Perfumes and associated allergens: A brief review

History of perfumes

The history of perfumes dates back to antiquity when scented balms and ointments were blended for Egyptian elites who otherwise routinely used fragrant oils, considered as the sweat of the sun God Ra, for cleansing and bathing. Ancient Romans used incense for religious ceremonies and sprinkled rose-scented water to mask the foul smell of city life. The ancient Greeks believed that fragrances improved health and vitality and wearing a sweet-smelling fragrance was pleasing to the Gods. The use of scents also spread throughout the ancient world and to other cultures including the Iranians and Chinese. The use of perfume and art of perfumery in India dates back to Indus civilization (3300–1300 BC) and finds mention of Ittar in ancient Indian texts of Charaka Samhita and Sushruta Samhita. Although Hungarians were first to introduce modern perfume, the modern-day perfumery evolved more in France that till date remains the center of the European perfume trade and design with significant contribution from Germany and England in the modernization of art of perfumery.

Composition of perfumes

A perfume is prepared by combining three different ingredients; synthetic or natural essential oils for fragrance (for instance, citral, jasmine, granial, sandalwood oil, ylang-ylang oil) constituting about 15–30% in a solvent (water 2% and alcohol 98%) to dissolve perfume oils. In general, the major constituent of a perfume is fragrance materials or substances having pleasant odors which are complex mixtures of natural or manmade chemical substances. Fragrances are added to a cosmetic product to impart a pleasant odor when applied to the body or to mask an unpleasant odor of some other ingredients to enhance acceptability and the experience of its usage by signaling cleanliness or freshness, creating a sense of well-being, and make it more pleasing to the user or the companions. Over the years there has been a significant advancement in the science of perfumery and fragrances sourced from plants and animals (e.g., musk deer) in more scientific ways for preparing new chemicals and controlling their quality and composition. The knowledge of the physical, chemical, biochemical, and biological properties of the various substances to be used as fragrances is imperative. Additionally, several other factors such as desired strength of the scent, degree of volatility, compatibility, interaction, and properties of each ingredient to produce the desired odor when applied to the skin, and the effect of heat, light, and packaging on its stability also need to be considered to formulate a fragrance.^[7] The interplay of these properties is important to achieve a desired aesthetically pleasing final effect. Alcohol acts as a preservative and antimicrobial and helps in spreading the fragrance. The fixatives (benzyl alcohol, benzyl benzoate) are added to reduce the evaporation of volatile ingredients.^[8,9] A fixative can be an odorless substance or the fragrance material itself characterized by low volatility.

Perfumes can be classified into two broad types depending on, (a) the concentration of fragrance ingredients and its lasting effect and, (b) the “perfume essence” or what actually makes the scent, usually a combination of essential oils (cedarwood, sandalwood, lime, etc), absolutes (jasmine, neroli, rose), animal extracts (musk, ambergris), and synthetic fragrances [Table 1].^[8,9] A perfume generally constitutes a few to several hundred fragrance materials in a predetermined optimal strength of which 300–400 are of natural origin.^[10] The volatility of all raw materials plays an important role as the fragrance character evolves over time after application. There are three essential parts of a perfume called “notes” used to formulate a scent that is more harmonious. The most volatile ingredients the “top notes” fade away quickly and are recognized first after the application. The middle notes, the “bouquet” or “heart notes” take a longer time to fade away and form the main concept of the perfume. They mainly conceal the displeasing initial “base notes” or “bottom” or the “dry out” which are long-lasting materials remaining on the skin and providing solidity and depth to a perfume.^[10] However, perfume is usually developed for a particular purpose, to be used in cosmetics or household products, and to retain the same fragrance its composition may need to be restructured depending on the type of product [Table 2.^[10,11]

Epidemiology of perfume allergy

Although the exact prevalence of fragrance allergy in India remains understudied, up to 4.5% of the European adults have a contact allergy to one or more fragrances with an estimated prevalence of 1.9% for clinically relevant fragrance contact allergy.^[12] Allergy to cosmetic ingredients, fragrances, in particular, is four times more prevalent in females than in males and most patients are between the age of 20 and 55 years.^[13,14] This generally alludes to greater use of cosmetics by women and consequently the higher chances of exposure to many allergenic ingredients in cosmetics.

