j. Soc.Cosmet. Chem., 40, 321-333 (November/December1989)

Comedogenicityand irritancy of commonlyused ingredients in skin care products

JAMESE. FULTON, JR., AcneResearch Institute, 1236 Somerset, NewportBeach, CA 92660.

ReceivedSeptember 3, 1989. Presentedat the Southern California Section, CaliforniaChapter, Society of CosmeticChemists, Spring 1989.

Synopsis A survey,using the rabbitear, of the comedogenicityand irritancyof severalgroups of skin careproducts indicatesthat manycontain follicular and surfaceepithelial irritating ingredients. These ingredients fall into severalchemical classes. Certain generalizations can be deducedby examiningthe results:(1) me- dium-chain-lengthfatty acidsare more potent than short- or long-chainfatty acidsin producingfollicular keratosis,(2) the comedogenicityand irritancyof an organicmaterial can be reducedby combiningthe moleculewith a polarsugar or a heavymetal, (3) increasingthe degreeof ethoxylationin a moleculetends to reducethe comedogenicityand irritancyof the chemical,and (4) the longerchain lipids, i.e., , appeartoo large to producea reaction.By followingthe guidelinesdeveloped in thisstudy, it is possibleto formulatenonirritating, noncomedogenicmoisturizers, sunscreens, hair pomades,, and condi- tioners.

INTRODUCTION

The possibilityof comedogenicityand irritancyof facialskin careproducts has been well documented(1- 3). Becauseof this work and an increasingpublic awareness, productsthat are lesscomedogenic are now becomingavailable (4). However, other skin careproducts such as hair conditioners,hair pomades,, sunscreens, and evenacne treatment products may be a sourceof cosmeticacne. By taking these productsapart, testing their ingredients,and putting them back together and retesting them, an extensiveingredient listing hasbeen created. By studyingthis list, the cos- metic chemistcan beginto be selectivein developingformulas for lessirritating and lesscomedogenic products. The rabbit ear assayhas been used since the mid-1950sas a methodof measuring follicularkeratinization by externallyapplied compounds (5). The advantageof this rapidscreening tool is that it takesonly two weeksto developfollicular impactions in the rabbitear, whileit maytake six months to developsimilar reactions on humanskin. The disadvantageof the modelis its extremesensitivity. The fragile,protected epithe- lium of the inner ear is extremelysensitive. Not everythingthat irritatesthis model will alsoirritate humanskin. However,this extensivescreening of cosmeticformula-

321 322 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS tionsand their ingredientswould not havebeen possible without the useof this animal model.We havenow extended the modelto includean indexof surfaceskin irritancy as well as of follicularhyperkeratosis.

METHODS

Ingredientsare mixed in propyleneglycol at a 9 to 1 dilution for testingunless other- wise indicated(10% concentration).A colonyof New Zealandalbino rabbits that has geneticallygood ears and is free from mitesis used.Three rabbits,weighing two to threekilograms, are usedfor eachassay. Animals are housed singly in suspendedcages and fed Purina Rabbit Chow and water ad libitum. Animals are maintained on a 12-hour light and 12-hourdark cycle.A doseof 1 ml of the testmaterial is appliedand spread oncedaily to the entireinner surfaceof oneear five daysper weekfor two weeks.The oppositeuntreated ear of eachanimal serves as an untreatedcontrol. Follicular keratosis is judged both macroscopically(visually) and microscopicallywith a micrometerto measurethe width of the follicularkeratosis. The macroscopicresponse is determined by averagingthe measurementsof the width of six folliclesusing a Mitutoyo Dial Micrometer(#536-724). A similarmicroscopic micrometer measurement is obtained by averagingthe width of six folliclesunder a magnificationof 430 x after a 6-ram biopsyspecimen is fixed in formalin,sectioned at six microns,and stainedwith hema- toxylin-eosin.The resultsare then combinedon a scaleof one to five: Micrometerreading Grade 0.009 in or less 0 No significantincrease in follicularkeratosis 0.010 in-.014 in 1

