Allergic contact dermatitis from methyldibromo glutaronitrile--clinical cases from 2003.

Of the 766 patients with eczematous skin disease patch tested in 2003 at the Department of Dermatology, University Clinic Gentofte, 38 (4.9%) showed a positive reaction to methyldibromo glutaronitrile (MDBGN), and in an additional 2 patients, a doubtful positive patch test reaction was found to be of relevance. Among these, 27 had hand eczema, with a relevant exposure predominantly from wash-off products, either liquid soaps or shampoos, in 24 patients. Following identification of the allergen by patch testing and subsequent avoidance of products containing MDBGN, the hand eczema either improved or cleared in 19 patients. Chemical analysis showed 11 p.p.m. to 473 p.p.m. MDBGN in products used by the patients. Based on the present clinical study and accumulated evidence in the literature, it is concluded that MDBGN is not suitable for use in any type of cosmetic product.

Is hypoallergenic a credible term?

Hypoallergenic is a term that is frequently applied to cosmetics and is intended to imply a very low likelihood of developing or potentiating allergic cutaneous reactions. However there are neither industry standards nor legal requirements which must be fulfilled in order to make this claim. We describe a 25-year-old woman referred with worsening eczema which she related to the use of two skincare products. Both had been promoted as hypoallergenic and 'preservative free'; chemical analysis using HPLC confirmed the presence of methyldibromoglutaronitrile and formaldehyde, both at robust concentrations. We consider it unlikely that these were present as contaminants and suggest that the term hypoallergenic must be interpreted with caution.

Further important sensitizers in patients sensitive to fragrances.

The aim of this study was to determine the frequency of responses to selected fragrance materials in consecutive patients patch tested in 6 dermatological centres in Europe. 1855 patients were evaluated with the 8% fragrance mix (FM) and 14 other frequently used well-defined fragrance chemicals (series I). Each patient was classified regarding a history of adverse reactions to fragrances: certain, probable, questionable, none. Reactions to FM occurred in 11.3% of the subjects. The 6 substances with the highest reactivity following FM were Lyral (2.7%), citral (1.1%), farnesol P (0.5%), citronellol (0.4%), hexyl cinnamic aldehyde (0.3%), and coumarin (0.3%). 41 (2.2%) of the patients reacted only to materials of series I and not to FM. 6.6% of 1855 patients gave a history of adverse reactions to fragrances which was classified as certain. This group reacted to FM only in 41.1%, to series I and FM in 12.0% and to series I only in 7.2%. 74.3% of the 39 patients reacting to both FM and 1 of the materials of series I had any type of positive fragrance history, which was significantly higher in comparison to those with isolated reactions to series I (53.6% of 41), p = 0.04. The study identified further sensitizers relevant for patch testing of patients with contact dermatitis, of which Lyral is the most important single chemical.

Further important sensitizers in patients sensitive to fragrances.

In order to find sensitizers additional to the current fragrance mix (FM) a series of fragrance materials (series II) was evaluated in 6 dermatological centres in Europe. 11 of the test materials were essential oils, the remaining 7 being either mixtures of isomers or simple chemicals of frequent usage in the perfume industry. 1606 patients were consecutively tested with series II and 8% FM. Each patient was classified regarding a history of adverse reactions to scented products: certain, probable, questionable, none. Reactions to FM occurred most frequently in 11.4% of the subjects. The 6 materials with the highest reactivity after the FM were ylang-ylang oil (YY) I (2.6%), YY II (2.5%), lemongrass oil (1.6%), narcissus absolute (1.3%), jasmine absolute (1.2%) and sandalwood oil (0.9%). 48 (3.0%) of the patients reacted only to materials of series II and not to FM. 6.0% of 1606 patients gave a history of adverse reactions to fragrances which was classified as certain. This group reacted to FM only in 22.9%, to series II and FM in 15.6% and to series II only in 5.2%. 63.5% of the patients reacting to both FM and 1 of the materials of series II had some type of positive fragrance history, which was higher in comparison to those with isolated reactions to FM (46.2% of 121) or to series II, respectively, (45.8% of 48). However, this difference was not statistically significant. In conclusion, the materials of series II identified a further subset of patients with a fragrance problem, which would have been missed by the current FM as the single screening tool for patch testing.

Fragrance chemicals in domestic and occupational products.

