COD. Summary. Contact Dermatitis. Magnus Bruze 1, An Goossens 2 and Marléne Isaksson 1

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1 Contact Dermatitis Original Article COD Contact Dermatitis Recommendation to increase the test concentration of methylchloroisothiazolinone/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, An Goossens 2 and Marléne Isaksson 1 1 Department of Occupational and Environmental Dermatology, Skåne University Hospital, Lund University, SE Malmö, Sweden and 2 Contact Allergy Unit, Department of Dermatology, U.Z.K.U., Leuven 3000, Belgium doi: /cod Summary Background. Methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI) in aqua is present in the European baseline patch test series at 100 ppm, whereas 200 ppm has been used in Sweden since 1986, in Spain in the late 1980s, and, in recent years, also in the United Kingdom and Ireland. Objectives. With regard to MCI/MI, to investigate the data on contact allergy rates in dermatitis patients, the frequencies of allergic contact dermatitis in the same group, and adverse reactions, particularly patch test sensitization in tested dermatitis patients, and to find the optimal patch test concentration as dose in mg/cm 2. Materials and methods. We performed a survey of the literature found via the National Library of Medicine (PubMed, last accessed 20 February 2014). Results. MCI/MI at 200 ppm aq. diagnosis substantially more contact allergy and allergic contact dermatitis, without any registered increase in patch test sensitization, than the presently used concentration of 100 ppm. Conclusion. MCI/MI at 200 ppm aq. is recommended to be included in the European baseline patch test series. To avoid patch test sensitization, a dose of mg/cm 2 must not be exceeded, which means a volume of 15 μl for Finn Chambers (Ø 8 mm). Key words: adverse reactions; allergic contact dermatitis; CAS no ; contact allergy; dose in mg/cm 2 ; Kathon CG; MCI/MI; micropipette; patch test sensitization; preservative. Any baseline patch test series should constantly be subjected to consideration concerning changing in its composition regarding the inclusion and exclusion of sensitizers as well as modifications of present test Correspondence: Marléne Isaksson, Department of Occupational and Environmental Dermatology, Skåne University Hospital, SE Malmö, Sweden. Tel: ; Fax: marlene.isaksson@med.lu.se Conflict of interests: The authors declare no conflicts of interests. Accepted for publication 22 February 2014 preparations (1). For the European baseline patch test series, the major responsibility for this process has been delegated to the European Environmental Contact Dermatitis Research Group by the European Society of Contact Dermatitis. Methylisothiazolinone (MI) is the most recent allergen preparation to be included in the European baseline patch test series (2). Just prior to that, the concentration of formaldehyde in the same baseline series was modified from 1.0% to 2.0% aq. (3). Fragrance mix II 14% pet. and hydroxyisohexyl 3-cyclohexene carboxaldehyde (Lyral ) 5% pet. were included in the European baseline patch test series in 2008 (4). Still earlier, the Contact Dermatitis, 71,

2 preservative methyldibromo glutaronitrile 0.5% pet. was included (5). However, in 2008 its use in cosmetics was banned in the EU, not only for leave-on but also for rinse-off products (6). This will certainly result in an important decrease in the frequency of contact allergy to it, but it may also give rise to the return of the strong allergenic mixture methylchloroisothiazolinone (MCI)/methylisothiazolinone. MI alone was introduced in industrial products around the year 2000 and in cosmetics in 2005 to replace the mixture, as it is Table 1. Examples of commercial preservatives containing methylchloroisothiazolinone (MCI)/methylisothiazolinone (MI), their producers, and product types for application of the preservatives according to producers Trade name (all registered names acknowledged) Additional preservatives in the product Producer Recommended use according to producer Acticide MV14 Thor GmbH Cosmetics Acticide SPX Thor GmbH Cosmetics Aqucar CM 14 The Dow Chemical Company Industrial applications Aqucar CM 1P5 The Dow Chemical Company Industrial applications Euxyl K100 Benzyl alcohol Shülke & Mayr Cosmetics Euxyl K 510 DMDM hydantoin Shülke & Mayr Cosmetics Euxyl K727 Phenoxyethanol, methyldibromo Shülke & Mayr Cosmetics glutaronitrile 