JiaDe Yu, MD, MS

The American Contact Dermatitis Society (ACDS) selected sulfites as the 2024 Allergen of the Year.¹ Due to their preservative and antioxidant properties, sulfites are prevalent in a variety of foods, beverages, medications, and personal care products; however, sulfites also have been implicated as a potential contact allergen. In this article, we review common sources of sulfite exposure, clinical manifestations of allergic contact dermatitis (ACD) to sulfites, and patch testing considerations for this emerging allergen.

What Are Sulfites?

Sulfiting agents are compounds that contain the sulfite ion SO₃^2-, including sulfur dioxide, sodium disulfite (sodium metabisulfite), and potassium metabisulfite.² Sulfites occur naturally in the environment and commonly are used as preservatives, antibrowning agents, and antioxidants in various foods, beverages, medications, cosmetics, and skin care products. As antibrowning agents and antioxidants, sulfites help maintain the natural appearance of foods and other products and prevent premature spoiling by inactivating oxidative enzymes.³ It should be noted that sulfites and sulfates are distinct and unrelated compounds that do not cross-react.¹

Common Sources of Sulfite Exposure

From a morning glass of juice to an evening shower, in the pharmacy and at the hair salon, sulfite exposure is ubiquitous in most daily routines. Sulfites are present in many foods and beverages, either as a byproduct of natural fermentation or as an additive to prevent spoiling and color change. The Table provides examples of foods with high sulfite content.^1,4-6 In particular, dried fruit, bottled lemon juice, wine, grape juice, sauerkraut juice, and pickled onions have high sulfite content.

Topical medications and personal care products represent other potential sources of sulfite exposure. A number of reports have shown that sulfites may be included in topical steroids,⁷ antibiotics,⁸ antifungals,⁹ hemorrhoidal preparations,¹⁰ local anesthetics,¹¹ and urinary catheterization gel,¹² highlighting their many potential applications. In addition, a comprehensive ingredient analysis of 264 ophthalmic medications found that 3.8% of the products contained sodium disulfite.¹³ Sulfites may be found in personal care products, including facial and hand cleansers, shampoos, moisturizers, and toothpastes. Hair dyes also commonly contain sulfites,⁷ which are listed in as many as 90% of hair dye kits in the ACDS Contact Allergen Management Program database.¹

Occupational exposures also are widespread, as sulfites are extensively utilized across diverse industries such as pharmaceuticals, health care, leather manufacturing, mineral extraction, food preparation, chemical manufacturing, textiles, alcohol brewing, and wine production.¹

Sulfites also are used in the rubber industry—­particularly in gloves—due to their anticoagulant and preservative properties.⁴ This is relevant to health care providers, who may use dozens of disposable gloves in a single day. In an experimental pilot study, ­researchers detected sulfites in 83% (5/6) of natural rubber latex gloves, 96% (23/24) of synthetic (nitrile) gloves, and 0% (0/5) of polyvinyl chloride gloves.¹⁴ While this study was limited to a small sample size, it demonstrates the common use of sulfites in certain rubber gloves and encourages future studies to determine whether there is a quantitative threshold to elicit allergic reactions.

Sulfite Allergy

In 1968, an early case report of ACD to sulfites was published involving a pharmaceutical worker who developed hand eczema after working at a factory for 3 months and had a positive patch test to potassium metabisulfite.¹⁵ There have been other cases published in the literature since then, including localized ACD as well as less common cases of systemic contact dermatitis following oral, injectable, and rectal sulfite exposures.¹⁶

The North American Contact Dermatitis Group found that, among 132 (2.7%) of 4885 patients with positive patch tests to sodium disulfite from 2017 to 2018, the most commonly involved body sites were the face (28.8%) and hands (20.5%) followed by a scattered/generalized distribution (13.6%). Involvement of the face and hands may correlate with the most frequent sources of exposure that were identified, including personal care products (particularly hair dyes)(18.9%), medications (9.1%), and foods (7.6%).¹⁷ A multicenter analysis of patch test results from Germany, Austria, and Switzerland from 1999 to 2013 showed that 357 (2.9%) of 12,156 patients had positive reactions to sodium disulfite, with the most commonly identified exposure sources being topical pharmaceutical agents (59.3%); cosmetics, creams, and sunscreens (13.6%); and systemic drugs (6.8%).¹⁸ However, it is not always possible to determine the clinical relevance of a positive patch test to sulfites.¹

Other than the face and hands, there have been other unexpected anatomic locations for sulfite ACD (eg, the lower back), and systemic contact dermatitis has manifested with widespread rashes due to oral, rectal, and parenteral exposure.^4,16,19 There is no definitive link between sulfite contact allergy and patient sex, but there seems to be a higher prevalence in patients older than 40 years, perhaps related to overall lifetime exposure.¹

Immediate hypersensitivity reactions to sulfites also have been reported, including urticaria, angioedema, and anaphylaxis.⁴ Due to multiple cases of severe dermatologic and respiratory reactions to food products containing sulfites,²⁰ the US Food and Drug Administration prohibited their use in fresh fruit and vegetables as antibrowning agents in 1986 and required labels on packaged foods that contained sulfites at more than 10 parts per million.²¹ However, food and drinks produced in restaurants, bakeries, and cafes as well as those that are distributed directly to consumers from the preparation site are exempt from these rules.¹⁷

In addition, consuming high amounts of dietary sulfites has been linked to headaches through unclear (ie, not necessarily allergic) mechanisms.^4,22 One study found that wine with a higher sulfite concentration was associated with increased risk for headaches in participants who had a history of headaches related to wine consumption.²²

Patch Testing to Sulfites

The North American Contact Dermatitis Group has tested sodium disulfite since 2017 and found an increased frequency of positive patch tests from 2.7% (N=4885) in 2017 and 2018¹⁷ to 3.3% (N=4115) in 2019 and 2020²³ among patients referred for testing. Similarly, patch testing to sodium disulfite in nearly 40,000 patients in 9 European countries showed a pooled prevalence of reactions of 3.1%.¹⁷ However, this contact allergy may go unrecognized, as sulfites are not included in common patch test series, including the thin-layer rapid use epicutaneous test and the ACDS Core Allergen Series.^24,25 The relatively high patch test positivity to sulfites along with the prevalence of daily exposures supports the addition of sulfites to more patch test screening series.

The recommended patch test concentration for sodium disulfite is 1% in petrolatum.⁵ Testing in aqueous solutions is not recommended because they can cause sulfites to break down, potentially producing false-positive or irritant patch test reactions.^7,26,27

Recommendations for Patients With Sulfite Allergies

Individuals with contact allergies to sulfites should be counseled on exposure sources and should be given resources providing a list of safe products, such as the ACDS Contact Allergen Management Program (https://www.acdscamp.org/login) or SkinSAFE ­(https://www.skinsafeproducts.com/). Prescribers should be cognizant of sulfites that are present in prescription medications. Just because a patient has a positive patch test to sulfites does not automatically imply that they will need to modify their diet to avoid sulfite-containing foods; in the absence of cheilitis or a distribution suggestive of systemic contact dermatitis (eg, vesicular hand/foot dermatitis, intertriginous eruptions), this step may be unnecessary. On the other hand, individuals who have experienced immediate hypersensitivity reactions to sulfites should avoid sulfite-containing foods and carry an epinephrine autoinjector.

Final Interpretation

Sulfites are ubiquitous compounds found in various foods, beverages, medications, and personal care products in addition to a range of occupational exposures. The face and hands are the most common sites of sulfite ACD. Despite patch test positivity in as many as 3% of tested patients,^17,23 sulfite allergy may be missed due to lack of routine testing on standard screening series.

The American Contact Dermatitis Society (ACDS) selected sulfites as the 2024 Allergen of the Year.¹ Due to their preservative and antioxidant properties, sulfites are prevalent in a variety of foods, beverages, medications, and personal care products; however, sulfites also have been implicated as a potential contact allergen. In this article, we review common sources of sulfite exposure, clinical manifestations of allergic contact dermatitis (ACD) to sulfites, and patch testing considerations for this emerging allergen.

What Are Sulfites?

Sulfiting agents are compounds that contain the sulfite ion SO₃^2-, including sulfur dioxide, sodium disulfite (sodium metabisulfite), and potassium metabisulfite.² Sulfites occur naturally in the environment and commonly are used as preservatives, antibrowning agents, and antioxidants in various foods, beverages, medications, cosmetics, and skin care products. As antibrowning agents and antioxidants, sulfites help maintain the natural appearance of foods and other products and prevent premature spoiling by inactivating oxidative enzymes.³ It should be noted that sulfites and sulfates are distinct and unrelated compounds that do not cross-react.¹

Common Sources of Sulfite Exposure

From a morning glass of juice to an evening shower, in the pharmacy and at the hair salon, sulfite exposure is ubiquitous in most daily routines. Sulfites are present in many foods and beverages, either as a byproduct of natural fermentation or as an additive to prevent spoiling and color change. The Table provides examples of foods with high sulfite content.^1,4-6 In particular, dried fruit, bottled lemon juice, wine, grape juice, sauerkraut juice, and pickled onions have high sulfite content.

Topical medications and personal care products represent other potential sources of sulfite exposure. A number of reports have shown that sulfites may be included in topical steroids,⁷ antibiotics,⁸ antifungals,⁹ hemorrhoidal preparations,¹⁰ local anesthetics,¹¹ and urinary catheterization gel,¹² highlighting their many potential applications. In addition, a comprehensive ingredient analysis of 264 ophthalmic medications found that 3.8% of the products contained sodium disulfite.¹³ Sulfites may be found in personal care products, including facial and hand cleansers, shampoos, moisturizers, and toothpastes. Hair dyes also commonly contain sulfites,⁷ which are listed in as many as 90% of hair dye kits in the ACDS Contact Allergen Management Program database.¹

Occupational exposures also are widespread, as sulfites are extensively utilized across diverse industries such as pharmaceuticals, health care, leather manufacturing, mineral extraction, food preparation, chemical manufacturing, textiles, alcohol brewing, and wine production.¹

Sulfites also are used in the rubber industry—­particularly in gloves—due to their anticoagulant and preservative properties.⁴ This is relevant to health care providers, who may use dozens of disposable gloves in a single day. In an experimental pilot study, ­researchers detected sulfites in 83% (5/6) of natural rubber latex gloves, 96% (23/24) of synthetic (nitrile) gloves, and 0% (0/5) of polyvinyl chloride gloves.¹⁴ While this study was limited to a small sample size, it demonstrates the common use of sulfites in certain rubber gloves and encourages future studies to determine whether there is a quantitative threshold to elicit allergic reactions.

