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Methylisothiazolinone

Castanedo-Tardana, Mari Paz MD*; Zug, Kathryn A. MD*†

doi: 10.1097/DER.0b013e31827edc73
CONTACT ALLERGEN OF THE YEAR

The preservative methylisothiazolinone (MI) is the American Contact Dermatitis Society Contact Allergen of the Year for 2013. Because the use of MI in cosmetics and toiletries in the United States rises, MI exposure also rises. Although it might seem likely that testing with methylchloroisothiazolinone (MCI)/MI would be adequate to pick up contact allergy to MI alone, the mix misses approximately 40% of allergy to MI, likely because of the low concentration of MI in the MCI/MI combination patch test. In Europe, several groups have documented frequency of allergy to this preservative of approximately 1.5%. The frequency of allergy to this preservative in the United States is unknown. If you are not testing for allergy to this preservative, you may be overlooking the importance of a very relevant preservative allergen that, to date, has managed to stay under the radar in the United States. This report reviews the background and reasons for adding MI to our routine screening patch testing series.

From the *Dartmouth-Hitchcock Medical Center, Section of Dermatology, Lebanon, NH; and †Geisel School of Medicine at Dartmouth, Hanover, NH.

Address reprint requests to Kathryn A. Zug, MD, Section of Dermatology, Department of Surgery, Geisel School of Medicine at Dartmouth and Dartmouth-Hitchcock Medical Center, 1 Medical Center Dr, Lebanon, NH 03756. E-mail: Kathryn.A.Zug@hitchcock.org.

The authors have no conflicts of interest to declare.

If you are not testing it, it is likely that you are missing allergy to it. Methylisothiazolinone (MI) is a preservative whose use is on the rise. More opportunities for exposure mean more opportunities for contact allergy to this preservative, which is categorized as a moderate-strong sensitizer.1,2 Methylisothiazolinone was approved for use as a preservative in cosmetics in 2005 at a maximum concentration of 100 ppm (0.01%). Since then, a striking rising use of this preservative in cosmetic, toiletry, and sunscreen products can be appreciated. In the European Union, where recent investigations of MI allergy have been well described, frequency of allergy to this preservative is already reported to be at the same level as other preservatives that have been on the market for numerous years.3 Because methylisothiazolinone is not routinely tested in any standard screening series, it is likely that allergy to this preservative is being widely overlooked.

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A Short History of Methylchloroisothiazolinone/Methylisothiazolinone and Methylisothiazolinone

Methylchloroisothiazolinone (MCI) and MI in a 3:1 combination (MCI/MI; trade names: Kathon CG, Euxyl K 400) is a widely used preservative in both industrial and consumer products. Animal and clinical studies have shown that both MCI and MI can cause contact allergy; MCI is the more potent allergen in this combination.4 MCI/MI is one of the most common causes of preservative contact allergy and dermatitis.5 North America Contact Dermatitis Group (NACDG) data from 2009 to 2010 show that MCI/MI (100 ppm aq) had a 2.5% frequency of positive reactions of 4302 patients tested. Thisallergen was the fifth most commonly positive preservative behind formaldehyde 1% aq (5.8% positive), quaternium 15.2% pet (5.8% positive), iodopropynyl butyl carbamate 0.5% pet (4.3% positive), and methyldibromoglutaronitrile/phenoxyethanol 2.0% pet (3.8% positive). Of these 5 preservatives, the relevance assigned to MCI/MI was the highest; definite and probable relevance was 54.6%, whereas possible relevance was 38.9%.6

Rates of contact allergy to MCI/MI rose to levels of up to 8% when it was first introduced as a preservative in 1980.7,8 This was thought to be secondary to high concentrations found in “leave-on” cosmetic products; this prompted more strict use concentration recommendations from expert panels in both the European Union and the United States. In 1989, the Cosmetics Directive of the European Union considered the recommendations given by the Scientific Committee on Consumer Safety and limited the concentration of MCI/MI to 15 ppm in both “leave-on” and “rinse-off” products.9 A few years later, in 1992, the US Cosmetic Ingredient Review recommended an even lower concentration limit of 7.5 ppm MCI/MI in “leave-on” cosmetic products.10 Despite these modifications in use concentrations, sensitization prevalence to MCI/MI has remained fairly stable at 1% to 4%, according to the European Surveillance System on Contact Allergy Network.11 In the United States, the NACDG data indicate a stable frequency of positive reactions to MCI/MI from between 2.2% and 3.6% over the period from 2001 to 2010.6 The most recent NACDG data show a frequency of 2.5%; this is similar to lanolin alcohol, diazolidinyl urea, and imidazolidinyl urea frequency of positive patch reactions in this selected population of patch-tested patients.6

