COD. Summary. Contact Dermatitis. Magnus Bruze 1, Malin Engfeldt 1, Margarida Gonçalo 2 and An Goossens 3

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1 Contact Dermatitis Original Article COD Contact Dermatitis Recommendation to include methylisothiazolinone in the European baseline patch test series on behalf of the European Society of Contact Dermatitis and the European Environmental and Contact Dermatitis Research Group Magnus Bruze 1, Malin Engfeldt 1, Margarida Gonçalo 2 and An Goossens 3 1 Department of Occupational and Environmental Dermatology, Skåne University Hospital, Lund University, Malmö, Sweden, 2 Department of Dermatology, Faculty of Medicine and University Hospital, Coimbra, Portugal, and 3 Department of Dermatology, Contact Allergy Unit, University Hospital KU Leuven, Leuven, Belgium doi: /cod Summary Background. Methylisothiazolinone (MI) is used as a preservative in occupational and household products, and cosmetics. It is a part of the preparation of methylchloroisothiazolinone (MCI)/MI, which is patch tested in water in the European baseline series. However, this preparation fails to detect a significant percentage of allergic contact reactions to MI. Objectives. To investigate whether a separate test preparation with MI should be included in the European baseline series. Methods. Literature survey. Results. In consecutively tested dermatitis patients, the contact allergy rate for MI varies between 0.6% and 6%, with a marked increase in recent years. The contact allergy rate for MI alone, not detected with MCI/MI, varies between 0% and 1.6%. Most cases are relevant, as shown by repeated open application test studies, and are mainly related to exposure from cosmetic products. Conclusions. Owing to the increase in contact allergy to MI not detected with MCI/MI, it is recommended that MI in water at 2000 ppm be included in the European baseline series. With the Finn Chamber (diameter, 8 mm) technique, a volume of 15 μl should be applied, giving a dose of 60 μg/cm 2. Key words: allergic contact dermatitis; contact allergy; dose in μg/cm 2 ; European baseline series; MCI/MI; methylisothiazolinone; micropipette; patch test sensitization; preservative. Any baseline patch test series should be regularly reviewed for consideration of its composition regarding inclusion and exclusion of sensitizers, as well as modifications of test Correspondence: Magnus Bruze, Department of Occupational and Environmental Dermatology, Skåne University Hospital, S Malmö, Sweden. Tel: +46 (0) ; Fax: +46 (0) magnus.bruze@med.lu.se Conflicts of interest: The authors declare no conflict of interests. Accepted for publication 11 August 2013 concentrations of test preparations (1). For the European baseline patch test series, the responsibility for this process has been delegated to the European Environmental and Contact Dermatitis Research Group by the European Society of Contact Dermatitis. Another recent modification of the European baseline series is the increase in the concentration (actually dose/cm 2 skin) of formaldehyde to 2% aqua (2). In 2008, fragrance mix II in petrolatum at 14% and hydroxyisohexyl 3-cyclohexene carboxaldehyde in pet. at 5% were included in the baseline series (3). The Contact Dermatitis, 69,

2 preservative methyldibromo glutaronitrile in pet. at 0.5% was included in 2005 (4); however, since 2008, there has been a total ban on the use of methyldibromo glutaronitrile in cosmetics in the EU. This prohibition has led to a decrease in the frequency of contact allergy to it, but there has been an increase in the frequency of allergy to the 3:1 mixture of methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) (5 7). Additionally, since 2005, MI by itself has been permitted in cosmetics; MI is a less potent sensitizer than MCI, but is also less active as a preservative, and higher concentrations are needed for preservation; up to 100 ppm in leave-on and rinse-off cosmetics is permitted. With the widespread use of this moderate sensitizer in higher concentrations, a rise in contact allergy to MI is currently being observed