0.015 in-.019 in 2 A moderate increase in follicular keratosis 0.020 in-.025 in 3

0.025 in-.029 in 4 An extensive increasein follicular keratosis 0.030 in or more 5

Grade5 is the presenceof largecomedones throughout the ear, similarto thoseinduced by the applicationof our standard"positive" testing agent, isopropylmyristate. As reportedin our previousstudies, a minimal gradeof 0 to 1 is not consideredsignificant. Grade2 to 3 is borderline.However, a gradeof 4 to 5 is uniformallyreproduceable and consideredpositive. The irritancyproduced by the repeatedapplication of a chemicalor skincare product on the surfaceepidermis in the rabbit ear is alsoevaluated on a similar scaleof 0 to 5. The gradesare summarizedas follows: 0 No irritation 1 Few scales,no erythema 2 Diffusescaling, no erythema 3 Generalizedscaling with erythema 4 Scaling,erythema, and edema 5 Epidermalnecrosis and slough To studythe effectsof differentvehicles on comedogenicityand irritancy,several fatty acidsand the D&C red pigment#36 are reexaminedin differentsolvents. The fatty COMEDOGENICITY 323

acids are dissolved in either a volatile solvent or sunflower oil. The D&C red #36 pigmentis testedin mineraloil, propyleneglycol, polyethylene glycol 400, andpen- taerythritaltetra capra/caprylate.

RESULTS AND DISCUSSION

Cosmeticacne was first reportedby Frenchdermatologists in the mid-forties.They reportedon brilliantinesand hair pomadescausing flareups on the templeand forehead facial regions.They attributed the problemsto impuritiesin the brilliantines(6). In 1970, Kligman requestedthat Gerd Piewig and I examineover 700 men to find some with normal facial skin. Much to our chagrin, the majority had cosmeticacne (7). About 70% showedsome evidence of follicularkeratoses on the foreheadand temples. Occasionallythe eruptionswere noted on the cheeksdown to the jawline area. The lesionswere usually noninflammatory, closed comedones. A few lesionsdeveloped into small inflammatorypapules. However, there were no casesof severe,cystic inflamma- tory acne. Histologically, the comedonesfrom pomadeacne caseswere identical to biopsiestaken from comedonesof classicacne vulgaris patients. In surveyingthe hair carepreparations, we felt that the actualingredients and not tracecontaminants were offenders.Interestingly, very few of the subjectsattributed their folliculareruptions to their daily useof a hair pomade.This studystimulated us to examineother skin care productsand ingredients. In 1972 Kligman and Mills reportedon acnecosmetica in their surveyat the Acne Clinic at the Universityof Pennsylvania(1). Approximatelyone third of the adult womenhad a low-grade,persistent acne in the cheekarea, consistingof closedcomedones quite similar to thosefound in pomadeacne. This appearedmore frequently in womenafter agetwenty and may explainone of the reasonsfor epidemicadult acnein womenin the 1970sand 1980s.In 1976 and 1984, Fultonpublished results on actualcosmetic lines and on ingredients,and proposedthe developmentof noncomedogeniccosmetics using ingredientsthat werenonoffenders in the rabbitear assay (2,3). Severalmajor cosmetic manufacturershave now producedthese types of products.However, our screening indicatesthat work is still neededon many skin careformulations. It becameapparent during our researchinto potentialnoncomedogenic ingredients that severalhypotheses could be developed: (1) In orderfor an ingredientto be comedogenic, it must penetrateinto the follicle, and (2) once in the follicle, the chemicalmust producethe follicularreaction of "retentionhyperkeratosis" (8). In addition, the overall penetratibilityof the moleculemay be relatedto (1) the water/oilpartition coefficient of the compound(HLB balance)and (2) the relativemolecular weight of the ingredient. The ingredientappears to havethe mostpotential if it is fairly solublein bothwater and oil (HLB around 10 to 12) and hasa rangeof molecularweight between200 and 300. The comedogenicityof an ingredientmay be reducedby addinga large constituent (i.e., polymersof PEGs), by addinga chargedmolecule (i.e., sugars),or by addinga heavymetal (i.e., zinc or lithium). This often relatesto raisingthe HLB balanceto above 12. Examplesof this conceptof water/lipidsolubility and molecularweights are apparent in eachclass of chemicalsexamined (Table I). Amongthe lanolins,the classicanhydrous lanolinsare not as comedogenicas the moderatelyethoxylated derivatives (laneth 10). 324 JOURNAL OF THE SOCIETY OF COSMETICCHEMISTS

