Patch tests for fragrance contact allergy include preparations that combine several fragrance ingredients. They can test multiple ingredients at once, but can a mixture’s result alone tell us which ingredient a person reacted to? And how much additional diagnostic information can be gained by testing the same ingredient separately?
In 2014, a Swedish research group examined these questions using test results from more than 10,000 dermatitis patients at six centres. The study concerned fragrance mix II (FM2), a mixture of six fragrance substances, and HICC, one of its ingredients. Its central question was not simply whether there were positive reactions, but how best to combine the two tests.
The mixture already contained HICC
HICC is a synthetic substance formerly used as a fragrance ingredient. The FM2 preparation used here contained a total fragrance concentration of 14%, including 2.5% HICC. The separate HICC preparation contained 5%. Both were diagnostic preparations in a petrolatum base.
In other words, this was not a comparison between a test containing no HICC and a test of HICC alone. It examined how many additional people were identified when HICC was tested separately at twice its concentration in the mixture. These concentrations are not formulation concentrations for perfumes or cosmetics.
Testing 10,010 dermatitis patients
The participants were 10,010 people tested at six dermatology centres in Sweden between 2006 and 2011. Starting dates differed slightly between centres. The preparations remained on the skin for 48 hours, and reactions were assessed on day 3 or 4 and on day 7.
FM2 produced positive reactions in 337 people, or 3.4% of the total. Separate HICC testing was positive in 171 people, or 1.7%. Both tests were positive in 148 people, while 23 were negative to FM2 but positive to HICC alone.
Those 23 people represented about 0.2% of everyone tested. With the 171 HICC-positive patients as the denominator, however, they represented 13.5%. The same result has a different meaning depending on whether we ask how much the additional test contributed across all patients, or what proportion of HICC-reactive patients the mixture failed to identify.
Routine additional testing and follow-up after a positive result have different roles
The authors considered the value of routinely including separate HICC alongside FM2 in the Swedish baseline series at that time to be small. Testing approximately 10,000 people identified an additional 0.2%, which they judged insufficient under the then-current criteria for inclusion in the baseline series. They therefore suggested considering removal of the separate HICC preparation from that series.
They did not, however, conclude that HICC no longer needed to be tested. They strongly recommended testing HICC and the other individual ingredients in people positive to FM2. A positive reaction to the mixture alone cannot identify the particular ingredient responsible for contact allergy.
Their emphasis was on identifying the specific ingredient so that people could more readily avoid exposure in everyday life. They also argued that individual testing was important for continuing surveillance of which ingredients cause fragrance allergy and how frequently it occurs.
What can we learn from this historical diagnostic study?
The participants were people undergoing medical testing because of dermatitis. The figure of 1.7% is not the probability that someone in the general population will develop a rash from HICC. Nor does a positive diagnostic patch test automatically mean that a particular cosmetic is causing a person’s current skin symptoms; actual use and exposure history also need to be considered.
The recommendation about the composition of the test series reflects the authors’ judgment in 2014. Subsequently, under an EU regulation adopted in 2017, placing cosmetics containing HICC on the market was prohibited from August 2019, and making them available on the market from August 2021. The exposure situation and diagnostic debate at the time cannot simply be applied to all products today.
This was also a study of allergic skin reactions to one ingredient, not of effects from inhalation or a comparison of the overall safety of synthetic and natural fragrances. Testing and identifying the cause of skin symptoms are matters to discuss with a dermatologist.
The conflict-of-interest statement reports that one author served on an expert panel of the fragrance research organization RIFM, and another had served on European Commission scientific committees concerned with consumer safety and related issues.
Summary
FM2 provides a clue to fragrance contact allergy, but some HICC-positive patients were not identified by the mixture alone. At the same time, adding separate HICC testing for everyone increased detection by only about 0.2% of the total patient population.
Taking both findings into account, the authors distinguished the design of a widely used baseline series from detailed investigation of the responsible ingredient in patients with positive results. The important implication was not simply to increase the number of tests, but to provide a step from mixture testing to individual ingredients, supporting specific exposure avoidance and continuing surveillance.
References
Isaksson, M., Inerot, A., Lidén, C., Lindberg, M., Matura, M., Möller, H., Stenberg, B., & Bruze, M. (2014). Multicentre patch testing with fragrance mix II and hydroxyisohexyl 3-cyclohexene carboxaldehyde by the Swedish Contact Dermatitis Research Group. Contact Dermatitis, 70, 187–189. DOI: 10.1111/cod.12156 / Full original article.
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
European Commission (2017). Commission Regulation (EU) 2017/1410.