in European countries. Currently, based on the current literature, inclusion of MI in the European baseline test series is recommended. MI background Since the early 1980s, preservatives based on the combination of MCI and MI at a ratio of 3:1 have been used in industrial products, household products, and cosmetics; contact allergy to it has been important in recent decades. MI alone was introduced into industrial products in the early 2000s, and in 2005 it was allowed as a preservative in cosmetics at a maximum concentration of 100 ppm (8); there has been an increase in its use since then (9, 10). The first reports on contact allergy to and allergic contact dermatitis caused by MI appeared in 1987 (11) and 2004 (12), respectively, with the first report concerning cosmetics appearing in 2010 (13). Sensitization potency In 1987, MI was reported to be a weak sensitizer in the guinea-pig (14), but was classified as a strong sensitizer in the local lymph node assay (15). Risk assessment Besides knowledge about sensitization potency, exposure conditions (16) are decisive in the risk assessment regarding the induction of sensitization and the subsequent development of allergic contact dermatitis. A recent US safety assessment of MI concluded that cosmetic products formulated to contain concentrations of MI of 100 ppm would not be expected to pose a sensitization risk. Accordingly, MI was considered to be safe when used as a preservative in cosmetics up to that concentration (17). Many products intended for occupational and domestic use may be preserved with chemicals containing MI. Examples of preservatives containing MI are listed in Table 1. Contact allergy Contact allergy to MI has been reported in consecutively tested dermatitis patients in Sweden, Denmark, Germany, Finland, and the United Kingdom (Table 2) (6 7, 9, 18 20, DI Orton, CM Willis, pers. comm. 2013). All centres except the German ones have only used water as vehicle for MI, with concentrations varying between 200 and 2000 ppm. The contact allergy rates reported vary between 0.5% and 6%. The highest rates are reported from the United Kingdom, where an increase was seen in Amersham from 2.5% in 2009 to 6.0% in 2011 (DI Orton, CM Willis, pers. comm. 2013), and an increase in Leeds from 0.6% in 2009 to 4.6% in 2012 (7). In Denmark an increase was seen from 1.4% in 2009 to 3.1% in 2011 (21). Aimed testing of MI has been performed in Germany, where MI has been tested at 500 ppm in pet. and water (6, 22). This testing identified an increasing rate of contact allergy to MI, from 0.5% before 2009 to 4.4% in A male predominance has been reported from the United Kingdom (DI Orton, CM Willis, pers. comm. 2013), Denmark (19), Germany (22), and Sweden (18). For many years, MCI/MI has been part of the European baseline series (3). Most clinics test with it at 100 ppm, although 200 ppm has been used in Sweden since 1986 (23), in Spain since the late 1980s (24), and in the United Kingdom since the 2000s (DI Orton, CM Willis, pers. comm. 2013, 7). The number of additional cases with contact allergy to MI detected by testing with MI simultaneously with testing with MCI/MI at 200 or 100 ppm in a baseline series varies between 0% and 1.6% for 200 ppm and between 0.5% and 0.8% for 100 ppm (Table 2). In the two German reports on aimed testing, the rate of additional contact allergy to MI, excluding those with a simultaneous contact allergy to MCI/MI, is %. Cross-reactivity In patients allergic to MI, contact allergy seems to represent two routes of sensitization. Previously, the most common was sensitization to MCI with crossreactions to MI; however, the most recent data show that MI is now the primary sensitizer in most cases. Interestingly, the cross-reaction pattern seems to differ according to whether MI is the primary or secondary sensitizer. There are both human and animal studies supporting this (11, 14, 18, 26, 27). With chlorinated (monochlorinated and dichlorinated) MI as the sensitizer in guinea-pig maximization tests, no cross-reactions with MI and octylisothiazolinone were noted (Fig. 1). 264 Contact Dermatitis, 69,

