Sunscreen Allergens
PABA and its esters were among the earliest UV absorbers to be introduced in the United States, and sensitization was documented as early as 1947.[23] PABA is a member of the "para" group of antigens; these antigens are frequent sensitizers and consist of chemicals with a free amino group in the para position of a benzene ring.[24] PABA is a potent UVB absorber but does not absorb UVA.[25] PABA requires an alcohol vehicle for use in sunscreen commercial products. It may stain clothing, and it has been associated with a number of adverse reactions, including allergic and photoallergic contact dermatitis.[1] Ester derivatives of PABA include octyl dimethyl PABA, amyl dimethyl PABA (padimate A), and glycerol PABA. These derivatives have become more popular for use in sunscreen products because of a higher compatibility with other cosmetic vehicles and a decreased propensity for staining. Reports of photoallergy to PABA and its ester counterparts, however, have led to their near removal from sunscreen manufacturing. Today, PABA products are used only rarely in sunscreen formulations. The promotion of PABA-free sunscreens is now common.[1,21,26]
In addition to demonstrating allergic reactions, patients may report a transient stinging or burning sensation after application of PABA-containing products. This phenomenon is deemed to be more common than true allergy and may lead patients to falsely believe they are allergic to this chemical. As a result, several sunscreen products have been marketed as "hypoallergenic" because they are PABA free, but they may obviously still contain other chemical UV absorbers to which patients may become allergic.
The mechanism leading to the formation of common allergenic haptens remains unclear. The haptens deemed to be responsible in the case of PABA and its cross-reacting compounds are quinine amines, oxidation products of para-amino chemicals.[25] The degree of allergenic cross-reactivity between different para-amino compounds is variable and may be explained by the ability of different patients to transform these products into their quinolamine metabolites.
Patients allergic to PABA may also react to other para-amino allergens such as para-phenylenediamine, para-aminosalicylic acid ester anesthetics, sulfonamides, and azo dyes.[4]Uter and colleagues conducted a retrospective review of the cross-sensitivity to para-amino compounds in clinical patch testing.[24] They examined the results of 638 patients who were patch-tested with a "para-amino series" that included PABA, para-aminophenol, para-toluenediamine, sulfanilamide, Disperse Orange 3, para-aminoazobenzene, 4,4'-diaminodiphenylmethane, and para-phenylenediamine. They found a heterogeneous pattern of reactivity to different para-amino compounds among their patients and suggested that patch-test screening should use several para-amino compounds to ascertain an individual's spectrum of allergic contact sensitization to these products. The most common para-amino sensitizer in their study was para-aminoazobenzene, which induced positive reactions in 16.2% of patients tested.
Recommended patch-test concentrations for PABA have ranged from 1 to 10%. False-negative results may occur if petrolatum is used as a vehicle.[27] Table 1 lists the most common para-amino compounds found in sunscreens and indicates their suggested patch-test concentrations.
Benzophenones were first used in sunscreen products in the 1950s.[28] Benzophenone-3 (2-hydroxy-4-methoxybenzophenone) is the most frequently used benzophenone in the United States and is currently one of the most common causes of photocontact allergy.[4] It is marketed elsewhere under the names oxybenzone, Eusolex 4360 (Merck), methanone, Uvinul M40 (BASF Japan Ltd., Tokyo, Japan), and diphenylketone.[27] Benzophenones are primarily UVB absorbers although benzophenone-3 and sulisobenzone absorb UVB through UVA II (321-340 nm) and are considered broad-spectrum chemical sunscreens.[27] In addition to their use as chemical sunscreens, benzophenones may also function as preservatives. They are known to protect against sunlight-induced discoloration of cosmetic products and are often incorporated for similar purposes into textiles, plastics, paints, and rubber products.[29]
The first description of a contact reaction to benzophenones in sunscreen products was published in 1972 by Ramsay and colleagues, who described a 54-year-old African American man with a papular eruption in photodistributed areas of the ears, face, neck, and arms.[30] The patient exhibited not only an immediate positive wheal and flare response to scratch testing with two benzophenones (1% sulisobenzone and 2-hydroxy-4-methoxybenzophenone) but also a delayed hypersensitivity reaction to 5% sulisobenzone in water.