Table I Ingredientsand Their Comedogenicityand Irritancy

Grade (0- 5) Grade (0- 5)

Ingredient Comedo.? Irrit. ½ Ingredient Comedo.? Irrit.½

I. Lanolins and derivatives Myristylalcohol 2 4 Acetylatedlanolin 0 0 2 2 Acetylatedlanolin alcohol 4 2 Isocetylalcohol 4 4 Anhydrouslanolin 0-1' 0 Cetearylalcohol 2 1 Lanolin alcohol 0-2* 0 Oleyl alcohol 4 2 Lanolin oil 0-1' 0 Stearylalcohol 2 2 PEG 16 lanolin (Solulan 16) 4 3 Cetearylalcohol q- PEG 75 lanolin 0 0 ceteareth 20 4 Laneth- 10 2 1 Ceteareth-20 2 3 PPG 12 PEG 65 lanolin oil 2 0 Propyleneglycol 0 0 Butyleneglycol 1 0 II. Fatty acidsand their derivatives Hexyleneglycol 0-2* 0- Caprylicacid 1 3 PG caprylate/caprate 2 2 Capricacid 2 2 Lauric acid 4 PG dicaprylate/caprate 1 0 PG dipelargonate 2 2 3 0 PG laurate 0 3 2 0 PG monostearate 0- 3 0- 2 - 3' 0 Ethyleneglycol Eicosanoic acid 2 0 monostearate 0 0 0 0 Glucoseglutamate 0 0 Ascorbylpalmitate 2 0 Sorbitol 0 0 Behenylerucate 0 0 Sorbitan laurate 1- 2' !- 2 Butyl stearate 3 0 Sorbitansesquinoleate 0- !* 0 Cetyl acetate 4 2 Sorbitan oleate 3 0 Cetyl esterNF 1 1 Sorbitan stearate 0 Cetyl palmitate 0 0 Sorbitan isostearate 1-2' 0 Decyl oleate 3 0 PEG 40 sorbitan laurate 0 0 Di (2 ethylhexyl)succinate 2 0 Polysorbate20 0 0 Dioctyl malate 3 1 Polysorbate80 0 0 Dioctyl succinate 3 2 Glycerin 0 0 Diisopropyladipate 0 0 Glycereth-26 0 0 Diisopropyldimerate 0 0 Glyceryl-3-diisostearate 4 0 Ethylhexylpalmitate 4 0 Glycerylstearate NSE 1 0 Ethylhexylpelargonate 2 3 Glycerylstearate SE 3 2 Isodecyloleate 2- 3' 1- 2 Glyceryltricapylo/caprate 1 1 Isopropylisostearate 5 0 Behenyltriglyceride 0 0 Isopropyllinolate 4 2 Pentaerythritaltetra Isopropyl myristate 5 3 isostearate 2 0 Isopropylpalmitate 4 1 Pentaerythritaltetra capra/ Isostearylneopentanoate 3 3 caprylate 0 0 Isostearylisostearate 4 1 Wheat germ glyceride 3 2 Myristyl lactate 4 2 Polyglyceryl-3-diisostearate 4 0 Myristyl myristate 5 2 Polyethyleneglycol (PEG Octyldodecylstearate 0 0 400) ! 0 Octyldodecylstearoyl Sucrose distearate 0 2 stearate 0 0 Sucrose stearate 0 0 Stearylheptanoate 4 0 PEG 120 methyl glucose Tridectyl neopentanoate 0 3 dioleate 0 0 III. Alcohols•sugars and their derivatives PEG 8 stearate 3 SD alcohol 40 0 0 PEG 20 stearate ! 0 Isopropylalcohol 0 0 PEG 100 stearate 0 0 COMEDOGENICITY 325

