j. Soc.Cosmet. Chem.,48, 307-317 (November/December 1997)

The skin irritationpotentialof quaternaries M. M. RIEGER, MorrisPlains,NJ 07950.

Accepted for publication November 7, 1997.

Synopsis

It is frequentlyreportedthat the relativeskin irritancyof surfactants dependson the ionic speciesformed by the surfactant. Thusthe irritationpotentialof surfactants is widelyassumed to followthe patternbelow in which quaternaries are the most irritating: quaternaries> amphoterics> anionics> nonionics.The basis of this relativeratingis examinedbelow,with the conclusion that it requiresmodificationfor topicallyused quaternaries and surfactants in general.

INTRODUCTION

The evidencefor the relativeskin irritancyrating of surfactants--quaternaries > amphoterics> anionics> nonionics--datesback to the period following World War II when eyeand skin irritancywere assessed via the well-knownDraize animal procedures [asdetailedin 1959 in ref. (1)]. In addition,the potentialof anysurfactantto causeskin irritation can be established by a varietyof alternativetoxicologicaltest procedures, as reviewedby Drobeck(2). It is the objectiveof this reviewto examinethe pertinenceof theseand relatedtestsfor the assessment of skin irritation that may resultfrom accidentalor deliberatecontactwith quaternarysurfactants. In orderto completethis effort, it will be necessary to includesomedetailsof the testingof irritancyof othergroupsof surfactants.

DEFINITION

OF SKIN

IRRITATION

Skin irritation is definedsimplyasa transitoryadverseresponse of skin to contactwith the irritating species. Irritation mayresultfrom anycorrosive or toxicsubstance, i.e., one that attacksthe integument.Skin exposureto sucha substance under normalcosmetic usemay leadto changesin transepidermal waterloss,dryness,tautness,scaling,andeven erythema.The earlyinvestigators werelimited to relying on erythemaasthe markerfor skinirritationsincetheyhadno othermeansof assessing damage.Thusmuchof the data refersto the rate andlevelof reddeningand the effectof concentration of the eliciting substance. It must be clearlyrecognizedthat erythemais a late effect of irritation, requiringthat the appliedsubstanceitself reachesthe dermal vasculatureor that the 307

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JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

substance triggersthe releaseor formationof a compoundwithin the skin that upon furtherpermeation(or via feedback)causes the hyperemia. Erythema-•evenin the absenceof urticaria--is alsoa signof sensitization, but this is a reactionthat is distinctfrom that of irritation.The elicitationof immuneresponses can be the resultof thepresence of epidermalimmunocompetent cellsor maytakeplaceonly after systemicprocessing of the allergen.Immune responses to the applicationof quaternariesto the skin will not be discussed sincethey are evidentlyrare. Skin irritation in this reviewis, therefore,definedasa dermal reactionto topicaladministration.It is unrelatedto dermalmanifestations resultingfrom systemicadministration of an irritant or to systemictoxicity.

DEFINITION

OF QUATERNARY

In this review a quaternaryis definedas a compoundin which a nitrogenatom is covalentlyboundto four alkyl groupsreg,•rd/ess ofpH and, therefore,carriesa positive chargereg,•rd/ess of pH. Thus aminesand amphoterics,in which the chargeon the nitrogen atom variesas a function of pH, are excluded.Despite this limitation, the numberof cosmetically usefulquaternaries is well over 500. For clarification,the defining quaternarystructureis shownbelow: R• I