Perfume allergens and sources of their exposure

As stated earlier fragrances remain the major allergens in perfumes or other products of daily use including cosmetics. Since an extensive review on individual fragrances and essential oils is beyond the scope of this article, more details are available to the interested readers in an excellent review by deGroot.^[4] Reportedly, there are about 162 fragrances, both single and complex mixtures of chemicals (methyl ionones), or essential oils (Evernia furfuracea (treemoss) extract, E. prunastri (oakmoss) extract, Ferula gummosa gum, Narcissus poeticus flower extract, Viola odorata leaf extract) that have caused contact allergy/allergic contact dermatitis.^[9] Depending upon the evidence available these have been categorized as ‘established,” “possible,” or “likely” contact allergens on the basis of positive results in the general population and/or in patients/individuals with positive results in suspected contact dermatitis to fragrances [Table 3].^[9,15]

Cosmetics and personal care products such as personal perfume(s), deodorant, aftershave lotion/gel, eau de cologne, and eau de toilette with the highest concentrations of fragrances are complex mixtures of perfumes, emulsifiers, various lipids, preservatives, stabilizers, and higher alcohols. These may not be the only source but remain the major source of exposure to perfumes and fragrances. Additionally, many household products also contain fragrance materials unless specified otherwise. Even the so-called “fragrance free” products may contain perfume or essential oil to mask the unpleasant odor of an ingredient or the final product itself. Flavoring agents such as carvone and menthoxypropanediol in toothpaste or lip cosmetics are other considered contact sensitizers.^[16,17] For the records, it may be mentioned here that a mixture of methylisothiazolinone and its chlorinated derivative methylchloroisothiazolinone (Kathon CG), a preservative, both in rinse-off (shampoos, liquid soaps) and leave-on (wet wipes facial skin-care products, body lotions, deodorants) cosmetic products have caused contact allergic reactions in epidemic proportions worldwide in recent years.^[18,19] Polyhexamethylene biguanide (syn. polyaminopropyl biguanide, polyhexanide), a disinfectant and antiseptic, has shown to be another potential allergen in wet wipes and facial make-up cleansers, inducing both delayed-type eczematous and severe immediate-type reactions—contact urticaria syndrome.^[20]–^[22]

Adverse reactions due to fragrances in perfumes

[Table 4] lists various adverse effects and relevant fragrances in detail.^[9,23] Exposure to fragrances in perfumes can cause a variety of adverse effects including irritant contact dermatitis, allergic contact dermatitis, contact urticaria, photoallergic reaction, pigmented contact (cosmetic) dermatitis, or systemic reactions such as respiratory symptoms, headache, and attacks of migraine in some individuals following systemic exposure.^[10] Allergic contact dermatitis accounts for the most adverse effects related to fragrance ingredients in perfumes affecting 1–3% of the European population while 16% of eczema patients are sensitized to fragrance ingredients.^[24,25] Colophony, Myroxylon pereirae, lanolin, formaldehyde, vanillin, musk mix, rose oil, cetostearyl alcohol, fragrances, and antiseptics such as cetrimide and triclosan in cosmetics have caused vide array of dermatological problems including primary irritant reactions, allergic contact dermatitis, photosensitivity and photodermatitis, contact urticaria, skin dyspigmentation, and brittle nails and hair.Ylang-ylang oil, jasmine absolute, Cananga oil, benzyl salicylate, hydroxyl citronellal, sandalwood, geraniol are common fragrances to cause pigmentary changes.^[8,26] Bergamot oil in eau-de-cologne and tar derivatives in cosmetics have been implicated for hyperpigmentation in Riehl’s melanosis, erythrosis pigmentata faciei of Brocq, poikiloderma of Civatte, and Berloque dermatitis.^[27] A subclinical contact dermatitis and postinflammatory cytolysis of melanocytes have been implicated often for this increased pigmentation involving mainly the face or neck. Excipients, the inert substances used to solubilize, foam, lubricate, thicken, emulsify, sequester, or color the active component in a formulation, may act as irritants in higher concentrations or cause allergic contact dermatitis when applied directly with the allergen-containing formulation. Gallate mix (dodecyl gallate, octyl gallate, propyl gallate), used as antioxidant and preservative in leave-on creams, moisturizers, body lotions, and another rinse-off hair and body cleansers and topical formulations, has been implicated for rising propyl gallate allergy in recent years.^[28,29]