Epidemiological studies have described an increasing prevalence of fragrance allergy and indicated an association with hand eczema. 59 domestic and occupational products intended for hand exposure were subjected to gas chromatography-mass spectrometric (GC-MS) analyses to test the hypothesis that fragrance chemicals known to have the potential to cause contact allergy but not included in fragrance mix (FM) may be common ingredients in these products. A quantitative analysis of 19 selected fragrances was performed by GC-MS. Further analysis of GC-MS data revealed the presence of 43 other fragrance chemicals/groups of fragrance chemicals in the products investigated. Among the 19 target substances the most commonly detected were limonene in 78%, linalool in 61% and citronellol in 47% of the products investigated. The FM ingredients were present in these products with the following frequencies: oak moss (evernic acid methylester) 2%, cinnamic alcohol 2%, cinnamic aldehyde (cinnamal) 3%, isoeugenol 5%, alpha-amylcinnamic aldehyde (amyl cinnamal) 8%, hydroxycitronellal 12%, eugenol 27%, and geraniol 41%. Thus, the chemical analyses of domestic and occupational products indicates that investigation of potential contact allergy related to these products types should consider fragrance allergens additional to those in the FM, since these may occur with high frequency.

Allergic contact dermatitis from sodium dihydroxycetyl phosphate, a new cosmetic allergen?

Sodium dihydroxycetyl phosphate (trade name Dragophos S 2/918501) was identified as a contact allergen in a herbal moisturizing cream causing severe acute contact dermatitis on the hands and face of a 41-year-old woman. Sodium dihydroxycetyl phosphate is a complex mixture of phosphate esters of dihydroxycetyl alcohol, and subsequent analysis and testing revealed hexadecane-1,2-diol as 1 of the allergenic ingredients. Another possible allergen in the compound appears to be hexadecane-1,2-diol, 2-isopropyl ether.

Testing with fine fragrances in eczema patients: results and test methods.

The frequencies of contact allergic reactions to 2 fine fragrances were studied by patch testing. Further, a comparison was made of test results before and after evaporation of the solvent. A total of 480 consecutive eczema patients were included, 100 in the Dortmund clinic and 380 in the Gentofte clinic. Patch testing was done with 2 international brand prestige fragrances. Each fragrance was tested in duplicate. One was applied immediately and the other was allowed to dry for 5 min before application. Testing procedures and assessment of reactions followed the international recommendations. In Dortmund 11% (11/100) and in Gentofte 5.8% (22/380) gave a positive patch test reaction to one or both of the fine fragrances. Assessments done in Gentofte showed that in 73% of the cases the positive reaction indicated a clinically relevant fragrance allergy. More irritant reactions were found to the wet, non-evaporated form of the fragrances compared with the dried form, while the method of testing did not significantly influence the number of positive reactions. It is recommended that patch testing be performed with hydro-alcoholic fragrance products after evaporation of the solvent.

Analytical control of preservative labelling on skin creams.

Contents of 23 preservatives (22 permitted and 1 non-permitted) were analysed in 67 skin creams to verify whether these products complied with the Cosmetic Directive with respect to ingredient labelling, as well as with respect to maximum allowed concentrations of the respective preservatives. The preservatives selected for the analysis were: parabens, 2-phenoxyethanol, benzoic acid, 4-hydroxybenzoic acid, sorbic acid, salicylic acid, formaldehyde and formaldehyde releasers, 3:1 mixture of 5-chloro-2-methyl-4-isothiazolin-2-one and 2-methyl-4-isothiazolin-2-one (Kathon CG), 2-bromo-2-nitropropane-1,3-diol (Bronopol), 5-bromo-2-nitro-1,3-dioxane (Bronidox) and methyldibromo glutaronitrile. 1 or more parabens were present in 87% (n=58) of the investigated products, 2-phenoxy ethanol in 49% (n=33) of the products, and formaldehyde/formaldehyde releasers were present in 51% (n=34) of the products. Kathon CG was found in 3 products, acid preservatives (except salicylic acid) in 8 products, Bronopol in 5 products, and methyldibromo glutaronitrile was present in 4 products. The contents of all of the target preservatives in the skin creams were within the maximum allowed concentrations of the respective substances. Incorrect ingredient labelling with respect to paraben content was found in 10% (n=7) of the investigated products, 33% (n= 22) of the products were not declared for the content of formaldehyde/formaldehyde releaser, and 7% (n=5) products were incorrectly labelled for the content of 2-phenoxyethanol. In 1 of the products containing Kathon CG, the ratio of 5-chloro-2-methyl-4-isothiazolin-2-one to 2-methyl-4-isothiazolin-2-one (1.4:1) was not correct. 4 of the 8 products containing acid preservatives were not labelled for the content of these substances. All in all, in 45% (n=30) of the investigated skin creams ingredient labelling was incorrect with respect to preservative contents. The proportion of incorrect labelling is reduced to 23% (n = 15), when the formaldehyde content in skin creams below 30 ppm is not accounted.

