The safety of hydroquinone: A dermatologist's response to the 2006 Federal Register

Published:April 28, 2007DOI:https://doi.org/10.1016/j.jaad.2007.02.020
      Recently, the US Food and Drug Administration proposed a ban on over-the-counter hydroquinone mainly on the basis of high absorption, reports of exogenous ochronosis in humans, and murine hepatic adenomas, renal adenomas, and leukemia with large doses over extended time periods. Systemic exposure to hydroquinone from routine topical application is no greater than that from quantities present in common foods. While murine hepatic adenomas increased, murine hepatocellular carcinomas decreased, suggesting a protective effect. Renal tumors are sex, species, and age specific and therefore do not appear relevant to humans after decades of widespread use. Murine leukemia has not been reproducible and would not be expected from small topical doses. Finally, a literature review of exogenous ochronosis and clinical studies employing hydroquinone (involving over 10,000 exposures under careful clinical supervision) reveal an incidence of exogenous ochronosis in the United States of 22 cases in more than 50 years. Therefore, the proposed ban appears to be unnecessarily extreme.

      Abbreviations used:

      CPN ( chronic progressive nephropathy), DESI ( drug efficacy safety implementation), FDA ( Food and Drug Administration), NDA ( new drug application), NTP ( National Toxicology Program), OTC ( over-the-counter), TFM ( tentative final monograph)
      To read this article in full you will need to make a payment
      AAD Member Login
      AAD Members, full access to the journal is a member benefit. Use your society credentials to access all journal content and features
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

      1. Department of Health and Human Services. Food and Drug Administration. Skin Bleaching Drug Products For Over-the-Counter Human Use; Proposed Rule. 71 Federal Register 51146-5115521 (2006) (codified at 21 CFR Part 310).

        • Nordlund J.J.
        • Grimes P.E.
        • Ortonne J.P.
        The safety of hydroquinone.
        J Eur Acad Dermatol Venereol. 2006; 20: 781-787
        • Fitzpatrick T.B.
        • Arndt K.A.
        • el-Mofty A.M.
        • Pathak M.A.
        Hydroquinone and psoralens in the therapy of hypermelanosis and vitiligo.
        Arch Dermatol. 1966; 93: 589-600
        • Spencer M.C.
        Hydroquinone bleaching.
        Arch Dermatol. 1961; 84: 181-184
        • Bucks D.A.W.
        • McMaster J.R.
        • Guy R.H.
        • Maibach H.I.
        Percutaneous absorption of hydroquinone in humans: effect of 1-dodecyclazacycloheptan-2-one (azone) and the 2-ethylhexyl ester of 4-(dimethylamino) benzoic acid (Escalol 507).
        J Toxicol Environ Health. 1988; 24: 279-289
        • Wester R.C.
        • Melendres J.
        • Hui X.
        • Cox R.
        • Serranzana S.
        • Zhai H.
        • et al.
        Human in vivo and in vitro hydroquinone topical bioavailability, metabolism, and disposition.
        J Toxicol Environ Health A. 1998; 54: 301-317
      2. Tri-Luma Summary Basis of Approval (SBOA). Available at: http://www.fda.gov/cder/foi/nda/2002/21-112_Tri-Luma.htm. Accessed November 22, 2006.

      3. Tri-Luma [package insert]. Available at: http://www.triluma.com/prescribing_info.pdf. Accessed January 14, 2007.

        • DeCaprio A.P.
        The toxicology of hydroquinone — relevance to occupational and environmental exposure.
        Crit Rev Toxicol. 1999; 29: 283-330
        • Hardman J.G.
        • Limbird L.E.
        Goodman & Gilman's The pharmacologic basis of therapeutics.
        9th ed. McGraw-Hill, New York1996 (p. 20)
        • Deisinger P.J.
        • Hill T.S.
        • English C.
        Human exposure to naturally occurring hydroquinone.