Sulfite Allergy

In 1968, an early case report of ACD to sulfites was published involving a pharmaceutical worker who developed hand eczema after working at a factory for 3 months and had a positive patch test to potassium metabisulfite.¹⁵ There have been other cases published in the literature since then, including localized ACD as well as less common cases of systemic contact dermatitis following oral, injectable, and rectal sulfite exposures.¹⁶

The North American Contact Dermatitis Group found that, among 132 (2.7%) of 4885 patients with positive patch tests to sodium disulfite from 2017 to 2018, the most commonly involved body sites were the face (28.8%) and hands (20.5%) followed by a scattered/generalized distribution (13.6%). Involvement of the face and hands may correlate with the most frequent sources of exposure that were identified, including personal care products (particularly hair dyes)(18.9%), medications (9.1%), and foods (7.6%).¹⁷ A multicenter analysis of patch test results from Germany, Austria, and Switzerland from 1999 to 2013 showed that 357 (2.9%) of 12,156 patients had positive reactions to sodium disulfite, with the most commonly identified exposure sources being topical pharmaceutical agents (59.3%); cosmetics, creams, and sunscreens (13.6%); and systemic drugs (6.8%).¹⁸ However, it is not always possible to determine the clinical relevance of a positive patch test to sulfites.¹

Other than the face and hands, there have been other unexpected anatomic locations for sulfite ACD (eg, the lower back), and systemic contact dermatitis has manifested with widespread rashes due to oral, rectal, and parenteral exposure.^4,16,19 There is no definitive link between sulfite contact allergy and patient sex, but there seems to be a higher prevalence in patients older than 40 years, perhaps related to overall lifetime exposure.¹

Immediate hypersensitivity reactions to sulfites also have been reported, including urticaria, angioedema, and anaphylaxis.⁴ Due to multiple cases of severe dermatologic and respiratory reactions to food products containing sulfites,²⁰ the US Food and Drug Administration prohibited their use in fresh fruit and vegetables as antibrowning agents in 1986 and required labels on packaged foods that contained sulfites at more than 10 parts per million.²¹ However, food and drinks produced in restaurants, bakeries, and cafes as well as those that are distributed directly to consumers from the preparation site are exempt from these rules.¹⁷

In addition, consuming high amounts of dietary sulfites has been linked to headaches through unclear (ie, not necessarily allergic) mechanisms.^4,22 One study found that wine with a higher sulfite concentration was associated with increased risk for headaches in participants who had a history of headaches related to wine consumption.²²

Patch Testing to Sulfites

The North American Contact Dermatitis Group has tested sodium disulfite since 2017 and found an increased frequency of positive patch tests from 2.7% (N=4885) in 2017 and 2018¹⁷ to 3.3% (N=4115) in 2019 and 2020²³ among patients referred for testing. Similarly, patch testing to sodium disulfite in nearly 40,000 patients in 9 European countries showed a pooled prevalence of reactions of 3.1%.¹⁷ However, this contact allergy may go unrecognized, as sulfites are not included in common patch test series, including the thin-layer rapid use epicutaneous test and the ACDS Core Allergen Series.^24,25 The relatively high patch test positivity to sulfites along with the prevalence of daily exposures supports the addition of sulfites to more patch test screening series.

The recommended patch test concentration for sodium disulfite is 1% in petrolatum.⁵ Testing in aqueous solutions is not recommended because they can cause sulfites to break down, potentially producing false-positive or irritant patch test reactions.^7,26,27

Recommendations for Patients With Sulfite Allergies

Individuals with contact allergies to sulfites should be counseled on exposure sources and should be given resources providing a list of safe products, such as the ACDS Contact Allergen Management Program (https://www.acdscamp.org/login) or SkinSAFE ­(https://www.skinsafeproducts.com/). Prescribers should be cognizant of sulfites that are present in prescription medications. Just because a patient has a positive patch test to sulfites does not automatically imply that they will need to modify their diet to avoid sulfite-containing foods; in the absence of cheilitis or a distribution suggestive of systemic contact dermatitis (eg, vesicular hand/foot dermatitis, intertriginous eruptions), this step may be unnecessary. On the other hand, individuals who have experienced immediate hypersensitivity reactions to sulfites should avoid sulfite-containing foods and carry an epinephrine autoinjector.

Final Interpretation

Sulfites are ubiquitous compounds found in various foods, beverages, medications, and personal care products in addition to a range of occupational exposures. The face and hands are the most common sites of sulfite ACD. Despite patch test positivity in as many as 3% of tested patients,^17,23 sulfite allergy may be missed due to lack of routine testing on standard screening series.

The American Contact Dermatitis Society (ACDS) selected sulfites as the 2024 Allergen of the Year.¹ Due to their preservative and antioxidant properties, sulfites are prevalent in a variety of foods, beverages, medications, and personal care products; however, sulfites also have been implicated as a potential contact allergen. In this article, we review common sources of sulfite exposure, clinical manifestations of allergic contact dermatitis (ACD) to sulfites, and patch testing considerations for this emerging allergen.

What Are Sulfites?

Sulfiting agents are compounds that contain the sulfite ion SO₃^2-, including sulfur dioxide, sodium disulfite (sodium metabisulfite), and potassium metabisulfite.² Sulfites occur naturally in the environment and commonly are used as preservatives, antibrowning agents, and antioxidants in various foods, beverages, medications, cosmetics, and skin care products. As antibrowning agents and antioxidants, sulfites help maintain the natural appearance of foods and other products and prevent premature spoiling by inactivating oxidative enzymes.³ It should be noted that sulfites and sulfates are distinct and unrelated compounds that do not cross-react.¹

Common Sources of Sulfite Exposure

From a morning glass of juice to an evening shower, in the pharmacy and at the hair salon, sulfite exposure is ubiquitous in most daily routines. Sulfites are present in many foods and beverages, either as a byproduct of natural fermentation or as an additive to prevent spoiling and color change. The Table provides examples of foods with high sulfite content.^1,4-6 In particular, dried fruit, bottled lemon juice, wine, grape juice, sauerkraut juice, and pickled onions have high sulfite content.

Topical medications and personal care products represent other potential sources of sulfite exposure. A number of reports have shown that sulfites may be included in topical steroids,⁷ antibiotics,⁸ antifungals,⁹ hemorrhoidal preparations,¹⁰ local anesthetics,¹¹ and urinary catheterization gel,¹² highlighting their many potential applications. In addition, a comprehensive ingredient analysis of 264 ophthalmic medications found that 3.8% of the products contained sodium disulfite.¹³ Sulfites may be found in personal care products, including facial and hand cleansers, shampoos, moisturizers, and toothpastes. Hair dyes also commonly contain sulfites,⁷ which are listed in as many as 90% of hair dye kits in the ACDS Contact Allergen Management Program database.¹

Occupational exposures also are widespread, as sulfites are extensively utilized across diverse industries such as pharmaceuticals, health care, leather manufacturing, mineral extraction, food preparation, chemical manufacturing, textiles, alcohol brewing, and wine production.¹

Sulfites also are used in the rubber industry—­particularly in gloves—due to their anticoagulant and preservative properties.⁴ This is relevant to health care providers, who may use dozens of disposable gloves in a single day. In an experimental pilot study, ­researchers detected sulfites in 83% (5/6) of natural rubber latex gloves, 96% (23/24) of synthetic (nitrile) gloves, and 0% (0/5) of polyvinyl chloride gloves.¹⁴ While this study was limited to a small sample size, it demonstrates the common use of sulfites in certain rubber gloves and encourages future studies to determine whether there is a quantitative threshold to elicit allergic reactions.

Sulfite Allergy

In 1968, an early case report of ACD to sulfites was published involving a pharmaceutical worker who developed hand eczema after working at a factory for 3 months and had a positive patch test to potassium metabisulfite.¹⁵ There have been other cases published in the literature since then, including localized ACD as well as less common cases of systemic contact dermatitis following oral, injectable, and rectal sulfite exposures.¹⁶

The North American Contact Dermatitis Group found that, among 132 (2.7%) of 4885 patients with positive patch tests to sodium disulfite from 2017 to 2018, the most commonly involved body sites were the face (28.8%) and hands (20.5%) followed by a scattered/generalized distribution (13.6%). Involvement of the face and hands may correlate with the most frequent sources of exposure that were identified, including personal care products (particularly hair dyes)(18.9%), medications (9.1%), and foods (7.6%).¹⁷ A multicenter analysis of patch test results from Germany, Austria, and Switzerland from 1999 to 2013 showed that 357 (2.9%) of 12,156 patients had positive reactions to sodium disulfite, with the most commonly identified exposure sources being topical pharmaceutical agents (59.3%); cosmetics, creams, and sunscreens (13.6%); and systemic drugs (6.8%).¹⁸ However, it is not always possible to determine the clinical relevance of a positive patch test to sulfites.¹

Other than the face and hands, there have been other unexpected anatomic locations for sulfite ACD (eg, the lower back), and systemic contact dermatitis has manifested with widespread rashes due to oral, rectal, and parenteral exposure.^4,16,19 There is no definitive link between sulfite contact allergy and patient sex, but there seems to be a higher prevalence in patients older than 40 years, perhaps related to overall lifetime exposure.¹

Immediate hypersensitivity reactions to sulfites also have been reported, including urticaria, angioedema, and anaphylaxis.⁴ Due to multiple cases of severe dermatologic and respiratory reactions to food products containing sulfites,²⁰ the US Food and Drug Administration prohibited their use in fresh fruit and vegetables as antibrowning agents in 1986 and required labels on packaged foods that contained sulfites at more than 10 parts per million.²¹ However, food and drinks produced in restaurants, bakeries, and cafes as well as those that are distributed directly to consumers from the preparation site are exempt from these rules.¹⁷

In addition, consuming high amounts of dietary sulfites has been linked to headaches through unclear (ie, not necessarily allergic) mechanisms.^4,22 One study found that wine with a higher sulfite concentration was associated with increased risk for headaches in participants who had a history of headaches related to wine consumption.²²

Patch Testing to Sulfites

The North American Contact Dermatitis Group has tested sodium disulfite since 2017 and found an increased frequency of positive patch tests from 2.7% (N=4885) in 2017 and 2018¹⁷ to 3.3% (N=4115) in 2019 and 2020²³ among patients referred for testing. Similarly, patch testing to sodium disulfite in nearly 40,000 patients in 9 European countries showed a pooled prevalence of reactions of 3.1%.¹⁷ However, this contact allergy may go unrecognized, as sulfites are not included in common patch test series, including the thin-layer rapid use epicutaneous test and the ACDS Core Allergen Series.^24,25 The relatively high patch test positivity to sulfites along with the prevalence of daily exposures supports the addition of sulfites to more patch test screening series.

The recommended patch test concentration for sodium disulfite is 1% in petrolatum.⁵ Testing in aqueous solutions is not recommended because they can cause sulfites to break down, potentially producing false-positive or irritant patch test reactions.^7,26,27

Recommendations for Patients With Sulfite Allergies

Individuals with contact allergies to sulfites should be counseled on exposure sources and should be given resources providing a list of safe products, such as the ACDS Contact Allergen Management Program (https://www.acdscamp.org/login) or SkinSAFE ­(https://www.skinsafeproducts.com/). Prescribers should be cognizant of sulfites that are present in prescription medications. Just because a patient has a positive patch test to sulfites does not automatically imply that they will need to modify their diet to avoid sulfite-containing foods; in the absence of cheilitis or a distribution suggestive of systemic contact dermatitis (eg, vesicular hand/foot dermatitis, intertriginous eruptions), this step may be unnecessary. On the other hand, individuals who have experienced immediate hypersensitivity reactions to sulfites should avoid sulfite-containing foods and carry an epinephrine autoinjector.

