Nature-Derived Epoxy Resin Monomers with Reduced Sensitizing Capacity─Isosorbide-Based Bis-Epoxides.

Epoxy resin systems (ERSs) are a class of thermosetting resins that become thermostable and insoluble polymers upon curing. They are widely used as components of protective surfaces, adhesives, and paints and in the manufacturing of composites in the plastics industry. The diglycidyl ether of bisphenol A (DGEBA) is used in 75-90% of ERSs and is thus by far the most used epoxy resin monomer (ERM). Unfortunately, DGEBA is a strong skin sensitizer and it is one of the most common causes of occupational contact dermatitis. Furthermore, DGEBA is synthesized from bisphenol A (BPA), which is a petroleum-derived chemical with endocrine-disruptive properties. In this work, we have used isosorbide, a renewable and nontoxic sugar-based material, as an alternative to BPA in the design of ERMs. Three different bis-epoxide isosorbide derivatives were synthesized: the diglycidyl ether of isosorbide (1) and two novel isosorbide-based bis-epoxides containing either a benzoic ester (2) or a benzyl ether linkage (3). Assessment of the in vivo sensitizing potency of the isosorbide bis-epoxides in the murine local lymph node assay (LLNA) showed that all three compounds were significantly less sensitizing than DGEBA, especially 2 which was nonsensitizing up to 25% w/v. The peptide reactivity showed the same order of reactivity as the LLNA, i.e., 2 being the least reactive, followed by 3 and then 1, which displayed similar peptide reactivity as DGEBA. Skin permeation of 2 and 3 was compared to DGEBA using ex vivo pig skin and static Franz cells. The preliminary investigations of the technical properties of the polymers formed from 1-3 were promising. Although further investigations of the technical properties are needed, all isosorbide bis-epoxides have the potential to be less sensitizing renewable replacements of DGEBA, especially 2 that had the lowest sensitizing potency in vivo as well as the lowest peptide reactivity.

Nature-derived epoxy resins: Synthesis, allergenicity, and thermosetting properties of pinoresinol diglycidyl ether.

We describe a novel nature-derived epoxy resin monomer (ERM) derived from the plant lignan pinoresinol. Epoxy resins are thermosetting materials in global usage owing to their excellent technical properties such as flexibility and durability. However, their adverse health effects are often not considered and affect users of epoxy resins worldwide. Components of epoxy resin systems are strong skin sensitizers and cause allergic contact dermatitis. The reported prevalence attributable to epoxy chemicals is between 11.7 and 12.5% of all cases of occupational allergic contact dermatitis. We are committed to developing epoxy resins with reduced allergenic effect, while maintaining their excellent properties. The novel ERM, pinoresinol diglycidyl ether (PinoDGE), was synthesized in one step from pinoresinol and epichlorohydrin in 88% yield. It was not classified as a skin sensitizer in the in vivo local lymph node assay, at concentrations up to 0.17 m, as it did not cause a stimulation index >3 compared to control. Pinoresinol diglycidyl ether reacted with the model peptide AcPHCKRM in a reactivity assay and was predicted to be a skin sensitizer in the KeratinoSens assay. Preliminary cross-linking studies indicate that it has promising properties compared to commercially used ERMs. Pinoresinol diglycidyl ether could be seen as a lead compound for further development of alternative ERMs with a better safety profile based on natural and renewable sources for construction of epoxy resin polymers.

One hundred years of allergic contact dermatitis due to oxidized terpenes: What we can learn from old research on turpentine allergy.

Although in recent years the focus on sensitizing terpene oxidation products has been on oxidized limonene and linalool, the autoxidation of terpenes in relation to allergic contact dermatitis is not new and dates back to the early part of the 20th century with the use of turpentine causing occupational contact dermatitis in painters. This review is written in a way as to allow us to get closer to the work of the scientists in earlier days, to participate in the successes, and also to observe the weak points. The researchers concluded that the main culprit in Scandinavian turpentine was Δ3 -carene hydroperoxides. This explains its high sensitizing effect compared with French turpentine which is of the Iberian type with no or only traces of Δ3 -carene. Historical exposure to turpentine showed that ending the industrial exposure stopped the occupational skin sensitization. Patch test studies demonstrated that monoterpene hydroperoxides, far from being an obsolete source of contact allergy solely related to turpentine, is a common cause of contact allergy in the population. A hundred years of extensive chemical and clinical studies worldwide should be sufficient to meet the evidence requirement regarding allergic contact dermatitis caused by terpenes.