        J Toxicol Environ Health. 1996; 47: 31-46
      4. Gebhardt SE, Thomas RG. Nutritive value of foods. Home Garden Bull. October 2002, No. 72. Washington (DC): US Dept of Agriculture. Agricultural Research Service. Available at: http://www.nal.usda.gov/fnic/foodcomp/Data/HG72/hg72_2002.pdf. Accessed November 20, 2006.

        • O'Donoghue J.L.
        Hydroquinone and its analogues in dermatology—a risk-benefit viewpoint.
        J Cosmet Dermatol. 2006; 5: 196-203
        • National Toxicology Program
        Toxicology and carcinogenesis studies of hydroquinone in F-344/N rats and B6C3F1 mice.
        National Institutes of Health Publication No. 90-2821, Research Triangle Park (NC)1989 (Available at:) (Accessed November 24, 2006)
      5. US Food and Drug Administration. Center for Drug Evaluation and Research. Postmarketing study commitments. Available at: http://www.accessdata.fda.gov/scripts/cder/pmc/index.cfm. Accessed January 14, 2007.

        • David R.M.
        • English J.C.
        • Totman L.C.
        • Moyer C.
        • O'Donoghue J.L.
        Lack of nephrotoxicity and renal cell proliferation following subchronic dermal application of a hydroquinone cream.
        Food Chem Toxicol. 1998; 36: 609-616
        • International Agency for Research on Cancer
        Hydroquinone.
        Monogr Eval Carcinog Risks Hum. 1999; 71: 691-719
        • Findlay G.H.
        • Morrison J.G.
        • Simson I.W.
        Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams.
        Br J Dermatol. 1975; 93: 613-622
        • Beddard A.P.
        • Plumtre C.M.
        A further note on ochronosis associated with carboluria.
        Quart J Med. 1912; (pp. 505-7)
        • Fisher A.A.
        Exogenous ochronosis from hydroquinone bleaching cream.
        Cutis. 1998; 62: 11-12
        • Bruce S.
        • Tschen J.A.
        • Chow D.
        Exogenous ochronosis resulting from quinine injections.
        J Am Acad Dermatol. 1986; 15: 357-361
        • Howard K.L.
        • Furner B.B.
        Exogenous ochronosis in a Mexican-American woman.
        Cutis. 1990; 45: 180-182
        • Levin C.Y.
        • Maibach H.
        Exogenous ochronosis. An update on clinical features, causative agents and treatment options.
        Am J Clin Dermatol. 2001; 2: 213-217
        • Kaufmann D.
        • Wegmann W.
        [Exogenous ochronosis after L-dopa treatment.].
        Pathologe. 1992; 13 (German): 164-166
        • Yoshimura K.
        • Momosawa A.
        • Watanabe A.
        • Sato K.
        • Matsumoto D.
        • Aiba E.
        • et al.
        Cosmetic color improvement of the nipple-areola complex by optimal use of tretinoin and hydroquinone.
        Dermatol Surg. 2002; 28 (discussion 1158): 1153-1157
        • Yoshimura K.
        • Harii K.
        • Aoyama T.
        • Shibuya F.
        • Iga T.
        A new bleaching protocol for hyperpigmented skin lesions with a high concentration of all-trans retinoic acid aqueous gel.
        Aesthet Plast Surg. 1999; 23: 285-291
        • Yoshimura K.
        • Sato K.
        • Aiba-Kojima E.
        • Matsumoto D.
        • Machino C.
        • Nagase T.
        • et al.
        Repeated treatment protocols for melasma and acquired dermal melanocytosis.
        Dermatol Surg. 2006; 32: 365-371
        • Yoshimura K.
        • Momosawa A.
        • Aiba E.
        • Sato K.
        • Matsumoto D.
        • Mitome Y.
        • et al.
        Clinical trial of bleaching treatment with 10% all-trans retinol gel.
        Dermatol Surg. 2003; 29 (discussion 160): 155-160
        • Yoshimura K.
        • Harii K.
        • Aoyama T.
        • Iga T.
        Experience with a strong bleaching treatment for skin hyperpigmentation in Orientals.
        Plast Reconstr Surg. 2000; 105: 1097-1108
        • Yoshimura K.
