ALLERGEN FOCUS

sitization and subsequent ACD without further exposure following a single ac- UPDATE ON cidental exposure.3 The authors con- cluded 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- , are common synthetic biocides/ 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 prod- ucts. Also, discussed is the historical use of isothiazolinones and the current epi- demic 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 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 isothia- zolinone 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 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 of products “hypoallergenic,” “gentle,” “sensitive,” (R.E.D)16 (containing the evaluation of should be abandoned. They emphasized “organic,” “100% natural,” and “der- chemicals, conclusions of potential hu- that this continuing epidemic of ACD matologist-recommended,” can contain man health and environmental risks, and due to this preservative might have been MI. One study surveyed 2 major retail decisions and conditions under which prevented if a more critical evaluation of

® 44 May 2016 | The Dermatologist | www.the-dermatologist.com ALLERGEN FOCUS its sensitizing potential before market- ing was done. The researchers concluded, “New chemicals should undergo exten- sive toxicological evaluation before their use in cosmetics is allowed. Ingredient labeling should be made a legal require- ment.”19 Furthermore, in 1996, Connor and colleagues20 reported MCI/MI to be a potent sensitizer and bacterial mutagen. Three of the 5 evaluated products that had listed MCI/MI were found to be direct acting mutagens, while the re- maining 2 products were considerably more toxic than the other products and could not be evaluated for mutagenic- ity. Based on these findings and the re- ported skin sensitization by Kathon CG, the researchers recommended that addi- tional testing be done to assure the safe- Figure. North American Contact Dermatitis Group methylchloroisothiazolinone/methylisothiazolinone (MCI/MI) positive patch tests results 1994-2012. Doubling (1994 vs 2012) of positive reactions to MCI/MI is consistent with the epidemic of allergy to this ty of products containing Kathon CG.20 preservative seen in Europe and does not account for those reactions to MI alone that may be missed by testing with this allergen Year after year, new associations and combination and the likely culprit for this increase.27 risks have been revealed related to iso- thiazolinone exposure: from airborne Significance-Prevalence Index Number ed MI was added in 2012, sensitization associated contact dermatitis, first re- (SPIN) number is a rated positivity score rates doubled from 5.15% to 10.9% by ported in 1997, to MCI/MI to skin weighted by relevance. For MCI/MI, the the next year. exposure leading to severe chemical SPIN number was 273 (rank No.4) for The current and unprecedented in- burns.21,22 More than 250 articles to date 2011-2012. This is a substantial jump in crease in contact allergy to MI in Europe in PubMed have spoken to the health ranking from the No. 16 allergen (SPIN led Schwensen and colleagues30 to evalu- risks associated with MCI/MI in sham- 128) in 2009-2010. 26,27 In their most re- ate temporal trends of preservative con- poos, conditioners, skincare lotions, and cent data, the NACDG suggested that tact allergy used in cosmetic products to other cosmetic products. this increase in SPIN number for MCI/ address failures in risk assessment and risk MI was likely due to the impact of MI management. The researchers concluded THE SECOND ISOTHIAZOLINONE EPIDEMIC sensitization and that their data points to that the rapidly increased overall burden “We are in the midst of an outbreak of the “beginning of an epidemic” in North of skin diseases caused by preservatives allergy to a preservative [methylisothia- America.27,28 Of note, the 2013-2014 was attributed to the introduction of new zolinone] which we have not seen be- NACDG screening series now includes preservatives in Europe with inadequate fore in terms of scale in our lifetime…. methylisothiazolinone alone, at a con- premarket risk assessment. I would ask the cosmetic industry not centration of 0.2% (2000 parts per mil- to wait for legislation but to…address lion [ppm]). REGULATORY ISSUES the problem before the situation gets A 2012-2014 retrospective review by In the 1980s, in response to the newly worse,” stated John McFadden, FRCP, the Cleveland Clinic for patients sus- recognized isothiazolinone allergens, ex- consultant dermatologist at St. John’s pected of ACD reported a patch test pert panels from the United