Ethylhexylglycerin: a low-risk, but highly relevant, sensitizer in hypo-allergenic cosmetics

Transcription

1 Contact Dermatitis Original Article COD Contact Dermatitis Ethylhexylglycerin: a low-risk, but highly relevant, sensitizer in hypo-allergenic cosmetics Olivier Aerts 1, Lien Verhulst 2 and An Goossens 2 1 Department of Dermatology, Antwerp University Hospital (UZA) and University of Antwerp (UA), 2650 Antwerp, Belgium and 2 Department of Dermatology, University Hospitals K.U. Leuven, 3000 Leuven, Belgium doi: /cod Summary Background. Ethylhexylglycerin is a relatively new cosmetic ingredient that is used for its surfactant, emollient, skin-conditioning and antimicrobial properties. Since 2002, it has been occasionally reported as a contact allergen. Objectives. To report on 13 patients who presented with allergic contact dermatitis caused by ethylhexylglycerin, evaluated at two Belgian university patch test clinics during the period Patients and methods. The patients were patch tested with the European baseline series, a cosmetic series, and if indicated additional series. Both the cosmetic products used and their single ingredients were patch tested. Results. All but one of the ethylhexylglycerin-allergic patients were female, with a median age of 43 years (range: years), most often suffering from dermatitis on the face, and sometimes on the hands and/or axillae. As the culprit products, leave-on cosmetics were identified, including a high number of proclaimed hypo-allergenic and preservative-free facial creams, sun protection creams, and deodorants. Conclusions. Ethylhexylglycerin is a rare, but highly relevant, cosmetic sensitizer, even in those products advertised to be safe for consumers. Targeted patch testing with ethylhexylglycerin 5% pet. is very useful, and routine patch testing in a cosmetic series may be considered. Higher test concentrations might be indicated in selected cases. Key words: allergic contact dermatitis; CAS no ; cosmetics; deodorants; ethylhexylglycerin; octoxyglycerin; patch testing; preservative; skin conditioner; sunscreens. Ethylhexylglycerin (CAS no ), also known as octoxyglycerin or 3-(2-ethylhexyloxy)propane-1,2-diol, belongs to the family of alkyl-glyceryl ethers, and is used for its surfactant, skin-conditioning, emollient and antimicrobial properties in a wide variety of cosmetics (1) (Fig. 1). Although it was originally considered to be a non-sensitizer in animals (1), a few cases of allergic Correspondence: Dr Olivier Aerts, Department of Dermatology, University Hospital Antwerp, Wilrijkstraat 10, B-2650 Antwerp, Belgium. Tel: ; Fax: olivier.aerts@gmail.com Conflicts of interest: The authors declare no conflict of interests. Accepted for publication 5 January 2016 contact dermatitis have been reported (2 7). We published our first case in 2002 (2), and 12 more cases are described here. Patients and Methods A total of 10 patients [including the first patient published; case 1 in Table 1 (2)] were observed at the K.U. Leuven department in the period from January 1990 to October 2015, and 3 more at the Antwerp dermatology department between January 2014 and October In all subjects, patch tests were performed with the European baseline series (except in case 4), a cosmetic series, the patient s own personal care products, and whenever available their individual components. Contact Dermatitis, 74,

2 Fig. 1. Structural formula of ethylhexylglycerin, the condensation product of glycerin (hydrophilic head) with an alkyl group (hydrophobic tail). Depending on the patient s history, additional patch tests with a fragrance, pharmaceutical, textile and/or hair series were also sometimes performed. The baseline allergens were provided by Chemotechnique (Vellinge, Sweden), both in Leuven and Antwerp. In all cases, ethylhexylglycerin was present in at least one of the cosmetics brought in and/or suspected by the patients to be the cause of their dermatitis. Leave-on cosmetic products were always patch tested as is. Ethylhexylglycerin