In addition to causing contact and photocontact delayed-type hypersensitivity reactions, benzophenone-3 has been reported to induce photocontact urticaria, contact urticaria, and anaphylaxis.[31,32,33,34] Bourrain and colleagues reported on a 31-year-old man with recurrent facial dermatitis exacerbated by sunlight.[31] The patient demonstrated normal results on MED testing. Patch testing and photopatch testing was performed with benzophenone-3 and benzphenone-10 as well as with the patient's own sunscreen, which contained benzophenone-3. Urticarial reactions occurred within minutes of irradiation to the aforementioned test sites and disappeared within 30 minutes. Nonirradiated sites were unaffected. Furthermore, no delayed reactions were found at readings performed at 48 and 96 hours. Yesudian and King reported a similar case of a 40-year-old woman who developed a pruritic eruption on the face, trunk, and limbs after applying sunscreen to her daughter.[35] On patch testing, she developed an urticarial wheal and flare reaction to benzophenone-3 (photopatch testing was not performed on this patient). Emonet and colleagues reported on a 22-year-old woman with an atopic diathesis who developed generalized urticaria, dyspnea, and fainting after the application of an oxybenzone-containing sunscreen to normal skin.[32] Patch tests with the sunscreen demonstrated a local wheal and flare reaction within 5 minutes of application and a similar reaction to oxybenzone after 15 minutes. Results of skin-prick tests with both the patient's personal sunscreen product and oxybenzone were positive as well.
The severity of a urticarial reaction to benzophenone may depend on the body surface area to which it is applied. A small and localized application may induce only a local contact urticaria whereas the application of larger amounts may lead to an anaphylactic reaction. Benzophenone-3 has been shown to cross the epidermal barrier, and its metabolites are known to be excreted in the urine after widespread topical application.[32]
For patch testing, a 10% oxybenzone concentration in petrolatum is recommended and generally serves as a marker for allergy to benzophenones.[36] Detection of allergy to this product may be complicated by the combination of this chemical sunscreen with other sunscreen agents. Patients must be alerted to the other names for benzophenone-3 when practicing avoidance. Table 2 lists the most common benzophenones found in sunscreens and indicates their recommended patch-test concentrations.
The cinnamates are a group of related substances used in flavorings, fragrances, and (less frequently) sunscreens.[27] In sunscreen products, they are often used in combination with the benzophenones.[37] The cinnamates are primarily UVB absorbers. Given their poor water solubility, they are often used in sunscreens marketed as "waterproof." The most commonly used cinnamate in sunscreens is ethylhexyl-p-methoxycinnamate, also known as Parsol MCX (Roche Vitamins Inc., Parsippany, NJ). 2-Ethoxyethyl-p-methoxycinnamate, or cinoxate, is less commonly used.
Allergy to cinnamates is deemed to be infrequent.[4] Journe and colleagues evaluated 370 French patients with suspected contact or photocontact allergy to sunscreens by patch testing and photopatch testing.[16] Their cinnamate markers included e-ethylhexyl-p-methoxycinnamate and isoamyl p-methoxycinnamate. Photoallergy alone to e-ethylhexyl-p-methoxycinnamate was demonstrated by two patients. No cases of allergy or photoallergy were detected among those patients tested with isoamyl p-methoxycinnamate. Whereas allergy to these cinnamate sunscreen ingredients is uncommon, more significant is their cross-reactivity with flavorings and fragrances that include balsam of Peru, coca leaves, cinnamic acid, cinnamic aldehyde, and cinnamon oils.[37]
An extensive literature search revealed no reports of contact urticaria from cinnamates used in sunscreen products. Urticaria from cinnamates used in other cosmetic products has been reported, however, and cross-reaction with cinnamates in sunscreen agents is certainly possible.[38,39] According to Nater and colleagues, cinnamic aldehyde has a "histamine-liberating" effect resulting in nonimmunologic urticaria.[39]
For patch testing, cinnamic aldehyde is used as a 1% preparation in petrolatum and serves as a marker for cinnamate allergy on the NACDG standard series.[12] Table 3 lists the most common cinnamates used in sunscreen preparations and indicates their suggested patch-test concentrations.