Methylisothiazolinone (technical name/synonym: 2-methyl-4-isothiazolin-3-one; CAS no.: 2682-20-4; Trade names: Neolone 950, Microcare MT, OriStar MIT, RH-24,573, and the industrial microbicides: Kordek 573T and RH-573T)12 constitutes 25% of MCI/MI, thus a maximum MI concentration of 3.5 ppm in all rinse-off products and 1.8 ppm in leave-on products sold in the United States.

Because MI is believed to be a weaker sensitizer than MCI, in the early 2000s, MI alone was released as an individual preservative for industrial products. In 2005, MI was approved for use as a preservative in cosmetics and household products. Both the Cosmetic Ingredient Review in the United States and the European Scientific Committee on Consumer Safety evaluated MI—which alone is a less effective biocide than MCI/MI—and concluded that 100 ppm was a safe concentration to use in cosmetics.13 The introduction of MI alone has therefore resulted in a more than 25-times increase in the permitted concentration of MI in cosmetics from 3.75 ppm in rinse-off and 1.8 ppm in leave-on products to 100 ppm.13 Currently, no limitations exist for the concentration of MI in industrial products.

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Methylisothiazolinone Sensitization

Based on animal local lymph node assays, Basketter et al14 categorized MI as a moderate sensitizer. However, the United Nations Globally Harmonized System of Classification and Labeling of Chemicals have classified MI as a strong allergen.15 Rohm and Haas (now Dow Chemicals, Midland, Mich) has performed a series of both animal and human studies to assess the sensitization potential of MI. They concluded that MI sensitized only at high concentrations (>1000 ppm).16 In 1994, Rohm and Haas evaluated the sensitization potential of 98% MI using repeated insult patch test studies. Eighty human subjects were tested with 5 test concentrations of MI (50, 100, 250, 500, and 1000 ppm). Methylisothiazolinone was applied for 23 hours daily for 21 consecutive days. After a 10- to 14-day rest period, the subjects were challenged for 23 hours. At challenge, 2 subjects in the 1000-ppm dose group had mild reactions and were considered sensitized. The authors concluded that the sensitization threshold for 98% MI was at or approximately 1000 ppm.16 In a later series of repeated insult patch test studies also performed by Rohm and Haas, the sensitization potential of 50% MI was evaluated at 200, 300, 400, 500, and 600 ppm. During the induction phase, MI was applied 3 times a week for 3 weeks with occlusive patches for 24 hours. After a 7- to 15-day rest period, subjects were challenged on a virgin site for 24 hours with the same induction concentration. Only 1 subject in each of the 400-ppm and 500-ppm dose groups had an erythema response. The authors concluded that up to a concentration of 600 ppm, MI is not a dermal sensitizer.16

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Methylisothiazolinone Elicitation

In a small repeat open application test (ROAT) study performed by Lundov et al,17 11 MI-allergic patients were exposed to MI via a ROAT test that resembled the use of a leave-on cream preserved with 5, 50, and 100 ppm of MI. Of MI allergic patients, 64% reacted to 100 and 50 ppm, whereas 18% also reacted to the 5-ppm–containing cream used in this ROAT test. Importantly, the authors concluded that the eliciting concentration for MI can be as low as 5 ppm.

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Contact Allergy to MI Alone

The first occupational cases of MI contact allergy were reported by Isaksson et al18 in 2004 and Thyssen et al19 in 2006, from occupational exposure to a wallpaper glue and paint, respectively. In 2010, Garcia-Gavin et al20 published the first 7 nonoccupational cases stemming from the use of cosmetics/toiletries that contained MI alone. Of the 7 patients, 6 had perianal dermatitis from the use of MI-containing moist toilet paper, whereas the remaining patient had eyelid dermatitis from the use of an MI-containing makeup remover.

