et al.. Exposure source for skin sensitizing hydroperoxides of limonene and linalool remains elusive: an analytical market surveillance. Food and Chemical Toxicology, Elsevier, 2019, 127, pp. AbstractReports about positive patch test reactions to oxidized linalool and limonene remain frequent. These terpenes are fragrance ingredients widely present in consumer products. The main sensitizing ingredients in the oxidation mixtures of these terpenes are hydroperoxides (HP). Currently, it is not clear whether fragranced consumer products are a relevant exposure source for HP. Analytical methodologies had been developed and validated in blind-coded ring-trials in multiple laboratories allowing quantification of the HP in different consumer products. The analytical approach had been successfully transferred to an independent third party laboratory and was now used in the analytical investigation of consumer products. In total, 104 products were analysed with a method based on hydroperoxide reduction followed by GC-MS. Samples included aged and new samples from the same brand, products which were suspected by patch test positive patients to elicit their symptoms and some products containing high levels of essential oils. Only four samples contained > 50 µg/g of at least one of four analysed HP by the reduction method. Confirmatory analysis by LC-MS methods directly testing for presence of the hydroperoxide indicated that levels are even below those observed by the conservative reduction method. The samples retrieved from patch-test positive samples were below detection limit for all four target analytes by GC-MS, and LC analysis with three methods confirmed this negative result. This independent market surveillance indicates that concentrations of HP in investigated consumer products and patient products are orders of magnitude below reported sensitizing or elicitating doses. No evidence for hydroperoxide accumulation in aged products or products used by patients could be found. The nature and source of the inducing agent responsible for the frequent positive patch test reactions to oxidized terpenes remains elusive. The analytical work with GC-MS at SOLVIAS was funded by IDEA. The analysis by LC-MS was funded by the three participating laboratories (Firmenich, IFF and Givaudan). The study management was funded by IDEA. Manuscript writing was funded by Givaudan Schweiz AG. The synthesis of reference standards and sample collection was funded by the IDEA project. We thankfully acknowledge all donors of samples, in particular the Spanish dermatological network collecting samples from patients (GEIDAC, Grupo Español de Investigación en Dermatitis Alérgica de Contacto). Other members of the IDEA HP taskforce are gratefully acknowledged for fruitful discussions during various workshops. IDEA management team: Hans J. Bender; Industry scientists: Alain Chaintreau, Hugues Brévard and Neil Owen; Scientists from Academia:

The fragrant terpenes limonene and linalool can form skin‐sensitizing hydroperoxides (HPs) upon prolonged exposure to air. Sources of exposure of consumers to sensitizing doses of HPs have not been identified, and it is not clear whether fragranced products are a relevant source. Previously this question was addressed via analytical studies on fine fragrances; however, linalool and limonene are widely used in different consumer products, especially in other leave‐on toiletries. Hence, analytical methods also need to be able to detect potential HPs in more complex consumer product matrices. Here we applied different simple extraction methods and a toolbox of analytical methods to creams and lotions. Blinded samples of a commercial skin cream and a body lotion were spiked with four different HPs at different doses. Five laboratories analysed the samples with a method based on HP reduction in the sample, followed by Extrelut® NT extraction and GC‐MS to quantify the formed alcohols. This method found an average recovery of spiked levels of 80–105%, with a relative standard deviation between laboratories of 11–25% in samples spiked with 100–200 μg g−1. Quantification was also possible in samples spiked with 20–50 μg mL−1, with a relative standard deviation between laboratories of 11–38%. Thus, this method can indirectly detect low levels of HPs in complex bases. In parallel, the same samples were analysed with three LC‐based methods directly detecting the parent HPs: LC coupled with chemiluminescence, LC‐Q‐TOF‐MS, and LC‐orbitrap‐MS. On average, the different analytes were detected with a recovery of 80–143%. No HPs were detected in the non‐spiked products, despite the fact that they do contain linalool and limonene. Results of these studies indicate that consumer exposure can now be studied routinely in different product types as the required methods are ready for roll‐out.