High rate of sensitization to Kathon CG, detected by patch tests in patients with suspected allergic contact dermatitis,

Anais

Brasileiros

de

Dermatologia

INVESTIGATION

High

rate

of

sensitization

to

Kathon

CG,

detected

by

patch

tests

in

patients

with

suspected

allergic

contact

dermatitis

夽,夽夽

Eliane

Aparecida

Silva

_,

_Marcia

_Regina

_Miras

_Bosco

_,

_Rejane

_Rojas

_Lozano

_,

Ana

Carla

Pereira

Latini

_,

_Vânia

_Nieto

_Brito

_de

_Souza

a_{SectorofImmunology,InstitutoLaurodeSouzaLima,Bauru,SP,Brazil} b_{SectorofPharmacology,InstitutoLaurodeSouzaLima,Bauru,SP,Brazil}

Received1November2018;accepted1September2019 Availableonline31January2020

KEYWORDS Additivesin cosmetics; Dermatitis,allergic contact; Hypersensitivity, delayed; Skintests Abstract

Background: KathonCG,acombinationofmethylchloroisothiazolinoneand methylisothiazoli-none, is widelyused as preservativein cosmetics, as wellin household cleaning products, industrialproductssuchaspaintsandglues.Ithasemergedasanimportantsensitizingagent inallergiccontactdermatitis.

Objectives: Thisstudyevaluatedthereactivitytothissubstanceinpatientssubjectedtopatch testsattheDermatologyInstituteinBauru,SãoPaulofrom2015to2017anditscorrelation withotherpreservatives,theprofessionalactivityandlocationofthelesions.

Methods: Thepatientsweresubmittedtostandardseriesofepicutaneoustests,standardized bytheBrazilianGroupStudiesonContactDermatitis.

Results: Outthe267patientstested,192presentedpositivitytoatleastonesubstanceand29 ofthepatients(15.10%)presentedreactiontoKathonCG,withpredominanceofthefemale gen-der(n=27);mainprofessionalactivityassociatedwithKathonCGsensibilizationwascleaning (17.24%), followed by aesthetic areas (13.79%) and health care (10.34%). The most preva-lent sensitizationsamong thesubstances tested were nickel sulphate (56.3%), followed by cobaltchloride(23.4%),neomycin(18.2%),potassiumdichromate(17.7%),thimerosal(14.5%), formaldehyde(13.2%),paraphenylenediamine(9.3%),andfragrancemix(8.3%).

Studylimitations: We donothave datafrom patients thatwere submitted topatch testa decadeagoinordertoconfronttocurrentdataandestablishwhetherornosensitizationto KathonCGhasincreased.

夽 _{Howtocitethisarticle:SilvaEA,BoscoMRM,LozanoRR,LatiniAC,SouzaVNB.HighrateofsensitizationtoKathonCG,detectedby}

patchtestsinpatientswithsuspectedallergiccontactdermatitis.AnBrasDermatol.2020;95:194---9.

夽夽_{StudyconductedattheInstitutoLaurodeSouzaLima,Bauru,SP,Brazil.} ∗_{Correspondingauthor.}

E-mail:elianeasil@gmail.com(E.A.Silva). https://doi.org/10.1016/j.abd.2019.09.026

0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC BYlicense(http://creativecommons.org/licenses/by/4.0/).

Conclusion: High positivity toKathonCG corroborates therecent findings intheliterature, suggestingmoreattentiontoconcentrationofthissubstance,usedincosmeticsandproducts fordomesticuse.

©2020SociedadeBrasileira deDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Introduction

AllergicContact Dermatitis (ACD) is an inflammatory pro-cess mediated by immunological mechanisms that has a significant socioeconomic impact,1 _{since it constitutes an}

important cause of dermatology appointments and even removalofpatientsfromtheiractivities,withgreat reper-cussiononthequalityoflifeandoccupationalcommitment. Therangeofclinicallyrelevantallergens,whichmaybe organicandinorganicsubstances,naturalorsynthetic,has increased,especiallyinthe moreindustrializedcountries. In addition,factors related tolifestyle alsoinfluence the occurrence of ACD. Until 1995, it was estimated that six million chemical substances were present in the environ-ment; three thousand had already been cited as contact sensitizers, and 30 wereresponsible for 80% of the cases ofACD.1,2