Benzyl salicylate was the first cosmetic sunscreen used in the United States.[40] Currently, octyl salicylate is the major salicylate component of sunscreens.[41] The salicylates are weak UVB absorbers; as such, they are used in high concentrations.[41] Salicylates have been used as a standard for determining sun protection factors because of their safety profile. Furthermore, they are able to solubilize insoluble sunscreens like the benzophenones but are themselves insoluble in water. They are easily incorporated into other agents and are thus often used in cosmetic products that are marketed as concomitant sunscreens.
Allergic contact dermatitis from salicylates has been reported only rarely.[21] The first report dates back to 1968 and cites benzyl salicylate as a potential allergen in soaps and detergents.[42] In 1978, Rietschel and Lewis reported two cases of contact dermatitis with follicular accentuation from benzyl salicylate found in sunscreen products.[40] The authors postulated that hapten conjugation was occurring with an unknown substance found only in the infundibular region of the hair follicle. A literature search revealed no reports of contact urticaria from salicylates used in sunscreen products.
For patch testing, octyl salicylate is used at a 5% concentration in petrolatum. Other salicylates commonly used in patch testing are 2-ethylhexyl salicylate, menthyl salicylate, benzyl salicylate, and homosalate. Their patch-test concentrations are listed in Table 4 .
The dibenzoylmethanes were introduced as sunscreens in Europe in 1980.[43] In 1997, 4-tert-butyl-4'-methoxy-dibenzoylmethane (more commonly known as Parsol 1789 [Roche Vitamins Inc.,] or avobenzone) was approved for use in the United States. The dibenzoylmethanes possess a broad absorption spectrum with maximal absorption in the UVA range,[44] and their use has increased as a result of reported sensitivities to benzophenones and PABA products.[14]
Both contact allergy and photocontact allergy to dibenzoylmethanes have been reported.[43,45,46] Most of the reports describe photoallergy to isopropyl dibenzoylmethane (Eusolex 8020, Merck & Co., Inc., Whitehouse Station, NJ). In Schauder and Ippen's study, 15.4% (62 of 402) of patients who were evaluated for suspected photosensitive dermatitis had either contact allergy or photocontact allergy to isopropyl dibenzoylmethane.[14] This product was removed from the market in 1993 owing to its photosensitizing effects.[4] Currently, 4-tert-butyl-4'-methoxy-dibenzoylmethane is the most common dibenzoylmethane found in sunscreen products in the United States. Reports of allergies to 4-tert-butyl-4'-methoxy-dibenzoylmethane exist, but several of these allergies may have resulted from cross-reactivity caused by prior exposure to the isopropyl derivative (Eusolex 8020).[21,44,46]
Avobenzone is often combined with UVB-blocking agents in commercial sunscreens for broad-spectrum protection, and physicians must be aware of this when patch-testing patients with the patients' personal sunscreen products. The recommended patch-test concentration for 4-tert-butyl-4'-methoxy-dibenzoylmethane is 10% in petrolatum.[36]
Anthranilates are derivatives of ortho-aminobenzoic acid. They absorb UVA radiation of wavelengths between 322 and 350 nm. They are often combined with UVB absorbers to give broad-spectrum protection. Unlike their para-amino counterparts, anthranilates are not common sensitizers.[41] A comprehensive literature search found no reports of allergy or photoallergy to these chemicals. Anthranilates are currently part of the sunscreen series recommended for photopatch testing by the NACDG. Methylanthranilate is tested at 5% in petrolatum.
