Balsam of Peru is the most widely used marker for diagnosis of fragrance allergy. This natural resin extracted from Myroxylon pereirae, a tree that grows in Central and South America, was originally used to heal wounds and cure infections.34 In 1974, the use of natural balsam of Peru as a fragrance ingredient was prohibited, and the use of its extracts and distillates in commercial products was restricted to a maximum concentration of 0.4%. Today, we find it in perfumes, cleaning products, topical medications, dental cement and liquids, cosmetic products, and food aroma compounds. Balsam of Peru is composed of 250 chemical substances; the structure of at least 189 is known. Some of these components are fragrance allergens (eg, cinnamyl alcohol, cinnamic aldehyde, eugenol, and isoeugenol).35

In 1948, Bonnevie36 reported that balsam of Peru was a common allergen and identified cinnamic aldehyde as an important allergic ingredient. Hausen37 tested the components of balsam of Peru in 102 patients who had a positive reaction to this marker and found the main culprit allergen to be a fragrance, cinnamyl alcohol. The second fragrance identified, eugenol, was the sixth most common allergen. The role of balsam of Peru as a marker of allergy to fragrances is more complex and heterogeneous than that of fragrance mix I.2 Balsam of Peru obtains a positive result in approximately 50% of cases of fragrance allergy, and has been reported to cross-react with colophony, balsam of Tolu, cinnamates, benzoates, benzylsalicylates, coumarin, farnesol, propolis, and diethylbestrol.35

Fragrance mix I, the second mixture used to test for fragrance allergies, was introduced as a marker in the standard series after the publications by Larsen38,39 in the late seventies. It has 8 components, namely, 7 synthetic fragrances and 1 natural fragrance. Initially, each of the fragrances was tested at 2% (total of 16%); however, this approach generated a large number of false-positive results because of irritant action. Therefore, in 1984, the concentration was reduced to 1% (total of 8%).

Table 1 lists important information on the components of fragrance mix I.

In some of the series marketed, sorbitan sesquioleate 5% is used as an emulsifier in both balsam of Peru and fragrance mix I. Enders et al40 demonstrated that sorbitan sesquioleate improved the diagnostic value of these markers because it acts as a vehicle for the fragrances. The only disadvantage of this emulsifier is its occasional allergenic capacity. Consequently, some authors recommend including sorbitan sesquioleate in the specific fragrance series1,2,9 to rule it out as an allergen. In patients who have a positive reaction to both balsam of Peru and fragrance mix I, up to 17.7% of reactions are false-positive and the patients are in fact allergic to the emulsifier.1

The clinical relevance of these markers varies according to the series, with values ranging from 79% to 92.8% for fragrance mix I and from 66% to 85.71% for balsam of Peru in studies from Spanish hospital centers.1,41 These figures are very high if we compare them with those reported in other international series. We believe this is mainly because the authors who obtain the highest clinical relevance are those who consider fragrance allergy an exacerbating factor in patients with other underlying skin diseases (eg, atopic or irritant dermatitis) when patch testing is positive for fragrances.

Recent studies showed that the 2 fragrance markers in the current GEIDAC standard series—balsam of Peru and fragrance mix I—continue to be efficacious and detect between 70% and 90% of fragrance-allergic patients.1,2,42 Some authors have even identified fragrance allergy in up to 85% of patients using only fragrance mix I. Nevertheless, in the last few years, new fragrance markers have been developed that reflect advances in the industry, which brings products with new fragrances onto the market. Recent findings show that around 15% of fragrance-allergic patients are not detected by these 2 markers.43 Since 2005, experts have been studying the use of fragrance mix II and hydroxyisohexyl 3-cyclohexane carboxaldehyde (lyral) as markers of sensitization to fragrance in some standard series in Europe.