TheprevalenceofACDbyagivenantigendependsonits sensitizingpotential,aswellasthefrequencyandtimeof exposure.Thus,thesensitizationprofileofagiven popula-tionchangesconstantlyasthepresenceandexposuretothe sensitizerschangesovertime.3

Several studies emphasize the importance of identify-ingthesubstance thatcantrigger ACD.4---6_{In thiscontext,}

recentstudieshave shownanincrease inthesensitization tothe commercially-known substance Kathon CG or Euxil K100, a combination of Methylchloroisothiazolinone (MCI) andMethylisothiazolinone(MI).7,8_{AccordingtoGeieretal.,}

thisraisecouldbeduetoincreasedsensitizationtotheMI component.9

TheMCI/MIcombination,consistingofthreepartsofMCI andonepartofMI,iswidelyusedinBrazil,aspreservativein concentrationsof0.0015%(15ppm)incosmetics,household cleaning andindustrialproducts suchaspaintsand glues. In the standard test series, the substance is used at the concentrationof0.5%inpetrolatum.4

DatafromtheNorthAmericanAllergicContact Dermati-tisGroupfrom2009to2010revealeda2.5%rateofMCI/MI sensitization among4032 patients tested. The global fre-quency of sensitized patients remained constant around 2.1%from1998to2009,butincreasedto3.9%in2011.9---11

In 2014 in Brazil, Scherrer and Rocha, demonstrated an increaseinpositivitytoMCI/MIduringthe2009---2012period, where 11.14% of the patients showed positivity to this substance, contrasting with3.35% positivityin the period 2006---2009.7

As ACD to Kathon CG (MCI/MI) is a relatively common dermatosis in adults at the productive phase of life and studieshaveshownthatthefrequencyofpositivitytothis compoundhasincreased,weconsiderrelevanttoconduct aretrospective studyof theresultsof thepatchtest per-formedinpatientsattendedattheInstituteLaurodeSouza

LimaInstitute,Bauru(SP)inordertoevaluatethemagnitude oftheprobleminthesepatients.

Methods

A retrospective study was carried out at the Immunol-ogySection of Lauro de Souza Lima Institute, Bauru(SP) basedontheresultsof theepicutaneoustestsin patients with the diagnostic hypothesis of ACD or other delayed typehypersensitivityreactionwithcutaneousimpact, dur-ingtheperiodofJanuary2015toJune2017.Thefollowing parameterswereevaluated:sex,age,occupationalactivity, locationofthelesionsandfrequencyofsensitizationtothe substancestested.

The standard series tested are recommended by the Brazilian Group of Studies onContact Dermatitis(GBEDC, 1996),4 _{manufactured byFDA-Allergenic/Immunothec (RJ,}

Brazil),composedof30substances(Table1).Inallthecases FINNChambers(Oy,Finland)typeretainerswereused,and thereadingsweredonein48and96h,accordingtothe Inter-nationalContactDermatitisResearchGroup(ICDRG,1981), inaccordancewith:(−)negativereaction;dubiousreaction; (+)mild reaction, withmild erythema andsome papules; (++)moderatereaction,witherythema,papulesandsome vesicles;(+++)intensereaction,witherythema,papulesand confluentvesicles.Irritationreactionswerenotconsidered. ThesedatawereinsertedintoanExcel®_(Microsoft®_)file,

fromwhich the quantification and descriptive analysis of theresultswasdone.Nonparametricstatisticalcalculations usingthechi-squaretestwereusedtocompareproportions withregardtothestudiesoftheBrazilianGroupofContact Dermatitis4_{andtheoneaccomplishedatSantaCasadeSão}

Pauloduring2006---2011.12_{Abinarylogisticregressionmodel}

wasusedtoassesstheassociationofsensitivitytoKathonCG withsexandoccupation.Theconcomitanceofpositive reac-tions to different preservative substances was calculated usingFisher’sexacttest.Thesignificanceleveladoptedwas

p≤0.05.

ThestudywasapprovedbytheResearchEthics Commit-teeof the Laurode Souza Lima Institute (number: 2 903 882).