Table I (continued)

Grade (0-5) Grade (0 - 5)

Ingredient Comedo.•- Irrit. :• Ingredient Comedo.•- Irrit.:•

PEG 100 distearate 2 0 Sesame oil 3(1)** 0 PEG 150 distearate 2 0 Corn oil 3 0 PEG 200 dilaurate 3 2 Avocado oil 3(2) 0 Laureth-4 5 4 Evening primroseoil 3 2 Laureth-23 3 0 Mink oil 3(2) Steareth-2 2 2 Soybeanoil 3 0 Steareth- 10 4 3 Shark liver oil 3 2 Steareth-20 2 1 Cotton 3 2 Steareth- 100 0 0 Peanut oil 2 0 Oleth-3 5 2 Olive oil 2(1) 0 Oleth-5 3 2 Sandalwood seed oil 2 0 Oleth- 10 2 1 oil 2(I) 0 Oleth-20 1 0 Apricot kernel oil 2(1) 0 Oleth-3 phosphate 2 2 Hydrogenated Triacetin 0 0 polyisobutane 1 2 PPG 5 Ceteth 10 phosphate 4 2 1 0 PPG 2 myristyl propionate 3 2 Hydrogenatedcastor oil 1 0 PPG 10 cetyl ether 3 1 Chaulmoograoil 1 0 PPG 30 cetyl ester 0 0 Babassu oil 1 0 PPG 50 cetyl ester 0 0 Squalane 1 0 PEG 78 glyceryl Maleatedsoybean oil 0 0 monococoate 0 1 oil 0 0 PEG 8 castor oil 1 1 Sunflower oil 0 0 PEG 40 castor oil 0 0 Mineral oil 0-2 0 Polypentaerythrital tetralaurate 0 0 VII. Pigments D & C red #3 IV. Waxes D & C red #4 Candelilla 1 0 D & C red #6 Carnuba wax 1 0 D & C red #7 Ceresin wax 0 0 D & C red #9 Beeswax 0- 2 * 0 D & C red # 17 Lanolin wax 1 0 D & C red # 19 Jojobaoil 0-2* 0 D & C red #21 Sulfatedjojoba oil 3 2 D & C red #27 Emulsifyingwax NF 0 0- 2' D & C red #30 D & C red #33 V. Thickeners D & C red #36 Carboxymethylcellulose 0 0 D & C red #40 Carboxypropylcellulose 1 0 Ultamarine violet Hydroxypropylcellulose 1 0 Iron oxides Magnesiumaluminum Carmine silicate 0 0 Titanium dioxide Carbomer 940 1 0 Bentonite 0 0 VIII. Silicones Kaolin 0 0 Simethicone Talc 1 0 Dimethicone PVP 0 0 Cyclomethicone

VI. Oils* IX. SteroIs Cocoa butter 4 0 0 Coconut butter 4 0 Soyasterol 0 Hydrogenatedvegetable oil 3 0 Peg 5 soyasterol 0 (continued) 326 JOURNALOF THE SOCIETYOF COSMETICCHEMISTS

Table I (continued)

Grade (0-5) Grade (0 - 5)

Ingredient Comedo.? Irrit. $ Ingredient Comedo.? Irrit.