States and Institution of Dermatology in London, sensitivity in 2014 to MI only (6.8%), European Union recommended more in a 2013 article in The Telegraph.23 MCI/MI only (0.9%), and both MCI/ strict concentrations in cosmetic prod- Because MCI was believed to be a MI and MI (4.7%). They also reported ucts. The Scientific Committee on Con- more potent allergen than MI,24 MI was that MI sensitivity increased from 2.5% sumer Safety (SCCS) recommended to approved for use as an individual pre- in 2012 to 6.8% in 2014. Notably, the the Cosmetic Directive of the Euro- servative in industrial products in 2000 investigators increased their MI patch pean Union to limit the concentration and in cosmetics in 2005.15,25 Comparing test concentration from 200 ppm to of MCI/MI to 15 ppm in leave-on and pooled prevalence rates from the previous 2000 ppm in 2013, attributing their rise rinse-off products, while the US Cos- decade (2001-2010) to the 2011-2012 in prevalence rates to increased detec- metic Ingredient Review recommend data, the North American Contact Der- tion.29 Gameiro and colleagues28 report- a lower concentration limit of 7.5 ppm matitis Group (NACDG), a self-elected ed in their retrospective review from the in leave-on cosmetic products.31,32 De- research group based in Canada and university hospital at Coimbra, Portu- spite these restrictions made on MCI/ the United States, reported statistically gal, that their prevalence rate of MCI/ MI concentrations in cosmetics, by the higher positive reaction rates to MCI/ MI rose from <1% in 2005 to 3.28% in 2000s MCI/MI sensitization was report- MI (doubling to 5.0%) (Figure). The 2008. After additional testing to isolat- ed to be as high as 4% by the European

® May 2016 | The Dermatologist | www.the-dermatologist.com 45 ALLERGEN FOCUS

Table 2. COMMON PATCH TESTING SCREENING SERIES OF ISOTHIAZOLINONES SUBSTRATES Bill S 1014 was referred to the com- mittee on Health, Education, Labor and Type of Patch Test MCI/MI Concentration MI Concentration Pensions and will need to be passed by T.R.U.E test 4 mcg/cm2 in Povidone Not included the Senate, House and President to be implemented. MedWatch is the FDA’s MCI 2.4 mcg/MI 0.8 mcg program for reporting serious reactions, NACDG series 100 ppm 2000 ppm product quality problems, therapeutic (MCI 75 ppm/MI 25 ppm) inequivalence/failure, and product use ACDS core allergen series 100 ppm 2000 ppm errors with human medical products, (MCI 75 ppm/MI 25 ppm) including cosmetics.37 The MedWatch online reporting form can be accessed at European baseline series S-1000 200 ppm 2000 ppm MCI 150 ppm/MI 50 ppm https://www.accessdata.fda.gov/scripts/ medwatch/index.cfm?action=reporting. Abbreviations: ACDS, American Contact Dermatitis Society; MCI, methylchloroisothiazolinone; MI, methylisothiazolinone; ppm, parts per million; home. Consumers may also submit vol- NACDG, North American Contact Dermatitis Group. untary adverse event reports by calling Surveillance System on Contact Allergy ined their 100 ppm concentration limit 800-FDA-1088. Network and 3.6% by the NACDG.33,34 placed on MI in leave-on and rinse-off These consumer filed reports gen- In 2005, the SCCS in the European products. They have maintained their erate a Manufacturer and User Facil- Union and the Cosmetic Ingredient Re- opinion that “MI is safe for use in rinse- ity Device Experience (MAUDE). The view in the United States reported that off cosmetic products at concentrations MAUDE database houses medical de- 100 ppm of MI alone was a safe con- up to 100 ppm and safe in leave-on cos- vice reports submitted to the FDA by centration for its use in cosmetic prod- metic products when they are formu- mandatory reporters (manufacturers, ucts.31,32 This resulted in a more than 25 lated to be nonsensitizing, which may importers, and device user facilities) and time increase in allowable concentration be determined based on a quantitative voluntary reporters such as health care of MI in rinse-off products (formerly 3.75 risk assessment.”32 professionals, patients, and consumers.38 ppm) and a more than 50 time increase for Currently, FDA regulations mandate A review of available MAUDE data leave-on products (formerly 1.875 ppm). cosmetic products to label only the on April 14, 2016 revealed that only Of note, no regulatory amount limitations net quantity of all items—such as the 10 reports had been filed to date: 3 on were set on industrial products. weight of the whole moisturizer bottle. methylisothiazolinone, 4 on methyl- In 2013, MI was named allergen of Although a list of ingredients from the chloroisothiazolinone, and 3 on