Results

In the evaluated period, 267 patients, with a mean age of 43±16 yearsof which 191 (72.9%) were female,were submittedto the allergiccontact test and, of these, 192 (71.91%) presented positivity to at least one substance tested. Cephalic segment including head, face and neck (44.79%),hands(42.18%)andupperlimbs(35.41%)werethe mostfrequentlyaffectedlocationofdermatitis(Fig.1).

Table1 StandardBrazilianseriesofthecontacttestrecommendedbytheBrazilianGroupofStudiesonContactDermatitis, 1996.

Substance Concentration Substance Concentration

Anthraquinone 2.0% Neomycin 20.0%

BalsamofPeru 25.0% Nitrofurazone 1.0%

Benzocaine 5.0% Parabens(2) 12.0%

Potasssiumdichromate 0.5% Paraphenylenediamine 1.0%

P-tertiarybutylphenol 3.0% Perfume-mix(3) 8.0%

Carba-mix(1) 3.0% PPD-mix(4) 0.6% Cobaltchloride 1.0% Promethazine 1.0% Colophony 20% Propyleneglycol 1.0% Ethylenodiamine 1.0% Quaternium 2.0% Formaldehyde 2.0% Quinoline-mix(5) 5.0% Hydroquinone 1.0% Epoxyresin 1.0% Irgasan 1.0% Nickelsulphate 5.0% KathonCG 0.5% Turpemtine 10.0% Lanolin 20.0% Thimerosol 0.1% Mercaptobenzothiazole 1.0% Thiuram-mix(6) 1.0% Source:GBEDC,2000.

*_{Allsubstancesdilutedinpetrolatun,withtheexceptionofformaldehydedilutedinwater.}

(1)Diphenylguanidine;(2)Butyl,ethyl,propyl,methylparaben,3.0%each;(3)Eugenol,isoeugenol,cinamicalcohol,cinamicaldehide, geraniol,hidroxicitronellal,alpha-amylcinamicalcohol,oakmossabsolute,1.0%each;(4)N-phenyl-n-cyclo-hexyl-p-phenylenediamine, N-iso-N-phenyl-p-phenylenediamine,N-diphenyl-p-phenylenediamine,0.2%each;(5)Clioquinol,clorquinaldol,3.0%each;(6) tetram-ethylthiuramdisulfitetetramethylthiurammonosulfitetetraetiltiuramdisulfitedipentametilenethiurammonosulfite,0.25%each.

Head, face and neck 44,79

42,18 35,41 28,64 22,39 10,93 Hands Upper limbs Lower limbs Trunk and abdomen Feets

Figure1 Locationandfrequencyoflesionsinpatientswithpositivetests(percentage).

Among the tested substances, the most prevalent was nickel sulphate (56.25%), followed by cobalt chlo-ride (23.43%), neomycin (18.22%), potassium bichro-mate (17.70%), Kathon CG (15.10%), thimerosal (14.58%), formaldehyde(13.02%),paraphenylenediamine(9.37%)and fragrancemix(8.33%),asshownintable2.

When comparing the positivity rates to allergic sub-stances between the groups of patients evaluated in our studyandthosestudiedbytheBrazilian GroupofContact Dermatitis(2000) and the Santa Casa deSão Paulo group (2006---2011),wefoundaconcomitantsignificantdifference ofincreasedpositivityforeightsubstances,withthose pre-sentingwiththehighestpositivitybeingnickelsulfateand cobaltchloride(Table3).

Ofthe29patientswhopresentedwithapositivereaction toKathonCG,93.10%werefemale(Fig.2).The mainACD sitesofthebodyofpatientswithsensitizationtoKathonCG were:hands(58.6%),head,faceandneck(48.3%),followed by upper limbs (44.8%). The most prevalent professional activity was cleaning (17.24%), followed by beautician (13.79%)andhealth occupations(10.73%).Amongthe two malesubjects who tested positive for this substance one was a bricklayer and the other worked in the cosmetics

industry. By using binary logistic regression we observed that the positivity to Kathon CG is related to females (OR=9.7;95%CI: 1.3---76.9);however,noassociation with occupationwasobservedinthisstudy.