R2-N +-R 3 I

R4

Up to threeof the covalentlybondedR groupsmaybepart of the samecyclicor aromatic system,as,e.g., in the well-knownpyridiniumsalts.The hydrophobicity of quaternaries can be modifiedby the inclusionof a (poly)oxyethylene group in one or moreof the substituentR groups.The counterionto the positivelychargedN- atom can be a halogen,a sulfate(ethosoulfate), a carboxylicacid, or, in fact, any speciesthat canform an anion.In somecases, the anion-forming groupmaybepart of oneof the alkyl groups. A typicalexampleof this is a betainein whicha zwitterionicspecies canbe formedover a limited pH range. Quaternarymoleculesare not unusualin nature.The N- atom in phosphatidylcholine is a true quaternary,and lecithin is a ubiquitousconstituentof animalandplant tissue. Even though it is a quaternary,it is not regardedas toxic or irritant. The safetyof lecithin leadsto its use in parenteralnutrition. On the other hand, most of the cosmeticallyor pharmaceutically usefulquaternaries aresyntheticsubstances. Their ingestion or injection into mammals has elicited some toxic responses,especiallyat the dosagescommonlyemployedby toxicologists.

The purity of syntheticquaternarysubstances is almostneverdescribedin the toxicologicalliterature.In the earlytoxicologicalliterature,identificationwasby (commercial) tradename(3). In retrospect,it is likely that mostsubstances testedduring this period includedsomeaminesand remnantsof the alkylatingagents.Unfortunately,detailsof this type are irretrievablylost, even though their significanceto any skin irritation potentialcouldbe important.

SKIN IRRITATION EARLY

SKIN

TESTING

POTENTIAL OF QUATERNARIES

PROCEDURES

AND

309

RESULTS

The studyof the skin and eye irritation potential of quaternariesbeganabout the time of WW II, andthe rankingof surfactants wasbasedprimarilyon the resultsof the Draize rabbit skin test. A few of the earlydata are shownin Table I, which is basedon results of rabbitskin tests,asdescribed by Draize(1). The datain Table I wereobtainedin 1967 using 0.5 ml of the undilutedquaternary(or 0.5 g of the dry) materialon intact and abradedrabbit skin, establishingthe high irritation potentialof quaternaries(3). The concentrations testedare unrealisticand make it difficult to assess their pertinenceto

humanskin irritancyat moremodest(use)concentrations. It is alsonext to impossible to relate the resultsof theseand similar tests to the irritancy potential of modern commerciallyavailablequaternaries;in addition, someof the trade-namedtest compoundsare no longeravailable.Theseearly investigators wereforcedto examinequaternariesthat did not differ greatly from eachother but were producedby different suppliers.Much of the earlytestingwasprobablytendentiousand designedto confirm the innocuousness of the sponsor's compound.The excellentand comprehensive review by CutlerandDrobeck(3) showsthe divergence of resultsdueto differingtestprotocols that wereinadequatelycontrolled.Their reviewcorrectlynotesthat moststudiesconcern irritation by accidentalcontactwith antimicrobialquaternaries usedin high concentrations.The effortsto categorizetheseresultsoften resultedin someunexplainableirritancy ratings.

As noted, many of the studiesreviewedby Cutler and Drobeck(3) were companysponsored and not recordedin the published(journal)literature.Retrievalof thesedata todayis difficult,andmuchof the materialin the followingparagraphs is basedon their review.

In anotherstudyreviewedby Cutler and Drobeck(3), dihydrogenated tallow benzyldimonium chlorideat 5% wasrated as mild. It is alsonoteworthythat in a third study C•2_•6alkyl dimethylbenzylammoniumchloride(0.3%) wasfoundonly mildly irritating.

During the period up to about 1965-1970, it was commonpracticeto rate dermal irritancyon the basisof (Draize) rabbit eye tests.Thesetestssometimesfollowedthe protocoland includedseven-day readings,while at other times scoringwasterminated at the 48-hour reading. Table

I

Irritancy Ratingsof Quaternaries(Draize Rabbit Skin Test)*

Test material Di Cs_•oalkyl benzylmethyl ammoniumchloride(53.5%) Di Cs_•oalkyl dimethylammoniumchloride(50.6%) Didecyl dimethyl ammoniumchloride(55.7%) C•2_•6alkyl dimethyl benzylammoniumchloride(50%) C•2_•6alkyl dimethylbenzylammoniumchloride(92.6% powder,i.e., Zephiran ©) C•2_•salkyl dimethyl ethylbenzylammoniumchlorideplus C•246 alkyl dimethyl benzyl ammoniumchloride(50%)

* Reportedby Cutler and Drobeck(3), basedon databy Dupreyand Hoppe (1970).