isothia- the year by the ACDS due to its grow- most frequent to the least frequent ap- zolinone. The Dermatitis Academy is ing recognition as a sensitizer and its pears on the product label, declaring tracking these MAUDE reports on the increased use in cosmetics as a preser- actual amounts of each ingredient is FDA website on http://dermatitisacad- vative.9 Margarida Goncalo, president not required. Moreover, products used emy.com/methylisothiazolinone-page/. of the European Society of Contact solely at professional establishments not Given the current medical evidence Dermatitis, stated in a letter to the sold for retail use, as well as free samples of an epidemic being reported from US European Commission, “This new do not require ingredient declarations as patch test tertiary care centers, this marks a epidemic of allergic contact dermatitis these do not fall under the Fair Pack- significant underreporting by consumers. from isothiazolinones is causing harm aging and Labeling Act. These sample to European citizens….Urgent action products are not required to list any in- PATCH TESTING AND AVOIDANCE is required.”23 In 2013, the SCCS rec- gredient declarations at all.35 Critical work by the NACDG has ommended to the European Commis- On April 20, 2015, Sen Dianne Fein- been performed in patch testing.39 sion to ban MI in all leave-on body stein (D, California) introduced a bill From 1985 to 1987, members of the products as they found that “for leave- that aims to address the lack of cosmetic NACDG tested more than 1100 pa- on cosmetic products (including ‘wet product regulation. Specifically, S 1014 tients with MCI/MI at a concentration wipes’), no safe concentrations of MI focuses on amending the FDA label- of 100 ppm, and noted 13 reactions to for induction of contact allergy or elic- ing policies to ensure cosmetic labels the aqueous and 10 to the petrolatum- itation have been adequately demon- “include the amounts of a cosmetic’s based materials, deeming around half strated.”31 Following this recommenda- ingredients.”36 The bill also attempts the reactions as clinically relevant. This tion, the European cosmetic industry to address safety by limiting the sales work supported testing MCI/MI mix voluntarily agreed to remove MI from of cosmetics with any “ingredient that at a 100 ppm concentration.39 leave-on skin products (including wet- is not safe, not safe under the recom- Diagnostic accuracy and technique wipes). The SCCS also concluded that mended conditions of use, or not safe were further evaluated by Stejskal and concentrations of up to 15 ppm were in the amount present in the cosmetic.” colleagues40 utilizing a lymphocyte trans- safe for use in rinse-off products. Moreover, it would require cosmetic formation (proliferation) test (LTT) for Regulation in the United States has companies to “report to the FDA any isothiazolinones. The researchers detected yet to follow. In 2013, The Cosmetic In- serious adverse health event associated memory cells in the patients’ blood con- gredient Review expert panel re-exam- with their cosmetics.” firming immunologic reaction (activa-

® 46 May 2016 | The Dermatologist | www.the-dermatologist.com ALLERGEN FOCUS tion) to the inducing agent. Furthermore, Table 3. RESOURCE GUIDE to establish clinical relevance of the LTT results, the investigators had 12 patients American Contact Dermatitis Society Contact Allergen Management Program who had been positive to MCI on patch www.contactderm.org testing undergo “use test” (self-application Contact Allergen Replacement Database of a lotion containing 15 ppm MCI in the www.allergyfreeskin.com same test site) for at least 7 days or until skin reaction occurred. Four of 5 (80%) Consumer Support Groups of LTT-positive patients were use-test- Allergy to Isothiazolinones positive suggesting a value of use test and www.facebook.com/Allergy-to-Isothiazolinone-Methylisothiazolinone-and-Benzisothiazoli- the LTT in detecting patient’s allergens.40 none-307128722674171/ Patch testing remains the gold standard Methylisothiazolinone Victims Public Group to confirm ACD. However, some studies www.facebook.com/groups/527024000762338/ have shown that 33% to 60% of patients that are MI sensitive may be missed when Dermatitis Academy testing using only the combined MCI/MI www.dermatitisacademy.com preparation.9 The lower concentrations of Environmental Working Group MCI/MI or by failure to test MI alone www.ewg.org/skindeep may lead to a potential false negative re- sult. Subsequent testing at a higher con- GoodGuide centration (ie, 2000 ppm of MI), may be www.goodguide.com needed if still