3 Table 1. Examples of commercial preservatives containing methylisothiazolinone (MI), their producers, and the product types in which MI is found Trade name Other preservatives in the commercial preparation Producer Uses (according to producer) Containing MI Acticide M10S Thor GmbH Personal care Bioban 425 Octylisothiazolinone The Dow Chemical Company Household, industrial and institutional wipes Euxyl K220 Ethylhexylglycerin Shülke & Mayr Personal care Kordek LX5000 The Dow Chemical Company Metalworking fluids Kordek MLX Biocide The Dow Chemical Company Paints Methylisothiazolinone Chemerisia Ltd Personal care Microcare MEM Methylparaben, ethylparaben Thor Specialities (UK) Ltd Personal care Microcare MT Thor Specialities (UK) Ltd Personal care Microcare MTB Polyaminopropyl biguanidine Thor Specialities (UK) Ltd Personal care Microcare MTB/MTB7 Polyaminopropyl biguanidine Thor Specialities (UK) Ltd Personal care Microcare MTC/MTC2 Chlorphenesin Thor Specialities (UK) Ltd Personal care Microcare MTD1/MTD2 Decylene glycol Thor Specialities (UK) Ltd Personal care Microcare MTI/MTO Iodopropynyl butylcarbamate Thor Specialities (UK) Ltd Personal care Microcare MTP Methylparaben, propylparaben Thor Specialities (UK) Ltd Personal care Microcare PDM Glycol Thor Specialities (UK) Ltd Personal care Microcare SI Benzoisothiazolinone Thor Specialities (UK) Ltd Personal care Neolone CapG Caprylyl glycol The Dow Chemical Company Personal care Neolone PE Phenoxyethanol The Dow Chemical Company Personal care Neolone PH100 Phenoxyethanol The Dow Chemical Company Personal care Neolone M-10 The Dow Chemical Company Household and industrial products Neolone MxP Phenoxyethanol, methylparaben, propylparaben The Dow Chemical Company Personal care Neolone Ds Methylparaben, propylparaben The Dow Chemical Company Personal care Neolone 950 The Dow Chemical Company Personal care Nipacide BSM Benzisothiazolinone Aako BV Personal care/cleaning products Optiphen MIT International Speciality Products (ISP) Personal care Optiphen MIT ultra Phenylpropanol, propylene glycol International Speciality Products (ISP) Personal care Optiphen MIT plus Phenethyl alcohol, PPG-2-methyl ether International Speciality Products (ISP) Personal care Parmetol MBX Benzisothiazolinone, N-(3-aminopropyl)-N-dodecylpropane-1,3-diamine Schulke & Mayr Household products, technical products Rocima 550 The Dow Chemical Company Paints and adhesives Rocima Bromo-2-nitropropane-1,3-diol The Dow Chemical Company Paints and adhesives Rocima MBX Benzisothiazolinone The Dow Chemical Company Paints and adhesives Containing Methylchloroisothiazolinone (and) MI Acticide MV14 Thor GmbH Personal care ActicideE SPX Thor GmbH Personal care Aqucar CM 14 The Dow Chemical Company Industrial applications Aqucar CM 1P5 The Dow Chemical Company Industrial applications Euxyl K100 Benzyl alcohol Shülke & Mayr Personal care Euxyl K 510 DMDM hydantoin Shülke & Mayr Personal care Euxyl K727 Phenoxyethanol, methyldibromo glutaronitrile Shülke & Mayr Personal care Contact Dermatitis, 69,

4 Table 1. Continued Trade name Other preservatives in the commercial preparation Producer Uses (according to producer) Fennosan IT21 Kemira Industrial water treatment Grotan TK2 (Ethylenedioxy)dimethanol Shülke & Mayr Metalworking fluids Kathon 886 MW The Dow Chemical Company Metalworking fluids Kathon 7 TL The Dow Chemical Company Cooling water systems Kathon CF 1400 The Dow Chemical Company Cooling water systems, paper mill applications Kathon CF 400 The Dow Chemical Company Cooling water systems, polymer latex preservation Kathon CG The Dow Chemical Company Personal care Kathon WT 1.5% The Dow Chemical Company Household and industrial products Koralone C-204 Octylisothiazolinone The Dow Chemical Company Household and industrial products Mergal MSDSs for the different preservatives are not accessible through the webpage Troy corporation Nipacide CFX4 Ethyl glycol bis-hemiformal Aako BV Personal care Nipacide IB 2-Bromo-2-nitropropane-1,3-diol Aako BV Personal care/cleaning products Nipaguard CMB Triethylene glycol, benzyl