Irritancyrating Severe Severe Severe Severe Moderate Severe

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JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Finally, the Draize eyetestprocedurewasmodifiedby instillationof gradedconcentrations (in saline)from 0.063% up to 0.5% in orderto assess the relativeirritancyof variousquaternaries.This test was intended to identify safe-uselevelsfor surfactants used in finished formulations. The results [for details consult Table 2 in Cutler and

Drobeck(3)] can be summarizedas follows:quaternariesthat includea benzylgroup (benzalkoniumtypes)appearto be milder than thosewith two fatty alkyl groups. Nevertheless,there is no compellingreasonto concludethat human dermal irritancy showsthe samepattern as eye damagein the Draize test. Table II below showsthe maximum

tolerated

concentrations

of active surfactants.

Draize'sdataand the ensuingdiscussion during the May 1952 Toilet GoodsAssociation meeting(4) are important.Draize notedthat differentgradesof sodiumlauryl sulfate and differentlots of the (supposedly) identicalcommercialgradeeliciteddifferentlevels of eyedamage.AlthoughDraize'sreadingssuggestthat 100% concentration of sorbitan esterswere tolerated,one questionerreportedthat in his testsmany non-ionicselicited cornealopacity. These important commentsare included as an Appendix since few readerstodayhavereadyaccessto the TGA proceedings.

Despite theseuncertainties,Hazelton (5) confirmsthe previouslyestablished order of cationics> anionics> nonionicsasthe bestinitial criterionfor predictingeyeirritation potential.How and wherethe samepattern was established for human skin irritation remainsa mystery.

The intenseresearch activity of the earlyfiftieswasfollowedby a hiatus.Researchers and formulatorsacceptedthe ratingsof surfactants asskin irritantson the basisof the classic model (5).

The work of van der Valk eta/. (6) initiatedthe periodof research in whichrabbit eye irritation and erythemawerereplacedby parametricmeasurements on humansubjects. The work was basedon the conceptthat skin exposedto surfactantswould show enhancedTEWL long beforevisible eythemaappeared.Their ranking of irritancy of surfactants (2%) basedon evaporimetricscoresis: sodiumlauryl sulfate> cocobetaine > sodium laurate > polysorbate60. Thesestudiesincludeda quaternarysurfactant,as definedabove,and their approachwas followedby Berardesca eta/, (7), who included

another quaternary. Briefly,0.03ml/cm 2 of fourdifferent surfactants at different concentrations wereapplied to eightsubjects oncedailyforthreedaysto 16-cm 2 testsites Table Maximum

Tolerated

Surfactant

II

Concentrations*

of Active Surfactants

Concentration (%)

Lauralkonium

chloride

0.5

Benzalkonium

chloride

0.5

Benzethonium

chloride

0.5

Cetethyl dimonium chloride Stearalkonium

chloride

Sodiumlauryl sulfate Octoxynol-9 Polysorbate80

0.8 3.0

20.0 5.0 100.0

* Rabbit eye instillation;concentrationat which no cornealor iris lesionswere evident by the seven-day reading(4).

SKIN IRRITATION

POTENTIAL OF QUATERNARIES

311

andallowedto dry. On the fourthday,the siteswereoccludedfor 24 hoursto produce

hydration, andtheskinsurface waterloss(g/m2hr) wasthenrecorded continuously for up to 25 minutes.The initially high skin surfacewaterlossdecayedin an exponential fashion.The data for a commercialskin washare excludedhere, sincethe component descriptionis imprecise,and lacticacidwasincludedat pH 5.0. On the otherhand,the data for the four surfactants exposedto this so-calledPOST (post-occlusion stresstest) are most revealing(Table III). Clinicalsignsof irritation(erythemaandmicrovesiculation) occurredat the alkyl sulfate site.Benzalkonium chlorideappears to be the mostirritating overall,in light of the low concentration tested.Unfortunately,no datawereobtainedat comparablylow concentrationsof the alkyl sulfate.The dataarecrucialfor establishing somerelativerankings. The innocuousness of the betainein this testis surprisingsinceit is a quaternary.These databearonly little resemblance to the Draize eyetest resultsof Hazelton(4), someof which are included

in Table IV.