suspected to be the underly- ing cause. Additionally, some reviews have tem reaches a threshold and subsequent suggested that more studies are needed to exposure results in eliciting a cutane- Disclosure: The authors report no relevant financial optimize patch test concentrations of MI ous response.41 Repeated avoidance is relationships. to effectively detect a true positive patch required to stay in remission. Avoiding References test without inducing sensitization.9 Ta- specific allergens in personal care prod- 1. Bickers DR, Lim HW, Margolis D, et al. The ble 2 shows a list of common patch test ucts can be a difficult task, however, burden of skin diseases: 2004 a joint project of the American Academy of Dermatology Association screening series available for use. there are programs available that make it and the Society for Investigative Dermatology. easier. The American Contact Dermati- J Am Acad Dermatol. 2006;55(3):490-500. PEARLS OF TREATMENT: EVERY DOSE COUNTS tis Society’s (ACDS) CAMP provides a 2. Warshaw EM, Furda LM, Maibach HI, et al. Ano- In refractory cases of dermatitis involv- guideline for products devoid of known genital dermatitis in patients referred for patch test- ing the hands, facial, and perianal regions, allergens. The database contains a com- ing: retrospective analysis of cross-sectional data from the North American Contact Dermatitis Group, ACD to isothiozolinones should be con- prehensive ingredient list of thousands 1994-2004. Arch Dermatol. 2008;144(6):749-755. sidered. Patch testing may be the only of common consumer products in most 3. Kanerva L, Tarvainen K, Pinola A, et al. A single way to elicit the underlying cause. A thor- major product categories and is updated accidental exposure may result in a chemical burn, ough history of personal and household every 18 months.10,42 The Contact Al- primary sensitization and allergic contact dermati- products is essential to eliminate products lergen Replacement Database43 will also tis. Contact Dermatitis.1994;31(4):229-235. 4. Consumer Product Safety Commission. Hazard- containing isothiazolinones. Exposure produce a list of products free of specific ous substances and articles; administration and en- can also come just as easily from public allergens that a provider can give to a forcement regulations: final rule; revisions to supple- environments and should also be consid- patient for their use. These programs can mental definition of “strong sensitizer.” Published ered. For example, air fresheners in public also exclude cross-reactors. Education February 14, 2014. http://www.cpsc.gov/en/regula- bathrooms can induce a systematized re- for patients can also be accessed through tions-laws--standards/federal-register-notices/2014/ hazardous-substances-and-articles-administration- sponse in a sensitized person. online programs via the Dermatitis and-enforcement-regulations-final-rule-revisions- Education about preservatives as a Academy and the ACDS (Table 3). n to-supplemental-definition-of-strong-sensitizer/. potential cause of ACD is vital in order Accessed April 26, 2016. for consumers to make informed deci- Dr Lipp is the Dermatitis Academy Methyl- 5. Jacob SE. Focus on T.R.U.E. test allergen #17 methylchloroisothiazolinone/methylisothiazoli- sions about the products they buy, and to isothiazolinone Research Scholar. none. The Dermatologist. 2006;14(7). break the cycle of ACD. Additionally, it Ms Bertolino is a Montessori teacher at Hope 6. Gadberry JR. Ingredient review: the safety of is important for consumers to be aware Montessori Academy in Saint Louis, MO. She is paraben substitutes. Skin Inc. April 2008. that products labeled as hypoallergenic a dedicated contact dermatitis educator. 7. Methylisothiazolinone. GoodGuide website. or dermatologist-recommended may still Dr Goldenberg is a PGY1, dermatology resi- http://www.goodguide.com/products?filter=met hylisothiazolinone. Accessed April 26, 2016. contain common allergens. dency track, UCSD, and research advisor to the 8. Methylisothiazolinone. Environmental Working Exposure to a contact allergen can be Dermatitis Academy. Group website. http://www.ewg.org/search/site/ for days to years before subsequent sen- Dr Jacob is the Section Editor of Allergen Fo- Methylisothiazolinone. Accessed April 26, 2016. sitization occurs and ACD is clinically cus, a pediatric contact dermatitis dermatologist at 9. Castanedo-Tardana MP, Zug KA. Methyliso- apparent. With every exposure, there Loma Linda University, and founder and CEO thiazolinone. Dermatitis. 2013;24(1):2-6. is the possibility that the immune sys- of the Dermatitis Academy.