Final Interpretation

Sulfites are ubiquitous compounds found in various foods, beverages, medications, and personal care products in addition to a range of occupational exposures. The face and hands are the most common sites of sulfite ACD. Despite patch test positivity in as many as 3% of tested patients,^17,23 sulfite allergy may be missed due to lack of routine testing on standard screening series.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Eyelid dermatitis is a common dermatologic concern representing a broad group of inflammatory dermatoses and typically presenting as eczematous lesions on the eyelids.¹ One of the most common causes of eyelid dermatitis is thought to be allergic contact dermatitis (ACD), a type IV delayed hypersensitivity reaction caused by exposure to external allergens.² Although ACD can occur anywhere on the body, dermatitis on the face and eyelids is quite common.^1,2 This article aims to explore the clinical manifestation, evaluation, and management of eyelid ACD.

Pathophysiology of Eyelid ACD

Studies have shown that ACD is the most common cause of eyelid dermatitis, estimated to account for 46% to 72% of cases worldwide.^3-6 Allergic contact dermatitis is a T cell–mediated type IV hypersensitivity reaction to external antigens that manifests as eczematous lesions at the site of contact with the allergen that may spread.⁷ Allergic contact dermatitis is a common condition, and it is estimated that at least 20% of the general worldwide population has a contact allergy.^8,9 Histologically, ACD manifests as spongiotic dermatitis, though this is not unique and also may be seen in atopic dermatitis (AD) and irritant contact dermatitis.² Allergic contact dermatitis is diagnosed via epicutaneous patch testing, and treatment involves allergen avoidance with or without adjuvant topical and/or systemic immunomodulatory treatments.⁷

The eyelids are uniquely prone to the development of ACD given their thinner epidermis and increased susceptibility to irritation. They frequently are exposed to allergens through the direct topical route as well as indirectly via airborne exposure, rinse-down products (eg, shampoos), and substances transferred from an individual’s own hands. The occluded skin folds of the eyelids facilitate increased exposure to trapped allergens.^10,11 Additionally, the skin of the eyelids is thin, flexible, highly vascularized, and lacking in subcutaneous tissue, making this area more susceptible to antigen penetration than other locations on the body.^1,2,10,12,13

Clinical Manifestations

Eyelid ACD is more common in females than males, which is thought to be related to increased use of cosmetics and fragrances.^1,3,12,14-16 Clinical manifestations may resemble eczematous papules and plaques.¹ Eyelid ACD commonly spreads beyond the eyelid margin, which helps to differentiate it from AD and irritant contact dermatitis. Symptoms of ACD on the eyelids typically include pruritus, redness, swelling, tearing, scaling, and pain.² Persistent untreated eyelid dermatitis can lead to eyelash loss, damage to meibomian glands, and hyperpigmentation.^2,17,18

Patterns of Eyelid ACD

Allergic contact dermatitis on the eyelids can occur due to direct application of allergens onto the skin of the eyelids, runoff of products from the hair/scalp (eg, shampoo), transfer of allergens from the hands, or contact with airborne allergens.^1,2,11,12 Some reports have suggested that eyelid ACD more often is caused by products applied to the scalp or face rather than those applied directly to the eyelids.¹¹ Because the scalp and face are less reactive to contact allergens, in some cases the eyelids may be the only affected site.^10,12,13

The specific pattern of dermatitis on or around the eyelids can provide clues to the allergenic source. Dermatitis present around the eyelids and periorbital region with involvement of the bilateral upper and lower eyelids suggests direct exposure to a contact allergen, such as makeup or other cosmetic products.¹ Unilateral involvement of only 1 eyelid can occur with ectopic transfer of allergens from the hands or nails.^1,19 Involvement of the fingers or nails in addition to the eyelids may further suggest ectopic transfer, such as from allergens in nail polish.¹⁰ Unilateral eyelid dermatitis also could be caused by unique exposures such as a microscope or camera eyepiece.¹⁹ Distribution around the lower eyelids and upper cheeks is indicative of a drip or runoff pattern, which may result from an ophthalmic solution such as eye drops or contact lens solution.^1,19 Finally, dermatitis affecting the upper eyelids along with the nasolabial folds and upper chest may suggest airborne contact dermatitis to fragrances or household cleaning products.^1,11

Common Culprits of Eyelid ACD

Common causes of eyelid ACD include cosmetic products, ophthalmic medications, nail lacquers, and jewelry.^10,13,20 Within the broader category of cosmetics, allergens may be found in makeup and makeup removers, cosmetic applicators and brushes, soaps and cleansers, creams and sunscreens, antiaging products, hair products, nail polish and files, and hair removal products, among many others.^10,13,16,20 Additionally, ophthalmologic and topical medications are common sources of ACD, including eyedrops, contact lens solution, and topical antibiotics.^10,13,21 Costume jewelry commonly contains allergenic metals, which also can be found in eyelash curlers, eyeglasses, toys, and other household items.^22,23 Finally, contact allergens can be found in items such as goggles, gloves, textiles, and a variety of other occupational and household exposures.

Allergic contact dermatitis of the eyelids occurs predominantly—but not exclusively—in females.^16,20,24 This finding has been attributed to the traditionally greater use of cosmetics and fragrances among women; however, the use of skin care products among men is increasing, and recent studies have shown the eyelids to be a common location of facial contact dermatitis among men.^16,24 Although eyelid dermatitis has not been specifically analyzed by sex, a retrospective analysis of 1332 male patients with facial dermatitis found the most common sites to be the face (not otherwise specified)(48.9%), eyelids (23.5%), and lips (12.6%). In this cohort, the most common allergens were surfactants in shampoos and paraphenylenediamine in hair dyes.²⁴

Common Allergens

Common contact allergens among patients with ACD of the eyelids include metals, fragrances, preservatives, acrylates, and topical medications.^{3,10,16,20,25-27} Sources of common contact allergens are reviewed in Table 1.

Metals—Metals are among the most common causes of ACD overall, and nickel frequently is reported as one of the top contact allergens in patients with eyelid dermatitis.^16,27 A retrospective analysis of 2332 patients with eyelid dermatitis patch tested by the North American Contact Dermatitis Group from 1994 to 2016 found that 18.6% of patients with eyelid ACD had a clinically relevant nickel allergy. Sources of nickel exposure include jewelry, grooming devices, makeup and makeup applicators, and eyelash curlers, as well as direct transfer from the hands after contact with consumer products.¹⁶

Other metals that can cause ACD include cobalt (found in similar products to nickel) and gold. Gold often is associated with eyelid dermatitis, though its clinical relevance has been debated, as gold is a relatively inert metal that rarely is present in eye cosmetics and its ions are not displaced from objects and deposited on the skin via sweat in the same way as nickel.^{4,16,20,28-30} Despite this, studies have shown that gold is a common positive patch test reaction among patients with eyelid dermatitis, even in patients with no dermatitis at the site of contact with gold jewelry.^20,29,31 Gold has been reported to be the most common allergen causing unilateral eyelid dermatitis via ectopic transfer.^16,19,20,29 It has been proposed that titanium dioxide, present in many cosmetics and sunscreens, displaces gold allowing its release from jewelry, thereby liberating the fine gold ions and allowing them to desposit on the face and eyelids.^30,31 Given the uncertain clinical relevance of positive patch test reactions to gold, Warshaw at al¹⁶ recommend a 2- to 3-month trial of gold jewelry avoidance to establish relevance, and Ehrlich and Gold²⁹ noted that avoidance of gold leads to improvement.

Fragrances—Fragrances represent a broad category of naturally occurring and man-made components that often are combined to produce a desired scent in personal care products.³² Essential oils and botanicals are both examples of natural fragrances.³³ Fragrances are found in numerous products including makeup, hair products, and household cleaning supplies and represent some of the most common contact allergens.³² Common fragrance allergens include fragrance mixes I and II, hydroperoxides of linalool, and balsam of Peru.^12,32,34 Allergic contact dermatitis to fragrances typically manifests on the eyelids, face, or hands.³³ Several studies have found fragrances to be among the top contact allergens in patients with eyelid dermatitis.^{3,12,20,25,34} Patch testing for fragrance allergy may include baseline series, supplemental fragrance series, and personal care products.^32,35

Preservatives—Preservatives, including formaldehyde and formaldehyde releasers (eg, quaternium-15 and ­bronopol) and methylchloroisothiazolinone/­methylisothiazolinone, may be found in personal care products such as makeup, makeup removers, emollients, shampoos, hair care products, and ophthalmologic solutions and are among the most common cosmetic sources of ACD.^13,36-39 Preservatives are among the top allergens causing eyelid dermatitis.²⁰ In particular, patch test positivity rates to methylchloroisothiazolinone/methylisothiazolinone have been increasing in North America.⁴⁰ Sensitization to preservatives may occur through direct skin contact or transfer from the hands.⁴¹

Acrylates—Acrylates are compounds derived from acrylic acid that may be found in acrylic and gel nails, eyelash extensions, and other adhesives and are frequent causes of eyelid ACD.^4,10,42 Acrylate exposure may be cosmetic among consumers or occupational (eg, aestheticians).^42,43 Acrylates on the nails may cause eyelid dermatitis via ectopic transfer from the hands and also may cause periungual dermatitis manifesting as nail bed erythema.¹⁰ Hydroxyethyl methacrylate is one of the more common eyelid ACD allergens, and studies have shown increasing prevalence of positive reaction rates to hydroxyethylmethacrylate.^10,44Topical Medications—Contact allergies to topical medications are quite common, estimated to occur in 10% to 17% of patients undergoing patch testing.⁴⁵ Both active and inactive ingredients of topical medications may be culprits in eyelid ACD. The most common topical medication allergens include antibiotics, steroids, local anesthetics, and nonsteroidal anti-inflammatory drugs.⁴⁵ Topical antibiotics such as neomycin and bacitracin represent some of the most common causes of eyelid dermatitis^4,10 and may be found in a variety of products, including antibacterial ointments and eye drops.¹ Many ophthalmologic medications also contain corticosteroids, with the most common allergenic steroids being tixocortol pivalate (a marker for hydrocortisone allergy) and budesonide.^10,20 Topical steroids pose a particular dilemma, as they can be either the source of or a treatment for ACD.¹⁰ Eye drops also may contain anesthetics, β-blockers, and antihistamines, as well as the preservative benzalkonium chloride, all of which may be contact allergens.^21,39

Differential Diagnosis of Eyelid Dermatitis

Although ACD is reported to be the most common cause of eyelid dermatitis, the differential diagnosis is broad, including endogenous inflammatory dermatoses and exogenous exposures (Table 2). Symptoms of eyelid ACD can be nonspecific (eg, erythema, pruritus), making diagnosis challenging.⁴⁶