It is difficult to assess the validity of earlytestingvia rabbiteyeor skintestsin light of moremoderntest approaches. The differences betweenthe POST on humansof Berardescaet al. (7) (Table III) and the rabbit eye test scoresof Hazelton (5) (Table IV) are significantandstronglysuggestthat skin irritancy,presumablymeasured via TEWL, is not the samephenomenonas eye opacityin the Draize rabbit eye test. A detailed interpretationof Hazelton'sdata is difficult. The concentrations of the surfactants--as shownin Table IV--might not havebeenthe concentrations introduced into rabbit eyes.Even if all substances were usedat the level of 1% as mentioned elsewherein the text, the quaternaries areclearlythe mostdamaging.On the otherhand, Hazeltonobserved differences in the eyeirritancypotentialof nonionicethers(laureth-4 vs polysorbate80). It is still a questionableapproachto equateskin irritancy potential with irritation observed in rabbiteyetests.The approach takenby vanderValk etal. (6) andBerardesca et•l. (7) differsradicallyfromearlierattemptsto assess skinirritancy:the skinof normal humansubjectsis used,and irritancyis quantifiedby water loss.

Water imbibition by the stratum corneum(8) is evidentlymaximal for the tested anionicsurfactant.The water lossdata after 25 minutesof drying suggestthat the betaineandthe quaternary affectthe skinby a mechanism differentfromthat of sodium lauryl sulfate.It would seemwise, therefore,to abandoneffortsto searchfor a single mechanismfor explainingthe skin irritancyof surfactants. Table

III

Skin Surface Water Loss in POST

Skinsurface waterloss(g/m2/h) Surfactant

Concentration (%)

Sodiumlauryl sulfate

7

Cocamido betaine Benzalkonium chloride Sorbitan monolaurate

7 1 10

Water (control)

1st Min

25th Min

64.0

27.1

44.7 33.8 36.1

12.1 10.3 7.8

40.5

8.7

312

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table Irritation

Potential

IV in Draize

Test Irritation

Surfactant

Concentration (%)

Roccal (benzalkonium chloride) Hyamine 2389 (CTAC)

Type

50 50-52

potential*

Cationic

1

Cationic

1

50

Anionic

20

Ivory soap

100

Anionic

> 10

Tween 80 (polysorbate 80) Brij 30 (laureth-4)

100

Nonionic

100

100

Nonionic

20

DuponolWAT (TEA lauryl sulfate)

* As gradedby Hazelton(5).

The parametricapproachbasedon the work of van der Valk et •l. (6) and Berardesca et az/.(7) fails to meet the needsof the formulatorto identify the transitoryor minimal irritancy causedby surfactant-containing productsusedon the skin. Avoidanceof the phenomena of scalingandtightnessarelikely to benefitconsumers morethan additional patch testingwith conclusions basedon erythema.Nevertheless, Willis et M. (9) performedclosedpatchtestsof benzalkonitu-n chlorideandsodiumlauryl sulfateat different concentrations. Their testson 42 healthymalesshowedthe followingpattern of total positivepatchtestsafter48 hours(15 lal/FinnChamber): Surfactant concentration Benzalkonium

chloride

Sodium lauryl sulfate

0.5 %

1.0 %

10

7

--

6

2%

5%

12

2O

There can be little doubt about the fact that irritancybasedon acutepatch testingis higher for benzalkoniumchloride than for sodium lauryl sulfate.Most of theseand relatedstudiesare flawed by uncertaintiesabout the test substances: Cocamidopropyl betainemay containunalkylatedderivativesof N,N-dimethylpropylamine.Sodiurnlauryl sulfateis a genericmix that may be basedon naturalor syntheticalkanols.Benzalkonium chlorideis a notoriouslyvariablemix of alkyl-derivedquaternaries.Thus the investigators and future studentscannotbe certainof exactlywhat wastested.