        • Harii K.
        A new treatment for senile lentigines.
        J Jpn P R S. 1997; 17: 630-639
        • West T.B.
        • Alster T.S.
        Effect of pretreatment on the incidence of hyperpigmentation following cutaneous CO2 laser resurfacing.
        Dermatol Surg. 1999; 25: 15-17
        • Wang C.C.
        • Hui C.Y.
        • Sue Y.M.
        • Wong W.R.
        • Hong H.S.
        Intense pulsed light for the treatment of refractory melasma in Asian persons.
        Dermatol Surg. 2004; 30: 1196-1200
        • Verallo-Rowell V.M.
        • Verallo V.
        • Graupe K.
        • Lopez-Villafuerte L.
        • Garcia-Lopez M.
        Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma.
        Acta Derm Venereol Suppl (Stockh). 1989; 143: 58-61
        • Vazquez M.
        • Sanchez J.L.
        The efficacy of a broad-spectrum sunscreen in the treatment of melasma.
        Cutis. 1983; 32: 92-96
        • Torok H.
        • Taylor S.
        • Baumann L.
        • Jones T.
        • Wieder J.
        • Lowe N.
        • et al.
        A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads.
        J Drugs Dermatol. 2005; 4: 592-597
        • Torok H.M.
        • Jones T.
        • Rich P.
        • Smith S.
        • Tschen E.
        Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and efficacious 12-month treatment for melasma.
        Cutis. 2005; 75: 57-62
        • Taylor S.C.
        • Torok H.
        • Jones T.
        • Lowe N.
        • Rich P.
        • Tschen E.
        • et al.
        Efficacy and safety of a new triple-combination agent for the treatment of facial melasma.
        Cutis. 2003; 72: 67-72
        • Swinyer L.J.
        • Wortzman M.
        Study of hydroquinone USP 4%, 0.05% tretinoin, and in combination in UV-induced dyschromia with actinic photodamage.
        Cosmet Dermatol. 2000; 3: 13-18
        • Stanfield J.W.
        • Feldman S.R.
        • Levitt J.
        Sun protection strength of a hydroquinone 4%/retinol 0.3% preparation containing sunscreens.
        J Drugs Dermatol. 2006; 5: 321-324
        • Spencer M.C.
        • Becker Jr., S.W.
        A hydroquinone effect.
        Clin Med (Northfield II). 1963; 70: 1111-1114
        • Spencer M.C.
        Topical use of hydroquinone for depigmentation.
        JAMA. 1965; 194: 962-964
        • Sarkar R.
        • Kaur C.
        • Bhalla M.
        • Kanwar A.J.
        The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: a comparative study.
        Dermatol Surg. 2002; 28 (discussion 832): 828-832
        • Sanchez J.L.
        • Vazquez M.
        A hydroquinone solution in the treatment of melasma.
        Int J Dermatol. 1982; 21: 55-58
        • Ross E.V.
        • Grossman M.C.
        • Duke D.
        • Grevelink J.P.
        Long-term results after CO2 laser skin resurfacing: a comparison of scanned and pulsed systems.
        J Am Acad Dermatol. 1997; 37: 709-718
        • Rizer R.
        • Sklar J.
        • Hino P.D.
        • Wortzman M.
        The effectiveness & safety of Lustra® (hydroquinone USP 4%) in dyschromia.
        Skin & Aging. 1999 (April); : 4-8
        • Rizer R.
        • Sklar J.
        • Hino P.D.
        • Wortzman M.
        Evaluation of Lustra® (hydroquinone USP 4%) on the skin's antioxidant system.
        Skin & Aging. 1999 (April); : 9-12
        • Rendon M.I.
        Utilizing combination therapy to optimize melasma outcomes.
        J Drugs Dermatol. 2004; 3: S27-S34
        • Piamphongsant T.
        Treatment of melasma: a review with personal experience.
        Int J Dermatol. 1998; 37: 897-903
        • Petit L.
        • Pierard G.E.