Peg 10 soyasterol 0 1 XlI. Miscellaneous Choleth24 0 0 Octyl dimethylPABA 0 0 Sterolesters 0 0 Oxybenzone 0 0 Phytantriol 2 2 Octyl methoxycinnamate 0 0 Octyl salicylate 0 0 X. Vitaminsand herbs Acetone 0 0 A & D additive 2 0 Tocopherol* 0-3' 0-3' Ethylether 0 0 Tocopherylacetate 0 0 Diethyleneglycol Blackwalnut extract 0 0 monoethylether 0 0 Papain 0 0 Ethyleneglycol Chamomileextract 0 0 monomethylether 0 0 VitaminApalmitate 1-3' 1-3' (EGME) 4 3 Panthenol 0 0 XyleneLithium stearate 1 0 XI. Preservativesand additives Magnesium stearate 1 0 Methylparaben 0 0 Zinc oxide 1 0 Propylparaben 0 0 Zinc stearate 0 0 Phenoxyethylparaben 0 0 Triethanolamine 2 0 Allantoin 0 0 Stearic acid: TEA 3 2 Hydantoin Amoniomethylpropinate 0 0 Sodiumhyaluronate 0 0 SodiumPCA 0 0 Chondroitinsulfate 0 0 Hydrolyzedanimal protein 0 0 Precipitatedsulfur 0 0 Water-soluble sulfur 3 0

? Comedogenicityor ability of testsubstance to produce follicular hyperkeratosis. $ Irritancyor abilityof testsubstance to produce surface epithelial irritation. * Resultsdepend on sourceof raw material. ** Parenthesesindicate results using "reftned"oil.

The higherethoxylated derivatives with HLBsabove 12 aremore water-soluble and noncomedogenicand nonirritating(PEG 75 lanolin).Two of the lanolinderivatives studiedrequire special comments: (1) Theacetylated lanolin alcohols are both comedo- genicand irritating,not becauseof the acetylatedlanolin but becauseof the cetyl acetateadditive (Figure 1), and(2) PEG 16 lanolin(Solulan 16) is quitecomedogenic andirritating, perhaps secondary to the combination ofnonlanolin additives: ceteth-16, oleth-16, and steareth-16. Amongthe fatty acids and esters a similar analogy is found.The mid-chain-length fatty acids,such as lauric acid and myristic acid and its analogscause follicle hyperkeratosis. As the molecularweight of thefatty acid becomes larger and the effective charge of the overallmolecule is reduced,less follicular reaction is produced.When the fatty acidis esterifiedwith a small- to mid-sizealcohol, the combinationbecomes more potent than the fatty aciditself. The cousinsof isopropylmyristate, such as myristylmyristate, isopropylisostearate, isostearyl neopentanoate, butyl stearate, and decyl oleate, are all comedogenic(Figure 2). Also,when branched-chain fatty acids are used, the derivatives maybe more comedogenic. Large molecular weight esters, such as behenyl erucate and cetylpalmitate, are not a problem. COMEDOGENICITY 327

Figure 1. The key ingredientis acetylatedlanolin alcohol -- cetylacetate--is not only comedogenic,but it is also an irritant.