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 Cosmetics Kathon LXE The Dow Chemical Company Industrial products 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 Troy Corporation are not accessible through the web page Nipacide CFX4 Ethyl glycol bis-hemiformal Aako BV Cosmetics Nipacide IB 2-Bromo-2-nitropropane-1,3-diol Aako BV Cosmetics/cleaning products Nipaguard CMB Triethylene glycol, benzyl alcohol, Aako BV Cosmetics propylene glycol 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, technical 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 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, The Dow Chemical Company Industrial products, paints benzisothiazolinone Rocima GT Quaternary ammonium compound, The Dow Chemical Company Industrial products, paints formaldehyde and formaldehyde donor Rokonsal KS-4 Propylene glycol, benzyl alcohol Ashland Cosmetics Rokonsal S-1 Ashland Cosmetics MSDS, Material data safety sheet. MI/MCI 10:1. 36 Contact Dermatitis, 71, 35 40

3 less allergenic, but it is also less active, so higher concentrations are needed. However, MCI/MI-sensitive patients also react to it (7, 8). Currently, there is no recommendation on elimination of an allergen from the baseline test series but, as stated above, there is a recommendation on the inclusion of MI (2) and a change in test concentration (dose per area skin) for formaldehyde (3). In this article, a recommendation to increase the patch test concentration for MCI/MI is presented. Methylchloroisothiazolinone/ methylisothiazolinone MCI/MI 100 ppm aq. has been included in the European baseline patch test series since the late 1980s (9). The decision to choose 100 ppm was most likely based on a 21-day cumulative irritancy assay, where the upper arm or back was tested in healthy volunteers (10), rather than on patch test data. In Sweden, a concentration of 200 ppm has been used since the mid-1980s (11). The Swedish decision was based on investigations using defined volumes (15 μl in a small Finn Chamber, Ø 8 mm) on the elicitation capacity of MCI/MI when it is tested with serial dilutions, and when it is tested to find the irritant threshold, as well as data on patch test sensitization (11). MCI/MI Background Initially, MCI/MI at 300 ppm was used in southern Sweden. The positive patch test reactions showed, as today for testing with 200 ppm, morphological features of both an allergic and an irritant nature, and neither did the result of patch testing with serial dilutions of MCI/MI facilitate interpretation of the patch test reactions. Starting with the concentration of an allergen giving a moderate patch test reaction, it is usually possible to decrease this concentration by up to 100 times without losing the capacity to elicit a positive patch test reaction. On the other hand, the ability to elicit an irritant reaction is usually lost with minute dilution steps from the concentration giving a moderate irritant reaction (11). When the MCI/MI concentration was decreased from 300 to 30 ppm, the reactivity was lost in 76% of the reactors (11, 12). Simultaneous patch testing with MCI/MI at 300 and 1000 ppm in the baseline series with readings on D3 resulted, for the 1000 ppm solution, in reactions morphologically consistent with irritant reactions and different from those obtained previously for concentrations of < 1000 ppm. In 10 of 40 patients, these irritant reactions occurred with the aqueous 1000 ppm solution (12). Thus, the irritant threshold for MCI/MI in patch testing is between 300 and 1000 ppm ( mg/cm 2 ). In addition to the irritant reactions, late reactions to MCI/MI appeared days after the patch test application. When these patients were retested, positive reactions were already obtained on D3. Thus, MCI/MI at 1000 ppm is both irritant to the skin and may induce sensitization at patch testing. Patch test sensitization to MCI/MI at 300 and 250 ppm has also been noted, at rates of 1% (11), and in occasional patients tested with 200, 150 or 100 ppm (13 15). MCI/MI is commonly used in many [now rinse-off and regulated in the EU (16)] cosmetics, household products, and occupational products and processes (17, 18). MCI/MI also has a number of trade names and is present in various preservatives (Table 1). The CAS no. for MCI/MI 3:1 is , and the CAS no. for MI is The chlorinated part, MCI, is never present without MI. The information on MCI/MI-containing preservatives in Table 1 was retrieved by