        Analytic quantification of solar lentigines lightening by a 2% hydroquinone-cyclodextrin formulation.
        J Eur Acad Dermatol Venereol. 2003; 17: 546-549
        • Pathak M.A.
        • Fitzpatrick T.B.
        • Parrish J.A.
        • Sanchez N.P.
        • Sanchez J.L.
        Treatment of melasma with hydroquinone.
        J Invest Dermatol. 1981; 76: 324
        • Pathak M.A.
        • Fitzpatrick T.B.
        • Kraus E.W.
        Usefulness of retinoic acid in the treatment of melasma.
        J Am Acad Dermatol. 1986; 15: 894-899
        • Nanda S.
        • Grover C.
        • Reddy B.S.
        Efficacy of hydroquinone (2%) versus tretinoin (0.025%) as adjunct topical agents for chemical peeling in patients of melasma.
        Dermatol Surg. 2004; 30 (discussion 389): 385-388
        • Murad H.
        • Shamban A.T.
        • Moy L.S.
        Polka-dot syndrome: a more descriptive name for a common problem.
        Cosmet Dermatol. 1993; 4: 57-58
        • Momosawa A.
        • Yoshimura K.
        • Uchida G.
        • Sato K.
        • Aiba E.
        • Matsumoto D.
        • et al.
        Combined therapy using Q-switched ruby laser and bleaching treatment with tretinoin and hydroquinone for acquired dermal melanocytosis.
        Dermatol Surg. 2003; 29: 1001-1007
        • Mills O.H.
        • Kligman A.M.
        Further experience with a topical cream for depigmenting human skin.
        J Soc Cosmet Chem. 1978; 29: 147-154
        • Melli M.C.
        [Clinical evaluation of the efficacy of a topical preparation containing 2% hydroquinone in chloasma.].
        G Ital Dermatol Venereol. 1987; 122: 65-67
        • Martin J.P.
        • de Arocha J.R.
        • Loker D.B.
        Estudio clinico doble ciego en el tratamiento del melasma entre acido azelaico versus hidroquinona.
        Med Cutan Ibero Lat Am. 1988; 16: 511-514
        • Mahe A.
        • Blanc L.
        • Halna J.M.
        • Keita S.
        • Sanogo T.
        • Bobin P.
        [An epidemiologic survey on the cosmetic use of bleaching agents by the women of Bamako (Mali)].
        Ann Dermatol Venereol. 1993; 120 (French): 870-873
        • Lim J.T.
        • Tham S.N.
        Glycolic acid peels in the treatment of melasma among Asian women.
        Dermatol Surg. 1997; 23: 177-179
        • Lim J.T.
        Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid.
        Dermatol Surg. 1999; 25: 282-284
        • Lawrence N.
        • Cox S.E.
        • Brody H.J.
        Treatment of melasma with Jessner's solution versus glycolic acid: a comparison of clinical efficacy and evaluation of the predictive ability of Wood's light examination.
        J Am Acad Dermatol. 1997; 36: 589-593
        • Lam A.Y.
        • Wong D.S.
        • Lam L.
        • Ho W.
        • Chan H.H.
        A retrospective study on the efficacy and complications of Q-switched alexandrite laser in the treatment of acquired bilateral nevus of Ota-like macules.
        Dermatol Surg. 2001; 27: 937-942
        • Kligman A.M.
        • Willis I.
        A new formula for depigmenting human skin.
        Arch Dermatol. 1975; 111: 40-48
        • Kang W.H.
        • Chun S.C.
        • Lee S.
        Intermittent therapy for melasma in Asian patients with combined topical agents (retinoic acid, hydroquinone and hydrocortisone): clinical and histological studies.
        J Dermatol. 1998; 25: 587-596
        • Kakita L.S.
        • Lowe N.J.
        Azelaic acid and glycolic acid combination therapy for facial hyperpigmentation in darker-skinned patients: a clinical comparison with hydroquinone.
        Clin Ther. 1998; 20: 960-970
        • Javaheri S.M.
        • Handa S.
        • Kaur I.