was patch tested in the following concentrations and vehicles: 10% pet. (an in-house preparation; originally used in Leuven), 5% pet. (diluted from the 10% pet. preparation), and, recently, the commercially available patch test material (ref. E-027) from Chemotechnique, Vellinge, Sweden; also, the commercial preparation 0.3% in liquid paraffin (kindly provided by a cosmetic manufacturer) was tested in 2 cases from Antwerp. In Leuven, first van der Bend (Van der Bend, Brielle, The Netherlands) and later IQ Ultra (Chemotechnique) patch test chambers were used, covered with Mefix (Mölnlycke, Göteborg, Sweden); in Antwerp, the patch test chambers used were from Van der Bend or from Allergeaze (SmartPractice, Calgary, Canada), fixed with Fixomull stretch (BSN Medical GmbH, Hamburg, Germany). Chambers were applied on the upper back of the patients in both departments. Following occlusion for 2 days, readings were performed at day (D) 2 and D4, according to the recently published guidelines from the European Society of Contact Dermatitis (8). Results Table 1 shows the patient characteristics, culprit cosmetic products, and patch test results. In total, between November 1990 and the end of October 2015, 557 patients were tested for ethylhexylglycerin in the Contact Allergy Unit in Leuven, and the 10 cases included here (1.8%) all showed a relevant contact allergy to it. The same applies to the 3 cases observed in Antwerp [comprising 2 patients who underwent targeted testing in 2014, and 1 patient of 382 patients (0.3%) routinely tested between January 2015 and the end of October 2015]. Nearly all of the patients were women (9/10 in Leuven and 3/3 in Antwerp), with a median age of 43 years (range: years). All 13 patients showed positive patch test reactions to the ethylhexylglycerin-containing cosmetic products that they were using (except for a facial serum in case 13), and to this allergen separately (1+ reactions in 8 of 13; 2+ in 2 of 13; and 3+ in 3 of 13). All reactions to ethylhexylglycerin were found to be of current and certain relevance; that is, ethylhexylglycerin was present in cosmetics contributing to the dermatitis for which the patients consulted. In 9 of 13 cases, reactions were also observed to other contact allergens (fragrances, preservatives, hair dyes, panthenol, castor oil, and metals), and these were sometimes also relevant for the patients dermatitis. For all patients, except cases 10 and 13, in whom a facial scrub and a cleanser were involved, only leave-on products were identified as the cause of the dermatitis. In 11 cases, facial skin care creams were the causal products; in 6 of them, the cream was a particular cream from the same brand (marketed as hypo-allergenic ), which was also the causal product in the first case previously reported (2). Tinted moisturizers (foundations: 2 cases) and anti-aging products (2 cases) were also involved. The other (most important) culprits were sunscreens (5 cases) and deodorants (4 cases). Some patients reacted to several ethylhexylglycerin-containing products that they had been using. Mainly, (parts of) the face (11/13), in some cases extending to the neck (4/13), sometimes together with the hands, were affected. Also, axillary dermatitis was noted in 5 of 13 patients. Sometimes, more generalized (spreading) lesions were present; rare anatomical sites were the abdomen, arms, legs, and genitals (perineum). Figure 2 shows extremely severe hand dermatitis (case 11) in a female patient, following the application of sun protection creams with her right hand onto her children s skin. In 2012, she had suffered from a similar reaction on the same hand after the use of another sunscreen product. However, primary sensitization had apparently taken place already in August 2010 on the abdomen, following the use of a cream to treat abdominal stretch marks during pregnancy. Figure 3 shows a recurrent facial dermatitis (case 13) caused by multiple products containing the respective allergen, which were partly labelled hypo-allergenic. 282 Contact Dermatitis, 74,

