Limonene and linalool are unsaturated terpenes commonly found as major components in many essential oils, and both are easily oxidized by atmospheric oxygen to form hydroperoxides. The hydroperoxides of both limonene and linalool are known to be sensitizers capable of causing allergic contact dermatitis, but with different potency. In addition, positional isomers of limonene hydroperoxide have been demonstrated to have different allergenic potencies. This creates a need for an analytical method that is capable of differentiating hydroperoxides derived from different terpenes, including the various positional isomers. The standard iodometric titration methods [peroxide value (POV) methods] typically used to measure hydroperoxide levels in essential oils provide only a total level of all oxidizing species, including hydroperoxides. These POV methods are not capable of species differentiation and therefore may not reliably correlate well with the skin sensitizing potency of a particular sample. A high‐performance liquid chromatographic (HPLC) method using a post‐column reaction to produce chemiluminescence via luminol oxidation was developed to address the need for a species‐differentiating method. Copyright © 2015 John Wiley & Sons, Ltd.
The fragrant terpenes limonene and linalool can form skin sensitizing hydroperoxides upon prolonged exposure to air. Recently, high frequencies of positive patch tests to oxidized linalool and limonene were reported from multiple dermatological centres. However, there is a lack of data indicating potential sources of consumer exposure to sensitizing doses of terpene hydroperoxides which explains this frequent contact allergy. Within the IDEA project (International Dialogue for the Evaluation of Allergens; http://ideaproject.info/), a taskforce was formed to drive analytical method development and evaluation. In an inter‐laboratory study in five laboratories, a method based on hydroperoxide reduction combined with GC–MS was tested for reproducibility. Blinded samples of commercial fine fragrances were spiked with four different hydroperoxides. In samples spiked with 100–200 μg/ml, an average recovery of 86–105% with a relative standard deviation between laboratories of 7.4–22% was found. In samples spiked with 20–50 μg/ml, the recovery was 85–91%. The reduction approach offers a transferable and reproducible method to indirectly detect low levels of hydroperoxides, at least in fine fragrances. Ideally, one would prefer to directly detect the parent hydroperoxide. Therefore the same samples were further tested with three LC‐based methods directly detecting the parent hydroperoxide. LC coupled to chemiluminescence, LC‐Q‐TOF‐MS or LC‐orbitrap‐MS were used. Results indicate that with specific gradients a separation of the four analytes and quantification in the fragrance matrix can be achieved. Results of this method evaluation study present a toolbox of methods to detect terpene hydroperoxides to further investigate consumer exposure.
Limonene and linalool are major components in many essential oils, and both readily autoxidize to form terpene hydroperoxides. These hydroperoxides are sensitizers capable of causing allergic contact dermatitis, so it is important to have accurate analytical methods for them in perfumery raw materials and formulations. This laboratory has previously reported a method to detect terpene hydroperoxides based on high‐performance liquid chromatography using a post‐column chemiluminescence reaction. Using this method, it was shown that peroxyhemiacetals formed by reaction of terpene hydroperoxides with endogenous aldehydes exist as components in common citrus oils. This was further substantiated by NMR analysis using a variety of techniques. Some percentage of the peroxyhemiacetals can dissociate back to the corresponding parent terpene hydroperoxides and aldehydes under certain conditions which are currently not fully understood, even if the polarity of the solvating environment appear to be important. However, gas chromatographic analysis indicates that there may also be alternative degradation pathways. The presence and chemical behaviour of peroxyhemiacetals must be studied further and analytically accounted for, if meaningful results are to be obtained in the context of the dermal sensitizing potency of a sample. Copyright © 2016 John Wiley & Sons, Ltd.
Limonene and linalool are major components in many essential oils, and both may autoxidize under certain conditions to form terpene hydroperoxides (THPs), which are reported to be sensitizers that may cause allergic contact dermatitis. This laboratory previously reported that peroxyhemiacetals (PHAs) may be present in some citrus oils, formed by reaction of THPs with endogenous aldehydes. It was also shown that PHAs can dissociate back to the corresponding THPs in polar solvation environments. Because of this potential for reversion to THPs, the analysis of PHAs is important in the context of measuring peroxide values in products. The fragrance industry currently utilizes iodometric titration to monitor THP levels in many raw materials; the currently accepted method requires that THPs in the sample are allowed to oxidize excess added iodide to molecular iodine for a one-minute reaction time. The iodine generated is then titrated with thiosulfate to give the peroxide value. This paper reports on the iodide reaction time required for PHAs to be quantitatively measured by such an iodometric titration technique, and on the implications to citrus oil raw material testing. K E Y W O R D Speroxide value titration, hydroperoxides, peroxyhemiacetal, citrus oil autoxidation
The quantification of hydroperoxides is crucial in several areas, in particular in the fragrance domain, because they have been identified as skin sensitizers. The reference compounds necessary to calibrate the instruments have very limited availability, and require drastic storage conditions (-78°C) due to their instability. To overcome these limitations, we propose a GC-FID approach involving their silylation, and the prediction of response factors. This procedure provides a good alternative to a full calibration down to a concentration level of 500 mg/kg, with an underestimation of about 20%. In the analysis of essential oils and fragrance concentrates, larger deviations are found; however, they are not inherent in the technique but rather in the chemistry of hydroperoxides that readily react with aldehydes to form peroxyhemiacetals, thereby decreasing the concentration of free hydroperoxides. These observations are in agreement with quantitative 1 H NMR and HPLC-Chemiluminescence analyses.
Many terpenes may autoxidize under certain conditions to form terpene hydroperoxides, which have been reported to be skin sensitizers that may cause allergic contact dermatitis. The fragrance industry is currently required to monitor terpene hydroperoxide levels in many raw materials by iodometric titration (aka; the peroxide value, or POV test), and to reject lots that exceed a specification limit. We have found that compounds containing the 2‐oxoacid moiety (the “pyruvic acid” moiety) react readily with organic hydroperoxides via an oxidative decarboxylation mechanism. The reaction products include an alcohol corresponding to the reduced hydroperoxide, carbon dioxide, and a carboxylic acid that is one carbon shorter than the starting 2‐oxoacid. Because the hydroperoxide is irreversibly consumed by this reaction, the POV of a 2‐oxoacid‐treated sample is effectively lowered. It follows that the skin sensitizing potential of the treated sample should also be lowered as a result of the hydroperoxide removal.
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.
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