Atopic dermatitis represents another common cause of eyelid dermatitis, accounting for 14% to 39.5% of cases.^3-5,49Atopic dermatitis of the eyelids classically manifests with lichenification of the medial aspects of the eyelids.⁵⁰ Atopic dermatitis and ACD may be difficult to distinguish, as the 2 conditions appear clinically similar and can develop concomitantly.⁵¹ Additionally, atopic patients are likely to have comorbid allergic rhinitis and sensitivity to environmental allergens, which may lead to chronic eye scratching and lichenification.^1,51 Clinical features of eyelid dermatitis suggesting allergic rhinitis and likely comorbid AD include creases in the lower eyelids (Dennie-Morgan lines) and periorbital hyperpigmentation (known as the allergic shiner) due to venous congestion.^1,52

Seborrheic dermatitis is an inflammatory reaction to Malassezia yeast that occurs in sebaceous areas such as the groin, scalp, eyebrows, eyelids, and nasolabial folds.^1,53,54

Irritant contact dermatitis, a nonspecific inflammatory reaction caused by direct cell damage from external irritants, also may affect the eyelids and appear similar to ACD.¹ It typically manifests with a burning or stinging sensation, as opposed to pruritus, and generally develops and resolves more rapidly than ACD.¹ Personal care products are common causes of eyelid irritant contact dermatitis.¹⁶

Patch Testing for Eyelid ACD

The gold standard for diagnosis of ACD is patch testing, outlined by the International Contact Dermatitis Research Group.^55-57 Patch testing generally is performed with standardized panels of allergens and can be customized either with supplemental panels based on unique exposures or with the patient’s own personal care products to increase the sensitivity of testing. Therefore, a thorough history is crucial to identifying potential allergens in a patient’s environment.

False negatives are possible, as the skin on the back may be thicker and less sensitive than the skin at the location of dermatitis.^2,58 This is particularly relevant when using patch testing to diagnose ACD of the eyelids, where the skin is particularly thin and sensitive.² Additionally, ingredients of ophthalmic medications are known to have an especially high false-negative rate with standard patch testing and may require repeated testing with higher drug concentrations or modified patch testing procedures (eg, open testing, scratch-patch testing).^1,59

Treatment

Management of ACD involves allergen avoidance, typically dictated by patch test results.¹⁰ Allergen avoidance may be facilitated using online resources such as the Contact Allergen Management Program (https://www.acdscamp.org/) created by the American Contact Dermatitis Society.^10,18 Patient counseling following patch testing is crucial to educating patients about sources of potential allergen exposures and strategies for avoidance. In the case of eyelid dermatitis, it is particularly important to consider exposure to airborne allergens such as fragrances.¹⁶ Fragrance avoidance is uniquely difficult, as labelling standards in the United States currently do not require disclosure of specific fragrance components.³³ Additionally, products labelled as unscented may still contain fragrances. As such, some patients with fragrance allergy may need to carefully avoid all products containing fragrances.³³

In addition to allergen avoidance, eyelid ACD may be treated with topical medications (eg, steroids, calcineurin inhibitors, Janus kinase inhibitors); however, these same topical medications also can cause ACD due to some ingredients such as propylene glycol.¹⁰ Topical steroids should be used with caution on the eyelids given the risk for atrophy, cataracts, and glaucoma.¹

Final Interpretation

Eyelid dermatitis is a common dermatologic condition most frequently caused by ACD due to exposure to allergens in cosmetic products, ophthalmic medications, nail lacquers, and jewelry, among many other potential sources. The most common allergens causing eyelid dermatitis include metals (particularly nickel), fragrances, preservatives, acrylates, and topical medications. Eyelid ACD is diagnosed via patch testing, and the mainstay of treatment is strict allergen avoidance. Patient counseling is vital for successful allergen avoidance and resolution of eyelid ACD.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Fragrances are complex organic compounds that are sufficiently volatile to produce an odor—most often a pleasant one—or at times intended to neutralize unpleasant odors. They can be further divided into natural fragrances (eg, essential oils) and synthetic ones. Fragrances are found in abundance in our daily lives: in perfumes; colognes; lotions; shampoos; and an array of other personal, household, and even industrial products (Table). These exposures include products directly applied to the skin, rinsed off, or aerosolized. A single product often contains a multitude of different fragrances to create the scents we know and love. To many, fragrances can be an important part of everyday life or even a part of one’s identity. But that once-intoxicating aroma can transform into an itchy skin nightmare; fragrances are among the most common contact allergens.

Given the widespread prevalence of fragrances in so many products, understanding fragrance allergy and skillful avoidance is imperative. In this review, we explore important aspects of fragrance allergic contact dermatitis (ACD), including chemistry, epidemiology, patch test considerations, and management strategies for patients, with the goal of providing valuable clinical insights for treating physicians on how patients can embrace a fragrance-free lifestyle.

How Fragrances Act as Allergens

A plethora of chemicals emit odors, of which more than 2000 are used to create the fragranced products we see on our shelves today.¹ For many of these fragrances, contact allergy develops because the fragrance acts as a hapten (ie, a small molecule that combines with a carrier protein to elicit an immune response).² Some fragrance molecules require “activation” to be able to bind to proteins; these are known as prehaptens.³ For example, the natural fragrance linalool is generally considered nonallergenic in its initial form. However, once it is exposed to air, it may undergo oxidation to become linalool hydroperoxides, a well-established contact allergen. Some fragrances can become allergenic in the skin itself, often secondary to enzymatic reactions—these are known as prohaptens.³ However, most fragrances are directly reactive to skin proteins on the basis of chemical reactions such as Michael addition and Schiff base formation.⁴ In either case, the end result is that fragrance allergens, including essential oils, may cause skin sensitization and subsequent ACD.^5,6

Epidemiology

Contact allergy to fragrances is not uncommon; in a multicenter cross-sectional study conducted in 5 European countries, the prevalence in the general population was estimated to be as high as 2.6% and 1.9% among 3119 patients patch tested to fragrance mix I (FMI) and fragrance mix II (FMII), respectively.⁷ Studies in patients referred for patch testing have shown a higher 5% to 25% prevalence of fragrance allergy, largely depending on what population was evaluated.¹ Factors such as sociocultural differences in frequency and types of fragrances used could contribute to this variation.

During patch testing, the primary fragrance screening allergens are FMI, FMII, and balsam of Peru (BOP)(Myroxylon pereirae resin).⁷ In recent years, hydroperoxides of linalool and limonene also have emerged as potentially important fragrance allergens.⁸ The frequencies of patch-test positivity of these allergens can be quite high in referral-based populations. In a study performed by the North American Contact Dermatitis Group (NACDG) from 2019 to 2020, frequencies of fragrance allergen positivity were 12.8% for FMI, 5.2% for FMII, 7.4% for BOP, 11.1% for hydroperoxides of linalool, and 3.5% for hydroperoxides of limonene.⁸ Additionally, it was noted that FMI and hydroperoxides of linalool were among the top 10 most frequently positive allergens.⁹ It should be kept in mind that NACDG studies are drawn from a referral population and not representative of the general population.

Allergic contact dermatitis to fragrances can manifest anywhere on the body, but certain patterns are characteristic. A study by the NACDG analyzed fragrance and botanical patch test results in 24,246 patients and found that fragrance/botanical-sensitive patients more commonly had dermatitis involving the face (odds ratio [OR], 1.12; 95% CI, 1.03-1.21), legs (OR, 1.22; 95% CI, 1.06-1.41), and anal/genital areas (OR, 1.26; 95% CI, 1.04-1.52) and were less likely to have hand dermatitis (OR, 0.88; 95% CI, 0.82-0.95) compared with non–fragrance/botanical-sensitive patients.¹⁰ However, other studies have found that hand dermatitis is common among fragrance-allergic individuals.^11-13

Fragrance allergy tends to be more common in women than men, which likely is attributable to differences in product use and exposure.¹⁰ The prevalence of fragrance allergy increases with age in both men and women, peaking at approximately 50 years of age, likely due to repeat exposure or age-related changes to the skin barrier or immune system.¹⁴

Occupational fragrance exposures are important to consider, and fragrance ACD is associated with hairdressers, beauticians, office workers exposed to aromatherapy diffusers, and food handlers.¹⁵ Less-obvious professions that involve exposure to fragrances used to cover up unwanted odors—such as working with industrial and cleaning chemicals or even metalworking—also have been reported to be associated with ACD.¹⁶

Patch Test Considerations

Patch testing is essential to confirm fragrance allergy and guide treatment, but because there are so many potential fragrance allergens, there is no perfect patch test strategy. In a standard patch test series, the most important screening allergens are considered to be FMI, FMII, and BOP; tested together, they are thought to detect a large proportion of cases of fragrance allergy. Strikingly, in a large European study (N=1951), patch testing with the fragrance markers in the baseline panel failed to detect more than 40% of cases of allergy compared to testing with 26 individual fragrance allergens.¹⁷ Other studies have reported that a smaller proportion of fragrance allergies are missed by using baseline screening allergens alone.^18,19 Limonene and linalool hydroperoxides also are potentially important fragrance allergens to consider adding to the patch test panel, as unoxidized limonene and linalool commonly are used in many products and could theoretically undergo auto-oxidation under use conditions.⁸ However, because of the high number of irritant, questionable, and potentially false-positive reactions, the Information Network of Departments of Dermatology has recommended against adding these hydroperoxides to a standard screening tray for patch testing.²⁰ It must be remembered that a positive patch test to a fragrance does not necessarily represent ACD unless the patient has a clinically relevant exposure to the allergen.²¹

In patients who test negative to the baseline ­fragrance-screening allergens and in whom a high degree of suspicion remains, further testing with supplemental fragrance allergens (commercially available from patch test suppliers) is warranted.¹⁷ The thin-layer rapid use epicutaneous (T.R.U.E.) test (SmartPractice) includes FMI and BOP but not FMII or linalool or limonene hydroperoxides. More comprehensive patch test panels are available that include additional fragrances, such as the North American 80 Comprehensive Series and the American Contact Dermatitis Society Core Allergen Series.^22-24 It is important to remain vigilant and consider expanded patch testing if patients initially test negative but suspicion remains.

Furthermore, patch testing with the patient’s own products is an important consideration. Uter et al²⁵ evaluated patch testing using patients’ perfumes, deodorants, and shaving lotions, and approximately 41% (53/129) of patients who tested positive to their own product tested negative for fragrance-screening allergens. Although it can be difficult to ascertain which exact component of a commercial product is the culprit, a positive patch test may still provide clinically relevant information for patients and treating physicians. In cases of questionable or weak-positive results, repeat testing or repeated open application tests can help re-evaluate suspected products.