3 Table 1. Current report on allergic contact dermatitis caused by ethylhexylglycerin (tested 5% pet., unless otherwise indicated): patient characteristics,culprit cosmetic products,and patch test results (n = 13) Case Sex Age (years) Year of diagnosis Anatomical site of dermatitis Type of ethylhexylglycerin-containing cosmetic involved Patch test results D2 D4 1 F Face (periocular, perioral) Facial skin care product (day cream) Ethylhexylglycerin 10% pet. (5 control subjects negative) 2 F Face, neck Facial skin care product (day cream) Ethylhexylglycerin 10% pet F Face, hand Facial skin care product (day cream) MCI/MI 100 ppm aq Ethylhexylglycerin F Face (eyelids), neck Facial skin care product (day cream), Fragrance mix II + + deodorant, two tinted moisturizing p-phenylenediamine? + creams (foundation) HICC + + Toluene-2,5-diamine + + p-aminophenol + + Linalool hydroperoxides + + Ethylhexylglycerin + + MI 500 ppm F Face (eyelids) Facial skin care product (day cream) Ethylhexylglycerin F Face, hand Facial skin care product (day cream), Ethylhexylglycerin + + sunscreen (cream and spray) 7 M Face, legs Facial skin care product, sunscreen Ethylhexylglycerin + + Fragrance mix I? 8 F Face (nose), armpits, elbows, perineum Facial anti-aging cream (day cream), facial skin care product (day cream), sunscreen Methyldibromoglutaronitrile? Amylcinnamal + ++ Geraniol + + Ethylhexylglycerin + + Contact Dermatitis, 74,

4 Table 1. Continued Case Sex Age (years) Year of diagnosis Anatomical site of dermatitis Type of ethylhexylglycerin-containing cosmetic involved Patch test results D2 D4 9 F Face (periocular, earlobes), neck, armpits, abdominal folds Tinted moisturizing cream (foundation), facial anti-aging cream, deodorant 10 F Face, neck, scalp, armpits Facial skin care product (day cream), facial scrub, one deodorant, sunscreen Octylisothiazolinone 0.1% pet. Ethylhexylglycerin 0.3% in liquid paraffin and 5% pet.? + + Nickel Ethylhexylglycerin 0.3% in + + liquid paraffin Panthenol? + 11 F Abdomen, hand Anti-stretch mark product, sunscreen Fragrance mix II + + Citronellol + Limonene hydroperoxides + Ethylhexylglycerin Nickel F Armpits Deodorant Ethylhexylglycerin + ++ Linalool hydroperoxides + Limonene hydroperoxides + 13 F Face, armpits Cosmetic serum, make-up remover and facial skin care product, skin cleanser, facial skin care product Cobalt + + Nickel Chlorhexidine digluconate? Castor oil (pure) + + Ethylhexylglycerin + F, female; HICC, hydroxyisohexyl 3-cyclohexene carboxaldehyde; M, male; MCI, methylchloroisothiazolinone; MI, methylisothiazolinone. First case, published in 2002 (2). All from the same hypo-allergenic brand. 284 Contact Dermatitis, 74,

5 Fig. 2. Severe dermatitis of the right hand following the application of ethylhexylglycerin-containing sunscreens onto her children s skin (case 11). Fig. 3. Recurrent, and unevenly distributed, facial dermatitis following the use of several skin care cosmetics containing ethylhexylglycerin (case 13). Discussion Ethylhexylglycerin is a relatively new and synthetic cosmetic ingredient, manufactured and marketed by Schülke and Mayr GmbH (Norderstedt, Germany) under the trade name Sensiva SC 50, containing >99% pure ethylhexylglycerin, with α-tocopherol (added as an antioxidant to stabilize the formulation) and 2-ethylhexyl glycidyl ether as possible impurity (1). It has the appearance of a pale to colourless liquid, and is formed by a condensation reaction between 2-ethylhexanol and glycerin, yielding a surfactant with a hydrophilic head (glycerin) and a hydrophobic tail (alkyl group) (1) (Fig. 1). It can be found in a wide variety of cosmetics, including eye shadows and creams, mascaras, lip gloss, deodorants, facial skin cleansers and make-up removers, shampoos, shower gels, intimate hygiene products, depigmentation creams, hydrating and anti-aging creams, hand creams, shaving creams, self-tanning products, sunscreens, and wet wipes (also for babies). Concentrations