        • Kumar B.
        Safety and efficacy of glycolic acid facial peel in Indian women with melasma.
        Int J Dermatol. 2001; 40: 354-357
        • Jarratt M.
        Mequinol 2%/tretinoin 0.01% solution: an effective and safe alternative to hydroquinone 3% in the treatment of solar lentigines.
        Cutis. 2004; 74: 319-322
        • Hurley M.E.
        • Guevara I.L.
        • Gonzales R.M.
        • Pandya A.G.
        Efficacy of glycolic acid peels in the treatment of melasma.
        Arch Dermatol. 2002; 138: 1578-1582
        • Ho C.
        • Nguyen Q.
        • Lowe N.J.
        • Griffin M.E.
        • Lask G.
        Laser resurfacing in pigmented skin.
        Dermatol Surg. 1995; 21: 1035-1037
        • Herndon J.H.
        • Stephens T.J.
        • Sigler M.L.
        Efficacy of a tretinoin/hydroquinone-based skin health system in the treatment of facial photodamage.
        Cosmet Dermatol. 2006; 19: 255-262
        • Haddad A.L.
        • Matos L.F.
        • Brunstein F.
        • Ferreira L.M.
        • Silva A.
        • Costa Jr., D.
        A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma.
        Int J Dermatol. 2003; 42: 153-156
        • Gupta A.K.
        • Ryder J.E.
        Lustra®, Lustra-AF®, and Alustra™.
        Skin Therapy Lett. 2003; 8: 1-3
        • Guevara I.L.
        • Pandya A.G.
        Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma.
        Int J Dermatol. 2003; 42: 966-972
        • Guevara I.L.
        • Pandya A.G.
        Melasma treated with hydroquinone, tretinoin, and a fluorinated steroid.
        Int J Dermatol. 2001; 40: 212-215
        • Grimes P.
        • Kelly A.P.
        • Torok H.
        • Willis I.
        Community-based trial of a triple-combination agent for the treatment of facial melasma.
        Cutis. 2006; 77: 177-184
        • Grimes P.E.
        The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups.
        Dermatol Surg. 1999; 25: 18-22
        • Grimes P.E.
        A microsponge formulation of hydroquinone 4% and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation.
        Cutis. 2004; 74: 362-368
        • Goh C.L.
        • Dlova C.N.
        A retrospective study on the clinical presentation and treatment outcome of melasma in a tertiary dermatological referral centre in Singapore.
        Singapore Med J. 1999; 40: 455-458
        • Glenn M.J.
        • Grimes P.E.
        • Oulet M.
        • Pitts E.
        • Kelly A.P.
        Evaluation of clinical and light microscopic effects of various concentrations of hydroquinone.
        Clin Res. 1991; 39: 83A
        • Gladstone H.B.
        • Nguyen S.L.
        • Williams R.
        • Ottomeyer T.
        • Wortzman M.
        • Jeffers M.
        • et al.
        Efficacy of hydroquinone cream (USP 4%) used alone or in combination with salicylic acid peels in improving photodamage on the neck and upper chest.
        Dermatol Surg. 2000; 26: 333-337
        • del Giudice P.
        • Yves P.
        The widespread use of skin lightening creams in Senegal: a persistent public health problem in West Africa.
        Int J Dermatol. 2002; 41: 69-72
        • Gilchrest B.A.
        • Goldwyn R.M.
        Topical chemotherapy of pigment abnormalities in surgical patients.
        Plast Reconstr Surg. 1981; 67: 435-439
        • Garcia A.
        • Fulton Jr., J.E.
        The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions.
        Dermatol Surg. 1996; 22: 443-447
        • Gans E.H.
        • Christensen M.
        Cutaneous absorption and clinical effect of ascorbyl palmitate and tocopherol acetate antioxidants in Lustra® (hydroquinone USP 4%).
        Skin & Aging. 1999 (April); : 13-17
        • Gano S.E.
        • Garcia R.L.
        Topical tretinoin, hydroquinone, and betamethasone valerate in the therapy of melasma.