alcohol, propylene glycol Aako BV Personal care Parmetol A28 2-Bromo-2-nitropropane-1,3-diol Schulke & Mayr Household products, technical products Parmetol A28 beton 2-Bromo-2-nitropropane-1,3-diol Schulke & Mayr Concrete admixtures Parmetol A26 (Ethylenedioxy)dimethanol Schulke & Mayr Household products, technical products Parmetol DF35 (Ethylenedioxy)dimethanol Schulke & Mayr Household products, technical products Parmetol K20 Schulke & Mayr Household products, technicall products Parmetol K20 beton Schulke & Mayr Concrete admixtures Parmetol K40 Schulke & Mayr Household products Parmetol K60 Octylisothiazolinone Schulke & Mayr Household products Parmetol SL60 Glutaral Schulke & Mayr Household products Rocima 520S 2-Bromo-2-nitropropane-1,3-diol The Dow Chemical Company Paints and binders Rocima Bromo-2-nitropropane-1,3-diol The Dow Chemical Company Paints and binders Rocima 560 Ratio 10:1 MI/methylchoroisothiazolinone The Dow Chemical Company Paints and binders Rocima Bromo-2-nitropropane-1,3-diol The Dow Chemical Company Industrial products, paints Rocima 622 Formaldehyde The Dow Chemical Company Metalworking fluids, paints, binders Rocima Bromo-2-nitropropane-1,3-diol, benzisothiazolone The Dow Chemical Company Industrial products, paints Rocima GT Quaternary ammonium compound, formaldehyde, and formaldehyde donor The Dow Chemical Company Industrial products, paints Rokonsal KS-4 Propylene glycol, benzyl alcohol Ashland Personal care Rokonsal S-1 Ashland Personal care MSDS, material data safety sheet. 266 Contact Dermatitis, 69,

5 Table 2. Data on patch test preparations used and rates of contact allergy to methylisothiazolinone (MI) in various European publications Country (ppm) Vehicle Dose (μg/cm 2 ) Number of tested individuals Contact allergy rate (%) Rate of MI-positive, MCI/MI-negative (%) Years References Germany 500 Aqua NA (6) Denmark 2000 Aqua 60 a (19) Finland 300 Aqua NA (20) 1000 Aqua NA (20) United Kingdom 500 Aqua NA (2.5 6) 0.1 b * 200 Aqua NA NA 2009 (7) 200 Aqua NA NA 2010 (7) 200 Aqua NA NA 2011 (7) 200 Aqua NA NA 2012 (7) 2000 Aqua NA c 2011 (7) 2000 Aqua NA c 2012 (7) Sweden 475 Aqua b 2003 (25) 950 Aqua (25) 1000 Aqua (25) Germany 500 Pet. NA (2005) (22) 500 Aqua NA d 2009 (6) 500 Aqua NA d 2010 (6) 500 Aqua NA d 2011 (6) The data above the thick line concern consecutively tested dermatitis patients, and the data below the thick line concern aimed testing. MCI, methylchloroisothiazolinone; NA, not available. a (JD Johansen, pers. comm. 2013). b MCI/MI tested at 200 ppm. c The figure is only given for 2011 and 2012 together. MCI/MI was tested at 200 ppm. d Own calculations based on figures in (14) concerning an average of the years *(DI Orton, CM Willis, pers. comm. 2013). O O Cl S N S N 5-Chloro-2-methyl-4-isothiazolinone-3-one INCI: methylchloroisothiazolinone CAS no.: Methyl-4-isothiazolinone-3-one INCI: methylisothiazolinone CAS no.: O N Fig. 1. Molecular structures of methylchloroisothiazolinone, methylisothiazolinone, and octylisothiazolinone. S 2-octyl-4-isothiazolinone-3-one INCI: octylisothiazolinone CAS no.: On the other hand, simultaneous contact allergy to octylisothiazolinone seems to be over-represented in humans primarily sensitized to MI (18, 26). Crossreactivity with octylisothiazolinone is more likely with MI as the primary sensitizer, as octylisothiazolinone is chemically more closely related to MI than to MCI (26). Regardless of the possible different cross-reaction patterns for MCI and MI, we advise all individuals with contact allergy to MI to avoid/minimize exposure to products containing the preservatives listed in Table 1, in order to allow the dermatitis to heal and to avoid relapses of dermatitis. Contact Dermatitis, 69,

