In patch testing for contact allergy to fragrances, the concentration of the test preparation matters. Too low a concentration may miss reactions, whereas too high a concentration can cause irritation or potentially induce sensitization through the test itself.
A 2024 study sought to select concentrations for subsequent surveillance research on five fragrance materials that had not been adequately incorporated into routine testing. Among 373 dermatitis patients, no positive allergic reactions to the five components were observed. However, the main achievement was establishing conditions for testing larger populations, not declaring the materials safe for every use.
Checking what happens to people using products after they reach the market
The risk of skin sensitization to a fragrance, meaning the development of a state in which it can trigger an allergic reaction, is evaluated through quantitative risk assessment (QRA), which considers a material’s properties and the amount contacting the skin. This informs its use level in products, but post-market information is also needed to check whether the calculated risk management is effective in practice.
This study was a pilot preceding the long-term fragrance-allergy surveillance study EFISS. To monitor patients over time, centers need comparable concentrations and vehicles rather than different test materials at each location.
The five components were furaneol, trans-2-hexenal, 4,8-dimethyl-4,9-decadienal, longifolene, and benzaldehyde. The paper treats them as synthetic fragrance materials, although the same molecules may also occur in natural extracts. It was not a controlled comparison of fragrances from different sources.
Each increase in concentration was tested in a different patient group
From May to October 2022, adult dermatitis patients aged 18 and over participated at four centers in Portugal, the Netherlands, Sweden, and Croatia. There were 120 patients in the first, low-concentration stage, 104 in the second, intermediate stage, and 149 in the third, highest-concentration stage. Concentrations were not repeatedly increased in the same 373 people; different patients attending during each period were tested.
Petrolatum-based preparations were applied to the back for 48 hours, with readings on day 3 or 4 and day 7. Each stage was followed by at least three weeks of observation to watch for delayed reactions. The design allowed the next stage’s concentrations to be adjusted in light of irritation or late positive reactions.
No positive allergic reactions to the five materials were reported at any stage. At the initial low-concentration stage, there were two irritant reactions and one doubtful reaction, all negative by day 7. Neither irritant nor doubtful reactions were observed in the later two stages, and no reactions appearing after day 7 were reported.
What can zero positive results tell us?
Based on these findings, the authors judged that the highest-concentration preparations could be used in a subsequent study testing consecutive dermatitis patients. The conditions being evaluated were those for diagnostic test preparations.
However, only 149 people were tested at the highest concentrations. For zero positive cases, the paper reported an upper 95% confidence limit of 1.99% for the reaction rate. Observing no cases does not rule out uncommon reactions. The authors themselves stated that this sample was insufficient to establish reliably that consumer sensitization does not occur.
This study therefore cannot establish the safety of every product containing the five materials, at every concentration or under every pattern of use. Its participants were dermatitis patients attending for testing, and it did not investigate inhalation or systemic effects.
Some reactions were not detected by the usual mixture tests alone
In addition to the five materials, the study included standard fragrance-mixture tests and tests of individual components. Because the Croatian center included many patients with suspected or known fragrance allergy, reactions to other fragrances were summarized separately for the 288 patients from the other centers.
Of these, 47 tested positive to at least one preparation. Thirty-six were also positive to standard screening preparations, while the remaining 11 were identified through additional tests of other individual fragrance components. These 11 were not positive cases for the five materials undergoing the new concentration study.
The authors emphasized the usefulness of testing individual components as well as mixtures. Differences in detection may reflect, among other factors, the higher concentration of a component in an individual test than in a mixture. They called for further investigation of concentrations and combinations of test materials.
The study also compared conventional oakmoss and treemoss extracts with preparations containing greatly reduced trace levels of substances such as atranol. Some patients reacted only to the reduced preparations, but numbers were small and no significant difference was demonstrated. The findings cannot establish either that reduction is ineffective or that it increases danger; further studies are needed.
The IDEA program, which includes this research, is funded by the International Fragrance Association (IFRA). The authors include IFRA employees and others involved with the program, the president and CEO of test-reagent company Chemotechnique Diagnostics, and fragrance-safety expert-panel members. A device used to standardize sample quantities was developed by a coauthor and patented by that company.
Summary
This study selected concentrations of five fragrance materials for subsequent patch-test research while monitoring irritation and delayed reactions. The absence of positive reactions supported that choice, but did not demonstrate the absence of consumer sensitization risk.
The authors’ next goal was to monitor a larger patient population under these conditions and assess whether systems for managing ingredient use levels in products actually help prevent allergy. Standardized test preparations and the combination of individual-component testing with standard mixture screening support that surveillance. The testing methods and concentrations are medical and research conditions, not formulation guidance for experiments on your own skin.
References
Sukakul, T., Uter, W., Gonçalo, M., Huggard, J., Ljubojević Hadžavdić, S., Schuttelaar, M. L. A., Svedman, C., Vey, M., Isaksson, M., Niklasson, B., Rustemeyer, T., & Bruze, M. (2024). Results of patch testing with five fragrance materials hitherto not tested: A dose-finding study in the clinical population. Contact Dermatitis, 90(6), 566–573. DOI: 10.1111/cod.14525 / Full original article.
© 2024 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd. Original article license: CC BY-NC 4.0.