Cross-reactivity should be considered when patch testing for fragrances. Atwater et al¹⁰ found that cross-reactivity between FMI, FMII, and BOP was common; for instance, approximately 40% of patients testing positive to FMII or BOP also had positive reactions to FMI (522/1182 and 768/1942, respectively). Understanding this concept is important because in some cases (as detailed below) patients will need to avoid all fragrances, not just the ones to which they have previously been exposed, given the limitations on fragrance labeling in the United States. However, this may change with the Modernization of Cosmetic Regulation Act of 2022.²⁶

Avoiding Fragrances: Improving Patient Education and Outcomes

Once a relevant contact allergy to fragrance is established after patch testing, successful avoidance is critical but challenging, as there are numerous potential pitfalls. Missing just 1 hidden source of fragrance exposure will often be the difference between success or failure. Dermatologists play a crucial role in guiding patients through the intricate process of identifying and avoiding potential allergens.

Optimal Safety: Embracing a Fragrance-Free Lifestyle

For fragrance-allergic patients, it generally is safest to completely avoid fragrance.

First, if a patient only shows positive patch-test reactions to fragrance screening mixes (and not to the particular fragrances in these mixes), there is no way to be certain which fragrances the patient needs to avoid.

Second, even if specific fragrance allergens are identified, numerous chemically related fragrances to which the patient may be allergic are not commercially available for patch testing. One review provided evidence of 162 fragrance allergens that have been documented to cause contact allergy.¹ Dermatologists generally patch test to screening mixtures and/or the 26 fragrance chemicals required on labels in European products (European Directive fragrance).²⁷ Therefore, there are more than 100 known fragrance allergens that are not routinely tested to which patients could be allergic.

Third, certain fragrances, such as limonene and linalool, are found in many products with fragrance, and it is difficult to find products without these substances. Limonene and linalool themselves are not potent allergens; however, upon air exposure, they may auto-oxidize to hydroperoxides of limonene and linalool, which are increasingly common positive patch tests.¹⁹

Additionally, patients should be advised that many products labeled “fragrance free,” “unscented,” or “free and clear” are not truly fragrance free, and patients should not choose products based on these claims. There are no legal definitions for these claims in the United States, and industries are allowed to choose the definition they prefer. Numerous products labeled “unscented” use this term to indicate that the product had an odor, the company used a masking fragrance to hide the odor, and then the product can be considered unscented. In many holistic stores, most products labeled “fragrance free” are only free of artificial fragrances but contain essential oils. Of the 162 documented fragrance allergens, 80 are essential oils.⁶ Essential oils are perceived to be safe by the vast majority of the population because they are viewed as “natural” and “unprocessed” sources of fragrance.²⁸ However, numerous allergenic terpenes have been discovered in essential oils, including functionalized variations of alcohols (eg, geraniol, bisabolol) and aldehydes (eg, citronellal).⁶ Essential oils also consist of nonterpenic compounds produced through the phenylpropanoids pathway, including eugenol and cinnamaldehyde. One review showed that most essential oils contain one or more European Directive fragrance.²⁹ Therefore, many products labeled “unscented,” “fragrance free,” or “natural” are not free of fragrance and may be unsafe for fragrance-allergic patients.

Although not required, manufacturers sometimes voluntarily list one or more of the 162 currently identified fragrance allergens on product labels. Also, there are more than 50 potentially allergenic essential oils that can be listed on labels by their common names or by genus or species. In addition, there are synonyms for fragrance, such as aroma, parfum, perfume, and scent. Therefore, there are several hundred different ingredient names on labels that indicate the presence of fragrance, and patients are very unlikely to successfully identify fragrance-free products by trying to read product labels on their own.

Lastly, in the United States product labels only require products to state that they contain “fragrance” and do not mandate the listing of specific fragrances. If a patient is allergic to a specific fragrance, there is no way to determine if that fragrance is present in these products. This will change with the enactment of Modernization of Cosmetics Regulation Act of 2022, which empowers the US Food and Drug Administration to require manufacturers to disclose many, but not all, fragrance allergens on the labels of cosmetic and topical products.²⁶

For all these reasons, patients should be advised to use a medical database to choose safe alternative products instead of trying to read labels themselves to avoid fragrance. The American Contact Dermatitis Society’s Contact Allergen Management Program (CAMP) database (https://www.contactderm.org/resources/acds-camp) is designed to identify safe alternative products for patients with contact allergies. When CAMP is programmed to avoid “fragrance,” it will list only “safe” products free of all fragrances found in a comprehensive fragrance cross-reactor group.³⁰ This customizable database is available as an application that can be downloaded onto a patient’s mobile device. Fragrance-allergic patients should be encouraged to use the CAMP application or other similar applications (eg, SkinSAFE)(https://www.skinsafeproducts­.com/) to find all the products they use.

Potential Pitfalls in Fragrance Avoidance

Most physicians, even dermatologists, will not know which products on the market are fragrance free from a contact allergy standpoint. Patients should instruct their physicians to use the allergen-avoidance application of choice whenever recommending new topical products, whether prescription or nonprescription. In 2009, Nardelli and colleagues³¹ found that 10% of topical pharmaceutical products contained a total of 66 different fragrance substances.

Individuals who are allergic to fragrance also can react to fragrances used by close contacts (ie, consort dermatitis).³² Therefore, fragrance-allergic individuals who do not improve after changing their personal products should consider urging their spouses or significant others to choose their personal care products using an allergen-avoidance application. Also, physical contact with pets can cause reactions, and the use of a fragrance-free pet shampoo is recommended. Additionally, allergic individuals who are providing care for small children should select fragrance-free products for them.

Some of the most heavily fragranced products on the market are found at hair salons. One exposure to an allergen often can keep patients broken out for up to 4 weeks and occasionally longer, a typical frequency for salon visits—even if the individual is taking great care to avoid fragrance at home. Patients should be instructed to bring their own shampoo, conditioner, and styling products to the salon. These patients also should bring safe moisturizer and nail polish remover for manicures. Additionally, aromatherapy used in most massages can cause flare-ups, and it is recommended that allergic patients purchase fragrance-free massage oil to bring to their sessions.

Fragranced soaps and cleansers can leave a residue on the palmar surface of the hands and fingers. This residue may not meet the threshold for causing a reaction on the thick skin of these surfaces, but it is sufficient to passively transfer fragrance to other more sensitive areas, such as the eyelids. Passive transfer of fragrance can be a major source of allergen exposure and should not be overlooked. Allergic patients should be instructed to bring safe hand cleansers to friends’ houses, restaurants, or work.

Airborne fragrances in a patient’s environment can reach sufficient concentration to cause airborne contact dermatitis. In one case report, an Uber driver developed facial airborne ACD from a fragrance diffuser in his vehicle and his condition improved upon removing the diffuser.³³ Therefore, patients should be instructed to avoid fragranced diffusers, scented candles, room deodorizers, incense, and wax melts.

Fragrance in household products also can be an issue. Fragrance-allergic patients should be instructed to choose fragrance-free cleaning products and to avoid fragranced wipes on surfaces that may be touched. In addition, they should be instructed to use fragrance-free laundry products. It is not required for household products in the United States to list their ingredients, and the majority do not have complete ingredient lists. Therefore, it is imperative that the patient use an allergen-avoidance application that identifies products that have full ingredient disclosure and are free of fragrance.

For individuals who enjoy perfume and/or cologne, it may be possible for them to resume use of these products in some cases after their condition has fully cleared with complete fragrance avoidance. They should avoid spraying products into the air or applying them directly onto the skin and should instead dip a cotton swab into the perfume/cologne and dab a small amount onto their clothing. This technique can sometimes satisfy the patient and improve compliance.

If a patient who is allergic to fragrance does not clear after 6 weeks of complete fragrance avoidance, it is worth considering systemic contact dermatitis due to ingestion of fragrance-related substances in foods.³⁴ A large number of fragrance materials also are food flavorings. For patients allergic to a specific fragrance(s), systemic avoidance needs to be specific to the allergen, and the Flavor and Extract Manufacturers Association’s flavor ingredient library is most helpful (https://www.femaflavor.org/flavor-library). If the patient is allergic to the complex mixture BOP, a balsam-free diet can be attempted.^35,36

Final Thoughts

Dermatologists must equip themselves with the knowledge to educate fragrance-allergic patients on proper avoidance. The multifaceted nature of fragrance avoidance requires a personalized approach, combining label scrutiny, utilization of a safe-product application, and tailored recommendations for specific situations. By guiding patients through these complexities, dermatologists can empower patients to manage their fragrance allergy and enhance their quality of life.

Frontal fibrosing alopecia (FFA) is an increasingly common diagnosis, especially in middle-aged women, and was first described by Kossard¹ in 1994. It is a variant of lichen planopilaris (LPP), a progressive scarring cicatricial alopecia that affects the frontotemporal area of the scalp, eyebrows, and sometimes even body hair.¹ Although its etiology remains unclear, genetic causes, drugs, hormones, and environmental exposures—including certain chemicals found in sunscreens—have been implicated in its pathogenesis.^2,3 An association between contact allergy to ingredients in personal care products and FFA diagnosis has been suggested; however, there is no evidence of causality to date. In this article, we highlight the potential relationship between contact allergy and FFA as well as clinical considerations for management.

Clinical Features and Diagnosis

Frontal fibrosing alopecia typically manifests with gradual symmetric recession of the frontal hairline leading to bandlike hair loss along the forehead, sometimes extending to the temporal region.⁴ Some patients may experience symptoms of scalp itching, burning, or tenderness that may precede or accompany the hair loss. Perifollicular erythema may be visible during the early stages and can be visualized on trichoscopy. The affected skin may appear pale and shiny and may have a smooth texture with a distinct lack of follicular openings. Aside from scalp involvement, other manifestations may include lichen planus pigmentosus, facial papules, body hair involvement, hypochromic lesions, diffuse redness on the face and neck, and prominent frontal veins.⁵ Although most FFA cases have characteristic clinical features and trichoscopic findings, biopsy for histopathologic examination is still recommended to confirm the diagnosis and ensure appropriate treatment.⁴ Classic histopathologic features include perifollicular lymphocytic inflammation, follicular destruction, and scarring.

Pathophysiology of FFA

The pathogenesis of FFA is thought to involve a variety of triggers, including immune-mediated inflammation, stress, genetics, hormones, and possibly environmental factors.⁶ Frontal fibrosing alopecia demonstrates considerable upregulation in cytotoxic helper T cells (T_H1) and IFN-γ activity resulting in epithelial hair follicle stem cell apoptosis and replacement of normal epithelial tissue with fibrous tissue.⁷ There is some suspicion of genetic susceptibility in the onset of FFA as suggested by familial reports and genome-wide association studies.^8-10 Hormonal and autoimmune factors also have been linked to FFA, including an increased risk for thyroid disease and the postmenopausal rise of androgen levels.⁶

Allergic Contact Dermatitis and FFA

Although they are 2 distinct conditions with differing etiologies, allergic contact dermatitis (ACD) and FFA may share environmental triggers, especially in susceptible individuals. This may support the coexistence and potential association between ACD and FFA.