Regarding the response obtained in reading this test, we identified65.5%of patientswithpossiblerelevanceto KathonCG,becausethepositivityisassociatedwiththeuse ofthematerialbythepatient.

Whenweevaluatedthereactivitytootherpreservative substancestestedinthestandardbatterywefound positiv-ityof 13.02%toformaldehyde, 4.21%toIrgasan,2.60%to parabenand2.08%toquartenium15.However,withregard to concomitance of these preservatives with Kathon CG, we observed 27.58% of reactivity toformaldehyde among KathonCGreactivepatients,whichwasstatistically signifi-cant(p=0.0304)and6.89%positivityforeachoftheother preservativessubstances.

Discussion

KathonCGiscurrentlyoneofthemostfrequent causesof contactallergytopreservativesduetoitswideand gener-alizeduse inboth theprivateandprofessionalsettings.8,9

Table2 Prevalenceofreactivityforeachsensitizing sub-stance(n=192patientswithpositivetestsforatleastone substance).

Sensitizingsubstance Numberof positivetests Prevalence Nickelsulphate 108 56.25% CobaltChloride 45 23.43% Neomycin 35 18.22% Potassiumdichromate 34 17.70% KathonCG 29 15.10% Thimerosal 28 14.58% Formaldehyde 25 13.02% Paraphenylenediamin 18 9.37% Fragrancemix 16 8.33% Colophony 11 5.72% BalsamofPeru 9 4.68% Irgasan 8 4.21% Thiuranmix 6 3.12% Carbamix 6 3.12% Ethylenediamine 5 2.60% Parabens-mix 5 2.60% Quaternium15 4 2.08% Quinolinemix 4 2.08% Nitrofurazone 4 2.08% Epoxiresin 4 2.08% Lanolin 3 1.56% Mercaptobenzothiazole 3 1.56% Hydroquinone 2 1.04% PPDmix 2 1.04% Promethazine 2 1.04% Benzocaine 2 1.04% P-tertiaryButhylphenol 1 0.52% Turpentine 1 0.52% Anthraquinone 0 0.0% Propyleneglycol 0 0.0%

In thiscontext,our studyverifieda high positivitytothis substance(15.10%)inthepatientstested,whichisin agree-mentwitha retrospectivestudy carriedout inBrazil that showed11.14%ofsensitizationforMCI/MIinthe2009---2012

period,contrastingwith(3.35%) for the previous period.7

Thismaybeduetothewidespreaduseofthissubstancein cosmeticsandhouseholdproductsinBrazil.

Cosmetics are continuous use products that eventu-ally may trigger hypersensitivity reactions in genetically predisposed individuals, but the allergic reaction cannot be explained only by genetic factors, being considered multifactorial.13,14 _{Thus, the higher occurrence of Kathon}

CGpositivityinfemalescanberelatedtothesensitization duetofrequentuseofcosmetics,asobservedinthestudy byPónyaietal.(2016).15

Since the introduction of MCI/MI in the 1980s,1,16 _this

producthasmanifesteditselfasapotentsensitizer,which now has a reduced maximum concentration in cosmetics downto15ppm.4_{The frequencyofsensitizationremained}

stableinEuropebetween1%and4%17_{andinSpainbetween}

3%and4%18,19_{until2008.Sincethenthefrequencyof}

sensi-tizationhasdoubledtoreach8%in2012inSpain.20_Ourdata

showanevenhighersensitizationof15.10%.

The site of eczema is of great importance, with der-matitisonthefacebeingusuallyrelatedtocosmeticsand onhands with occupational factors.21 _{Our study confirms}

such data in relation to MCI/MI: the hands are the most affectedsite,followedbytheheadandneckarea, suggest-ingexposuretoagentsthatcauseallergysuchasshampoos, creams,cleaningproducts(detergents,stainremoversand fabricsofteners).ItshouldbementionedthatMCI/MIisalso presentinmetallurgicalfluids,wallpaints,lacquers,printer inksandglues,22_{whichcouldjustifythesourcesof}

sensiti-zationofthebricklayerpatientwhosesitesaffectedwere armsandhands.