Tracing colophonium in consumer products.

BACKGROUND: Colophonium (rosin) can cause allergic contact dermatitis, mainly due to autoxidation of abietic acid (AbA). Products containing ≥0.1% colophonium should be labeled with EUH208 - "Contains rosin; colophony. May produce an allergic reaction." How should this be measured? OBJECTIVE: To compare the results from different strategies for estimating colophonium levels in consumer products: (a) from AbA, and (b) the sum of all major resin acids. To investigate the ratio of 7-oxodehydroabietic acid (7-O-DeA)/AbA as indication of autoxidation. METHODS: Resin acids were extracted from consumer products, derivatized, and then separated by gas chromatography/mass spectrometry (GC/MS). RESULTS: Resin acids were detected in 9 of 15 products. No product contained colophonium ≥0.1%. Estimation based on AbA resulted in underestimation of the colophonium levels in four of nine products. For three products, the obtained levels from this strategy were only one of two compared to when estimating from the sum of all resin acids. The ratio 7-O-DeA/AbA varied from 74% to 1.4%. CONCLUSIONS: We propose to measure colophonium based on the sum of all detectable major resin acids, including 7-O-DeA. The ratio of 7-O-DeA/AbA should be used as a marker of autoxidation, indicating an increased risk of sensitization. The presented analytical method is simple to use and suitable for further screening studies.

Patch testing with purified and oxidized citronellol.

BACKGROUND: Citronellol is a commonly used fragrance terpene included in fragrance mix II. As with many other fragrance terpenes, citronellol is susceptible to autoxidation. Citronellol hydroperoxides are formed in large amounts and are the only oxidation products identified as sensitizers in oxidized citronellol. AIM: To compare frequencies of contact allergy to purified and oxidized citronellol and to investigate the pattern of concomitant reactions to fragrance markers of the baseline series, oxidized linalool, and oxidized limonene. METHODS: A total of 658 dermatitis patients were patch tested with purified and oxidized citronellol at 2.0%, 4.0%, 6.0%, and 1.0%, 2.0%, 4.0%, 6.0% petrolatum, respectively. The irritant properties of purified and oxidized citronellol were studied before patch testing. RESULTS: Few irritant reactions were observed in the pretest. Purified citronellol detected positive reactions in 0.15%-0.31% of patients, while oxidized citronellol detected positive reactions in 0.61%-4.5%. Among patients reacting to oxidized citronellol, 34%-50% showed concomitant reactions to fragrance markers of the baseline series and 75%-91% to oxidized linalool or oxidized limonene. CONCLUSION: Oxidized citronellol detects more cases of contact allergy than purified citronellol, and these cases are not all detected using fragrance mix II. Patch testing with oxidized citronellol will add to the tools in the diagnosis of fragrance allergy.

Contact allergy to citral and its constituents geranial and neral, coupled with reactions to the prehapten and prohapten geraniol.

BACKGROUND: Citral is commonly used as a fragrance and flavor material and consists of the aldehydes geranial and neral. Citral is included in fragrance mix (FM) II. Geranial and neral have also been identified in autoxidation of geraniol, a fragrance compound present in FM I. OBJECTIVES: To study contact allergy to citral, geranial, and neral, and concomitant reactivity to oxidized geraniol and fragrance markers of the baseline series. METHODS: A total of 1476 dermatitis patients with suspected allergic contact dermatitis were patch tested using geranial, neral, and citral, all 3.5% petrolatum (pet.) as well as geraniol 6.0% and oxidized geraniol 11% pet. in addition to the Swedish baseline series. RESULTS: Frequencies of positive reactions to citral, geranial, and neral were 2.9%, 3.4% and 1.9%, respectively. Together, citral and geranial gave 4.2% positive patch test reactions in consecutive dermatitis patients. In patients with positive reactions to citral or its components, 25% to 34% reacted to FM II and 61% reacted to oxidized geraniol. CONCLUSIONS: Patch testing with citral, its components, or oxidized geraniol detects contact allergic reactions not detected using the baseline series. Patch testing with pure geraniol was shown to be of little value. Geranial and neral, although closely chemically related, are concluded to be separate haptens.