6 Table 3. The European baseline series with the addition of methylisothiazolinone 2000 ppm Compound (%, wt/wt) in pet. except for those in aqua a (mg/cm 2 ) b Potassium dichromate p-phenylenediamine Thiuram mix TMTM TMTD TETD PTD Neomycin sulfate Cobalt chloride Benzocaine Nickel sulfate Clioquinol c Colophonium d Paraben mix Methylparaben Ethylparaben Propylparaben Butylparaben N-Isopropyl-N-phenyl phenylenediamine Lanolin (wool alcohols) Mercapto mix N-Cyclohexylbenzothiazyl sulfenamide Mercaptobenzothiazole Dibenzothiazyl disulfide Morpholinylmercaptobenzothiazole Epoxy resin Myroxylon pereirae e tert-Butylphenol formaldehyde resin Mercaptobenzothiazole Formaldehyde 2.0 a 0.6 Fragrance mix I 8.0 f 3.2 Cinnamyl alcohol Cinnamal Hydroxycitronellal α-amyl cinnamal Geraniol Eugenol Isoeugenol Evernia prunastri (oakmoss absolute) Sesquiterpene lactone mix Alantolactone Dehydrocostus lactone and costunolide Quaternium Primin Methylchloroisothiazolinone and 0.01 a methylisothiazolinone Budesonide Tixocortol pivalate Methyldibromo glutaronitrile Fragrance mix II Table 3. Continued Compound (%, wt/wt) in pet. except for those in aqua a (mg/cm 2 ) b Hydroxylisohexyl 3-cyclohexene carboxaldehyde Citral Farnesol Coumarin Citronellol α-hexyl cinnamal Hydroxyisohexyl 3-cyclohexene carboxaldehyde Methylisothiazolinone 0.20 a 0.06 PTD, dipentamethylenethiuram disulfide; TETD, tetraethylthiuram disulfide; TMTD, tetramethylthiuram disulfide; TMTM, tetramethylthiuram monosulfide. a In water. b Calculations based on the use of the Finn Chamber (diameter of 0.8 cm) technique with application of a 20 mg pet. preparation or, where appropriate (in water), 15 ml of an aqueous test solution. c Also known as chinoform and vioform. d Also known as colophony e Also known as balsam of Peru f Emulsifier: sorbitan sesquioleate 5%. Allergic contact dermatitis In the listed articles in Table 2, some information is given on the clinical relevance, which, on the whole, is considered to be very high. Occupational exposure is dominated by MI in paints (28, 29), whereas non-occupational exposure is dominated by MI in cosmetics and household products. Individual cases of allergic contact dermatitis caused by MI have been reported in painters (9, 12), from a waist reduction belt (30), from cosmetics, and particularly from wet wipes for intimate hygiene (13), hair cosmetics, facial cosmetics (9, 19), deodorants (31), and sunscreens (10). Airborne allergic contact dermatitis and systemic contact dermatitis have been attributed to MI release from recently painted walls (21, 32) and from a toilet cleaner (33). Usage tests A repeated open application test (ROAT) with MI at 100, 50 and 5 ppm in an aqueous vehicle with 10% ethanol and 0.4% phenoxyethanol was performed in 11 individuals who were hypersensitive to MI; 64% reacted to 100 and 50 ppm, and 18% also reacted to 5 ppm (35). Thirty-two MI-allergic patients participated in a ROAT with two skin care lotions containing 100 and 0 ppm, respectively. The lotions were applied twice daily for 1 week. Thirty per cent of the patients gave a positive ROAT result, and all of them were also allergic to MCI/MI (21). 268 Contact Dermatitis, 69,

7 Recommended test preparation To justify the inclusion of a substance in a baseline series, the contact allergy rate should be expected to be at least 0.5 1%, with a high degree of clinical relevance (1). MI fulfils the clinical relevance requirement, with a high degree of clinical relevance in the reports on contact allergy in consecutively tested dermatitis patients (6 7, 18 20, DI Orton, CM Willis, pers. comm. 2013) and case reports (9, 10, 12, 13, 19, 30, 31), as well as positive results in controlled and randomized ROATs (19, 20). Rates of contact allergy to MI exceed 1%, so the prevalence requirement is also fulfilled. However, not only the crude rate of contact allergy to MI should be considered, but also the additional contribution to the testing with MCI/MI already present in the European baseline series. Against this background, it may appear questionable to recommend inclusion of MI in the baseline series, particularly for those clinics testing MCI/MI at 200 ppm, as the percentage of missed MI allergies was below 0.5% until the recent UK report, where 1.6% of allergies were missed (7). However, most European clinics are presently testing MCI/MI at 100 ppm, and with this concentration the percentage of MI allergies not detected with MCI/MI is at least 