Myroxylon pereirae and vanillin, the common additives to cosmetics and skincare products, are often considered markers of fragrance allergy and are known to induce contact sensitivity. Citral, used as an individual fragrance ingredient, is also a potential irritant. Musk ambrette and 6-methyl coumarin had been responsible for a number of photoallergic contact reactions with actinic reticuloid syndrome in Europe in the 1970s and mid-1980s.^[30,31,32] Bergapten (5-methoxypsoralen) in citrus peel essential oils is a naturally occurring phototoxic furocoumarin that can cause phototoxic reactions.^[33] Cinnamic acid, cinnamal, and Myroxylon pereirae are also well recognized among several other fragrance allergens to induce contact urticaria.^[9]

Diagnosis of allergic contact sensitivity from fragrances

The diagnosis of contact sensitivity from a fragrant ingredient in a perfume or perfumed product rests on the detailed clinical history of the patient, clinical picture, identification of putative allergenic ingredient by patch testing and careful interpretation of patch test results for their clinical relevance, and improvement/healing of dermatitis after avoiding the culprit allergen. History of preexisting irritant dermatitis or atopic dermatitis is a predisposing factor for contact dermatitis from fragrances owing to their ubiquitous presence in topical formulations and other perfumed products of daily use. Microtrauma of shaving will facilitate contact sensitivity/dermatitis among men because of fragrances in aftershave or deodorants.

Clinically, after sensitization from cosmetics/products having fragrances in high concentration, new-onset dermatitis may appear or preexisting dermatitis worsens (as in perianal or vulvar dermatitis) or gets perpetuated to become chronic (as in hand dermatitis) even from the use of cosmetics, household or industrial products, and flavors with low fragrance levels. While new-onset dermatitis varying in severity from mild to severe with dissemination is an important feature, contact sensitivity from fragrances usually aggravates preexisting dermatitis of the hands, axillae, face, and neck. The axillae remain the most significant area predisposed for dermatitis from fragrances used in deodorants [Figure 1] as the skin is easily irritated due to occlusion and resultant warmth and moisture. Other sites where perfumes are dabbed directly (behind the ears, upper chest, cubital fossae, and wrists) or scented deodorant is applied (axillae) or sprayed (neck, chest, and axillae) will also develop patches of dermatitis [Figures 23–4] with a corroborating history of a similar rash previously. Pigmented contact (cosmetic) dermatitis [Figure 5] is another manifestation of contact allergy from above-stated fragrance ingredients in perfumes.

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Figure 1:

A patch of acute allergic contact dermatitis in the axilla caused by fragrance ingredients in antiperspirant deodorant. Other axilla was also involved similarly.

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Figure 2:

Allergic contact dermatitis of the chest from a perfume spray.

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Figure 3:

Contact dermatitis over neck because of dabbed perfume.

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Figure 4:

Allergic contact dermatitis of face and eyelids from a perfume sprayed playfully by her grandchild.

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Figure 5:

Pigmented contact dermatitis in the axilla caused by cologne spray.

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Patches of dermatitis because of sensitivity from fragrances with oozing and crusting occur in the acute phase of contact dermatitis or can resemble nummular eczema, seborrheic dermatitis, sycosis barbae, pustular contact dermatitis (in atopic individuals particularly), and sometimes may even mimic atopic dermatitis, erythema multiforme, or lupus erythematosus and bullous impetigo or toxic epidermal necrolysis when irritant dermatitis is severe and extensive. Occasionally, patients may experience photo-reaction from contact with a photo-allergen present in perfumed cosmetics and exposure to sunlight especially ultraviolet—A light or numerous allergic reactions due to fragrant products of daily use. Dyshidrotic hand eczema and widespread id-eruptions are also ascribed to systemic contact dermatitis from ingestion of spices and flavored foods and beverages.