Development of New Epoxy Resin Monomers - A Delicate Balance between Skin Allergy and Polymerization Properties.

Epoxy resin monomers (ERMs) are used as building blocks for thermosetting polymers in applications where strong, flexible, and lightweight materials are required. Most epoxy resins are polymers of diglycidyl ether of bisphenol A (DGEBA). It is highly allergenic and causes occupational allergic contact dermatitis and contact allergy in the general population. Thus, measures to prevent exposure by protective clothing and education are not enough. This work describes a continuation of our research aiming at reducing the skin-sensitizing potency of ERMs while maintaining the ability to form polymers. Alternative ERMs were designed and synthesized whereafter the sensitizing potency was determined using the murine local lymph node assay (LLNA). The reactivity of the diepoxides toward a nucleophilic peptide was investigated, and the differences in reactivity explained using computational studies. The diepoxides were reacted with triethylenetetramine, and the formed polymers were tested for technical applicability using thermogravimetric analysis. We had previously shown that the absence of an oxygen atom in the side chains or removal of aromaticity reduced the sensitizing potency compared to that of DGEBA. Thus, a cycloaliphatic analogue 1 of DGEBA without ether oxygen in the side chains was considered promising and was synthesized. As predicted, the sensitizing potency was considerably reduced (10 times) compared to that of DGEBA. However, the technical properties of the polymer of this compound were not considered sufficient. More polar aromatic analogues were investigated, but they could not compete with our previously described ERMs regarding polymerization properties and with 1 regarding low skin sensitization properties. Development of alternative epoxy materials is a delicate balance between allergenic activity and polymerization properties. Tuning of structural properties together with investigation of polymerization conditions combined with skin sensitization studies should be used in industrial research and development. ERM 1 could be used as a lead compound for further studies of aliphatic ERMs.

Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy?

BACKGROUND: Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol. OBJECTIVE: To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal. METHODS: Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively. RESULTS: Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing. CONCLUSION: The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important.

Contact allergy to oxidized geraniol among Swedish dermatitis patients-A multicentre study by the Swedish Contact Dermatitis Research Group.

BACKGROUND: Geraniol is a widely used fragrance terpene, and is included in fragrance mix I. Geraniol is prone to autoxidation, forming the skin sensitizers geranial, neral, and geraniol-7-hydroperoxide. Oxidized geraniol has previously been patch tested in 1 clinic, giving 1% to 4.6% positive reactions in consecutive patients when tested at 2% to 11%. AIM: To compare test reactions to pure and oxidized geraniol, to compare 2 different test concentrations of oxidized geraniol and to investigate the pattern of concomitant reactions to fragrance markers of the baseline series in a multicentre setting. METHODS: One thousand four hundred and seventy-six consecutive patients referred for patch testing were patch tested with geraniol 6% pet. and oxidized geraniol 6% and 11% pet. RESULTS: Pure geraniol 6% pet., oxidized geraniol 6% pet. and oxidized geraniol 11% pet. gave 1%, 3% and 8% positive patch test reactions and 0.7%, 3% and 5% doubtful reactions, respectively. Approximately 50% of the patients with doubtful reactions to oxidized geraniol 6% pet. had positive reactions to oxidized geraniol 11% pet. CONCLUSIONS: Oxidized geraniol 11% pet. provides better detection than oxidized geraniol 6% pet. As most patients reacted only to oxidized geraniol, it is important to explore further whether oxidized geraniol should be included in a baseline patch test series.

Comparative sensitizing potencies of fragrances, preservatives, and hair dyes.

The local lymph node assay (LLNA) is used for assessing sensitizing potential in hazard identification and risk assessment for regulatory purposes. Sensitizing potency on the basis of the LLNA is categorized into extreme (EC3 value of ≤0.2%), strong (>0.2% to ≤2%), and moderate (>2%). To compare the sensitizing potencies of fragrance substances, preservatives, and hair dye substances, which are skin sensitizers that frequently come into contact with the skin of consumers and workers, LLNA results and EC3 values for 72 fragrance substances, 25 preservatives and 107 hair dye substances were obtained from two published compilations of LLNA data and opinions by the Scientific Committee on Consumer Safety and its predecessors. The median EC3 values of fragrances (n = 61), preservatives (n = 19) and hair dyes (n = 59) were 5.9%, 0.9%, and 1.3%, respectively. The majority of sensitizing preservatives and hair dyes are thus strong or extreme sensitizers (EC3 value of ≤2%), and fragrances are mostly moderate sensitizers. Although fragrances are typically moderate sensitizers, they are among the most frequent causes of contact allergy. This indicates that factors other than potency need to be addressed more rigorously in risk assessment and risk management.