Identification of Lilial as a fragrance sensitizer in a perfume by bioassay-guided chemical fractionation and structure-activity relationships.

Fragrance materials are among the most common causes of allergic contact dermatitis. The aim of this study was to identify in a perfume fragrance allergens not included in the fragrance mix, by use of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships (SARs). The basis for the investigation was a 45-year-old woman allergic to her own perfume. She had a negative patch test to the fragrance mix and agreed to participate in the study. Chemical fractionation of the perfume concentrate was used for repeated patch testing and/or repeated open application test on the pre-sensitized patient. The chemical composition of the fractions giving a positive patch-test response and repeated open application test reactions was obtained by gas chromatography-mass spectrometry. From the compounds identified, those that contained a "structural alert" in their chemical structure, indicating an ability to modify skin proteins and thus behave as a skin sensitizer, were tested on the patient. The patient reacted positively to the synthetic fragrance p-t-butyl-alpha-methylhydrocinnamic aldehyde (Lilial), a widely used fragrance compound not present in the fragrance mix. The combination of bioassay-guided chemical fractionation and chemical analysis/structure-activity relationships seems to be a valuable tool for the investigation of contact allergy to fragrance materials.

Lyral is an important sensitizer in patients sensitive to fragrances.

Contact allergy to fragrances is a common problem world-wide. The currently used fragrance mix (FM) for patch testing has only eight constituents and does not identify all fragrance-allergic patients. As perfumes may contain 100 or more substances, the search for markers for allergy continues. The synthetic fragrance 4-(4-hydroxy-4-methylpentyl)-3-cyclohexene carboxaldehyde (Lyral) was tested together with the FM and 11 other fragrance substances on consecutive patients in six European departments of dermatology. All patients were carefully questioned regarding a history of reactions to scented products in the past and were grouped into four categories: 'certain', 'probable', 'questionable' and 'none'. Lyral (5% in petrolatum) gave a positive reaction in 2.7% of 1855 patients (range 1.2-17%) and ranked next to 11.3% with FM allergy. Twenty-four patients reacted to both Lyral and FM, but 21 (1.1%) reacted positively only to Lyral. Of 124 patients with a 'certain' history, 53.2% reacted to the FM and a further 7.2% to Lyral only. If any kind of history of fragrance intolerance was given, 80% (40 of 50) of Lyral positive patients had a 'positive' history while only 58.6% (123 of 210) of FM positive patients had such a history; this difference was significant at P < 0.01. Lyral was identified by gas chromatography-mass spectrometry in some products which had caused an allergic contact dermatitis in four typical patients who showed a patch test positive to Lyral and negative or doubtful to FM. In conclusion, we recommend the testing of 5% Lyral (in petrolatum) in patients suspected of contact dermatitis.

Contents of fragrance allergens in children's cosmetics and cosmetic-toys.

Fragrances are one of the major causes of allergic contact dermatitis from use of cosmetics. The aim of the current study was to assess the possible exposure of infants and children to fragrance allergens from cosmetic products and "toy-cosmetics". 25 children's cosmetics or toy-cosmetic products were analysed by gas chromatography - mass spectrometry. Target substances were the fragrance allergens from the fragrance mix and 14 other fragrance substances, most of which have been described as contact allergens. The fragrance mix ingredients were either not present in children's shampoos/shower gels and cream/lotions, or they were present in fairly low concentrations. In hydro-alcoholic products, such as eau de parfum, eau de toilette, several ingredients of the fragrance mix were found: geraniol was present in 7/7 products, hydroxycitronellal in 6/7 and isoeugenol in 2/7 products. Isoeugenol was present in a maximum concentration of 0.07%. In one cosmetic-toy, cinnamic alcohol was present at 3.7% which exceeds the current industry guideline for safe products by a factor of 5. In all types of products other fragrance allergens were frequently found. In conclusion, children are already exposed at an early age to well-known allergens, sometimes at concentrations which are considered to be unsafe. As contact allergy usually persists for life, manufacturers of children's cosmetics should be aware of their special responsibility and apply the highest possible safety standards.

Identification of coumarin as the sensitizer in a patient sensitive to her own perfume but negative to the fragrance mix.

