Vol. 38, Issue 2, Pages 28-29 (February 2007)

LESLIE S. BAUMANN, M.D.

DR. BAUMANN is director of cosmetic dermatology at the University of Miami. To respond to this column, or to suggest topics for future columns, write to Dr. Baumann at our editorial offices via e-mail at This e-mail address is being protected from spambots. You need JavaScript enabled to view it .

With a track record of safety and efficacy spanning more than 40 years, hydroquinone, a hydroxyphenolic derivative of benzene, is considered the most effective skin-lightening product for treatment of hyperpigmentary disorders (J. Eur. Acad. Dermatol. Venereol. 2006;20:781–7; Skin Therapy Lett. 2004;9:1–3). Globally, the most widely prescribed skin-lightening and depigmenting agents include magnesium l-ascorbyl-2-phosphate, hydroxyanisole, N-acetyl-4-S-cysteaminylphenol, arbutin (hydroquinone-b-d-glucopyranoside), and hydroquinone (Phytother. Res. 2006;20:921–34).

Used in over-the-counter products as well as prescription drugs, hydroquinone (HQ) is found in vegetables, fruits, and grains, as well as in plant-derived products such as coffee, tea, beer, and wine. It is known to reversibly inhibit cellular metabolism by affecting DNA and RNA synthesis.

For many years, HQ has been the first-line therapy for postinflammatory hyperpigmentation and melasma.

HQ exerts its depigmenting effect by efficiently inhibiting tyrosinase, decreasing its activity by 90%. It also is cytotoxic to melanocytes (Dermatol. Clin. 1988;6:185–92; J. Invest. Dermatol. 1984;82:308–10).

Besides HQ, other known inhibitors of tyrosinase include vitamin C, kojic acid, arbutin, mulberry extract, and licorice extract. Although HQ is useful as a sole therapeutic agent, it is often combined with other compounds such as tretinoin, glycolic acid, kojic acid, and azelaic acid.

The Search for Mutagenic Effects

Despite its long record of medical use, HQ raises concerns because it is derived from benzene and therefore has putative mutagenic properties. In addition, side effects have been associated with the long-term use of cosmetic products containing high HQ concentrations (J. Eur. Acad. Dermatol. Venereol. 2006;20:781–7). Indeed, HQ has been banned as a cosmetic skin-bleaching agent in Europe since January 2001 (Ned. Tijdschr. Geneeskd. 2004;148:768–71), and it is available there only in prescription form. The compound also is highly regulated in Asia.

Recently, investigators conducted a literature search focusing on the biochemistry and toxicology of HQ, benzene, and related molecules, with an eye toward the potential long-term side effects of HQ use in cosmetics. After surveying the large body of literature on the carcinogenicity of these compounds, particularly studies published since 1996, the investigators concluded that the long-term use of topical HQ does pose an increased risk of cancer, and they recommended that this benzene derivative no longer be used as a skin-lightening agent (J. Eur. Acad. Dermatol. Venereol. 2006;20:777–80).

Nevertheless, there are no reports in the medical literature of any human cutaneous or internal malignancies linked to HQ (J. Eur. Acad. Dermatol. Venereol. 2006;20:781–7). Animal experiments have linked HQ use to the induction of leukemia and renal adenomas.

In workers exposed to HQ, the most serious health effects have been pigmentation of the eye and, in a small number of cases, permanent corneal damage (Crit. Rev. Toxicol. 1999;29:283–330).

Because absorption of HQ is more rapid than its elimination through urine, daily use is now known to cause the agent to accumulate in the body (Ned. Tijdschr. Geneeskd. 2004;148:768–71).

Concerns about the effects of intermediate use of HQ, such as exogenous ochronosis and leukomelanoderma en confetti, contributed to the European ban on HQ in cosmetic products that was instituted in 2001 (J. Eur. Acad. Dermatol. Venereol. 2006;20:777–80; Ned. Tijdschr. Geneeskd. 2004;148:768–71).