3-(4-Methylbenzylidene) camphor (Eusolex 6300, Merck) is a sunscreen agent used in Europe.[22] It absorbs best in the UVB spectrum.[4] There have been several case reports of allergy and photoallergy to this chemical.[16,43,44] Buckley and colleagues reported on a 56-year-old woman with a photoinduced pruritic eruption after application of a personal sunscreen product containing 3-(4-methylbenzylidene) camphor and isopropyl dibenzoylmethane (a combination known as Eusolex 8021).[43] On photopatch testing, she demonstrated strong reactions to both chemicals as well as to her own sunscreen. Most of the 37 patients who demonstrated allergy or photoallergy to methylbenzylidene camphor in a study by Schauder and Ippen demonstrated concomitant photosensitization to isopropyl dibenzoylmethane.[44]
De Groot recommended patch-testing with methylbenzylidene camphor in petrolatum at a 2% concentration[47] although it is commercially available at a 10% concentration.[36,48]
Octyl triazone (2,4,6-trianalino-[p-carbo-2'-ethylhexyl-1'oxy] 1,3,5 triazine) is a UVB absorber unrelated to any of the aforementioned chemical sunscreens. It is highly polar and completely insoluble in water. A literature search found one case report of photoallergy to this compound. Sommer and colleagues described a 66-year-old woman with an erythematous bullous eruption on sun-exposed areas after sunscreen use.[49] She reacted to both octyl triazone and Parsol 1789 at UVA-irradiated patch-test sites only. Both products were found in her personal sunscreen. Patch-test concentrations were not reported.
2-Phenylbenzimidazole-5-sulfonic acid (also known as Eusolex 232 and Novantisol, Merck & Co., Inc.) absorbs in the UVA spectrum. Allergy to this chemical agent is rare. On routine photopatch testing of 355 patients with suspected photosensitivity in Sweden, Berne and Ros found two patients with photocontact allergy to this chemical.[50] Schauder and Ippen reported one allergic reaction and seven photoallergic reactions to this agent over a 15-year period.[14] Two additional cases were described in 1998.[51] Commercial sources provide 2-phenylbenzimidazole-5-sulfonic acid at a 10% concentration[36,38] although a 2% concentration is also recommended.[47]
Octocrylene (2-ethylhexyl-2-cyano-3,3-diphenylacrylate) is a UVB chemical photoprotectant that has been used in sunscreens for less than a decade.[52] It is sometimes grouped with the cinnamates because of structural similarities. Two patients with photoallergy to this unique agent were reported by Carotte-Lefebvre and colleagues in 2003.[52] These are the only known case reports of allergy to this relatively new agent. Octocrylene is tested in a petrolatum vehicle at a 10% concentration[36] although a 1% concentration has also been used.[47]
Other chemical sunscreen agents incorporated into commercial products include etocrilene (ethyl 2-cyano-3,3-diphenylacrylate), drometrizole trisiloxane, bisethylhexyloxyphenol methoxyphenol triazine, drometrizole (2-(2-hydroxy-5-methylphenyl)benzotriazole), dioctyl butamido triazone, and terephthalylidene dicamphor sulfonic acid (Mexoryl SX, L'Oreal, Aulnay Sous Bois, France). A literature search revealed no cases of allergy or photoallergy to these products, nor were any patch-test concentrations referenced.[53]
Some of the first physical UV blockers used in the United States were opaque formulations that scattered or reflected UV radiation.[1] Poor cosmetic acceptability initially limited the use of these products. Recently, however, microsized forms have become available. Titanium dioxide and zinc oxide are the most common physical UV blockers used today. These agents have not been reported to cause contact dermatitis or photoallergy.[4,21] Of interest, several sources in the literature do suggest that these agents may block the appearance of photoallergy to sunscreens or other agents because of their strong UV-blocking effects.[18,54]
Dermatitis. 2006;17(1):3-11. © 2006 American Contact Dermatitis Society
Cite this: Sunscreen Allergy: A Review of Epidemiology, Clinical Characteristics, and Responsible Allergens - Medscape - Mar 01, 2006.