CURRENT

APPROACHES

Skin irritancy of surfactantswithin the EEC playsa critical role becauseof the EEC's requirementsfor classification.As a result, the EuropeanSocietyof Contact Dermatitis has establishedguidelinesfor standardizedtesting of sodium lauryl sulfate (10) and notedthe contributionof (high) purity (99% sodiumdodecylsulfate)to irritancy.The paper of Tupker et •l. (10) notesthe lower irritancy from the 96.5% pharmacopeial grade.This meticulousapproachto chemicalandproceduralprotocols--histopathology, TEWL, colorimetry (of erythema), clinical scoring,exposureconditions(repetitive occlusivetestsor immersiontesting), age, race,sex, testing site, and environmentalconditions--waslackingin mostearlierstudiesof othersurfactants, includingquaternaries. The Tupker et•/. paperidentifiessodiumlauryl sulfateas "... a model irritant, suited for precisetesting..." Thus it comesasno surprisethat the four-hourclosedpatchtest recommendedby Basketterand colleagues(11-13) utilizes sodiumlauryl sulfate(20%)

SKIN IRRITATION

POTENTIAL OF QUATERNARIES

313

asthe standardirritant to eliminateintersubjectand othervariations.Someconclusions from theseinvestigationsfollow: 1. At moderatedoses,up to 5% sodiumdodecylsulfate,irritant responses are more prevalentat 7.0øC than at 16.5øC(outsideaveragedaily maximumtemperature). 2. The skin of Chinesesubjectsis more readilyirritated than that of British subjects. Surprisingly,German volunteerswere found to be more sensitivethan Chinese subjects.

3. The patternof irritancyof Skin Type VI individualsdid not differ materiallyfrom that of the total British group of volunteers.

4. The likelihoodof eliciting irritancyincreased with the contacttime (1, 2, 3, or 4 hours) of the patch.

York et al. (14) wishedto confirmthe EuropeanUnion's classifications (R-34 causes burns,R-38 is irritating to skin, and NC is not classified)without an animal test and throughuseof humanvolunteers. This research led to the nowwidelyadoptedfour-hour closedpatchtest, althoughthe methoddevelopmentstartedonly a few yearsago [as reviewedby Basketteret aL (13)]. The patch test procedureis conventional(Hill Top Chambers),and the customaryscoringis used(Fregert,S., Manual of Contact Dermatitis, Munksgaard,Copenhagen,1981). Sinceseverereactionsare undesirable,test materials are appliedprogressively for 15 and 30 minutesand for 1, 2, 3, and 4 hours.Any reactionduring theseperiodsis consideredpositive, and the panelist is not exposed further.After the maximumfour-hourpatchperiod,the siteis examinedat 24, 48, and 72 hours.The interpretationrequirescomparisonto the standardirritant (20% sodium lauryl sulfate).Table V presentssomeof the dataobtained(13,15). The datashowonly minor interlaboratoryvariation and do not suggestthat quaternariesat cosmetic-use concentrations are particularly irritating.

This programwasnot designedto comparethe irritancyof differentsurfactantgroups. Instead,the plan was to find a relativelyharmlessway of designinga predictivenonanimal skin irritation test. The test itself meetsreproducibilitycriteriaand shouldbe a useful alternative to the Draize rabbit skin test. During the test development,some additionaldata of interestwere reported(12). Atopicsand non-atopicswere testedvia the four-hourpatchtest procedure,with the resultsrecordedin Table ¾I. Atopicsand Table