Regardingthe agerangeof patients(mean age43±16 years), it is consistent with the period of greatest pro-fessionalactivityinthepopulation.This demonstratesthe needforgreaterawarenessfortheemployedpopulationand employerconcerningthemonitoringof occupational aller-gies,theirrisksandeffectsinthelongterm.

In the present study, MCI/MI contact allergy was also compared to the reactions of other preservative sub-stances present in the patch test. Our findings reinforce association and show concomitance between MCI/MI and formaldehyde (p=0.0304). The literature has shown an

n = 29 median age 42±14 27 females median age 42±15 02 males median age 38±07 01 bricklayer 01 industry of cosmetic 10,7% heath occupations 13,7% beautician 17,2% cleaner

Table3 FrequencyofsensitizationwithsignificantdifferenceinrelationtotwostudiesintheliteratureinBrazil(Brazilian GroupofContactDermatitis4_{andatSantaCasaofSãoPauloduring2006---2011}12_).

Substancesignificantdifference ILSL study % GBDC 2000 % Santa Casa % Chi-square p<0.05 GBDC×ILSL Chi-square p<0.05 SC×ILSL Nickelsulphate 56.25 25.1 28.16 73.4839(p<0.00001) 50.9494(p<0.00001) Cobaltchloride 23.43 11.0 10.52 21.8247(p<0.000003) 20.8348(p<0.000005) Neomycin 18.22 4.3 7.28 49.8009(p<0.00001) 19.7243(p<0.000009) Potassiumdichromate 17.7 8.1 11.7 17.0606(p<0.000004) 5.6508(p<0.017) KathonCG 15.1 2.2 2.43 64.9045(p<0.00001) 45.8274(p<0.00001) Formaldehyde 13.02 3.8 3.24 26.747(p<0.00001) 26.7292(p<0.00001) Colophony 5.72 2.6 2.75 5.2608(p<0.02) 3.8937(p<0.04) Irgasan 4.21 0.7 0.81 14.8632(p<0.00012) 10.4576(p<0.001)

Totalpatientswithpositivetests 192 967 618 ILSL,InstitutoLaurodeSouzaLima.

association between contact allergy toformaldehyde and MCI/MIinprevious studies.23,24 _{Theconcomitance of}

posi-tiveteststothese elementsoccurs, most of thetime,by co-sensitization,due tothesimultaneous exposureto dif-ferentmaterialscontainingtheseelements.Inthiscontext, ourfindings reflectconsumerbehaviour inrelationto cos-metics,aswellasdomesticcleaningproducts.25,26_Itisworth

mentioningthatMCI/MIandformaldehydearealsopresent inworkenvironments,andthesensitizationtotheseagents cancauseoccupationalcontactdermatitis,sometimesdue tounexpectedexposure,suchasthecaseofoneofthemale patientswhoseprofessionalactivityisinthebuildingsector, where hecould come in contactwith water-basedpaint, lacquerandproductsforwoodpolishes.

Fromthecorrectidentification ofthecosmetic compo-nentsand the industrialized products triggering allergies, thepatientshouldbeappropriatelyorientedinrelationto thechemical nameof thesubstance, synonyms and prod-uctswheretheirpresenceoccursandmainwaysofavoiding exposure.

Conclusion

Ourresults showhighpositivitytoKathonCG andsupport therecentfindingsoftheliterature.Moreover,theysuggest greater attention to the concentration of MCI/MIused in cosmetics,aswellasinproductsintendedfordomesticuse.

Financial

support

Nonedeclared.

Authors’

contributions

ElianeAparecida Silva: Statistic analysis; elaboration and writing of the manuscript; effective participation in researchorientation.

MarciaReginaMirasBosco:Obtaining,analysis,and inter-pretation of the data; effective participation in research orientation.

RejaneRojasLozano:Obtaining,analysis,and interpre-tationofthedata.

AnaCarla Pereira Latini: Statistic analysis;approval of thefinalversionofthemanuscript;obtaining,analysis,and interpretationofthedata;criticalreviewoftheliterature. VâniaNietoBritodeSouza:Approvalofthefinalversion ofthemanuscript;criticalreviewoftheliterature;critical reviewofthemanuscript.

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