Similar analogiesare apparentwith the alcohols,ethers, glycols, and sugars.Short- chainalcohols do not causea reaction.The mid-chain-lengthalcohols are comedogenic and more irritating than their fatty acid analogs(Figure 3). In the glycolseries, as the hydrocarboncomponent becomes more dominant, the compoundis moreeffective at producingcomedones. The puresugars are noncomedogenic. However, if theyare com- binedwith penetratingfatty acids,they may becomefollicular irritants. Also, if they are combinedwith anotherirritant, as in glycerylstearate (SE), which containsadded sodiumor potassiumstearate, the combinationbecomes more comedogenic.The in- creasingaddition of polyethyleneglycols to the fatty acidsincreases the HLB balance, reducesthe follicularirritancy, and appearsto preventhyperkeratosis. An exampleis the oleth 3, 5, 10, 20 series(Figure 4). Among the waxes,the hydrocarbonchains appear too long to penetrateunless the wax is modified,such as in sulfatedjojoba oil. In the caseof beeswaxesand jojobaoils, some commercialpreparations are more comedogenicthan others.This suggestsmore con- taminantsor irritants in someof the preparations.Emulsifying wax NF may be irri- tating, dependingon the concentrationof longer-chainalcohols such as cetearylal- cohol. Chemicalssuch as cellulosicpolymers, the silicates,and the carbomersused in the pharmaceuticaland cosmeticindustry to thickenlotions and creamsare not usuallya problem.The clays,bentonite, and kaolinare alsonot a problem.Neither is talc. Clinically,natural oils such as cocoa butter and coconut butter have long been known to causeproblems with pomadeacne. This is confirmedin the rabbit ear assay.Also, 328 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

- OCTYLDODECYL

ISOPROPYLMYRISTATE STEAROYLSTEARATE

Figure 2. Ingredienttesting in the rabbit ear assay--the macroscopicview of the resultsfrom testing isopropylmyristate. Microscopic examination confirmed the comedogenicityseen visually. Note that the ingredientis alsoan irritant comparedto a potentialsubstitute, octyl dodecyl stearoyl stearate.

hydrogenatedvegetable oil (Crisco©) appearsto containresidual irritating lipids. Among the natural oils suchas sesameoil, avocadooil, and mink oil, the resultsare improvedwhen a more refinedoil is used.However, it seemseasier to usesafflower oil and sunfloweroils, which are naturallyless comedogenic. Mineral oil presentsa com- plex problem:some sources are acceptable;others are not. D&C red colorsrepresent a perplexingmixture of differenttypes of red dyesand pig- ments. Someare mildly comedogenic;others are not. The commonpigments used in powderblushers (D&C red #6, bariumlake; D&C red #7, calciumlake; and D&C red #9, bariumlake) are relativelynoncomedogenic. However, the vehicleis alsoparticu- larly importantfor the D&C red colors.A dry compressedpowder or powdersuspended in an evaporatingvehicle such as propylene glycol may be noncomedogenic.The same dyeincorporated into a nonevaporatingoil can be comedogenic (Table II, Figure5). Carmine,which is a red dye obtainedfrom insectwings, is noncomedogenicand may be usedas a substitute.The iron oxides,chromium hydroxide, and titanium dioxideare not a problem. The siliconesand steroIs do not appearto be a problem.Among the vitamins,tocoph- erol is a follicularirritant. Tocopherolhas been advocated by the laymanfor yearsto increasewound healing and reducescar formation. However, it shouldnot be usedon acne-proneskin becauseof its potentialto producefollicular hyperkeratosis. The deriva- tive, tocopherylacetate, is noncomedogenic,and researchneeds to be doneto seeif it is an acceptablesubstitute. COMEDOGENICITY 329

.,.

!

&t,Cosoz ISOCETYL ALCOHOL

..

., ;,

_ .'-". , r•tl'.,.,'/'

Figure 3. The brsnched-½h•in•l½ohol is more ½ornedo•eni½•nd more irrit•tin• th•n the •l½ohol.