Adverse Clinical Effects

Ironically, exogenous ochronosis presents as yellow-brown or blue-black hyperpigmentary macules that can result from the treatment of other hyperpigmentary conditions with skin-bleaching formulations containing HQ (Int. J. Dermatol. 2005;44:112–5). Exogenous ochronosis occurs in the area of HQ application, usually after prolonged use of even low concentrations (2%) of HQ, and more often in patients with darker skin types.

This adverse response is thought to be caused by the inhibition of the enzyme homogentisic acid oxidase in the skin, resulting in the local accumulation of homogentisic acid that then polymerizes to form ochronotic pigment (J. Am. Acad. Dermatol. 2000;42:869–71).

Despite the widespread use of HQ in North America, the number of reported cases of exogenous ochronosis due to HQ use has been only 30 on this continent (Skin Therapy Lett. 2004;9:1–3). To limit the adverse effects seen with HQ, it is best to use it in 4-month cycles, alternating it with kojic acid, azelaic acid, and other bleaching agents.

Irritant and allergic contact dermatitis and nail discoloration have been associated with HQ use, with postinflammatory hyperpigmentation also resulting from contact dermatitis. Hypopigmentation also has been seen around sites treated with HQ. Discontinuing HQ therapy resolves these side effects (Skin Therapy Lett. 2004;9:1–3; Arch. Dermatol. 1995;131:1453–7).

In a study of 16 women with idiopathic melasma, patients nightly applied 5% ascorbic acid cream on one side of the face and 4% HQ cream on the other side for 16 weeks, and applied sunscreen daily. The best subjective results were seen on the HQ side (93% vs. 62.5%), although no statistical differences were identified through colorimetric analysis. The side effect profile strongly favored the ascorbic acid side, with adverse reactions seen in 11 of 16 HQ sides as opposed to only 1 of 16 ascorbic acid sides (Int. J. Dermatol. 2004;43:604–7).

Recently, the Pigmentary Disorders Academy came to a consensus that the ideal first-line approach to melasma consists of topical therapies, primarily those with triple combinations of effective agents. The recommended alternatives included single agents (4% HQ, 0.1% retinoic acid, or 20% azelaic acid) or agents with dual ingredients (HQ plus glycolic acid) (J. Am. Acad. Dermatol. 2006;54:S272–81).

Safety of Combination Agents

Because of escalating concerns about HQ monotherapy, numerous studies have included HQ in combination topical therapy. Although HQ, tretinoin, and topical corticosteroids are well established as effective single agents for treating melasma and hyperpigmentation, the once-daily triple combination cream containing 0.05% tretinoin, 4% HQ, and 0.01% fluocinolone acetonide (Tri-Luma) is the only commercially available combination of all three agents. In fact, it is the only HQ-containing product that has been approved by the Food and Drug Administration for treatment of facial melasma (Am. J. Clin. Dermatol. 2006;7:223–30).

Extensive studies have indicated an efficacious and safe profile for this triple combination cream in treating melasma (Am. J. Clin. Dermatol. 2006;7:223–30).

In a multicenter, open-label, 12-month study of once-daily application of Tri-Luma cream for facial melasma, which 173 out of 228 patients completed, the formulation was deemed safe and effective. Patient and physician assessment revealed complete or nearly complete clearing in more than 90% of cases. A total of 129 patients experienced at least one adverse event related to treatment, with most events categorized as mild and transient.

More evidence for the triple combination approach comes from an 8-week, multicenter, open-label, community-based study evaluating Tri-Luma cream in 1,290 patients of diverse races and ethnicities. Global evaluations at the end of the study period revealed that 75% of patients exhibited “moderate or marked improvement” or were deemed to be “almost clear” or “clear.”

A 12-month extension of a randomized, investigator-blinded, multicenter, 8-week trial evaluating the triple combination cream for facial melasma netted 389 patients completing 6 months of treatment and 327 patients completing 12 months. In all, 80% of patients exhibited complete or nearly complete clearance of lesions. This study reinforced a previous smaller study indicating that once-daily application of a triple combination cream containing HQ is effective, safe, and tolerable over a lengthy period for the treatment of moderate to severe melasma (J. Drugs Dermatol. 2005;4:592–7).