In 2005, Frosch et al.44,45 studied a new tool—fragrance mix II—with the aim of detecting a greater number of patients sensitized to fragrances, including those not diagnosed after application of the usual markers. Fragrance mix II is composed of 6 fragrances at different concentrations (Table 2). In 2005, this mix was included in the series of the German contact allergy group (Deutschen Kontaktallergie-Gruppe), and since 2008, it has formed part of the European standard series.46 In 2010, data collected by the Informationverbund Dermatologischer Kliniken were published on patients tested with this mix in several European centers between 2005 and 2008.47 Of the 35 633 patients included, 4.9% had positive results with fragrance mix II; the most common allergens detected with this series, in decreasing order of frequency, were as follows: lyral (in almost half of the sample), citral, farnesol, hexylcinnamal, coumarin, and citronellol.

Most studies analyzing the usefulness of this mix agree with the recommendation that it should be included in the standard series, since it detects a considerable number of fragrance-allergic patients who would not be diagnosed by fragrance mix I and balsam of Peru. Negative reactions to fragrance mix I have been recorded in 32% of patients with a positive reaction to fragrance mix II.44 Some European countries have already included this mix in their standard series, and GEIDAC recommended its inclusion in the Spanish standard series as of January 1, 2012 (Fig. 2).

Figure 2.

The introduction of new markers of fragrance allergy has enabled us to detect new cases and to improve the diagnosis of previously sensitized patients.

(0.14MB).

Hydroxyisohexyl 3-cyclohexane carboxaldehyde (lyral) is included in fragrance mix II at a concentration of 2.5%; however, most authors recommend its inclusion in the standard series at double this concentration (5%). The frequency of sensitization is 1% to 3.1%, and it is often detected in patients with hand eczema.46

When 1 or 2 fragrance markers in the standard series (fragrance mix I, balsam of Peru, or both) are positive, the specific fragrance series should be applied, although the yield is poorer when a positive result is obtained only for balsam of Peru, since in 75% of these cases we will not obtain a positive result for a specific fragrance.

The number of individual fragrance ingredients tested and the proportions used vary depending on the country and laboratory. The specific series from Martí Tor and Trolab contains each fragrance at 1%. Chemotechnique Diagnostics, however, have doubled the concentration to 2%. This increase has made it possible to detect a larger number of allergic patients, who would have gone undiagnosed with the lower concentration, but it also increases the number of false positives due to irritant reactions.

We believe that the specific series should include all the fragrances in fragrance mixes I and II individually. It should also include the 26 fragrances that must be specified on product labels, since a positive result for any of these substances would allow us to advise the patient to avoid only the specific fragrance(s). Sorbitan sesquioleate should be tested individually as part of this specific series, since it enables us to detect false positives in patients with a positive reaction to either of the mixes caused by allergy to the emulsifier rather than to the fragrance. Other authors9 recommend including this emulsifier in each of the fragrances to increase the diagnostic yield of the series and avoid false negatives.

We can complete the allergy workup by by testing the patients’ reaction to the products they use, especially if those products are suspected of causing dermatitis. Depending on the product, we can apply it as a patch test or a repeat open application test. The latter method is recommended in the case of highly irritant products, such as colognes or perfumes. In the case of products whose daily application involves removal or rinsing from the skin (eg, shampoos and shower gels), the undiluted product should not be used in patch tests or use tests. The concentration should be reduced to 1% aq or the repeat open application test method should be used, since these approaches can confirm the clinical relevance of the results in some cases.

Linalool (dimethyl octadienol) is a natural fragrance present in many essential oils that has very low sensitizing potential as a pure substance. In recent years, there has been growing awareness that the products of its oxidation are much more allergenic than the fresh or initial chemical substance.35 Matura et al.48 found positive results to linalool in 1.3% of 1511 consecutive patients.49

Trimethyl-benzenepropanolol (majantol) is another fragrance that is not included in the standard mixes or series; however, several studies50 have shown that 0.5% of consecutive patch test patients are sensitized to this ingredient. Larsen et al.51 recommend including majantol in the specific fragrance series.