The aim of this study was to identify the chemicals responsible for the sensitivity of a 44-year-old woman to her own perfume, but showing negative patch test results to the fragrance mix. For this purpose, the perfume concentrate from the eau de toilette was chemically fractionated. Each fraction obtained was afterwards tested on the patient using a ROAT and/or a patch test. Only 1 fraction gave a positive ROAT result. This fraction was analyzed and found to contain coumarin and ethyl vanillin. Coumarin, one of the most widely used fragrance compounds that is not present in the fragrance mix, was confirmed as being the sensitizer.

Deodorants: a clinical provocation study in fragrance-sensitive individuals.

Deodorants are one of the most marketed types of cosmetics and are frequently reported as a cause of dermatitis, particularly among fragrance-sensitive persons. The aim of this study was to investigate the ability of deodorants, which had previously caused axillary dermatitis in fragrance-mix-sensitive eczema patients, to provoke reactions on repeated open application tests on the upper arm and in the axillae, and to relate the findings to the content of fragrance-mix constituents in those deodorants. 14 eczema patients performed a 7-day use test with 1 or 2 deodorants that had caused a rash within the last 12 months. 2 applications per day were made in the axilla and simultaneously on a 25 cm2 area on the upper arm. A total of 20 deodorants were tested among the 14 patients. Afterwards, the deodorants were subjected to quantitative chemical analysis identifying constituents of the fragrance mix. 12/20 (60%) deodorants elicited eczema on use testing in the axilla. 8/12 deodorants were positive in the axilla on day (D) 7 and 4 both in the axilla and on the upper arm. 2 of the 4 developed a reaction in the axilla before it developed on the upper arm. Chemical analysis revealed that 18/19 deodorants contained between 1 and 6 of the fragrance-mix constituents, on average 3 being found. The mean concentration of fragrance-mix constituents was generally higher in the deodorants causing a positive use test, as compared with those giving a negative reaction, indicating that the differences between the deodorants in terms of elicitation potential were more related to quantitative aspects of allergen content than of a qualitative nature. It is recommended that deodorants are tested in the axilla in the case of a negative use test on the upper arm and a strong clinical suspicion.

Deodorants on the European market: quantitative chemical analysis of 21 fragrances.

Deodorants are one of the most frequently used types of cosmetics and side-effects from them are common. Recent studies relate perfume allergy to this type of product. 73 deodorants were analyzed by gas chromatography--mass spectrometry for the determination of the contents of 7 wellknown fragrance allergens from the fragrance mix and 14 other commonly used fragrance materials. The deodorants were purchased at retail outlets in 5 European countries. It was found that in general, fragrance mix ingredients were more frequently present in vapo- and aerosol sprays than in roll-on products. The levels of the fragrance mix substances ranged from 0.0001-0.2355%. The products investigated contained cinnamic aldehyde and isoeugenol less frequently (17% and 29% respectively), and eugenol and geraniol most frequently (57% and 76% respectively). The 14 other fragrance materials were found in 40-97% of the deodorants, with hedione and benzyl acetate the most frequently found substances. The concentration of these 14 substances ranged from 0.0001-2.7%. It is concluded that the levels of cinnamic aldehyde and isoeugenol found in the deodorants could prove to be relevant for elicitation of contact dermatitis. No conclusions could be drawn about the other fragrance mix constituents, as threshold levels in sensitized individuals have not been investigated. Furthermore, all of the fragrance materials investigated were frequently found in deodorants and, apart from the fragrance mix ingredients, the extent of problems with sensitization to these fragrance materials is largely unknown.

Fragrances and other materials in deodorants: search for potentially sensitizing molecules using combined GC-MS and structure activity relationship (SAR) analysis.

Deodorants are one of the most frequently-used types of cosmetics and are a source of allergic contact dermatitis. Therefore, a gas chromatography - mass spectrometric analysis of 71 deodorants was performed for identification of fragrance and non-fragrance materials present in marketed deodorants. Futhermore, the sensitizing potential of these molecules was evaluated using structure activity relationships (SARs) analysis. This was based on the presence of 1 or more chemically reactive site(s), in the chemical structure, associated with sensitizing potential. Among the many different substances used to formulate cosmetic products (over 3500), 226 chemicals were identified in a sample of 71 deodorants. 84 molecules were found to contain at least 1 structural alert, and 70 to belong to, or be susceptible to being metabolized into, the chemical group of aldehydes, ketones and alpha,beta-unsaturated aldehydes, ketone or esters. The combination of GC-MS and SARs analysis could be helpful in the selection of substances for supplementary investigations regarding sensitizing properties. Thus, it may be a valuable tool in the management of contact allergy to deodorants and for producing new deodorants with decreased propensity to cause contact allergy.