Subsequently, more toiletry-related cases of allergy to MI have been reported.21 In a retrospective study by Lundov et al3 in which 2536 Danish patients were patch tested with MI alone, a history of exposure to the allergen via cosmetics (both rinse-off and leave-on) was identified in 32% of the MI-positive cases. Hair care products were the most frequent cause of cosmetic exposure to MI in this study. Furthermore, cases of airborne contact dermatitis after exposure to MI (from carpet glue and paint for example) continue to emerge in the literature.20,22,23

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Sources of Exposure

Exposure to MI can derive from both cosmetic and occupational sources. Methylisothiazolinone can be found as a preservative in many cosmetic products, including baby products (lotion, oils, powders, and creams), bath products (soaps, detergents, and bubble bats), makeup (eyeliners, eye makeup remover, blushes, and face powders), hair care products (shampoo, conditioners, sprays, straighteners, rinses, and wave sets), hair-coloring products (dyes and colors, tints, and bleaches), nail care products, deodorants, shaving products (after shaves and shaving creams), skin care products (cleansers, creams, lotions, and moisturizers), suntan products, and sunscreens among others. Importantly, in the United States, full ingredient labeling is not always the case for sunscreen products, making recognition of MI among this type of product difficult for both the consumer, the patient, and their physician. Our first case of MI allergy occurred in a woman whom we suspected to have a sunscreen allergy; testing result to a sunscreen tray and the NACDG 2011-2012 allergen tray (including MCI/MI at 100 ppm) was entirely negative; testing to the sunscreen product itself was positive. The sunscreen contained MI, and further testing to 2000 ppm MI confirmed this allergen as causative in this patient’s severe, recurrent dermatitis of the face, neck, and arms.

According to information supplied to the US Food and Drug Administration by industry as part of the Voluntary Cosmetic Ingredient Registration Program, MI was used in a total of 1125 cosmetic products in the United States in 2007.24 (The information provided under the Voluntary Cosmetic Ingredient Registration Program, however, does not clearly indicate whether MI was used alone or in concomitance to MCI.) Of the 1125 products, 24% (n = 275) were shampoos, 18% (n = 206) were conditioners, and 10% (n = 117) were baby soaps and detergents. This illustrates that most products preserved with MI are in the rinse-off category. Wet wipes (baby wipes, moist towelettes, and moist toilet paper) for intimate hygiene are a well-identified sensitization source for MI; use of such leave-on products in nonkeratinized and occluded skin likely enhances penetration of this allergen.21 These wipes are not only used for babies, but they are also used in adults, and frequently in the aged or infirm, in circumstances when bathing is more difficult.

Further Food and Drug Administration data on the frequency of preservative use in cosmetic products show that the use of MI is on the rise. Recent data show that, in 2010, a total of 2408 US cosmetic products were preserved with MI alone.25 This means that the number of cosmetic products preserved with MI more than doubled from 2007 to 2010 (from 1125 to 2408 cosmetic products).

Actual use concentration of MI in products is a critical sensitization risk factor. An industry survey conducted in 2008 showed that the concentration of MI used to preserve cosmetics ranged from 0.000004% to 0.01% (0.01% = 100 ppm).26

Occupational sources of MI include paints, inks, glues, lacquers, varnishes, and cutting oils, among other industrial products. A recent study by Lundov et al3 showed that painters constitute the majority (nearly half) of occupational allergic contact dermatitis cases to MI alone. It is reasonable then to assume that MI is frequently used in paints. Currently, there is no maximum permitted concentration and no labeling requirements for MI in industrial products, including paints, which makes it difficult for allergic individuals to avoid contact with this allergen.22

Household products containing MI include dishwashing liquid soaps,27 laundry detergents, laundry stain removers, fabric softeners, all purpose cleansers, glass cleaners, and wood cleansers among others. Surprisingly, we have found that MI is also contained in some popular “green” household cleaning products.

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Prevalence of MI Contact Allergy

Because MI is not routinely tested in the United States, there is no US data reporting the frequency of positive reactions to this allergen. Three European groups have investigated the prevalence of MI contact allergy in patch test patients; despite using different patch test concentrations, the overall prevalence of contact allergy to MI in Europe has been shown to be in the area of 1.4% to 1.54% (Table 1).