V

Irritancy RatingsBasedon 4-Hour PatchTest Chemical

Tested concentration

No. of positive reactions a

Classification b

Benzalkonium chloride Cocotrimonium chloride

7.5% 35%

4/27; 15/29 8/32; 12/57

R38 NC

Sodiumdodecylsulfate Sodiumdodecylsulfate Sodiumdodecylsulfate Polysorbate 80 Dodecylbetaine C•2_•5pareth-5phosphate

1% 10% 20%

21/100; 15/100; 16/31 79/100; 53/100;42/64; 29/31 354/530

98% 20% >

1/25; 1/29 30/32 1/30

NC R38 R38 NC R38 NC

a Resultsfrom differentlaboratories are included:No. of reactors/No.of subjects.

bClassification based on AnnexI of theEC Dangerous Substances Directive: R-38 = irritancy to skin (significantirritation); NC = nonclassified (minor irritation).

314

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS Table

VI

Response of Atopicsand Non-Atopicsto 4-Hour PatchTest Procedure Positiveresponse Substance

Atopics

Non-atopics

Cocotrimonium chloride (35%)

3/29

5/29

Sodiumdodecylsulfate(20%) Hydrochloricacid (10%)

16/30

10/28

5/29

5/29

non-atopics evidentlydid not reactdifferently,and againthe quaternarydid not appear to be especiallyirritating. Skin irritation by quaternariesin normal cosmeticuse is difficult to assess because documentation is availablefor onlya few isolatedsubstances. Thereis little justification to judge humanskin irritation on the basisof the classicDraize eye test. Animal and humanpatchtestsof quaternaries rely almostexclusivelyon acute(single)applications, whereasit is knownthat in the caseof dilute anionicsurfactants, irritation responses are observedonly aftermultiple exposure. As notedabove,erythema--themostcommonly recordedend point--is a late event.Its relationshipto skin irritation (scaling,tautness) is undocumented. The assumptionthat a substance that underacuteand strenuous test conditionselicits eythemawill alsocauseskin irritation underlessstringentconditions may not be valid sincethe mechanisms causingthesephenomenamay not be the same. Thus, the formulatoris rarelyableto prejudgethe non-irritancyof a surfactantandmust rely on safety/irritationtestsof finishedformulations. Only a few quaternarieshave undergonea rigid irritancy review:(a) Dihydrogenated tallow dimonium chloride is graded as a mild irritant in rabbit patch tests. At a concentrationof 7.5% it reacheda mean primary irritation index of 0.26 out of a maximumof 8, after 15 alternating24-hourpatchtests.(b) Benzethonium and methylbenzethoniumchloridesproducedno irritancyin repeatedhumanpatchtestsat concentrationsbelow 0.5%. (c) Benzalkoniumchloride,by contrast,appearsto be much more irritating. Although repeatedpatch testing at 0.1% causedno irritant responses, testsat 0.5% or more produceda much higher response rate. The past useof benzalkonium chloridefor creatingof test protocolsis an unfortunatechoice.This substance and relatedcompoundsare toxic to microbiotaand probablyalsoto mammalianepidermal cells.It is not surprisingthat investigatorsconsistentlyfind this material irritating in closedpatch tests(16). Additional detailsabout the irritant characteristics of thesethree compoundscan be found in the reportsof the CosmeticIngredientReview [J. Am. Co//. Toxicol.1(2), 71, 1982; ibid. 4(5), 65, 1985; and ibid. 8(4), 589, 1989].

ASSESSMENT

OF SURFACTANT

IRRITANCY

The cosmeticuse of surfactantsvariesfrom product to product. Thus, a compound's irritancypotentialshouldbe expectedto dependon how it is used.The irritancyof a surfactantmay be quite high if it is allowedto remain in prolongedcontactwith the

SKIN IRRITATION

POTENTIAL OF QUATERNARIES

315

skin, while removalof the offendingsubstance may reducepotential irritancy to negligible.

