Contact Allergens Formed on Air Exposure of Linalool. Identification and Quantification of Primary and Secondary Oxidation Products and the Effect on Skin Sensitization

Abstract

Linalool (3,7-dimethyl-1,6-octadien-3-ol) is an important fragrance chemical, frequently used in scented products because of its fresh, flowery odor. Linalool is an unsaturated hydrocarbon and is therefore susceptible to oxidation in the presence of air. The primary oxidation products, that is, hydroperoxides, formed in the autoxidation process, are reactive compounds that can be suspected to act as sensitizers. In the present investigation, we studied the autoxidation of linalool with emphasis on the formation of hydroperoxides. The oxidation products were isolated using flash chromatography and preparative HPLC and were identified with NMR and GC/MS, using synthesized reference compounds. Two hydroperoxides and several different secondary oxidation products were identified, among which some contain structural features that make them potential allergens. The amounts of linalool and the major oxidation products were quantified over time, using GC and an HPLC-method, suitable for the analysis of thermolabile primary oxidation products. The hydroperoxide 7-hydroperoxy-3,7-dimethylocta-1,5-diene-3-ol was found to be present in 15% in an oxidized sample. The local lymph node assay (LLNA) was used to investigate the sensitizing potential of pure linalool, two samples of air-exposed linalool, and oxidation products of linalool (an alpha,beta-unsaturated aldehyde, a mixture of two hydroperoxides, and an alcohol). Pure linalool showed no sensitizing potential. The air-exposed samples of linalool produced clearly positive responses, and the hydroperoxides were the strongest allergens of the tested oxidation products. The study demonstrates the importance of autoxidation on the sensitizing potential of linalool. We also conclude that the sensitizing potential differs with the composition of the oxidation mixture and thus with the air exposure time.

Fragrance Compound Geraniol Forms Contact Allergens on Air Exposure. Identification and Quantification of Oxidation Products and Effect on Skin Sensitization

“…The concentration of geraniol started to decrease immediately on air exposure at room temperature. The rate of autoxidation was similar to that of linalool (3), that is, 80% of geraniol remained at 10 weeks of air exposure, whereas 20% remained at 45 weeks (Figure 2). The oxidation mixture polymerized with time, and the samples taken out beyond 45 weeks were no longer suitable for HPLC or GC analysis because of their viscosity.…”

“…Hydrogen peroxide is a well-known irritant, and the dose-response curve reflects its toxicity. The mixture of hydroperoxides 6 and 11 (5:3) was found to be strongly allergenic with an EC3 value of 0.077 M. The potency of these hydroperoxides is in the same range as that shown for the corresponding mixture of linalool hydroperoxides (3,15,29). According to our experience so far, all hydroperoxides tested show an EC3 value of 1% (15,29).…”

“…Geraniol is not electrophilic and should consequently not possess any contact allergenic activity. However, analogously to linalool (3), it has the potential to autoxidize on air exposure at normal handling and storage, but to the best of our knowledge, there are no published studies on the autoxidation of geraniol. Thus, it is important to investigate the pattern of geraniol autoxidation and to study the sensitizing capacity of the oxidation products formed.…”

Variabilidade sazonal e biossíntese de terpenóides presentes no óleo essencial de Lippia alba (Mill.) N. E. Brown (Verbenaceae)

“…38,39 Além desta, foi demonstrado que a auto-oxidação do linalol [4], pela sua exposição ao oxigênio do ar, também conduz ao óxido de linalol [6]. 40 A isomerização do GPP [1], obtida com a migração do grupamento difosfato do C1 para o C3, resulta no difosfato linalílico (LPP) [7]. A subseqüente rotação da ligação C2-C3 e ionização resultam no isômero do cátion linalíco [2'], que difere do primeiro por apresentar características espaciais favoráveis à ciclização molecular.…”

Biosynthesis and Therapeutic Properties ofLavandulaEssential Oil Constituents

“…European legislators have become increasingly aware of the allergenic properties of many common essential oil constituents, and in 2003, the 7th Amendment to the European Cosmetic Directive required that cosmetic products containing any of 26 natural products, including linalool, be labeled as potentially allergenic [20]. While linalool itself may have limited allergenic properties, it can auto-oxidize upon air exposure into a hyperoxide species [21] which can lead to contact allergy responses in mice [22]. In a study of 1511 dermatitis patients, auto-oxidized linalool was shown to induce allergenic responses in 1.3 % of those tested, with 1.1 % of patients sensitive to the linalool hyperoxide fraction, using patch tests [23].…”