a Google search by using the MeSH terms trade names and isothiazolinones and by further searching the separate web pages of the separate companies. Sensitizing Potency MCI/MI is an extreme sensitizer. When it was tested in baseline patch test series, the contact allergy rates in dermatitis patients varied between 2.1% and 4.1% (17, 19 22). In a European multicentre study, the contact Table 2. Examples of allergic contact dermatitis caused by methylchloroisothiazolinone/methylisothiazolinone via various products and processes that have been reported during the last decade Products/processes Country Year References Baby toilet tissues Belgium 2007 (8) Ironing water United Kingdom 2008 (30) Moist toilet or flushable wipes United States 2010 (31, 32) United States 2013 (33) Ireland 2013 (27) Paints Denmark 2012 (34) Contact Dermatitis, 71,

4 Table 3. The European baseline series with the change from 100 to 200 ppm methylchloroisothiazolinone/methylisothiazolinone; INCI names are used where appropriate Compound Concentration (%, wt/wt) in pet. except for Concentration 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 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 Amyl cinnamal Geraniol Eugenol Isoeugenol Evernia prunastri extract Sesquiterpene lactone mix Alantolactone Dehydrocostus lactone and costunolide Quaternium Primin Methylchloroisothiazolinone (150 ppm) 0.02 a and methylisothiazolinone (50 ppm) Budesonide Tixocortol pivalate Methyldibromo glutaronitrile Table 3. Continued Compound Concentration (%, wt/wt) in pet. except for Concentration those in aqua a (mg/cm 2 ) b Fragrance mix II Hydroxylisohexyl 3-cyclohexene carboxaldehyde Citral Farnesol Coumarin Citronellol 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 aqua. b Calculations based on the use of the Finn Chamber (Ø 0.8 cm) technique with application of a 20-mg pet. preparation or, where appropriate, 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%. allergy rate was fairly stable, at between 2% and 2.5%, over a period of 10 years (23). The corresponding figure for the following 7 years was from just over 3% to 2.6%, with variation between the eight participating countries (18). The European multicentre studies include figures obtained from patch testing MCI/MI at 100 ppm from the majority of clinics, but also 200 ppm from participating Swedish clinics (18, 23). When 20 years ago, aqueous MCI/MI solutions were tested simultaneously with 15 μl of solution micropipetted onto the patch unit (Ø 8 mm) in consecutively tested dermatitis patients, the 200 ppm solution diagnosed 100% more contact allergy (24). Interestingly, a similar proportion was found in a recent European multicentre study using the same concentrations and volumes applied onto Finn Chambers in 3000 consecutively tested dermatitis patients, with contact allergy rates of 1.2% and 2.1% for the 100 and 200 ppm solutions, respectively (25). A similar UK investigation and also an Irish investigation on MCI/MI at 100 and 200 ppm obtained the same results, with double the number of hypersensitive patients being diagnosed with the higher concentration (26, 27). Allergic Contact Dermatitis In the last decade, allergic contact dermatitis caused by MCI/MI via the various products and processes listed in Table 2 has been reported. Sometimes, a concentration of 38 Contact Dermatitis, 71, 35 40

5 200 ppm has been required to identify a clinically relevant contact allergy to MCI/MI, which was a major reason for the Swedish Contact Dermatitis Research Group including MCI/MI at 200 ppm in the Swedish baseline test series (11, 24). It was also found in a recent European study that 200 ppm was required to trace clinically relevant contact allergy to MCI/MI [(8) and unpublished observations by Magnus Bruze, Malmö, Sweden]. It should also be pointed out that positive use test results have been reported in persons not reacting to patch test concentrations of < 200 ppm (11, 28, 29). Conclusion It is recommended that the concentration of MCI/MI in the European baseline series be increased to 200 ppm (Table 3). With the Finn Chambers technique, the recommended volume is 15 μl for the aqueous solutions in the European baseline test series. To avoid patch test sensitization, it is important to micropipette the 15 μlonto the Finn Chamber, as the dose tested (0.006 mg/cm 2 )is close to the dose (0.009 mg/cm 2 ) that has caused patch test sensitization (11). It is thus patch