As for the miscellaneousitems, the usualsunscreen active ingredients are noncomedo- genic. Among chemicalsolvents, acetone, ether, and EGME are not problems,but xyleneis comedogenicand an irritant.When metallicbases, such as lithium, magne- sium,and zinc stearate, are added to the fattyacids, the metalappears to preventthe comedogenicreaction. Among bases, triethanolamine is morecomedogenic than ami- nomethylpropylamine.The classicformulation of a often involvesa salt bridgebetween stearic acid and triethanolamine.In testingdifferent ratios [4:1, 1:1, 1:4] of stearicacid to triethanolamine(stearic acid:TEA) in a coldcream base, all com- binationswere found to be comedogenic. The influenceof thevehicle or solventon the comedogenicityand irritancy of a chem- icalappears quite significant. For example, the useof rapidlyevaporating vehicles such as acetoneor etherreduces the comedogenicityof fatty acidswhen compared to the resultsobtained with sunfloweroil, a nonvolatilevehicle (Table III). The effectson irritancy are reversed.Fatty acidsare lessirritating when deliveredin a nonvolatile vehicle.As with the fatty acids,the vehicleor carrierfor the D&C red pigmentis extremelyimportant. Whereas the D&C red colormay be noncomedogenicin volatile propyleneglycol, it may be morecomedogenic in mineraloil. Possiblealternatives for mineraloil, suchas pentaerythrital tetra capra/caprylate and polyethylene glycol 400, alsoreduce the comedogenicityof the redcolor (Table II). We havechosen propylene glycolas the routinediluent for thesestudies, as it graduallyevaporates and leavesa concentrateof the rawmaterial to be tested.Also, lot afterlot of propyleneglycol has provento be nonirritatingand noncomedogenic. 330 JOURNAL OF THE SOCIETY OF COSMETICCHEMISTS

OLETH-iO

OLETH.2

Figure4. Oleth-3compared to oleicacid. The initialadditions of ethyleneglycols to potentiallycomedo- genicand irritating ingredients appear to increasethis propensity. Further additions of ethyleneglycols, such as oleth-10 and oleth-20, tend to reduce reactions.

Someingredient combinations--for example, the combinationof glycerylstearate with potassiumstearate (available commercially as glyceryl stearate S.E.) andalso the combi- nation of D&C red #36 and mineral oil--appear more comedogenicthan the indi- vidual compoundsthemselves. These synergistic reactions need to be studiedfurther. COMEDOGENICITY 331

Table II Comedogenicityof D&C Red #36 Dye in DifferentVehicles

Grade (0- 5)

Comedo. lrrit.

D&C red #36 in mineral oil 3 0 D&C red #35 in pentaerythritaltetra caprdcaprylate 2 0 D&C #36 in propyleneglycol 1 0 D&C red #36 in PEG 400 0 0

The oppositeis alsopossible. For example,the combinationproduced by the ingredient D&C red #36 and the vehiclepolyethylene glycol is lesscomedogenic than D&C red #36 whenincorporated into othervehicles. The cosmeticchemist may be able to take advantageof thesefindings in the future to customdesign noncomedogenic products.

SUMMARY

Thesestudies indicate that skin carepreparations that are nonirritatingand noncome- dogeniccan be made. Nonreactiveingredients can be usedto makeelegant products, and borderlineingredients can be combinedwith otheringredients to reducethe reac- tionsto acceptablelevels. In spiteof theseguidelines, new formulations must always be examinedwith the rabbit ear assaybefore the cosmeticchemist can be assuredthat his ideas work.

Figure 5. The comedogenicityof D&C red #36 whenincorporated into two differentvehicles. The ve- hiclemay increaseor decreasean ingredient'sability to producefollicular hyperkeratosis. 332 JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS

Table III Effectsof the Solventon Comedogenicityand/or Irritancy of FattyAcids

Organicsolvent* Sunfloweroil Grade (0- 5) Grade (0- 5)

Fattyacids Comedo. Irrit. Comedo. Irrit.

Caproicacid 0 4 2 2 Caprylicacid 1 3 1 1 Capricacid 2 2 3 1 Lauric acid 3 1 4 1 Myristicacid 1 0 3 0 Palrnitic acid 0 1 2 0 Stearic acid 0 1 2 0 Archidic acid 1 1 2 0 Behenic acid 1 0 1 0

* Ethyl etheror acetone.

