Update on Isothiazolinones

ALLERGEN FOCUS sitization and subsequent ACD without further exposure following a single ac- UPDATE ON cidental exposure.3 The authors concluded that these allergens described must be considered strong allergens. ISOTHIAZOLINONES YYet, MCI and MI are not included Isothiazolinones, including methylisothiazolinone, methylchloroisothiazolinone, and in the Consumer Product Safety Com- benzisothiazolinone, are common synthetic biocides/preservatives found in many skin and hair mission (CPSC) designated “strong al- products as well as industrial products. lergens”.4 These designated allergens are paraphenylenediamine, orris root, epoxy MICHAEL LIPP, DO, MISHA BERTOLINO, MA, ALINA GOLDENBERG, MD, MAS, AND resins systems containing any concentra- SHARON E. JACOB, MD tion of ethylenediamine, diethylenetri- amine, and diglycidyl ethers of molecu- lar weight less than 200, formaldehyde, and oil of bergamot. Notably, neither the FDA nor the CPSC has added any strong sensitizers to this list since 1961. This article highlights ACD in rela- tion to isothiazolinones, including MCI, MI, and benzisothiazolinone (BIT), which are common synthetic biocides/ preservatives found in many skin and hair products as well as industrial products. Also, discussed is the historical use of isothiazolinones and the current epidemic due to the rise in usage among consumer products. SOURCES OF EXPOSURE llergic contact dermatitis (ACD) on pathophysiology, risk of recurrence, The history of bathing began as a reli- is a socially and economically sig- and avoidance strategies should be initi- gious or ritual practice of “removing the Anificant condition. It is estimated ated to break the ACD cycle. stains of life.”5 Historically, these “stains” to affect more than 72 million Americans Experimental design studies indicate came from childbirth, touching the each year.1 In addition to physical mor- that antigenic potency in addition to the dead, murder, or contact with persons of bidity, ACD can have a significant impact concentration of antigen are important inferior caste and disease.5 Today, the act on quality of life leading to missed work factors in the determination of whether of bathing is to achieve good hygiene days and lost income, inability to enjoy an exposure to an antigen will result in as well as for relaxation, but it also pos- leisure activities, and loss of sleep. Often, sensitization. For weakly sensitizing al- es a potential risk of allergic reactions numerous doctor visits and medications lergens, exposures can occur over many via exposure to many preservatives and result in significant expenditures for the years before a reaction develops; where- other allergens from skincare products. patient before the underlying cause is as for strong sensitizers, sensitization can MCI/MI (in a fixed 3:1 ratio) were first discovered. In 2004, the total direct cost occur more rapidly. If there is skin bar- registered as preservatives in the United (eg, prescription drugs, office visits, etc.) rier compromise or exposure to a supra- States in 1977 under the trade name associated with treatment for contact potent antigen, even a single exposure Kathon CG.5 During the 1980s, isothia- dermatitis was 1.6 billion.1 could induce primary sensitization (eg, zolinone preservatives became exten- Patch testing is the gold standard for poison ivy). Kanerva and colleagues3 sively used in consumer personal care ACD diagnosis.2 Once the offending al- collected clinical cases in which a single and industrial products, because they are lergen is identified, avoidance is critical exposure had resulted in suspicion for compatible with surfactants and emulsi- for sustained remission. However, be- development of ACD. Six patients with fiers and able to maintain biocidal activ- cause ACD has a delayed-onset (time accidental occupational exposure and ity over a wide pH range (pH 2-9).5,6 between sensitization or exposure and no previous relevant skin symptoms A recent search on GoodGuide, a re- elicitation of the dermatitis) it may be were patch tested to demonstrate sen- source for searching more than 250,000 difficult to make the association. There- sitization. Methylchloroisothiazolinone available products on the market, listed fore, when ACD is suspected, a patient- (MCI) and methylisothiazolinone (MI) MI to be an ingredient in 6725 consum- centered educational approach focusing were found to have induced both sen- er products,7 while the Environmental ® May 2016 | THE DERMATOLOGIST | www.the-dermatologist.com 43 ALLERGEN FOCUS the use of products are eligible) on MI Table 1. EXPOSURE TO ISOTHIAZOLINONES states that “the agency determined that Consumer Products Industrial Products methylisothiazolinone is highly to very Dishwashing products Paints highly toxic” in mammalian