in cosmetics up to 2% and 8% have been reported in both leave-on and rinse-off products, respectively, although much lower concentrations (e.g. <1%) may be in use. Owing to its ability to inhibit the growth of odour-causing bacteria, ethylhexylglycerin may be used as an alternative to parabens (1), for instance in deodorants, and it may also enhance the efficacy of other cosmetic preservatives, such as phenoxyethanol, methylisothiazolinone, methylparaben, and glycols [(e.g. caprylyl glycol and pentylene glycol, to which a concomitant contact allergic reaction has also been reported (4)]. Several liquid cosmetic preservative mixtures are currently available on the market in which ethylhexylglycerin is present as a booster for the preservative action of other ingredients (e.g. Euxyl PE9010, in which it augments the preservative power of phenoxyethanol). Other examples include Euxyl K-701 and K-702, the former containing phenoxyethanol, benzoic acid, dehydroacetic acid, and ethylhexylglycerin, and the latter containing the same ingredients Contact Dermatitis, 74,

6 Table 2. Reports from other groups on allergic contact dermatitis caused by ethylhexylglycerin (n = 5) References Sex, age (years) Anatomical site Patch test with ethylhexylglycerin Control subjects Culprit cosmetics Stausbøl-Grøn and Female, 64 Face (hands, arms) 5% pet. 25 controls negative Day cream Andersen (3) ROAT 5% pet. Sunscreen positive as well Mortz et al. (4) Female, 68 Face 5% pet. 25 controls negative Two day creams Andersen (6) Female, 35 Face (atopic head and neck dermatitis) 5% pet. 784 other patients Day cream Dorschner and Shaw (5) Sasseville and Stanciu (7) Female, 66 Male, 16 Face and widespread Sun-exposed skin areas (including face) Flare-up of facial dermatitis during patch tests ROAT, repeated open application test. All from the same hypo-allergenic brand for sensitive skin, as in the currently reported series. Photo-patch and patch tests with these sun protection creams were of equal intensity. consecutively patch tested: 778 negative 6 doubtful reactions (+?) of unclear relevance 5% pet. 30 controls negative Two sunscreens 1%and0.1%ineth.: both + 0.1% and 0.01% in aq.: both + Glycerin 10% aq.: negative 5% pet. None stated Two sunscreens together with polyaminopropyl biguanide [recently also reported as a potentially upcoming contact allergen (9)]. Moreover, this component may also be present as an emollient in occupationally used, alcohol-based surgical hand disinfectants, in which it may again potentiate the efficacy of other antimicrobials, such as chlorhexidine gluconate and benzalkonium chloride, against, for example, Staphylococcus aureus (10). As one might expect in cases of contact dermatitis caused by cosmetics, nearly all previously published cases (Table 2), and also the current series (Table 1), concern adult females, except for our case 7 and for the case reported by Sasseville and Stanciu, describing a 16-year-old boy (7). Most patients are middle-aged (median: 43 years), an age group considered to be possibly at risk for allergic contact dermatitis caused by cosmetics, at least when other preservatives are considered (11, 12). As previously reported (Table 2), all but 2 of our cases primarily showed facial allergic contact dermatitis, sometimes with only partial involvement (e.g. exclusively on the eyelids or nose, or disseminated, non-evenly distributed facial lesions, as in case 13; Fig. 3), in some cases extending towards the neck. In a minority of these patients (cases 3 and 6), the hands (often used to apply the products) were simultaneously affected. Involvement of the axillary region (5/13) could almost always be attributed to the use of ethylhexylglycerin-containing deodorants. Notwithstanding its clear antimicrobial power, the substance is officially not included in the EU list of preservatives in cosmetics, and may thus also be present in so-called preservative-free products. Indeed, in nearly half of our cases (6/13), the same facial skin care