® May 2016 | The Dermatologist | www.the-dermatologist.com 47 ALLERGEN FOCUS 10. Scheman A, Severson D. American Contact thylisothiazolinone be prevented? Am J Contact 33. Uter W, Aberer W, Armario-Hita JC, et al. Cur- Dermatitis Society contact allergy management Dermat. 1998;9(1):11-14. rent patch test results with the European baseline program: an epidemiologic tool to quantify ingre- 23. Duffin C. Warning over ‘epidemic’ of skin al- series and extensions to it from the ‘European dient usage. Dermatitis. 2016;27(1)11-13. lergies from chemical in cosmetics and household Surveillance System on Contact Allergy’ network, 11. Schlichte MJ, Katta R. Methylisothiazolinone: products. The Telegraph. July 7, 2013. http://www. 2007-2008. Contact Dermatitis. 2012;67(1):9-19. an emergent allergen in common pediatric skin care telegraph.co.uk/news/health/news/10164452/ 34. Fransway AF, Zug KA, Belsito DV, et al. North products. Dermatol Res Pract. 2014;2014:132564. Warning-over-epidemic-of-skin-allergies-from- American Contact Dermatitis Group patch test 12. Chang MW, Nakrani R. Six children with chemical-in-cosmetics-and-household-products. results for 2007-2008. Dermatitis. 2013;24(1):10- allergic contact dermatitis to methylisothia- html. Accessed April 26, 2016. 21. zolinone in wet wipes (baby wipes). Pediatrics. 24. Bruze M, Dahlquist I, Fregert S, Gruvberger 35. FDA. Cosmetic labeling guide. http://www. 2014;133(2):e434-e438. B, Persson K. Contact allergy to the active in- fda.gov/Cosmetics/Labeling/Regulations/ 13. Hill H, Goldenberg A, Golkar L, Beck K, Wil- gredients of Kathon CG. Contact Dermatitis. ucm126444.htm. Accessed April 26, 2016. liams J, Jacob SE. Pre-emptive avoidance strategy 1987;16(4):183-188. 36. Personal Care Products Safety Act, S 1014, 114 (P.E.A.S.) - addressing allergic contact dermatitis 25. Lundov MD, Kolarik B, Bossi R, Gunnarsen Cong, 2nd Sess (2016). https://www.congress. in pediatric populations. Expert Rev Clin Immunol. L, Johansen JD. Emission of isothiazolinones gov/bill/114th-congress/senate-bill/1014/ac- 2016;12(5):551-561. from water-based paints. Environ Sci Technol. tions. Accessed April 26, 2016. 14. Latheef F, Wilkinson SM. Methylisothiazoli- 2014;48(12):6989-6994. 37. How consumers can report and adverse event none outbreak in the European Union. Curr Opin 26. Warshaw EM, Belsito DV, Taylor JS, et al. North or serious problem to the FDA. MedWatch website. Allergy Clin Immunol. 2015;15(5):461-466. American Contact Dermatitis Group patch test http://www.fda.gov/Safety/MedWatch/HowTo- 15. Schwensen JF, Lundov MD, Bossi R, et al. Me- results: 2009 to 2010. Dermatitis. 2013;24(2):50-59. Report/ucm053074.htm. Accessed April 26, 2016. thylisothiazolinone and benzisothiazolinone are 27. Warshaw EM, Maibach HI, Taylor JS, et al. North 38. Manufacturer and user facility device experi- widely used in paint: a multicentre study of paints American contact dermatitis group patch test results: ence. MAUDE website. https://www.accessdata. from five European countries. Contact Dermatitis. 2011-2012. Dermatitis. 2015;26(1):49-59. fda.gov/scripts/cdrh/cfdocs/cfmaude/search.cfm. 2015;72(3):127-138. 28. Gameiro A, Coutinho I, Ramos L, Goncalo Accessed April 26, 2016. 16. Enviromental Protection Agency. Registration M. Methylisothiazolinone: second ‘epidemic’ of 39. Rietschel RL, Nethercott JR, Emmett EA, eligibility decision: methylisothiazolinone. October isothiazolinone sensitization. Contact Dermatitis. et al. Methylchloroisothiazolinone-methylisothia- 1998. https://archive.epa.gov/pesticides/reregistra- 2014;70(4):242-243. zolinone reactions in patients screened for vehicle tion/web/pdf/3092.pdf. Accessed April 26, 2016. 29. Yu SH, Sood A, Taylor JS. Patch testing for and preservative hypersensitivity. 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