²

• Two small studies on lithographers and photographic processors yielded uncertain data due to the small numbers and questions about actual exposure.
• One study on film processing workers with greater numbers of malignancies—but the exposure was not limited to hydroquinone.
• A review of long-term exposure via manufacturing of hydroquinone itself or its use which actually revealed lower cancer rates in comparison to other population groups.

In recent randomized studies involving the use of topical formulations containing 4% hydroquinone, a retinoid (tretinoin), and a steroid by 641 women of all age and ethnicity groups there were no incidents of ochronosis.⁷

Current FDA Status

In 2009, the FDA renewed its call for additional studies on the safety of hydroquinone with the publication of a Nomination Profile which provides “Supporting Information for Toxicological Evaluation by the National Toxicology Program.” The request for evaluation focuses on uncovering the risks of skin disorders, cancer, and genetic mutations in humans from hydroquinone exposure. In terms of cancer and genetic mutations, the FDA did not name any additional studies or reviews to support its current or prior concerns, and again noted that the animal-study evidence was contradictory.¹

Further, the FDA itself acknowledged in this Nomination Profile that one review indicated that only 789 cases of ochronosis had been reported world-wide from 1955 through 2006—certainly supportive of the mainstream medical community’s current and continuing opinion of the rarity of this condition. In defense of their position requiring additional studies on the safety of dermatological use of hydroquinone, however, the FDA points to another study which suggests that ochronosis cases may be under-reported—based on a finding of two cases that were misdiagnosed as a failed treatment of melasma.¹

So where does this leave the consumer wondering about the safety of hydroquinone? We recommend that you discuss your options with your health care provider—including OTC, prescription, and other procedures. He or she can best assess your particular situation and specific risk factors for any adverse effects. To minimize any potential side effects, never use hydroquinone creams in different ways than recommended by your physician or the manufacturer (such as ingesting or over-application of the cream). In the meantime, if past history is any indicator of future action, we caution against expecting any quick decisions from the FDA.