        Cutis. 1979; 23: 239-241
        • Espinal-Perez L.E.
        • Moncada B.
        • Castanedo-Cazares J.P.
        A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma.
        Int J Dermatol. 2004; 43: 604-607
        • Draelos Z.D.
        Novel approach to the treatment of hyperpigmented photodamaged skin: 4% hydroquinone/0.3% retinol versus tretinoin 0.05% emollient cream.
        Dermatol Surg. 2005; 31: 799-804
        • Denton C.R.
        • Lerner A.B.
        • Fitzpatrick T.B.
        Inhibition of melanin formation by chemical agents.
        J Invest Dermatol. 1952; 18: 119-135
        • Burns R.L.
        • Prevost-Blank P.L.
        • Lawry M.A.
        • Lawry T.B.
        • Faria D.T.
        • Fivenson D.P.
        Glycolic acid peels for postinflammatory hyperpigmentation in black patients. A comparative study.
        Dermatol Surg. 1997; 23 (discussion 175): 171-174
        • Bernstein L.J.
        • Kauvar A.N.B.
        • Grossman M.C.
        • Geronemus R.G.
        The short- and long-term side effects of carbon dioxide laser resurfacing.
        Dermatol Surg. 1997; 23: 519-525
        • Bentley-Phillips B.
        • Bayles M.A.
        Cutaneous reactions to topical application of hydroquinone. Results of a 6-year investigation.
        S Afr Med J. 1975; 49: 1391-1395
        • Balina L.M.
        • Graupe K.
        The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream.
        Int J Dermatol. 1991; 30: 893-895
        • Astaneh R.
        • Farboud E.
        • Nazemi M.J.
        4% hydroquinone versus 4% hydroquinone, 0.05% dexamethasone and 0.05% tretinoin in the treatment of melasma: a comparative study.
        Int J Dermatol. 2005; 44: 599-601
        • Arndt K.A.
        • Fitzpatrick T.B.
        Topical use of hydroquinone as a depigmenting agent.
        JAMA. 1965; 194: 965-967
        • Amer M.
        • Metwalli M.
        Topical hydroquinone in the treatment of some hyperpigmentary disorders.
        Int J Dermatol. 1998; 37: 449-450
        • Abramovits W.
        • Barzin S.
        • Arrazola P.
        A practical comparison of hydroquinone-containing products for the treatment of melasma.
        Skinmed. 2005; 4: 371-376
        • Zawar V.P.
        • Mhasker S.T.
        Exogenous ochronosis following hydroquinone for melasma.
        J Cosmet Dermatol. 2004; 3: 234-236
        • Weiss R.M.
        • del Fabbro E.
        • Kolisang P.
        Cosmetic ochronosis caused by bleaching creams containing 2% hydroquinone.
        S Afr Med J. 1990; 77: 373
        • Tidman M.J.
        • Horton J.J.
        • MacDonald D.M.
        Hydroquinone-induced ochronosis—light and electronmicroscopic features.
        Clin Exp Dermatol. 1986; 11: 224-228
        • Snider R.L.
        • Thiers B.H.
        Exogenous ochronosis.
        J Am Acad Dermatol. 1993; 28: 662-664
        • Raynaud E.
        • Cellier C.
        • Perret J.L.
        [Depigmentation for cosmetic purposes: prevalence and side-effects in a female population in Senegal.].
        Ann Dermatol Venereol. 2001; 128 (French): 720-724
        • Phillips J.I.
        • Isaacson C.
        • Carman H.
        Ochronosis in black South Africans who used skin lighteners.
        Am J Dermatopathol. 1986; 8: 14-21
        • Petit A.
        • Cohen-Ludmann C.
        • Clevenbergh P.
        • Bergmann J.F.
        • Dubertret L.
        Skin lightening and its complications among African people living in Paris.
        J Am Acad Dermatol. 2006; 55 (Epub 2006 Aug 28): 873-878
        • Penneys K.B.
        • Smith C.J.
        • Allen J.C.
        Depigmenting action of hydroquinone depends on disruption of fundamental cell processes.