Assessment of cross-reactivity of new less sensitizing epoxy resin monomers in epoxy resin-allergic individuals.

BACKGROUND: Measures to prevent occupational exposure to epoxy resins, including education, medical examination, and voluntary agreements between employers and workers, have not been effective enough to protect against skin sensitization. Therefore, alternatives to the major epoxy resin haptens that have been found to be less sensitizing in the local lymph node assay have been developed. OBJECTIVES: To study the cross-reactivity of two newly designed epoxy resin monomers, with decreased skin-sensitizing potency and good technical properties as compared with diglycidyl ether of bisphenol A (DGEBA), in subjects with known contact allergy to epoxy resin of DGEBA type. PATIENTS AND METHODS: Eleven individuals with previous positive patch test reactions to epoxy resin of DGEBA participated in the study. The two alternative epoxy resin monomers were synthesized and patch tested in dilution series in parallel with epoxy resin of DGEBA from the baseline series (containing 92% DGEBA). RESULTS: All participants reacted to epoxy resin of DGEBA on retesting. Three participants reacted to monomer 1. No reactions were seen to monomer 2. CONCLUSIONS: The alternative monomers studied showed little or no cross-reactivity with epoxy resin of DGEBA. Decreasing the risk of sensitization by using less sensitizing compounds is important, as contact allergy to epoxy resins is common in spite of thorough preventive measures.

Oxidized limonene and oxidized linalool - concomitant contact allergy to common fragrance terpenes.

BACKGROUND: Limonene and linalool are common fragrance terpenes. Both oxidized R-limonene and oxidized linalool have recently been patch tested in an international setting, showing contact allergy in 5.2% and 6.9% of dermatitis patients, respectively. OBJECTIVE: To investigate concomitant reactions between oxidized R-limonene and oxidized linalool in consecutive dermatitis patients. METHODS: Oxidized R-limonene 3.0% (containing limonene hydroperoxides 0.33%) and oxidized linalool 6% (linalool hydroperoxides 1%) in petrolatum were tested in 2900 consecutive dermatitis patients in Australia, Denmark, Singapore, Spain, Sweden, and the United Kingdom. RESULTS: A total of 281 patients reacted to either oxidized R-limonene or oxidized linalool. Of these, 25% had concomitant reactions to both compounds, whereas 29% reacted only to oxidized R-limonene and 46% only to oxidized linalool. Of the 152 patients reacting to oxidized R-limonene, 46% reacted to oxidized linalool, whereas 35% of the 200 patients reacting to oxidized linalool also reacted to oxidized R-limonene. CONCLUSIONS: The majority of the patients (75%) reacted to only one of the oxidation mixtures, thus supporting the specificity of the reactions. The concomitant reactions to the two fragrance allergens suggest multiple sensitizations, which most likely reflect the exposure to the different fragrance materials in various types of consumer products. This is in accordance with what is generally seen for patch test reactions to fragrance materials.

Bioactivation of cinnamic alcohol forms several strong skin sensitizers.

Cinnamic alcohol is a frequent contact allergen, causing allergic contact dermatitis (ACD) in a substantial number of individuals sensitized from contacts with fragrances. Hence, cinnamic alcohol is one of the constituents in fragrance mix I (FM I) used for screening contact allergy in dermatitis patients. Cinnamic alcohol lacks structural alerts for protein reactivity and must therefore be activated by either air oxidation or bioactivation to be able to act as a sensitizer. In the present study, we explored the bioactivation of cinnamic alcohol using human liver microsomes (HLM), and the potential pathways for these reactions were modeled by in silico (DFT) techniques. Subsequently, the reactivity of cinnamic alcohol and its metabolites toward a model hexapeptide were investigated. In addition to cinnamic aldehyde and cinnamic acid, two highly sensitizing epoxides previously unobserved in studies of bioactivation were detected in the incubations with HLMs. Formation of epoxy cinnamic aldehyde was shown (both by the liver microsomal experiments, in which no depletion of epoxy cinnamic alcohol was observed after initial formation, and by the very high activation energy found for the oxidation thereof by calculations) to proceed via cinnamic aldehyde and not epoxy cinnamic alcohol.