0.5% (Table 2). Furthermore, with the increasing frequency of MI allergy reported from the United Kingdom (17, 18), Germany (6, 22), and Denmark (21), we consider it important to include MI in the baseline series to (i) detect cases with allergic contact dermatitis caused by MI, (ii) to follow the trends in various geographical areas, and (iii) to provide information for possible legislative measures to reduce consumer exposure and minimize the risk of sensitization to MI and the elicitation of allergic contact dermatitis caused by MI. What patch test concentration should be recommended? According to Table 2, seven different concentrations in the ppm range have been used. It should be understood that it is not the concentration as such that is important, but the number of molecules of the sensitizer on a defined area of skin, that is, the dose/cm 2 (1). The concentration can be used as a parameter for dose when patch test results are compared, provided that the same test unit has been used and that the same amount/volume of the sensitizer has been applied onto the test unit. The dose/cm 2 is only available from the Swedish and Danish studies (11, 12, 18, 35). With the aqueous preparations, the volume applied onto Finn Chambers at the other clinics may be the same or up to three times higher, depending on the application technique used (36). For the study using pet. (Table 2) as a vehicle for MI, the amount of pet. applied to Finn Chambers may vary between 10 and 50 mg, according to our published results (37) and unpublished experience from the Malmö Department concerning the amounts of pet. preparations applied in hands-on lectures at patch test courses with both national and international participants. Adverse patch test reactions to MI seem to be uncommon, regardless of the patch test concentration and vehicle used. There has been one case reported with suspected active sensitization to MI at 1000 ppm (15 μl applied to a Finn Chamber with a diameter of 8 mm; 30 μg/cm 2 ) (18). No active sensitization has been reported from testing with 2000 ppm (7, 19), including the experience in Malmö with testing of 3500 dermatitis patients, and in Gentofte with testing of 5000 patients with MI at 2000 ppm (60 μg/cm 2 ) (partly unpublished observations). On the basis of these results and experience, it is recommended that MI in aqua at 2000 ppm be tested in the European baseline series. The recommended volume of 15 μl for a small Finn Chamber (diameter of 8 mm) gives a dose of 60 μg/cm 2. To minimize the risk of adverse reactions, the use of a micropipette allowing the application of 15 μl is strongly recommended. The new European baseline patch test series, including the recent concentration change for formaldehyde (2) and the inclusion of MI, is shown in Table 3. References 1 Bruze M, Conde-Salazar L, Goossens A, Kanerva L, White I R. Thoughts on sensitizers in a standard patch test series. The European Society of Contact Dermatitis. Contact Dermatitis 1999: 41: Pontén A, Goossens A, Bruze M. Recommendation to include formaldehyde 2.0% in the European baseline patch test series. Contact Dermatitis 2013 (submitted). 3 Bruze M, Andersen K E, Goossens A. Recommendation to include fragrance mix 2 and hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral) in the European baseline patch test series. Contact Dermatitis 2008: 58: Bruze M, Goossens A, Gruvberger B. Recommendation to include methyldibromo glutaronitrile in the European standard patch test series. Contact Dermatitis 2005: 52: Svedman C, Andersen K E, Brandão F M et al. Follow-up of the monitored levels of preservative sensitivity in Europe: overview of the years Contact Dermatitis 2012: 67: Geier J, Lessmann H, Schnuch A, Uter W. Recent increase in allergic reactions to methylchloroisothiazolinone/methylisothiazolinone: is methylisothiazolinone the culprit? Contact Dermatitis 2012: 67: Urwin R, Wilkinson M. Methylchloroisothiazolinone and methylisothiazolinone contact allergy: a new epidemic. Contact Dermatitis 2013: 68: Contact Dermatitis, 69,

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