In one case report, a woman who developed facial eczema followed by FFA showed positive patch tests to the UV filters drometrizole trisiloxane and ethylhexyl salicylate, which were listed as ingredients in her sunscreens. Avoidance of these allergens reportedly led to notable improvement of the symptoms.¹¹ Case-control studies have found an association between the use of facial sunscreen and risk for FFA.¹² A 2016 questionnaire that assessed a wide range of lifestyle, social, and medical factors related to FFA found that the use of sunscreens was significantly higher in patients with FFA than controls (P<.001), pointing to sunscreens as a potential contributing factor, but further research has been inconclusive. A higher frequency of positive patch tests to hydroperoxides of linalool and balsam of Peru (BoP) in patients with FFA have been documented; however, a direct cause cannot be established.²

In a 2020 prospective study conducted at multiple international centers, 65% (13/20) of FFA patients and 37.5% (9/24) of the control group had a positive patch test reaction to one or more allergens (P=.003). The most common allergens that were identified included cobalt chloride (positive in 35% [7/20] of patients with FFA), nickel sulfate (25% [5/20]), and potassium dichromate (15% [3/20]).¹³ In a recent 2-year cohort study of 42 patients with FFA who were referred for patch testing, the most common allergens included gallates, hydroperoxides of linalool, and other fragrances.¹⁴ After a 3-month period of allergen avoidance, 70% (29/42) of patients had decreased scalp erythema on examination, indicating that avoiding relevant allergens may reduce local inflammation. Furthermore, 76.2% (32/42) of patients with FFA showed delayed-type hypersensitivity to allergens found in daily personal care products such as shampoos, sunscreens, and moisturizers, among others.¹⁴ Notably, the study lacked a control group. A case-control study of 36 Hispanic women conducted in Mexico also resulted in 83.3% (15/18) of patients with FFA and 55.5% (10/18) of controls having at least 1 positive patch test; in the FFA group, these included iodopropynyl butylcarbamate (16.7% [3/18]) and propolis (16.7% [3/18]).¹⁵

Most recently, a retrospective study conducted by Shtaynberger et al¹⁶ included 12 patients with LPP or FFA diagnosed via clinical findings or biopsy. It also included an age- and temporally matched control group tested with identical allergens. Among the 12 patients who had FFA/LPP, all had at least 1 allergen identified on patch testing. The most common allergens identified were propolis (positive in 50% [6/12] of patients with FFA/LPP), fragrance mix I (16%), and methylisothiazolinone (16% [2/12]). Follow-up data were available for 9 of these patients, of whom 6 (66.7%) experienced symptom improvement after 6 months of allergen avoidance. Four (44.4%) patients experienced decreased follicular redness or scaling, 2 (22.2%) patients experienced improved scalp pain/itch, 2 (22.2%) patients had stable/improved hair density, and 1 (1.1%) patient had decreased hair shedding. Although this suggests an environmental trigger for FFA/LPP, the authors stated that changes in patient treatment plans could have contributed to their improvement. The study also was limited by its small size and its overall generalizability.¹⁶

These studies have underscored the significance of patch testing in individuals diagnosed with FFA and have identified common allergens prevalent in this patient population. They have suggested that patients with FFA are more likely to have positive patch tests, and in some cases patients could experience improvements in scalp pruritus and erythema with allergen avoidance; however, we emphasize that a causal association between contact allergy and FFA remains unproven to date.

Most Common Allergens Pertinent to FFA

Preservatives—In some studies, patients with FFA have had positive patch tests to preservatives such as gallates and methylchloroisothiazolinone/methylisothiazolinone (MCI/MI).¹⁴ Gallates are antioxidants that are used in food preservation, pharmaceuticals, and cosmetics due to their ability to inhibit oxidation and rancidity of fats and oils.¹⁷ The most common gallates include propyl gallate, octyl gallate, and dodecyl gallate. Propyl gallate is utilized in some waxy or oily cosmetics and personal care items including sunscreens, shampoos, conditioners, bar soaps, facial cleansers, and moisturizers.¹⁸ Typically, if patients have a positive patch test to one gallate, they should be advised to avoid all gallate compounds, as they can cross-react.

Similarly, MCI/MI can prevent product degradation through their antibacterial and antifungal properties. This combination of MCI and MI is used as an effective method of prolonging the shelf life of cosmetic products and commonly is found in sunscreens, facial moisturizing creams, shampoos, and conditioners¹⁹; it is banned from use in leave-on products in the European Union and Canada due to increased rates of contact allergy.²⁰ In patients with FFA who commonly use facial sunscreen, preservatives can be a potential allergen exposure to consider.

Iodopropynyl butylcarbamate also is a preservative used in cosmetic formulations. Similar to MCI/MI, it is a potent fungicide and bactericide. This allergen can be found in hair care products, bodywashes, and other personal products.²¹

UV Light–Absorbing Agents—A systematic review and meta-analysis conducted in 2022 showed a significant (P<.001) association between sunscreen use and FFA.²² A majority of allergens identified on patch testing included UVA- and UVB-absorbing agents found in sunscreens and other products including cosmetics,^11,12 such as drometrizole trisiloxane, ethylhexyl salicylate, avobenzone, and benzophenone-4. Drometrizole trisiloxane is a photostabilizer and a broad-spectrum UV filter that is not approved for use in sunscreens in the United States.²³ It also is effective in stabilizing and preventing the degradation of avobenzone, a commonly used UVA filter.²⁴

Fragrances—Fragrances are present in nearly every personal and cosmetic product, sometimes even in those advertised as being “fragrance free.” Hydroperoxides of linalool, BoP, and fragrance mix are common allergens that are found in a variety of personal care products including perfumes, cosmetics, and even household cleaning supplies.²⁵ Simultaneous positive patch tests to BoP and fragrance mix are common due to shared components. Linalool can be found in various plants such as lavender, rose, bergamot, and jasmine.²⁶ Upon air exposure, linalool auto-oxidizes to form allergenic hydroperoxides of linalool. Among patients with FFA, positive patch test reactions to fragrance chemicals are common and could be attributed to the use of fragranced hair products and facial cosmetics.

Hair Dyes and Bleaches—Allergic reactions to hair dyes and bleaches can result in severe ACD of the head/neck and, in rare cases, scarring alopecia.²⁷ Chemicals found in these products include paraphenylenediamine (PPD) and ammonium persulfate. The most common hair dye allergen, PPD also is used in some rubbers and plastics. Ammonium persulfate is a chemical used in hair bleaches and to deodorize oils. One case study reported a patient with FFA who developed chemically induced vitiligo immediately after the use of a hair color product that contained PPD.²⁸ However, without patch testing to confirm the presence of contact allergy, other patient-specific and environmental risk factors could have contributed to FFA in this case.

In this endeavor to untangle the truth, it should be remembered that at the time of writing, the purported association between FFA and ACD remains debatable. Contact dermatitis specialists have voiced that the association between FFA and ACD, especially with regard to sunscreen, cannot be supported due to the lack of sufficient evidence.²⁹ A large majority of the research conducted on FFA and ACD is based on case reports and studies limited to a small sample size, and most of these patch test studies lack a control group. Felmingham et al³⁰ noted that the recent epidemiology of FFA aligns with increased sunscreen use. They also highlighted the limitations of the aforementioned studies, which include misclassification of exposures in the control group² and recall bias in questionnaire participants.^2,12 The most pressing limitation that permeates through most of these studies is the temporal ambiguity associated with sunscreen use. A study by Dhana et al³¹ failed to specify whether increased sunscreen use preceded the diagnosis of FFA or if it stems from the need to protect more exposed skin as a consequence of disease. Broad sunscreen avoidance due to concern for a possible association with hair loss could have detrimental health implications by increasing the risk for photodamage and skin cancer.

FFA Patch Testing

The avoidance of pertinent allergens could be effective in reducing local inflammation, pruritus, and erythema in FFA.^9,14,32 At our institution, we selectively patch test patients with FFA when there is a suspected contact allergy. Clinical features that may allude to a potential contact allergy include an erythematous or eczematous dermatitis or symptoms of pruritus along the scalp or eyebrows. If patients recall hair loss or symptoms after using a hair or facial product, then a potential contact allergy to these products could be considered. Patch testing in patients with FFA includes the North American 80 Comprehensive Series and the cosmetic and hairdresser supplemental series, as well as an additional customized panel of 8 allergens as determined by patch testing experts at the University of Massachusetts, Brigham and Women’s Hospital, and Massachusetts General Hospital (private email communication, November 2017). Patch test readings are performed at 48 and 96 or 120 hours. Using the American Contact Dermatitis Society’s Contact Allergen Management Program, patients are provided personalized safe product lists and avoidance strategies are discussed.

Final Interpretation

In a world where cosmetic products are ubiquitous, it is hard to define the potential role of contact allergens in the entangled pathogenesis of FFA and ACD. As evidenced by emerging literature that correlates the 2 conditions and their exacerbating factors, it is important for physicians to have a comprehensive diagnostic approach and heightened awareness for potential allergens at play in FFA (Table). The identification of certain chemicals and preservatives as potential triggers for FFA should emphasize the importance of patch testing in these patients; however, whether the positive reactions are relevant to the pathogenesis or disease course of FFA still is unknown. While these findings begin to unravel the intertwined causes of FFA and ACD, further research encompassing larger cohorts and prospective studies is imperative to solidify these associations, define concrete guidelines, and improve patient outcomes.

Frontal fibrosing alopecia (FFA) is an increasingly common diagnosis, especially in middle-aged women, and was first described by Kossard¹ in 1994. It is a variant of lichen planopilaris (LPP), a progressive scarring cicatricial alopecia that affects the frontotemporal area of the scalp, eyebrows, and sometimes even body hair.¹ Although its etiology remains unclear, genetic causes, drugs, hormones, and environmental exposures—including certain chemicals found in sunscreens—have been implicated in its pathogenesis.^2,3 An association between contact allergy to ingredients in personal care products and FFA diagnosis has been suggested; however, there is no evidence of causality to date. In this article, we highlight the potential relationship between contact allergy and FFA as well as clinical considerations for management.

Clinical Features and Diagnosis

Frontal fibrosing alopecia typically manifests with gradual symmetric recession of the frontal hairline leading to bandlike hair loss along the forehead, sometimes extending to the temporal region.⁴ Some patients may experience symptoms of scalp itching, burning, or tenderness that may precede or accompany the hair loss. Perifollicular erythema may be visible during the early stages and can be visualized on trichoscopy. The affected skin may appear pale and shiny and may have a smooth texture with a distinct lack of follicular openings. Aside from scalp involvement, other manifestations may include lichen planus pigmentosus, facial papules, body hair involvement, hypochromic lesions, diffuse redness on the face and neck, and prominent frontal veins.⁵ Although most FFA cases have characteristic clinical features and trichoscopic findings, biopsy for histopathologic examination is still recommended to confirm the diagnosis and ensure appropriate treatment.⁴ Classic histopathologic features include perifollicular lymphocytic inflammation, follicular destruction, and scarring.