studies, yet Shampoos Inks the agency also concluded that “the risks Household cleaners Glues to workers in most situations are not of Hair conditioners Lacquers concern and short-term risks of corro- Laundry detergents/softeners Varnishes sivity can be adequately managed, as nec- Soaps and cleansers Cutting oils essary. The agency further believes risks Air fresheners Jet fuels from secondary occupational exposures, Hand sanitizers Pesticides residential exposures, and postapplica- Baby wipes Paper manufacturing tion exposures are comparatively less and 16 Vaginal products Ultrasound gel also not of concern.” To mitigate the Sanitary napkin adhesives potential inhalation and dermal toxicity Sunscreens risk to workers, the agency requires the 16 Moisturizers use of personal protective equipment. Cosmetics In certain instances, it has been necessary Pharmaceuticals for painted walls to be treated with inor- Children’s crafting supplies ganic sulfur salt to inactivate the isothiazolinone component.5 Additionally, the R.E.D. environmental assessment states Working Group’s skin deep database stores of pediatric skincare products and that MI is also “highly toxic to freshwa- has 3234 cosmetic skincare products found that 30 of 152 products (19.7%) ter and estuarine/marine organism” and listed to contain MI as an ingredient.8 contained MI.11 Significant allergic re- that “quantitative risk assessment has not This is a substantial increase from pre- actions to MI found in baby wipes has been conducted.”16 vious reports estimating that the use of been documented.11,12 One pediatric MI nearly doubled between 2007 (1125 review of ACD ranked MCI/MI No. ISOTHIAZOLINONES SENSITIZATION CAUSES AN products) and 2010 (2408 products).9 8 (2.61%) among its top 10 allergens EPIDEMIC In 2016, Scheman and Severson10 found in personal hygiene products The first cases of ACD to MCI/MI analyzed 2013 data from the American across 5 studies.13 were reported in 1985 from cosmetic Contact Dermatitis Society’s (ACDS) The industrial and occupational set- use, marking the beginning of the first Contact Allergen Management Program tings are another source of isothia- epidemic to isothiazolinones.17 In 1988, (CAMP). For the study, 4660 consumer zolinone exposure. (Table 1). These de Groot and colleagues18 reported on products were evaluated by category preservatives can be found in a wide the significant ingredients responsible for and MI was found in dishwashing prod- range of products such as hand care and allergy to cosmetics. In the 119 patients ucts (64%), shampoos (53%), household surface-wipes, children’s craft paints, with cosmetic-related contact dermati- cleaners (47%), hair conditioners (45%), beauty products, water-based paints, tis, 56.3% were associated with skincare hair dyes (43%), laundry additives/soft- latex paints, lacquers, printer ink, cut- products. They also found that preser- eners (30%), soaps/cleansers (29%), and ting fluid, coolants, pesticides, and ultra- vatives were most frequently implicated surface disinfectants (27%).10 Nearly sound gel.14 Airborne contact dermatitis (32.0%), followed by fragrances (26.5%) 100% (except 1 product) contained MI has been recognized in people using and emulsifiers (14.3%). The most sig- (without MCI) in household cleaning, water-based paint which may contain nificant cosmetic allergen was Kathon dishwashing, and laundry products. Al- MCI, MI, or BIT and has been associ- CG, (a preservative system containing, though a small overall percentage of ated with dyspnea, as well as facial der- as active ingredients, a mixture of MCI makeup products (<5%) did contain MI, matitis.14 Unlike MCI/MI, BIT has not and MI) reacting in 33 patients (27.7%).18 when it did, it was always without MCI. been deemed safe to use as a preserva- Within 6 months de Groot and Herx- Other product categories that contained tive in cosmetic products.15 Notably, a heimer19 published another study on MI (without MCI) in high percentage multicenter study of paints from 5 Eu- a significant number of the cases of included moisturizers (82%), shaving ropean countries reported that BIT was Kathon CG (MCI/MI) allergy caused products (78%), sunscreens (71%), anti- found in 95.8%, MI in 93.0%, and MCI by products of the “leave-on” variety (eg, aging products (67%), hairstyling prod- in 23.9% of paints, and the use of iso- moisturizing creams) and stated that an ucts (56%), soaps and cleansers (30%), thiazolinones in paints is less regulated.15 epidemic had begun. Furthermore, they and hair dyes (20%).10 It is important to The Environmental Protection Agen- asserted that the use of isothiazolinone note that products that are marketed as cy’s Reregistration Eligibility Decision preservative in these types

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