product from one specific brand, marketed as hypo-allergenic and preservative-free (i.e. for sensitive, rosaceous or allergy-prone skin), was identified as the cause of the facial dermatitis. Interestingly, in 2 previously reported cases of facial allergic contact dermatitis, the same brand was involved (3, 4) (Table 2). In the case of Andersen, atopic head and neck dermatitis seemed to have been aggravated by an ethylhexylglycerin-containing facial skin care cream (6). We here report, for the first time, deodorants as the cause of axillary dermatitis: in cases 9,10, and 12, who had identified the culprit product at the time of consultation; and in cases 8 and 13, in whom the (former) use of such cosmetics had been highly suspected. It is of note that a similar observation has been made for other preservatives in deodorants [e.g. methylisothiazolinone (12, 13)]. A third important group of culprit cosmetics in our series were sunscreen products (5 of 13 patients), confirming previously published cases (3, 5, 7), in which 3 of 5 patients were sensitized by the use of (sometimes multiple) sunscreen products containing ethylhexylglycerin (Table 2). Data from an earlier study showed that it is neither a phototoxic substance nor a photoallergen 286 Contact Dermatitis, 74,

7 (1), which was confirmed in the case published by Sasseville and Stanciu (7), in which patch and photo-patch test reactions to two ethylhexylglycerin-containing sun protectors were of equal intensity. However, currently, a clear explanation is lacking for why this particular type of skin care product seems to be often involved. Theoretically, previously damaged skin (i.e. sunburned skin) might facilitate the occurrence of sensitization to a low-risk sensitizer, although this remains to be demonstrated. As a result of its limited solubility in water, ethylhexylglycerin is usually patch tested in pet., most often at 5%, and in Leuven also at 10% in 2 cases (2), although alcohol, and even water, have been reported as vehicles in one case (5). Also, 0.3% in liquid paraffin has been occasionally used (in Antwerp, in cases 9 and 10). The majority of our patients (8/13) showed a 1+ reaction to 5% pet., although, occasionally, more pronounced reactions (++ to +++) were observed. Two of the aforementioned patients (cases 9 and 10) reacted down to 0.3% (i.e. the use concentration in some of the products, as supplied by one cosmetic manufacturer). It should be stressed that most, but not all, of the ethylhexylglycerin-containing cosmetics gave positive patch test reactions, indicating the need for separate patch testing of this ingredient in an adequate test concentration. In one of the previously reported cases, a repeated open application test with ethylhexylglycerin 5% pet. also gave a positive result (3), and in another case (6) even a flare-up of facial dermatitis during the test session occurred, lending even more credibility to the causal relationship between this substance and the facial allergic contact dermatitis [for a review on flare-up reactions during patch testing, see Ref. (14)]. Although ethylhexylglycerin is chemically related to, and derived from, glycerin, no cross-reactivity is to be expected (5). Although it appears to be a rather rare sensitizer, contact allergy to ethylhexylglicerin was relevant in all of our cases, indicating that such a low-risk sensitizer may be well worth testing for, even routinely in a cosmetic series, as it may easily explain a patient s dermatitis (as is also the case, for example, for 2-bromo-2-nitropropane-1,3-diol in the cosmetic series). Moreover, no irritant or doubtful reactions were ever seen in our two centres. This is in accordance with animal data (1), classifying (undiluted) ethylhexylglycerine as a mild irritant to a non-irritant; likewise, in various publications, numerous control patients showed no reactions to ethylhexylglycerine 5% pet. [2 6 (together comprising 863 control patients)]. Andersen reported only 1 positive patient out of 785 