Pathophysiology of FFA

The pathogenesis of FFA is thought to involve a variety of triggers, including immune-mediated inflammation, stress, genetics, hormones, and possibly environmental factors.⁶ Frontal fibrosing alopecia demonstrates considerable upregulation in cytotoxic helper T cells (T_H1) and IFN-γ activity resulting in epithelial hair follicle stem cell apoptosis and replacement of normal epithelial tissue with fibrous tissue.⁷ There is some suspicion of genetic susceptibility in the onset of FFA as suggested by familial reports and genome-wide association studies.^8-10 Hormonal and autoimmune factors also have been linked to FFA, including an increased risk for thyroid disease and the postmenopausal rise of androgen levels.⁶

Allergic Contact Dermatitis and FFA

Although they are 2 distinct conditions with differing etiologies, allergic contact dermatitis (ACD) and FFA may share environmental triggers, especially in susceptible individuals. This may support the coexistence and potential association between ACD and FFA.

In one case report, a woman who developed facial eczema followed by FFA showed positive patch tests to the UV filters drometrizole trisiloxane and ethylhexyl salicylate, which were listed as ingredients in her sunscreens. Avoidance of these allergens reportedly led to notable improvement of the symptoms.¹¹ Case-control studies have found an association between the use of facial sunscreen and risk for FFA.¹² A 2016 questionnaire that assessed a wide range of lifestyle, social, and medical factors related to FFA found that the use of sunscreens was significantly higher in patients with FFA than controls (P<.001), pointing to sunscreens as a potential contributing factor, but further research has been inconclusive. A higher frequency of positive patch tests to hydroperoxides of linalool and balsam of Peru (BoP) in patients with FFA have been documented; however, a direct cause cannot be established.²

In a 2020 prospective study conducted at multiple international centers, 65% (13/20) of FFA patients and 37.5% (9/24) of the control group had a positive patch test reaction to one or more allergens (P=.003). The most common allergens that were identified included cobalt chloride (positive in 35% [7/20] of patients with FFA), nickel sulfate (25% [5/20]), and potassium dichromate (15% [3/20]).¹³ In a recent 2-year cohort study of 42 patients with FFA who were referred for patch testing, the most common allergens included gallates, hydroperoxides of linalool, and other fragrances.¹⁴ After a 3-month period of allergen avoidance, 70% (29/42) of patients had decreased scalp erythema on examination, indicating that avoiding relevant allergens may reduce local inflammation. Furthermore, 76.2% (32/42) of patients with FFA showed delayed-type hypersensitivity to allergens found in daily personal care products such as shampoos, sunscreens, and moisturizers, among others.¹⁴ Notably, the study lacked a control group. A case-control study of 36 Hispanic women conducted in Mexico also resulted in 83.3% (15/18) of patients with FFA and 55.5% (10/18) of controls having at least 1 positive patch test; in the FFA group, these included iodopropynyl butylcarbamate (16.7% [3/18]) and propolis (16.7% [3/18]).¹⁵

Most recently, a retrospective study conducted by Shtaynberger et al¹⁶ included 12 patients with LPP or FFA diagnosed via clinical findings or biopsy. It also included an age- and temporally matched control group tested with identical allergens. Among the 12 patients who had FFA/LPP, all had at least 1 allergen identified on patch testing. The most common allergens identified were propolis (positive in 50% [6/12] of patients with FFA/LPP), fragrance mix I (16%), and methylisothiazolinone (16% [2/12]). Follow-up data were available for 9 of these patients, of whom 6 (66.7%) experienced symptom improvement after 6 months of allergen avoidance. Four (44.4%) patients experienced decreased follicular redness or scaling, 2 (22.2%) patients experienced improved scalp pain/itch, 2 (22.2%) patients had stable/improved hair density, and 1 (1.1%) patient had decreased hair shedding. Although this suggests an environmental trigger for FFA/LPP, the authors stated that changes in patient treatment plans could have contributed to their improvement. The study also was limited by its small size and its overall generalizability.¹⁶

These studies have underscored the significance of patch testing in individuals diagnosed with FFA and have identified common allergens prevalent in this patient population. They have suggested that patients with FFA are more likely to have positive patch tests, and in some cases patients could experience improvements in scalp pruritus and erythema with allergen avoidance; however, we emphasize that a causal association between contact allergy and FFA remains unproven to date.

Most Common Allergens Pertinent to FFA

Preservatives—In some studies, patients with FFA have had positive patch tests to preservatives such as gallates and methylchloroisothiazolinone/methylisothiazolinone (MCI/MI).¹⁴ Gallates are antioxidants that are used in food preservation, pharmaceuticals, and cosmetics due to their ability to inhibit oxidation and rancidity of fats and oils.¹⁷ The most common gallates include propyl gallate, octyl gallate, and dodecyl gallate. Propyl gallate is utilized in some waxy or oily cosmetics and personal care items including sunscreens, shampoos, conditioners, bar soaps, facial cleansers, and moisturizers.¹⁸ Typically, if patients have a positive patch test to one gallate, they should be advised to avoid all gallate compounds, as they can cross-react.

Similarly, MCI/MI can prevent product degradation through their antibacterial and antifungal properties. This combination of MCI and MI is used as an effective method of prolonging the shelf life of cosmetic products and commonly is found in sunscreens, facial moisturizing creams, shampoos, and conditioners¹⁹; it is banned from use in leave-on products in the European Union and Canada due to increased rates of contact allergy.²⁰ In patients with FFA who commonly use facial sunscreen, preservatives can be a potential allergen exposure to consider.

Iodopropynyl butylcarbamate also is a preservative used in cosmetic formulations. Similar to MCI/MI, it is a potent fungicide and bactericide. This allergen can be found in hair care products, bodywashes, and other personal products.²¹

UV Light–Absorbing Agents—A systematic review and meta-analysis conducted in 2022 showed a significant (P<.001) association between sunscreen use and FFA.²² A majority of allergens identified on patch testing included UVA- and UVB-absorbing agents found in sunscreens and other products including cosmetics,^11,12 such as drometrizole trisiloxane, ethylhexyl salicylate, avobenzone, and benzophenone-4. Drometrizole trisiloxane is a photostabilizer and a broad-spectrum UV filter that is not approved for use in sunscreens in the United States.²³ It also is effective in stabilizing and preventing the degradation of avobenzone, a commonly used UVA filter.²⁴

Fragrances—Fragrances are present in nearly every personal and cosmetic product, sometimes even in those advertised as being “fragrance free.” Hydroperoxides of linalool, BoP, and fragrance mix are common allergens that are found in a variety of personal care products including perfumes, cosmetics, and even household cleaning supplies.²⁵ Simultaneous positive patch tests to BoP and fragrance mix are common due to shared components. Linalool can be found in various plants such as lavender, rose, bergamot, and jasmine.²⁶ Upon air exposure, linalool auto-oxidizes to form allergenic hydroperoxides of linalool. Among patients with FFA, positive patch test reactions to fragrance chemicals are common and could be attributed to the use of fragranced hair products and facial cosmetics.

Hair Dyes and Bleaches—Allergic reactions to hair dyes and bleaches can result in severe ACD of the head/neck and, in rare cases, scarring alopecia.²⁷ Chemicals found in these products include paraphenylenediamine (PPD) and ammonium persulfate. The most common hair dye allergen, PPD also is used in some rubbers and plastics. Ammonium persulfate is a chemical used in hair bleaches and to deodorize oils. One case study reported a patient with FFA who developed chemically induced vitiligo immediately after the use of a hair color product that contained PPD.²⁸ However, without patch testing to confirm the presence of contact allergy, other patient-specific and environmental risk factors could have contributed to FFA in this case.

In this endeavor to untangle the truth, it should be remembered that at the time of writing, the purported association between FFA and ACD remains debatable. Contact dermatitis specialists have voiced that the association between FFA and ACD, especially with regard to sunscreen, cannot be supported due to the lack of sufficient evidence.²⁹ A large majority of the research conducted on FFA and ACD is based on case reports and studies limited to a small sample size, and most of these patch test studies lack a control group. Felmingham et al³⁰ noted that the recent epidemiology of FFA aligns with increased sunscreen use. They also highlighted the limitations of the aforementioned studies, which include misclassification of exposures in the control group² and recall bias in questionnaire participants.^2,12 The most pressing limitation that permeates through most of these studies is the temporal ambiguity associated with sunscreen use. A study by Dhana et al³¹ failed to specify whether increased sunscreen use preceded the diagnosis of FFA or if it stems from the need to protect more exposed skin as a consequence of disease. Broad sunscreen avoidance due to concern for a possible association with hair loss could have detrimental health implications by increasing the risk for photodamage and skin cancer.

FFA Patch Testing

The avoidance of pertinent allergens could be effective in reducing local inflammation, pruritus, and erythema in FFA.^9,14,32 At our institution, we selectively patch test patients with FFA when there is a suspected contact allergy. Clinical features that may allude to a potential contact allergy include an erythematous or eczematous dermatitis or symptoms of pruritus along the scalp or eyebrows. If patients recall hair loss or symptoms after using a hair or facial product, then a potential contact allergy to these products could be considered. Patch testing in patients with FFA includes the North American 80 Comprehensive Series and the cosmetic and hairdresser supplemental series, as well as an additional customized panel of 8 allergens as determined by patch testing experts at the University of Massachusetts, Brigham and Women’s Hospital, and Massachusetts General Hospital (private email communication, November 2017). Patch test readings are performed at 48 and 96 or 120 hours. Using the American Contact Dermatitis Society’s Contact Allergen Management Program, patients are provided personalized safe product lists and avoidance strategies are discussed.

Final Interpretation

In a world where cosmetic products are ubiquitous, it is hard to define the potential role of contact allergens in the entangled pathogenesis of FFA and ACD. As evidenced by emerging literature that correlates the 2 conditions and their exacerbating factors, it is important for physicians to have a comprehensive diagnostic approach and heightened awareness for potential allergens at play in FFA (Table). The identification of certain chemicals and preservatives as potential triggers for FFA should emphasize the importance of patch testing in these patients; however, whether the positive reactions are relevant to the pathogenesis or disease course of FFA still is unknown. While these findings begin to unravel the intertwined causes of FFA and ACD, further research encompassing larger cohorts and prospective studies is imperative to solidify these associations, define concrete guidelines, and improve patient outcomes.

Frontal fibrosing alopecia (FFA) is an increasingly common diagnosis, especially in middle-aged women, and was first described by Kossard¹ in 1994. It is a variant of lichen planopilaris (LPP), a progressive scarring cicatricial alopecia that affects the frontotemporal area of the scalp, eyebrows, and sometimes even body hair.¹ Although its etiology remains unclear, genetic causes, drugs, hormones, and environmental exposures—including certain chemicals found in sunscreens—have been implicated in its pathogenesis.^2,3 An association between contact allergy to ingredients in personal care products and FFA diagnosis has been suggested; however, there is no evidence of causality to date. In this article, we highlight the potential relationship between contact allergy and FFA as well as clinical considerations for management.