Although about 75% of patients with positive patch test from fragrances may not be aware of their allergy, anamnesis analysis will show that most patients with contact sensitivity to fragrance ingredients are aware of their intolerance and often recall the name of product especially deodorants, colognes, eau de toilette, or another perfumed cosmetic that had initiated their disease at first instance.^[9,34] Nevertheless, many patients with positive patch test results seem to tolerate perfumes and scented products in daily life without developing allergic contact dermatitis from fragrance ingredients. It is also possible that individuals with positive results who are exposed to a putative allergen may not necessarily develop hypersensitivity clinically while many others who develop a rash from perfumes or scented products are not allergic by patch testing.^[35] This is perhaps because of false-positive (irritant effect) patch test reactions or immediate-type effects to fragrances, the relevant concentration of allergens is too low to elicit clinical contact reactions, allergens are not present in the products used, or simply because of technical limitations of patch testing procedures.^[15,36] Adequate testing is further limited by the fact that a perfume may contain more than 250 individual ingredients and the sensitizing fragrance ingredient is not included in the used patch test series.^[9]

The most baseline series, used routinely for patch testing in patients suspected of having contact dermatitis, contain the common fragrance allergens and the “indicators” of fragrance allergy that is fragrance mix I, fragrance mix II, and Myroxylon pereirae (balsam of Peru), and lichen acids indicative of allergy to treemoss and/or oakmoss extract (Indian baseline series has only fragrance mix I, Myroxylon pereirae, colophonium). Colophonium (rosin) was considered a marker for fragrance allergy previously is not an ideal fragrance allergy marker as it identifies very few cases otherwise not detected by other markers.^[34] However, when there is a strong clinical suspicion of fragrance allergy, testing with a “fragrance series” [Tables 5 and 6] along with additional fragrances and/or essential oils is strongly recommended to identify any additional cases of fragrance contact allergy. Patch testing with the patient’s own cosmetic products suspected of causing contact sensitivity is also important as in nearly 50% of cases relevant allergic reactions to perfumes, deodorants, and shaving lotions are not identified by any fragrance indicator.^[37] Furthermore, a much lower concentration of a contact sensitizer in end products may be another reason for a dissociation between the patch test results from individual ingredients and the tested product.^[38] It is also possible that ascertaining the relevance of all positive results may remain difficult as the manufacturers usually do not label all ingredients over a cosmetic package. However, repeated open application tests (ROAT), repeat testing, or use tests remain important to confirm the allergic nature of the doubtful (?+) or weak-positive (+) patch test reaction and to establish the relevance of fragrances/markers or perfumed products causing contact sensitivity in a user.

Safety regulation

Products containing fragrance ingredients must be safe for the consumers and requires the same regulations for safety as for other cosmetics ingredients. The fragrance ingredients are used in the commercial product only after testing and are generally recognized as safe when they comply with recommended safety criteria. The cosmetic products need to be labeled properly for users’ safety and is a legal responsibility of manufacturers and those who market them. However, there is usually incomplete or no labeling or declaration of the complete list of ingredients by the manufacturers on the pretext of proprietary/trade secret issues especially in countries where it is not binding legally. Although the safety of perfume ingredients is regulated by USFDA, it does not regulate the perfume industry per se and no approval is needed before their marketing. However, the scientific data on the safety of fragrances in consumer products generated by the Research Institute of Fragrance Materials, United States, is used by International Fragrance Association to monitor the safety of fragrances for use in consumer products, to create industry codes of practice and guidelines, to make recommendations on limiting or prohibiting the use of specific substances, and to test new fragrances to rule out toxicity before their marketing.^[39] On the other hand, European Union Cosmetic Regulation lists 26 fragrance ingredients and chemicals including all the ingredients present in fragrance mix I and II for patch testing [Table 7^[40] that need to be identified when present in concentrations greater than 0.01% (100 ppm) in rinse-off products and 0.001% (10 ppm) in leave-on products along with their category of allergens on cosmetics and detergent products. However, a general level of exposure of up to 0.8µg/cm² (0.01% in cosmetic products) for the fragrance of concern may be tolerated by most consumers including those with contact allergy to fragrance allergens.^[8] Central Drugs Standard Control Organization in India has also laid out a set of protocols for import, manufacturing, labeling, packing, sale, and distribution of cosmetics (as defined by the Drugs & Cosmetics Act 1940) under Cosmetics Rules 2020. It has been made mandatory for manufacturers to declare all ingredients of their products including those with concentrations of less than 1% for consumers to make more informed choices. The addition of raw materials as specified in Annexure-A of the Indian Standard IS: 4707 Part 2 (amended from time to time) in the cosmetic product(s) is also prohibited. Import or manufacturing of cosmetics that contain dyes, colors, and pigments other than the one specified by the Bureau of Indian Standards is also prohibited under this law. However, most regulatory agencies only specify perfumes as cosmetic products and not as allergens.