Epoxy resin monomers with reduced skin sensitizing potency.

Epoxy resin monomers (ERMs), especially diglycidyl ethers of bisphenol A and F (DGEBA and DGEBF), are extensively used as building blocks for thermosetting polymers. However, they are known to commonly cause skin allergy. This research describes a number of alternative ERMs, designed with the aim of reducing the skin sensitizing potency while maintaining the ability to form thermosetting polymers. The compounds were designed, synthesized, and assessed for sensitizing potency using the in vivo murine local lymph node assay (LLNA). All six epoxy resin monomers had decreased sensitizing potencies compared to those of DGEBA and DGEBF. With respect to the LLNA EC3 value, the best of the alternative monomers had a value approximately 2.5 times higher than those of DGEBA and DGEBF. The diepoxides were reacted with triethylenetetramine, and the polymers formed were tested for technical applicability using thermogravimetric analysis and differential scanning calorimetry. Four out of the six alternative ERMs gave polymers with a thermal stability comparable to that obtained with DGEBA and DGEBF. The use of improved epoxy resin monomers with less skin sensitizing effects is a direct way to tackle the problem of contact allergy to epoxy resin systems, particularly in occupational settings, resulting in a reduction in the incidence of allergic contact dermatitis.

Epoxyalcohols: bioactivation and conjugation required for skin sensitization.

Allylic alcohols, such as geraniol 1, are easily oxidized by varying mechanisms, including the formation of both 2,3-epoxides and/or aldehydes. These epoxides, aldehydes, and epoxy-aldehydes can be interconverted to each other, and the reactivity of them all must be considered when considering the sensitization potential of the parent allylic alcohol. An in-depth study of the possible metabolites and autoxidation products of allylic alcohols is described, covering the formation, interconversion, reactivity, and sensitizing potential thereof, using a combination of in vivo, in vitro, in chemico, and in silico methods. This multimodal study, using the integration of diverse techniques to investigate the sensitization potential of a molecule, allows the identification of potential candidate(s) for the true culprit(s) in allergic responses to allylic alcohols. Overall, the sensitization potential of the investigated epoxyalcohols and unsaturated alcohols was found to derive from metabolic oxidation to the more potent aldehyde where possible. Where this is less likely, the compound remains weakly or nonsensitizing. Metabolic activation of a double bond to form a nonconjugated, nonterminal epoxide moiety is not enough to turn a nonsensitizing alcohol into a sensitizer, as such epoxides have low reactivity and low sensitizing potency. In addition, even an allylic 2,3-epoxide moiety is not necessarily a potent sensitizer, as shown for 2, where formation of the epoxide weakens the sensitization potential.

Determination of allergenic hydroperoxides in essential oils using gas chromatography with electron ionization mass spectrometry.

Fragrance monoterpenes are widely used commercially due to their pleasant scent. In previous studies, we have shown that air-exposed monoterpenes form hydroperoxides that are strong skin sensitizers. Methods for detection and quantification of the hydroperoxides in essential oils and scented products are thus desirable. Due to thermolability and low UV absorbance, this is a complicated task. We have recently developed a sensitive LC-ESI-MS method, but with limited structural information and separation efficiency for positional isomers and stereoisomers. In the present study, we investigated derivatization with a trimethyl silyl reagent and subsequent GC with electron ionization MS for the determination of monoterpene hydroperoxides. All investigated monoterpene hydroperoxides could be chromatographed as thermostable trimethyl silyl derivatives and yielded the fragment m/z 89 ([OSi(CH3)3](+)) at a higher extent compared to corresponding alcohols. Limonene-2-hydroperoxide and four other hydroperoxide isomers of limonene were separated and detected in sweet orange oil autoxidized for two months. The concentration of limonene-2-hydroperoxide isomers was found to be 19 µg/mg in total. Also isomers of linalyl acetate hydroperoxide and linalool hydroperoxide were detected in autoxidized petitgrain oil (two months). The presented GC-MS method showed concentrations in the same order as previous LC-MS/MS analysis of the same type of oils.

Limonene hydroperoxide analogues show specific patch test reactions.