test sensitization rather than irritancy that is the limiting factor for MCI/MI. Therefore, when a patient has a doubtful reaction to 200 ppm and it is considered important to confirm or exclude contact allergy to MCI/MI, it is possible to test with 300 ppm without the risk of an irritant patch test reaction, provided that the dose applied onto the test chamber is only 50% higher than 200 ppm. Since the mid-1980s, this has been done at the Department of Occupational and Environmental Dermatology in Malmö in patients without any late reactions indicating patch test sensitization being seen. On the other hand, several cases with clinically relevant contact allergy to MCI/MI have been diagnosed in this way [(11) and unpublished observations by Magnus Bruze, Malmö, Sweden]. Like other patch test preparations in the baseline series, the new MCI/MI preparation should be subjected to constant consideration with regard to modifications needed and justified by new information, such as changes in the rates of contact allergy, allergic contact dermatitis, and adverse reactions, particularly patch test sensitization (1). References 1 Bruze M, Condé-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: Bruze M, Engfeldt M, Gonçalo M, Goossens A. 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. Contact Dermatitis 2013: 69: Pontén A, Goossens A, Bruze M. Recommendation to include formaldehyde 2.0% aqua in the European baseline patch test series. Contact Dermatitis 2013: 69: 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 methyldibromoglutaronitrile in the European standard patch test series. Contact Dermatitis 2005: 52: Commission Directive 2007/17/EC of 22 March Isaksson M, Gruvberger B, Bruze M. Occupational contact allergy and dermatitis from methylisothiazolinone after contact with wallcovering glue and after a chemical burn from a biocide. Dermatitis 2004: 15: Timmermans A, De Hertog S, Gladys K, Vanacker H, Goossens A. Dermatologically tested baby toilet tissues: a cause of allergic contact dermatitis in adults. 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6 21 Fransway A F, Zug K A, Belsito D V et al. North American Contact Dermatitis Group patch test results for Dermatitis 2013: 24: Uter W, Rämsch C, Aberer W et al. The European baseline series in 10 European Countries, 2005/2006 results of the European Surveillance System on Contact Allergies (ESSCA). Contact Dermatitis 2009: 61: Wilkinson J D, Shaw S, Andersen K E et al. Monitoring levels of preservative sensitivity in Europe. Contact Dermatitis 2002: 46: Färm G, Wahlberg J E. Isothiazolinones (MCI/MI): 200 ppm versus 100 ppm in the standard series. Contact Dermatitis 1991: 25: Bruze M, Isaksson M, Gruvberger B et al. Patch testing with methylchloroisothiazolinone/methylisothiazolinone in water at 200 ppm detects significantly more contact allergy than 100 ppm. A multicentre study within the European Environmental and Contact Dermatitis Research Group. Contact Dermatitis 2014: 71: Davies E, Orton D. Identifying the optimal patch test concentration for methylchloroisothiazolinone and methylisothiazolinone. Contact Dermatitis 2009: 60: Higgins E, Kirby B, Rogers S et al. Methylchloroisothiazolinone and methylisothiazolinone allergic contact dermatitis and the effect of patch test concentration. Dermatitis 2013: 24: Hannuksela M. Rapid increase in contact allergy to Kathon CG in Finland. Contact Dermatitis 1986: 15: Björkner B, Bruze M, Dahlquist I, Fregert S, Gruvberger B, Persson K. Contact allergy to the preservative Kathon CG, Letter to the editor. Contact Dermatitis 1986: 14: Hunter K J, Shelley J C, Haworth A E. Airborne allergic contact dermatitis to methylchloroisothiazolinone/methyliso thiazolinone in ironing water. Contact Dermatitis 2008: 58: Gardner K H, Davis M D, Richardson D M, Pittelkow M R. The hazards of moist toilet paper: allergy to the preservative methylchloroisothiazolinone/methylisothi azolinone. Arch Dermatol 2010: 146: Monroe H R, Hu J C, Chiu M W. Methylchloroisothiazolinone/methylisothi azolinone and moist wipe dermatitis. Dermatol Online J 2010: 16: Foote C A, Brady S P, Brady K L et al. Vulvar dermatitis from allergy to moist flushable wipes. J Low Genit Tract Dis 2014: 18: E16 E Mose A P, Lundov M D, Zachariae C et al. Occupational contact dermatitis in painters: an analysis of patch test data from the Danish Contact Dermatitis Group. Contact Dermatitis 2012: 67: Contact Dermatitis, 71, 35 40