Evenprolongedcontactof a surfactantwith the skin might not elicit irritancyeffects; adversereactionsmight dependon permeationto lower strataof the skin. For example, an oil-solublesurfactantmay exhibit adverseeffectsthat dependon the stratumcorneum lipid levels.A surfactantthat can blend into or mix with barrier lipids might have long-termeffectson the barriercompetencyof the skin. Penetrationinto or throughskin is a functionof the surfactant's molecularweight and shape.Unless the stratum corneumis damagedprior to or during the surfactant's application,high-molecular-weight compoundsshouldremainon the surface. Blendsof surfactants exhibit featuresthat might differ radicallyfrom the effectsof the individualcomponents. Formulatorsmustproceedcautiouslyin the blendingof surfactants sincethe resultsmight be unpredictableand might dependon the formationof mixed miceliar species. In light of olderaswell asmorerecentdata, the irritancyof diversetypesof surfactants on intact human skin shouldnot be judged on the basisof their ionization.Other characteristics and usageare likely to exert a far greaterimpact: Lowerskin irritancy

Higher skin irritancy

High molecularweight Water solubility Rinse-offproduct Little or no skin permeation

Low molecularweight Lipid solubility Leave-onproduct High skin permeation

Rationalanalysis,basedon someof the aboveconcepts,suggests that the water-insoluble stearalkoniumchloride,e.g., left on the skin is lesslikely to causeirritation than the lipid-soluble(and penetration-enhancing) laureth-4.

The mechanisms of skin irritancy manifestations suchas scalingand tautnessremain obscure.The literatureincludesmany suggestions for explainingskin irritancy after (repeated)mild exposureto dilute surfactantsolutions.Particularlynoteworthyare the reviewsby Rhein (17), Imokawa(18), Abraham(19), and Rawlingset aL (20). Despite much effort, no definitiveevidencehasbeenpublishedthat can explainthe phenomena of skin irritancyby surfactantexposure.Any attempt to explainthe phenomenacaused by differentsurfactants by a singlemechanismis likely to fail. Instead,it is morelikely that irritant responses in skin can be causedby severalmechanisms, either aloneor in concert,and might dependon the natureof the surfactant.

CONCLUSIONS

1. Skin irritancyby surfactants is relatedto the fate of the topicallyappliedsubstance. Permeationinto the epidermisis a primary requisite.Permeationthrough the epidermis is likely to elicit toxic responses,especiallyin the caseof quaternaries. Photodecomposition of surfactants remainingon the skinmight causeresponses that cannotbe assessed by patchtesting(21). The chemicalstructuresof quaternaries and their generalstability make them usefulin cosmeticproducts. 2. The tendencyof quaternaries to bond to negativelychargedsitesblockstheir ten-

316

JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

dency to permeateunlesshigh concentrationsare employed.

3. Formulatorsshouldnot reject the useof quaternariesin hair or skin careproducts becauseof earlierand probablyunjustifiedgeneralizations aboutirritancy. 4. It must be recognized that the proofof non-irritancyand safetyof everysurfactantcontainingproductmust be assessed beforemarketing.

APPENDIX

•

"MR. LATVEN: We haveinvestigatedbetween45 and 50 surface-active agentsfollowing instillation in the eye and found essentiallythe sameresult.

However, we have got to add one thing, namely, that the nonionicscan be just as irritating as the cationicsin specificinstances,as you have alreadypointed out. The incidence,however,is less.We find around25 per centof all nonionicsareirritating in consideration of cornealopacityand around62 per cent of anionicsfall into the opacification class,where it is 100 per cent with the cationics.

As you havealsopointedout, the importantquestionis whetheror not the final formulas producecornealopacity. That raisesa very important question,namely: When one investigatesa final formulationand obtainsresultssuchasthat, only oneout of nine or ten animals showsopacification.How can one interpret it? I must admit complete ignorance.