Clinical Features and Diagnosis

Frontal fibrosing alopecia typically manifests with gradual symmetric recession of the frontal hairline leading to bandlike hair loss along the forehead, sometimes extending to the temporal region.⁴ Some patients may experience symptoms of scalp itching, burning, or tenderness that may precede or accompany the hair loss. Perifollicular erythema may be visible during the early stages and can be visualized on trichoscopy. The affected skin may appear pale and shiny and may have a smooth texture with a distinct lack of follicular openings. Aside from scalp involvement, other manifestations may include lichen planus pigmentosus, facial papules, body hair involvement, hypochromic lesions, diffuse redness on the face and neck, and prominent frontal veins.⁵ Although most FFA cases have characteristic clinical features and trichoscopic findings, biopsy for histopathologic examination is still recommended to confirm the diagnosis and ensure appropriate treatment.⁴ Classic histopathologic features include perifollicular lymphocytic inflammation, follicular destruction, and scarring.

Pathophysiology of FFA

The pathogenesis of FFA is thought to involve a variety of triggers, including immune-mediated inflammation, stress, genetics, hormones, and possibly environmental factors.⁶ Frontal fibrosing alopecia demonstrates considerable upregulation in cytotoxic helper T cells (T_H1) and IFN-γ activity resulting in epithelial hair follicle stem cell apoptosis and replacement of normal epithelial tissue with fibrous tissue.⁷ There is some suspicion of genetic susceptibility in the onset of FFA as suggested by familial reports and genome-wide association studies.^8-10 Hormonal and autoimmune factors also have been linked to FFA, including an increased risk for thyroid disease and the postmenopausal rise of androgen levels.⁶

Allergic Contact Dermatitis and FFA

Although they are 2 distinct conditions with differing etiologies, allergic contact dermatitis (ACD) and FFA may share environmental triggers, especially in susceptible individuals. This may support the coexistence and potential association between ACD and FFA.

In one case report, a woman who developed facial eczema followed by FFA showed positive patch tests to the UV filters drometrizole trisiloxane and ethylhexyl salicylate, which were listed as ingredients in her sunscreens. Avoidance of these allergens reportedly led to notable improvement of the symptoms.¹¹ Case-control studies have found an association between the use of facial sunscreen and risk for FFA.¹² A 2016 questionnaire that assessed a wide range of lifestyle, social, and medical factors related to FFA found that the use of sunscreens was significantly higher in patients with FFA than controls (P<.001), pointing to sunscreens as a potential contributing factor, but further research has been inconclusive. A higher frequency of positive patch tests to hydroperoxides of linalool and balsam of Peru (BoP) in patients with FFA have been documented; however, a direct cause cannot be established.²

In a 2020 prospective study conducted at multiple international centers, 65% (13/20) of FFA patients and 37.5% (9/24) of the control group had a positive patch test reaction to one or more allergens (P=.003). The most common allergens that were identified included cobalt chloride (positive in 35% [7/20] of patients with FFA), nickel sulfate (25% [5/20]), and potassium dichromate (15% [3/20]).¹³ In a recent 2-year cohort study of 42 patients with FFA who were referred for patch testing, the most common allergens included gallates, hydroperoxides of linalool, and other fragrances.¹⁴ After a 3-month period of allergen avoidance, 70% (29/42) of patients had decreased scalp erythema on examination, indicating that avoiding relevant allergens may reduce local inflammation. Furthermore, 76.2% (32/42) of patients with FFA showed delayed-type hypersensitivity to allergens found in daily personal care products such as shampoos, sunscreens, and moisturizers, among others.¹⁴ Notably, the study lacked a control group. A case-control study of 36 Hispanic women conducted in Mexico also resulted in 83.3% (15/18) of patients with FFA and 55.5% (10/18) of controls having at least 1 positive patch test; in the FFA group, these included iodopropynyl butylcarbamate (16.7% [3/18]) and propolis (16.7% [3/18]).¹⁵

Most recently, a retrospective study conducted by Shtaynberger et al¹⁶ included 12 patients with LPP or FFA diagnosed via clinical findings or biopsy. It also included an age- and temporally matched control group tested with identical allergens. Among the 12 patients who had FFA/LPP, all had at least 1 allergen identified on patch testing. The most common allergens identified were propolis (positive in 50% [6/12] of patients with FFA/LPP), fragrance mix I (16%), and methylisothiazolinone (16% [2/12]). Follow-up data were available for 9 of these patients, of whom 6 (66.7%) experienced symptom improvement after 6 months of allergen avoidance. Four (44.4%) patients experienced decreased follicular redness or scaling, 2 (22.2%) patients experienced improved scalp pain/itch, 2 (22.2%) patients had stable/improved hair density, and 1 (1.1%) patient had decreased hair shedding. Although this suggests an environmental trigger for FFA/LPP, the authors stated that changes in patient treatment plans could have contributed to their improvement. The study also was limited by its small size and its overall generalizability.¹⁶

These studies have underscored the significance of patch testing in individuals diagnosed with FFA and have identified common allergens prevalent in this patient population. They have suggested that patients with FFA are more likely to have positive patch tests, and in some cases patients could experience improvements in scalp pruritus and erythema with allergen avoidance; however, we emphasize that a causal association between contact allergy and FFA remains unproven to date.

Most Common Allergens Pertinent to FFA

Preservatives—In some studies, patients with FFA have had positive patch tests to preservatives such as gallates and methylchloroisothiazolinone/methylisothiazolinone (MCI/MI).¹⁴ Gallates are antioxidants that are used in food preservation, pharmaceuticals, and cosmetics due to their ability to inhibit oxidation and rancidity of fats and oils.¹⁷ The most common gallates include propyl gallate, octyl gallate, and dodecyl gallate. Propyl gallate is utilized in some waxy or oily cosmetics and personal care items including sunscreens, shampoos, conditioners, bar soaps, facial cleansers, and moisturizers.¹⁸ Typically, if patients have a positive patch test to one gallate, they should be advised to avoid all gallate compounds, as they can cross-react.

Similarly, MCI/MI can prevent product degradation through their antibacterial and antifungal properties. This combination of MCI and MI is used as an effective method of prolonging the shelf life of cosmetic products and commonly is found in sunscreens, facial moisturizing creams, shampoos, and conditioners¹⁹; it is banned from use in leave-on products in the European Union and Canada due to increased rates of contact allergy.²⁰ In patients with FFA who commonly use facial sunscreen, preservatives can be a potential allergen exposure to consider.

Iodopropynyl butylcarbamate also is a preservative used in cosmetic formulations. Similar to MCI/MI, it is a potent fungicide and bactericide. This allergen can be found in hair care products, bodywashes, and other personal products.²¹

UV Light–Absorbing Agents—A systematic review and meta-analysis conducted in 2022 showed a significant (P<.001) association between sunscreen use and FFA.²² A majority of allergens identified on patch testing included UVA- and UVB-absorbing agents found in sunscreens and other products including cosmetics,^11,12 such as drometrizole trisiloxane, ethylhexyl salicylate, avobenzone, and benzophenone-4. Drometrizole trisiloxane is a photostabilizer and a broad-spectrum UV filter that is not approved for use in sunscreens in the United States.²³ It also is effective in stabilizing and preventing the degradation of avobenzone, a commonly used UVA filter.²⁴

Fragrances—Fragrances are present in nearly every personal and cosmetic product, sometimes even in those advertised as being “fragrance free.” Hydroperoxides of linalool, BoP, and fragrance mix are common allergens that are found in a variety of personal care products including perfumes, cosmetics, and even household cleaning supplies.²⁵ Simultaneous positive patch tests to BoP and fragrance mix are common due to shared components. Linalool can be found in various plants such as lavender, rose, bergamot, and jasmine.²⁶ Upon air exposure, linalool auto-oxidizes to form allergenic hydroperoxides of linalool. Among patients with FFA, positive patch test reactions to fragrance chemicals are common and could be attributed to the use of fragranced hair products and facial cosmetics.

Hair Dyes and Bleaches—Allergic reactions to hair dyes and bleaches can result in severe ACD of the head/neck and, in rare cases, scarring alopecia.²⁷ Chemicals found in these products include paraphenylenediamine (PPD) and ammonium persulfate. The most common hair dye allergen, PPD also is used in some rubbers and plastics. Ammonium persulfate is a chemical used in hair bleaches and to deodorize oils. One case study reported a patient with FFA who developed chemically induced vitiligo immediately after the use of a hair color product that contained PPD.²⁸ However, without patch testing to confirm the presence of contact allergy, other patient-specific and environmental risk factors could have contributed to FFA in this case.

In this endeavor to untangle the truth, it should be remembered that at the time of writing, the purported association between FFA and ACD remains debatable. Contact dermatitis specialists have voiced that the association between FFA and ACD, especially with regard to sunscreen, cannot be supported due to the lack of sufficient evidence.²⁹ A large majority of the research conducted on FFA and ACD is based on case reports and studies limited to a small sample size, and most of these patch test studies lack a control group. Felmingham et al³⁰ noted that the recent epidemiology of FFA aligns with increased sunscreen use. They also highlighted the limitations of the aforementioned studies, which include misclassification of exposures in the control group² and recall bias in questionnaire participants.^2,12 The most pressing limitation that permeates through most of these studies is the temporal ambiguity associated with sunscreen use. A study by Dhana et al³¹ failed to specify whether increased sunscreen use preceded the diagnosis of FFA or if it stems from the need to protect more exposed skin as a consequence of disease. Broad sunscreen avoidance due to concern for a possible association with hair loss could have detrimental health implications by increasing the risk for photodamage and skin cancer.

FFA Patch Testing

The avoidance of pertinent allergens could be effective in reducing local inflammation, pruritus, and erythema in FFA.^9,14,32 At our institution, we selectively patch test patients with FFA when there is a suspected contact allergy. Clinical features that may allude to a potential contact allergy include an erythematous or eczematous dermatitis or symptoms of pruritus along the scalp or eyebrows. If patients recall hair loss or symptoms after using a hair or facial product, then a potential contact allergy to these products could be considered. Patch testing in patients with FFA includes the North American 80 Comprehensive Series and the cosmetic and hairdresser supplemental series, as well as an additional customized panel of 8 allergens as determined by patch testing experts at the University of Massachusetts, Brigham and Women’s Hospital, and Massachusetts General Hospital (private email communication, November 2017). Patch test readings are performed at 48 and 96 or 120 hours. Using the American Contact Dermatitis Society’s Contact Allergen Management Program, patients are provided personalized safe product lists and avoidance strategies are discussed.

Final Interpretation

In a world where cosmetic products are ubiquitous, it is hard to define the potential role of contact allergens in the entangled pathogenesis of FFA and ACD. As evidenced by emerging literature that correlates the 2 conditions and their exacerbating factors, it is important for physicians to have a comprehensive diagnostic approach and heightened awareness for potential allergens at play in FFA (Table). The identification of certain chemicals and preservatives as potential triggers for FFA should emphasize the importance of patch testing in these patients; however, whether the positive reactions are relevant to the pathogenesis or disease course of FFA still is unknown. While these findings begin to unravel the intertwined causes of FFA and ACD, further research encompassing larger cohorts and prospective studies is imperative to solidify these associations, define concrete guidelines, and improve patient outcomes.