TABLE 1

TABLE 1

The Danish group3 patch tested 2536 patients with dermatitis with the European baseline series supplemented with MI (0.2% = 2000 ppm aq) from May 2006 to February 2010. The overall prevalence of MI contact allergy in this study was 1.5%, making MI the fourth most common preservative contact allergen in Denmark. According to the MOAHLFA index (male, occupational dermatitis, atopic dermatitis, hand eczema, leg dermatitis, facial dermatitis, age older than 40 years) calculated in this study, MI contact allergy was more often associated with occupational exposure, hand eczema, and age older than 40 years. Besides hand eczema, the anatomical sites of dermatitis included the face, the arms, and the legs.

The German group28 patch tested 13,433 patients to MI (0.05% aq = 500 ppm) from 2005 to 2009. Of 13,433 patients, 215 had a positive patch test reaction to MI, a prevalence of 1.54%. Similar to the Danish study, MI was associated with occupational dermatitis in which hands were often affected.

The Finnish group15 patch tested 10,821 patients to 2 different concentrations of MI—0.1% (1000 ppm) and 0.03% (300 ppm) from 2006 to 2008. 1.4%—and 0.6% showed a positive patch test reaction to 0.1% and 0.03%, respectively.

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The Problem

Few data exist concerning the cross-reaction patterns of MCI and MI. Bruze et al4 showed that a small proportion of patch test subjects sensitized to MCI/MI also reacted to MI. Isaksson et al29 also suggested that patients with high patch test reactivity to MCI may also react to high concentrations of MI (1000 ppm).

The percentage of concomitant reactions between MCI/MI and MI in the patch test population is relevant with regard to the diagnosis of MI-contact allergy. In the Danish study,3 only 40% of patients with a positive reaction to MI reacted also to MCI/MI. In the Finnish study,15 66% of MI positives reacted to MCI/MI, and in the German study,25 67% of patients with a positive reaction to MI also had a positive reaction to MCI/MI. This means that by patch testing to MCI/MI but not MI alone, MI allergy could be missed in 33% to 60% of the cases. This is likely because of the low concentration of MI in the MCI/MI patch test substance (75 ppm MCI/25 ppm MI).

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Patch Testing to MI

Experience with MI patch test concentrations is still limited. In the most recent report of the patch test results from the European Surveillance System on Contact Allergy Network11 published in July 2012, their members concluded that “MI warrants consideration for inclusion into the European Baseline Series.” They, however, did not comment on the ideal patch test concentration for MI.

As noted previously, MI has been tested at 300 ppm (0.03% aq), 500 ppm (0.05% aq), 1000 ppm (0.1% aq), and 2000 ppm (0.2% aq), all yielding a relatively similar percentage of positive patch test reactions. More studies are needed to establish the optimal patch test concentration for this allergen. As with any other allergen, the ideal patch test concentration should be able to detect as many cases of contact allergy as possible without causing irritant reactions or active sensitization.30 Preliminary results from Denmark suggest that 2000 ppm (0.2% aq) may be an appropriate patch test concentration.13 Methylisothiazolinone is commercially available at 2000 ppm from Chemotechnique Diagnostics, Vellinge, Sweden, in a standard preparation.

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CONCLUSIONS

Methylisothiazolinone alone is an important emerging “new” preservative allergen. It should be on the same suspect allergen list that would include quaternium 15, methylchloroisothiazolinone/methylisothiazolinone, diazolidinyl urea, imidazolidinyl urea, and iodopropynyl butylcarbamate, to name a few other important preservative allergens. It is concerning that a positive reaction to this allergen could be missed by testing with MCI/MI and not MI alone. Methylisothiazolinone should be considered as a potential suspect allergen among patients with suspected cosmetic dermatitis, facial dermatitis, and sunscreen allergy. The addition of MI to an allergen screening series in the United States and Europe will likely uncover otherwise undiagnosed cases of preservative contact allergy. Likely if we look (and test), we will find a surprising and important prevalence of MI contact allergy. Only then will we understand the extent of the problem, and perhaps, have some data to suggest something further be done about it.31

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References

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