The rabbit earassay remains important to the rapidevaluation of new ingredientsand the cosmeticchemist's formulations. Both the visualand microscopicevaluations of the rabbitear need to be donesimultaneously (9). Materialsfound to be noncomedogenicin the rabbit assayappear to be noncomedogenicin the human model (10). Whether highly comedogenicingredients in the rabbit ear assayare alwayscomedogenic in humansstill remainsuncertain. Currently, it is moreprudent to avoidthese offenders. The majoroffenders, such as isopropyl myristate, acetylated lanolin alcohol, and lauric acid derivativessuch as laureth-4, shouldbe usedwith cautionin skin careproducts. We are not convincedof the statementthat lower concentrationsof thesecompounds canbe safelyused with no comedogenicconsequences (11). Humanskin studies have beenused to give that statementcredence, but the backskin of humanvolunteers is relativelyinsensitive (7). However,when the rabbitear assay is positivebut the human back skin resultsare negativeafter only eight weeks'exposure, the resultsfrom the rabbitear assay should not be dismissed.The reactionmay take longer or the backskin may not be the ideal testingsurface. An additional"bonus" of the rabbit ear assayis detectionof the potentialof an ingre- dient or finishedproduct to producean epithelialirritant reaction.It is easyto keep trackof the surfaceirritancy while doing the follicularstudies. The stratumcorneum of the rabbitear is verythin andundeveloped. This resultsin an extremesensitivity of the skinto exposureto irritants.If thistest finding is confirmedby others,we mayfind it unnecessaryto usethe Draize rabbitdermal irritancy test. This paperis meantto be a surveyof the ingredientsused in skin careand hair care products.The surveyis not at all definitivebut simplydesigned to stimulateresearch, sothat new noncomedogenicproducts will becomeavailable for thoseof us with acne- pronecomplexions. This subject has recently received an excellent review by theAmer- icanAcademy of DermatologyInvitational Symposium on Comedogenicity(12).

REFERENCES

(1) A. M. Kligmanand O. H. Mills: Acnecosmetica, Arch. Dermatol., 106, 843-850 (1972). (2) J. E. Fulton,S. Bradley,et al, Noncomedogeniccosmetics, Cutis, 17, 344-351 (1976). COMEDOGENICITY 333

(3) J. E. Fulton,Jr., S. R. Pay,and JE FultonIII, Comedogenicityof current therapeutic products, cosmetics,and ingredientsin the rabbitear, J. Am. Acad.Dermatol., 10, 96-105 (1984). (4) W. R. Markland,Acne and cosmetic comedogenicity, Norda Briefi, 481, 1-6 (1977). (5) G. W. Hambrickand H. Blank,A microanatomicalstudy of the response ofthe pilosebaceous appa- ratusof the rabbits'ear canal.J. Invest.Dermatol., 26, 185-200 (1956). (6) H. Gougerot,A. Carteaud,and E. Grupper,Epidermie de coedons par les brillantines, crSmes etc. de gerer, Bull. Soc.Franc. Derm. Syph., 52, 124-125 (1945). (7) G. Piewig,J. E. Fulton,and A.M. Kligman,Pomade acne. Arch. Dermatol., 101, 580-584 (1970). (8) G. Piewig,J. E. Fulton,and A.M. Kligman,Dynamics of comedoformation in acnevulgaris, Arch. Derm. Forsch.242, 12-29 (1971). (9) A. Zatuloneand N. A. Konnerth,Comedogenicity testing of cosmetics,Cutis, 39, 521 (1987). (10) O. H. Mills and A.M. Kligman, Comedogenicityof sunscreens,Arch. Dermatol.,118, 417-419 (1982). (11) M. Lanzet,Comedogenic effects of cosmeticraw materials,Cosmet. Toiletr. 101, 63-72 (1986). (12) J. S. Straussand E. M. Jackson,American Academy of DermatologyInvitational Symposium on Comedogenicity,J Am. Acad. Dermatol., 20, 272-277 (1989).