Content and reactivity to product perfumes in fragrance mix positive and negative eczema patients. A study of perfumes used in toiletries and skin-care products.

The aim of the study was to investigate the elicitation potential of perfumes from 17 commonly sold lower-price cosmetic products. 8 of the perfumes were from stay-on cosmetics and 9 were from wash-off cosmetics. Each perfume was tested in 500 consecutive eczema patients, who also were tested with the European standard patch test series. 4.2% reacted to 1 or more of the wash-off product perfumes and 3.2% to 1 or more of the stay-on product perfumes. Concordant positive reactions between the fragrance mix and the product perfumes were found in 81.3% of positive reactions to the stay-on product perfumes and in 52.4% of the reactions to the wash-off product perfumes. Compared to the fragrance mix alone, only 1 additional case of contact allergy to the product perfumes was detected by balsam of Peru. Chemical analysis revealed that between 1 and 5 of the chemically-defined constituents of the fragrance mix were present in all of the product perfumes. Geraniol was found in 12 of the 17 perfumes and was most often detected. The concentration of the target fragrance materials ranged from 0.005%-1.35 w/v%. It is concluded that the allergenic constituents of the fragrance mix are impossible to avoid if perfumed cosmetics are used. Furthermore, patients suspected of perfume allergy need to be tested with their own perfumed products, as far from all cases of perfume allergy are detected by the fragrance mix and/or balsam of Peru in the European standard patch test series.

Iodopropynyl butylcarbamate: a new contact allergen.

Iodopropynyl butylcarbamate (IPBC) has been used for years as a fungicide and bactericide for wood and paint preservation without any reports of cutaneous side-effects. During the last few years, it has entered cosmetic products and is temporarily permitted in the EU Cosmetics Directive in a use concentration of 0.1%. In the present study, we report our preliminary experience with patch testing consecutive contact dermatitis patients with IPBC. A patch test concentration of 0.1% seems appropriate for initial screening but deserves further evaluation. Among 311 consecutive patch test patients, 3 patients with a positive patch test to IPBC have been identified. Contact allergy is likely in at least 1 case, based on clinical history, exposure history, patch testing with dilution series, ROAT and chemical analysis.

Contact allergy to popular perfumes; assessed by patch test, use test and chemical analysis.

The frequency of contact allergy to the 10 best-selling women's perfumes was studied in 335 consecutive female eczema patients by patch testing. The diagnostic ability of the fragrance mix, in relation to these products, was evaluated. Of eczema patients, 6.9% had a positive patch test to one or more of the perfumes, and 56.5% of these had a concurrent positive reaction to the fragrance mix. Hence, testing with the patients' own cosmetics is a significant part of diagnosing perfume allergy. The clinical relevance of the patch-test reactions to the commercial perfumes was equal to that of the fragrance mix, as judged from the patient's history and use testing with one of the perfumes. At least three of the chemically defined sensitizers in the fragrance mix were detected in all the perfumes by gas chromatography-mass spectrometry, which indicates that the fragrance mix is a good imitation of actual exposure.

Natural ingredients based cosmetics. Content of selected fragrance sensitizers.

In the present study, we have investigated 42 cosmetic products based on natural ingredients for content of 11 fragrance substances: geraniol, hydroxycitronellal, eugenol, isoeugenol, cinnamic aldehyde, cinnamic alcohol, alpha-amylcinnamic aldehyde, citral, coumarin, dihydrocoumarin and alpha-hexylcinnamic aldehyde. The study revealed that the 91% (20/22) of the natural ingredients based perfumes contained 0.027%-7.706% of 1 to 7 of the target fragrances. Between 1 and 5 of the chemically defined synthetic constituents of fragrance mix were found in 82% (18/22) of the perfumes. 35% (7/20) of the other cosmetic products (shampoos, creams, tonics, etc) were found to contain 0.0003-0.0820% of 1 to 3 of the target fragrances. Relatively high concentrations of hydroxycitronellal, coumarin, cinnamic alcohol and alpha-amyl cinnamic aldehyde were found in some of the investigated products. The detection of hydroxycitronellal and alpha-hexylcinnamic aldehyde in some of the products demonstrates that artificial fragrances, i.e., compounds not yet regarded as natural substances, may be present in products claimed to be based on natural ingredients.