        J Invest Dermatol. 1984; 82: 308-310
        • Olumide Y.M.
        • Elesha S.O.
        Hydroquinone induced exogenous ochronosis.
        Niger Med Pract. 1986; 11: 103-106
        • Olumide Y.M.
        Photodermatoses in Lagos.
        Int J Dermatol. 1987; 26: 295-299
        • Menke H.E.
        • Dekker S.K.
        • Noordhoek Hegt V.
        • Pavel S.
        • Westerhof W.
        Exogene ochronosis, een weinig bekende bijwerking van hydrochinon-bevattende cremes.
        Ned Tijdschr Geneeskd. 1992; 136: 187-190
        • Martin R.F.
        • Sanchez J.L.
        • Gonzalez A.
        • Lugo-Somolinos A.
        • Ruiz H.
        Exogenous ochronosis.
        P R Health Sci J. 1992; 11: 23-26
        • Mahe A.
        • Keita S.
        • Bobin P.
        [Dermatologic complications of the cosmetic use of bleaching agents in Bamako (Mali).].
        Ann Dermatol Venereol. 1994; 121 (French): 142-146
        • Mahe A.
        • Ly F.
        • Aymard G.
        • Dangou J.M.
        Skin diseases associated with the cosmetic use of bleaching products in women from Dakar, Senegal.
        Br J Dermatol. 2003; 148: 493-500
        • Lawrence N.
        • Bligard C.A.
        • Reed R.
        • Perret W.J.
        Exogenous ochronosis in the United States.
        J Am Acad Dermatol. 1988; 18: 1207-1211
        • Lang Jr., P.G.
        Probable coexisting exogenous ochronosis and mercurial pigmentation managed by dermabrasion.
        J Am Acad Dermatol. 1988; 19: 942-946
        • Kramer K.E.
        • Lopez A.
        • Stefanato C.M.
        • Phillips T.J.
        Exogenous ochronosis.
        J Am Acad Dermatol. 2000; 42: 869-871
        • Jordaan H.F.
        • Van Niekerk D.J.
        Transepidermal elimination in exogenous ochronosis. A report of two cases.
        Am J Dermatopathol. 1991; 13: 418-424
        • Jordaan H.F.
        • Mulligan R.P.
        Actinic granuloma-like change in exogenous ochronosis: case report.
        J Cutan Pathol. 1990; 17: 236-240
        • Jacyk W.K.
        Annular granulomatous lesions in exogenous ochronosis are manifestation of sarcoidosis.
        Am J Dermatopathol. 1995; 17: 18-22
        • Hull P.R.
        • Procter P.R.
        The melanocyte: an essential link in hydroquinone-induced ochronosis.
        J Am Acad Dermatol. 1990; 22: 529-531
        • Hoshaw R.A.
        • Zimmerman K.G.
        • Menter A.
        Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks.
        Arch Dermatol. 1985; 121: 105-108
        • Hardwick N.
        • Van Gelder L.W.
        • Van der Merwe C.A.
        • Van der Merwe M.P.
        Exogenous ochronosis: an epidemiological study.
        Br J Deratol. 1989; 120 (Erratum in: Br J Dermatol 1989;121:153): 229-238
        • Gonul M.
        • Cakmak S.K.
        • Kilic A.
        • Gul U.
        • Heper A.O.
        Pigmented coalescing papules on the dorsa of the hands: pigmented colloid milium associated with exogenous ochronosis.
        J Dermatol. 2006; 33: 287-290
        • Fisher A.A.
        Tetracycline treatment for sarcoid-like ochronosis due to hydroquinone.
        Cutis. 1988; 42: 19-20
        • Dogliotti M.
        • Leibowitz M.
        Granulomatous ochronosis — a cosmetic-induced skin disorder in Blacks.
        S Afr Med J. 1979; 56: 757-760
        • Diven D.G.
        • Smith E.B.
        • Pupo R.A.
        • Lee M.
        Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser.
        J Dermatol Surg Oncol. 1990; 16: 1018-1022
        • Davis T.L.