BACKGROUND: The fragrance terpene R-limonene is a very weak sensitizer, but forms allergenic oxidation products upon contact with air. The primary oxidation products of oxidized limonene, the hydroperoxides, have an important impact on the sensitizing potency of the oxidation mixture. One analogue, limonene-1-hydroperoxide, was experimentally shown to be a significantly more potent sensitizer than limonene-2-hydroperoxide in the local lymph node assay with non-pooled lymph nodes. OBJECTIVES: To investigate the pattern of reactivity among consecutive dermatitis patients to two structurally closely related limonene hydroperoxides, limonene-1-hydroperoxide and limonene-2-hydroperoxide. METHODS: Limonene-1-hydroperoxide, limonene-2-hydroperoxide, at 0.5% in petrolatum, and oxidized limonene 3.0% pet. were tested in 763 consecutive dermatitis patients. RESULTS: Of the tested materials, limonene-1-hydroperoxide gave most reactions, with 2.4% of the patients showing positive patch test reactions. Limonene-2-hydroperoxide and oxidized R-limonene gave 1.7% and 1.2% positive patch test reactions, respectively. Concomitant positive patch test reactions to other fragrance markers in the baseline series were frequently noted. CONCLUSIONS: The results are in accordance with the experimental studies, as limonene-1-hydroperoxide gave more positive patch test reactions in the tested patients than limonene-2-hydroperoxide. Furthermore, the results support the specificity of the allergenic activity of the limonene hydroperoxide analogues and the importance of oxidized limonene as a cause of contact allergy.

Characterization of skin sensitizers from autoxidized citronellol - impact of the terpene structure on the autoxidation process.

BACKGROUND: Citronellol is a frequently used fragrance compound in consumer products. It is present in fragrance mix II, which is used for screening of contact allergy to fragrances. Because of its chemical structure, citronellol could be susceptible to autoxidation. OBJECTIVES: To compare the behaviour of citronellol with that of the structurally similar compounds linalool and geraniol, in terms of ability to autoxidize, the products formed, and the sensitization potencies of these. METHODS: Citronellol was exposed to air, and autoxidation was followed by gas chromatography-mass spectrometry (GC-MS) analysis after derivatization of thermolabile compounds. The sensitizing potencies of the oxidation mixture and its major oxidation compounds were examined with the local lymph node assay. RESULTS: The concentration of citronellol decreased while the sensitization potency increased in air-exposed samples over time, with hydroperoxides being identified as the major oxidation products and main skin sensitizers. CONCLUSIONS: The present study shows the impact of the absence of the 2,3-double bond in the citronellol structure on the oxidation pathways for formation of oxidation products. The study also shows the usefulness of our new GC-MS method for quantification of the citronellol oxidation products, especially the hydroperoxides. The investigated citronellol hydroperoxides could be important allergens, owing to the high concentrations detected and frequent exposure to citronellol in the population.

Air-oxidized linalool elicits eczema in allergic patients - a repeated open application test study.

BACKGROUND: Linalool is a commonly used fragrance terpene that forms potent sensitizers upon oxidation. In a recent multicentre study, we found that 7% of 2900 patients showed positive patch test reactions to oxidized linalool at 6.0%. No elicitation studies have been performed. OBJECTIVE: To identify threshold concentrations for elicitation of allergic contact dermatitis caused by oxidized linalool in allergic individuals with repeated exposures. METHODS: Repeated open application tests were performed in 6 participants previously diagnosed with contact allergy to oxidized linalool. Creams containing 3.0%, 1.0% and 0.30% oxidized linalool (corresponding to 0.56%, 0.19% and 0.056% linalool hydroperoxides, respectively) and 'fine fragrance' containing 1.0%, 0.30% and 0.10% oxidized linalool (corresponding to 0.19%, 0.056% and 0.019% linalool hydroperoxides, respectively) were used twice daily for up to 3 weeks. Patch testing with a dilution series of oxidized linalool was performed. RESULTS: Five of 6 participants reacted to the cream containing 3% oxidized linalool. With 1% oxidized linalool, a reaction was seen in 3 (cream) and 4 (fine fragrance) participants, respectively. With 0.3% oxidized linalool, 2 (cream) and 1 (fine fragrance) participants reacted. CONCLUSION: Repeated exposure to low concentrations of oxidized linalool can elicit allergic contact dermatitis in previously sensitized individuals.