DR. DRAIZE: Occasionallyone seriousreactiononly is obtainedin a group of test subjects.Sucha singlereactionis deemedsignificant,sincein the generalpopulationan occasionalsensitiveindividual may be encountered,and from a standpointof overall safetysuchan individual may not be overlooked. MR. LATVEN: I wonderif I couldaskanotherquestionon your interpretation,namely, the insidiouscharacterof a number of thesesurface-active agentsis the fact that they don't producepain on instillation.... "

REFERENCES

(1) J. H. Draize, in Appraisalof theSaj•tyof Chemicals in Foods,Drags,and Cosmetics (Assoc.FoodDrug Officials,U.S., Topeka,Kansas,1959). (2) H. P. Drobeck,"CurrentTopicson the Toxicity of CationicSurfactants," in CationicS•factants,J. Crossand E.J. Singer,Eds.(MarcelDekker,New York, 1994). (3) R.A. Cutler and H.P. Drobeck, "Toxicologyof Cationic Surfactants,"in CationicS•rfactants,E. Jungermann,Ed. (Marcel Dekker, New York, 1970). (4) J. H. Draizeand E. A. Kelley, Toxicityto eye mucosaof certaincosmeticpreparations containing surface-active agents,Proc.Sci.Sect.ToiletGoods Assoc., 17, 1-4 (1952). (5) L. W. Hazelton,Relationof surfaceactivepropertiesto irritationof the rabbiteye,Proc.Sci.Sec.Toilet GoodsAssoc.,17, 5-9 (1952).

(6) P. C. M. Van der Valk, J.P. Nater, andE. Bleumink,Skin irritancyof surfactants asassessed by water vaporlossmeasurement,J. Invest.Dermatol., 82, 291-293 (1984). (7) E. Berardesca,D. Fideli, P. Gabba, G. Rabbiosi, and H.I. Maibach, Ranking of surfactantskin

* Discussion aftertheDraizeandKelleypresentation (4). Frompage4 of theProceedings oftheSdentific Section of theToiletGoods Association, 17, May 1952.

SKIN IRRITATION

POTENTIAL OF QUATERNARIES

317

irritancyin vivoin man,usingthe plasticocclusion stress test(POST),Contact Dermatitis, 23, 1-5 (1990). (8)

C. R. RobbinsandK. Fernee,Someobservations on the swellingof humanepidermalmembrane, J.

(9)

C. M. Willis, C.J. M. Stephens, andJ. D. Wilkinson,Experimentally-induced irritantcontact der-

(10)

R. A. Tupker,C. Willis,E. Berardesca, C. H. Lee,M. Fartasch, T. Agner,andJ. Serup, Guidelines on sodiumlaurylsulfate(SLS)exposure tests,Contact Dermatitis, 37, 53-69, 1997.

Soc.Cosmet. Chem.,34, 21-34 (1983).

matiris,Contact Dermatitis,18, 20-24 (1988).

D.A., Basketter,H.A. Griffith, X.M. Wang, K.-P. Wilhelm, andJ. M. McFadden,Individual, ethnic,and seasonal variabilityin irritantsusceptibility of skin:The implications for a predictive humanpatchtest,Contact Dermatitis, 35, 208-211(1996). (12) D. A. Basketter, L. Blaikie,andF. Reynolds, The impactof atopicstatuson a predictivehumantest of skinirritationpotential, Contact Dermatitis, 35, 33-39 (1996). M. Chamberlain, H. A. Griffith, M. Rowson,E. Whittle, andM. York, The classi(13) D. A. Basketter, ficationof skinirritantsby humanpatchtest,FoodChem. Toxicol., 35,845-852 (1997). (14) M. York,E. Griffith,andD. A. Basketter, Evaluation of a humanpatchtestfortheidentification and classification of skinirritationpotential, Contact Dermatitis, 34, 204-212(1996). (15) H. A. Griffith, K.-P. Wilhelm, M. K. Robinson,X.M. Wang, J. McFadden,M. York, and D. A. Basketter, Interlaboratory evaluation of a humanpatchtestfor the identification of skin irritation potential/hazard, Food Chem. Toxicol., 35, 255-260(1997). (16) J. E. Wahlberg, K. WrangsjiS, andA. Hietasalo, Skinirritancy fromnonanoic acid,Contact Dermatitis,

(11)

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