In 2004, a 12-week open-label study with 28 patients (25 of whom completed the study) evaluated the safety and efficacy of a then-novel formulation of 4% HQ with 0.15% retinol entrapped in microsponge reservoirs, which were used for the gradual release of HQ to extend treatment exposure and limit skin irritation. Patients applied the study cream to the full face in the morning and evening, and applied a broad-spectrum sunscreen 15 minutes after the morning application. Assessment at 4, 8, and 12 weeks showed improvement in all study end points, including melasma or postinflammatory hyperpigmentation disease severity and intensity, as well as lesion area. The HQ-retinol combination was deemed safe and effective, with only one patient dropping out because of an adverse reaction not judged to be serious.

Other studies of dual combination formulations have yielded encouraging results. A 16-week comparison study revealed that an emollient cream containing 4% HQ and 0.3% retinol more effectively eliminated signs of photodamage (dyspigmentation, fine wrinkles, and tactile roughness) than a 0.05% tretinoin emollient cream. According to the researchers, the cream may represent a viable therapy for hyperpigmentation associated with photoaging (Dermatol. Surg. 2005;31:799–804). Further, in a recent comparison study lasting 24 weeks, topical application of tazarotene plus HQ was found to be more effective in ameliorating the dyspigmentation associated with photodamage than tazarotene alone (J. Cosmet. Laser Ther. 2006;8:121–7).

Possible Alternatives

Several compounds have been proposed as safer alternatives to topical HQ, including azelaic, kojic, glycolic, and thioctic (a-lipoic) acids, as well as deoxyarbutin (Phytother. Res. 2006;20:921–34; J. Cosmet. Sci. 2006;57:291–308; Ned. Tijdschr. Geneeskd. 2004;148:768–71).

Small proteins found in soy, as well as niacinamide, a vitamin B3 derivative, also appear to have potential as alternatives. The soy proteins, such as soybean trypsin inhibitor and Bowman-Birk inhibitor, may inhibit skin pigmentation. These proteins have been found not only to exhibit depigmenting activity but also to prevent UV-induced pigmentation, both in vitro and in vivo (J. Invest. Dermatol. 2001;116:587–95). Niacinamide has also been demonstrated to inhibit melanosome movement from melanocytes to keratinocytes (Br. J. Dermatol. 2002;147:20–31).

Decision Time at the FDA

Hydroquinone has a long record of successful and safe use as a skin-lightening agent for dermatologic use. It is available over the counter in 2% concentrations and by prescription in 4% concentrations. Recently, this agent has come under greater scrutiny because of its putative potential for inducing adverse effects.

At press time, it was not known whether the FDA would finalize a rule it proposed last year to take over-the-counter HQ preparations off the market, a decision that would affect consumers who use skin-bleaching formulations (SKIN & ALLERGY NEWS, January 2007, p. 1). Neither is it known whether the FDA will ban the prescription-strength HQs that have not received FDA approval. In other words, Tri-Luma may soon be the only HQ product available on the market.

Several years ago, the FDA asked companies that sell HQ products to provide data that these products were safe. The only safety data that I know of that were turned in to the FDA were the Tri-Luma data that resulted in FDA approval of its use in melasma. Because of this lack, we are facing a ban on a terrific cosmetic ingredient.

If you treat patients with melasma or postinflammatory hyperpigmentation, you know how important HQ is as a therapy. If HQ is banned, many dermatologists might choose to have these products formulated for them in a pharmacy. (That's what they do in the United Kingdom.) The bad news is that it is difficult to stabilize a steroid, HQ, and tretinoin in a formulation, so this option may not be the best for your patients.

What are we going to do? I am going to cross my fingers that the FDA leaves HQ on the market.

The lesson learned here? The next time the FDA asks for safety data, we need to work together with the companies to ensure that it gets the data it needs, to avoid problems like this in the future.

PII: S0037-6337(07)70042-6

doi:10.1016/S0037-6337(07)70042-6

© 2007 Elsevier Inc. All rights reserved.