patients (or 0.1%) who were routinely patch tested (6). The same publication, however, did mention the occurrence of 6 doubtful (+?) reactions of unknown clinical relevance, possibly indicating that a higher test concentration, as previously used (2), might be considered in selected cases. Conclusion Although ethylhexylglycerin is nowadays widely used in cosmetics and is generally considered to be a low-risk cosmetic ingredient, it may still occasionally sensitize patients, and may be overlooked if it is not specifically tested for. Mainly facial care cosmetics (day creams), including even those marketed as hypo-allergic and preservative-free, and often regarded by patients (and even dermatologists!) as safer alternatives, seem to be of importance. Also ( hypo-allergic ) deodorants and sunscreens are involved. Besides targeted patch testing (i.e. performed whenever this ingredient is encountered in a suspected cosmetic product, as in the present case series), it might be worthwhile to routinely patch test with this ingredient, given the high clinical relevance of the allergen. Such routine testing, at least in a cosmetic series, was recently advised by the Belgian Contact and Environmental Dermatitis Group to its members. The recent introduction of a commercial patch test allergen by Chemotechnique now makes this very feasible, wheras no patch test material was commercially available previously (in most cases, it was supplied by cosmetic manufacturers who used it in their products, or it was obtained directly from the original manufacturer). Taking into account that doubtful reactions have been reported with the 5% test concentration, and knowing that up to 8% might actually be used in certain cosmetics, higher test concentrations (e.g. 10% pet.) may occasionally be necessary, although comparative studies between different concentrations are lacking, and might be considered in the future. Finally, given its actual use as a preservative, it could, perhaps, officially be categorized as such by the EU authorities. References 1 Johnson W, Bergfeld W F, Belsito D V et al. Safety assessment of alkyl glyceryl ethers as used in cosmetics. Int J Toxicol 2013: 32 (Suppl. 3): 5S 21S. 2 Linsen G, Goossens A. Allergic contact dermatitis from ethylhexylglycerin. Contact Dermatitis 2002: 47: Stausbøl-Grøn B, Andersen K E. Allergic contact dermatitis to ethylhexylglycerin in acream.contact Dermatitis 2007: 57: Mortz C G, Otkjaer A, Andersen K E. Allergic contact dermatitis to ethylhexylglycerin and pentylene glycol. Contact Dermatitis 2009: 61: Dorschner R A, Shaw D W. Allergic contact dermatitis from Contact Dermatitis, 74,

8 ethylhexylglycerin. Dermatitis 2012: 23: Andersen K E. Ethylhexylglycerin a contact allergen in cosmetic products. Dermatitis 2012: 23: Sasseville D, Stanciu M. Allergic contact dermatitis from ethylhexylglycerin in sunprotectors. Dermatitis 2014: 25: Johansen J D, Aalto-Korte K, Agner T et al. European Society of Contact Dermatitis guideline for diagnostic patch testing recommendations on best practice. Contact Dermatitis 2015: 73: Leysen J, Goossens A, Lambert J et al. Polyhexamethylene biguanide is a relevant sensitizer in wet wipes. Contact Dermatitis 2014: 70: Gaonkar T A, Geraldo I, Shintre M, Modak S M. In vivo efficacy of an alcohol-based surgical hand disinfectant containing a synergistic combination of ethylhexylglycerin and preservatives. J Hosp Infect 2006: 63: McFaddenJP,MannJ,WhiteJMLetal. Outbreak of methylisothiazolinone allergy targeting those aged > 40 years. Contact Dermatitis 2013: 69: Aerts O, Baeck M, Constandt L et al. The dramatic increase in the rate of methylisothiazolinone contact allergy in Belgium: a multicentre study. Contact Dermatitis 2014: 71: Amaro C, Santos R, Cardoso J. Contact allergy to methylisothiazolinone in a deodorant. Contact Dermatitis 2011: 64: Vigan M. Poussée réactionnelle et tests cutanés. In: Progrès en Dermato- Allergologie, Montpellier 2011:Paris, John Libbey Eurotext, 2011: pp Contact Dermatitis, 74,