        • Trapp C.F.
        • Grimwood R.E.
        Exogenous ochronosis occurring in a male.
        J Cutan Pathol. 1990; 17: 290
        • Cullison D.
        • Abele D.C.
        • O'Quinn J.L.
        Localized exogenous ochronosis.
        J Am Acad Dermatol. 1983; 8: 882-889
        • Connor T.
        • Braunstein B.
        Hyperpigmentation following the use of bleaching creams. Localized exogenous ochronosis.
        Arch Dermatol. 1987; 123 (105-6, 108)
        • Carey A.B.
        • Park H.K.
        • Burke W.A.
        • Strausbauch P.H.
        • Castellani W.J.
        Bleaching cream associated exogenous ochronosis.
        J Cutan Pathol. 1988; 15: 299
        • Camarasa J.G.
        • Serra-Baldrich E.
        Exogenous ochronosis with allergic contact dermatitis from hydroquinone.
        Contact Dermatitis. 1994; 31: 57-58
        • Huerta Brogeras M.
        • Sanchez-Viera M.
        Exogenous ochronosis.
        J Drugs Dermatol. 2006; 5: 80-81
        • Bowman P.H.
        • Lesher Jr., J.L.
        Primary multiple miliary osteoma cutis and exogenous ochronosis.
        Cutis. 2001; 68: 103-106
        • Bongiorno M.R.
        • Arico M.
        Exogenous ochronosis and striae atrophicae following the use of bleaching creams.
        Int J Dermatol. 2005; 44: 112-115
        • Bellew S.G.
        • Alster T.S.
        Treatment of exogenous ochronosis with a Q-switched alexandrite (755 nm) laser.
        Dermatol Surg. 2004; 30: 555-558
        • Adebajo S.B.
        An epidemiological survey of the use of cosmetic skin lightening cosmetics among traders in Lagos, Nigeria.
        West Afr J Med. 2002; 21: 51-55
        • Burke P.A.
        • Maibach H.I.
        Exogenous ochronosis: an overview.
        J Dermatol Treat. 1997; 8: 21-26
        • del Giudice P.
        • Raynaud E.
        • Mahe A.
        L'utilisation cosmetique de produits depigmentants en Afrique.
        Bull Soc Pathol Exot. 2003; 96: 389-393
        • Torok H.M.
        A comprehensive review of the long-term and short-term treatment of melasma with a triple combination cream.
        Am J Clin Dermatol. 2006; 7: 223-230
        • Balkrishnan R.
        • Kelly A.P.
        • McMichael A.
        • Torok H.
        Improved quality of life with effective treatment of facial melasma: the PIGMENT trial.
        J Drugs Dermatol. 2004; 3: 377-381
        • Balkrishnan R.
        • McMichael A.J.
        • Camacho F.T.
        • Saltzberg F.
        • Housman T.S.
        • Grummer S.
        • et al.
        Development and validation of a health-related quality of life instrument for women with melasma.
        Br J Dermatol. 2003; 149: 572-577
        • Balkrishnan R.
        • Housman T.S.
        • Allen B.
        • McMichael A.J.
        Predictors of health-related quality of life in women with melasma.
        Cosmet Dermatol. 2003; 16: 25-30
        • Draelos Z.D.
        Topicals for facial hyperpigmentation.
        Cosmet Dermatol. 2006; 19: 621-623
      6. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Questions and Answers on the Unapproved Drug Compliance Policy Guide (CPG). Available at: http://www.fda.gov/cder/compliance/CPG_QandA.htm. Accessed November 21, 2006.

      7. Galson SK. Statement of Steven K. Galson, M.D., M.P.H., Regarding Unapproved Prescription Drugs, June 8, 2006. Available at: http://www.fda.gov/cder/drug/unapproved_drugs/statement.htm. Accessed November 21, 2006.

      8. Guidance for FDA Staff and Industry, June 2006. Available at: http://www.fda.gov/CDER/guidance/6911fnl.htm. Accessed November 21, 2006.