j. Soc.Cosmet.
Chem.,40, 321-333 (November/December
1989)
Comedogenicity
andirritancyof commonly
usedingredients
in skincare products
JAMESE. FULTON, JR., AcneResearch
Institute,1236 Somerset,
NewportBeach,CA 92660.
Received
September
3, 1989. Presented
at theSouthern
CaliforniaSection,
CaliforniaChapter,Society
ofCosmetic
Chemists,
Spring1989.
Synopsis
A survey,usingthe rabbitear, of the comedogenicity
and irritancyof severalgroupsof skin careproducts
indicates
that manycontainfollicularand surfaceepithelialirritatingingredients.
Theseingredients
fall
into severalchemicalclasses.
Certaingeneralizations
can be deducedby examiningthe results:(1) medium-chain-length
fattyacidsaremorepotentthanshort-or long-chain
fattyacidsin producingfollicular
keratosis,
(2) the comedogenicity
and irritancyof an organicmaterialcanbe reducedby combiningthe
moleculewith a polarsugaror a heavymetal, (3) increasing
the degreeof ethoxylationin a moleculetends
to reducethe comedogenicity
and irritancyof the chemical,and (4) the longerchainlipids, i.e., waxes,
appeartoolargeto producea reaction.By followingthe guidelinesdeveloped
in thisstudy,it is possible
to
formulatenonirritating,noncomedogenic
moisturizers,sunscreens,
hair pomades,cosmetics,and conditioners.
INTRODUCTION
The possibilityof comedogenicity
and irritancyof facialskin careproductshasbeen
well documented
(1- 3). Because
of thiswork andan increasing
publicawareness,
facial
productsthat are lesscomedogenic
are now becomingavailable(4). However, other
skin careproductssuchas hair conditioners,
hair pomades,moisturizers,sunscreens,
and evenacnetreatmentproductsmay be a sourceof cosmeticacne.By taking these
products
apart,testingtheir ingredients,
andputtingthembacktogetherandretesting
them, an extensiveingredientlisting hasbeencreated.By studyingthis list, the cosmetic chemistcan beginto be selectivein developingformulasfor lessirritating and
lesscomedogenic
products.
The rabbit ear assayhasbeenusedsincethe mid-1950sas a methodof measuring
follicularkeratinizationby externallyappliedcompounds
(5). The advantage
of this
rapidscreening
tool is that it takesonlytwo weeksto developfollicularimpactions
in
the rabbitear, whileit maytakesixmonthsto develop
similarreactions
on humanskin.
The disadvantage
of the modelis its extremesensitivity.The fragile,protectedepithelium of the inner ear is extremelysensitive.Not everythingthat irritatesthis model
will alsoirritate humanskin. However,this extensivescreening
of cosmeticformula321
322
JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
tionsand their ingredientswould not havebeenpossiblewithout the useof this animal
model.We havenowextendedthemodelto includean indexof surface
skinirritancyas
well asof follicularhyperkeratosis.
METHODS
Ingredientsare mixed in propyleneglycolat a 9 to 1 dilution for testingunlessotherwise indicated(10% concentration).
A colonyof New Zealandalbinorabbitsthat has
geneticallygoodearsand is freefrom mitesis used.Threerabbits,weighingtwo to
threekilograms,areusedfor eachassay.Animalsarehousedsinglyin suspended
cages
and fed Purina Rabbit Chow and water ad libitum. Animals are maintained on a 12-hour
light and 12-hourdarkcycle.A doseof 1 ml of the testmaterialis appliedandspread
oncedaily to the entireinnersurfaceof oneearfive daysper weekfor two weeks.The
oppositeuntreatedearof eachanimalservesasan untreatedcontrol.Follicularkeratosis
is judged both macroscopically
(visually)and microscopically
with a micrometerto
measurethe width of the follicularkeratosis.The macroscopic
response
is determined
by averagingthe measurements
of the width of six folliclesusinga Mitutoyo Dial
Micrometer(#536-724). A similarmicroscopic
micrometermeasurement
is obtained
by averagingthe width of six folliclesundera magnificationof 430 x aftera 6-ram
biopsyspecimenis fixedin formalin,sectioned
at six microns,and stainedwith hematoxylin-eosin.The resultsare then combinedon a scaleof oneto five:
Micrometerreading
Grade
0.009 in or less
0
0.010 in-.014
in
1
0.015 in-.019
0.020 in-.025
in
in
2
3
A moderate increase in follicular keratosis
0.025 in-.029
in
4
An extensive increasein follicular keratosis
0.030
in or more
No significantincreasein follicularkeratosis
5
Grade5 is the presence
of largecomedones
throughoutthe ear, similarto thoseinduced
by the applicationof our standard"positive"testingagent, isopropylmyristate.As
reportedin our previousstudies,a minimal gradeof 0 to 1 is not considered
significant.
Grade2 to 3 is borderline.However,a gradeof 4 to 5 is uniformallyreproduceable
and
considered
positive.
The irritancyproducedby the repeated
applicationof a chemicalor skincareproducton
the surfaceepidermisin the rabbit earis alsoevaluatedon a similarscaleof 0 to 5. The
gradesare summarizedasfollows:
0
No irritation
1
Few scales,no erythema
2
3
4
5
Diffusescaling,no erythema
Generalizedscalingwith erythema
Scaling,erythema,andedema
Epidermalnecrosisand slough
To studythe effectsof differentvehicleson comedogenicity
and irritancy,severalfatty
acidsand the D&C red pigment#36 are reexamined
in differentsolvents.The fatty
COMEDOGENICITY
323
acids are dissolvedin either a volatile solvent or sunflower oil. The D&C red #36
pigmentis testedin mineraloil, propylene
glycol,polyethylene
glycol400, andpentaerythritaltetra capra/caprylate.
RESULTS
AND
DISCUSSION
Cosmeticacnewasfirst reportedby Frenchdermatologists
in the mid-forties.They
reportedon brilliantinesandhairpomades
causingflareupson the templeandforehead
facialregions.They attributedthe 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% showedsomeevidenceof follicularkeratoses
on the foreheadand temples.
Occasionallythe eruptionswere noted on the cheeksdown to the jawline area. The
lesionswereusuallynoninflammatory,
closedcomedones.
A few lesionsdevelopedinto
small inflammatorypapules.However,therewereno casesof severe,cysticinflammatory acne. Histologically, the comedones
from pomadeacne caseswere identical to
biopsies
takenfrom comedones
of classicacnevulgarispatients.In surveyingthe hair
carepreparations,we felt that the actualingredientsand not tracecontaminants
were
offenders.
Interestingly,veryfew of the subjects
attributedtheir folliculareruptionsto
their daily useof a hair pomade.This studystimulatedus to examineotherskin care
productsand ingredients.
In 1972 Kligman and Mills reportedon acnecosmetica
in their surveyat the AcneClinic
at the Universityof Pennsylvania
(1). Approximatelyonethird of the adult womenhad
a low-grade,persistentacnein the cheekarea, consistingof closedcomedones
quite
similarto thosefoundin pomadeacne.This appearedmorefrequentlyin womenafter
agetwentyand may explainoneof the reasons
for epidemicadult acnein womenin the
1970sand 1980s.In 1976 and 1984, Fultonpublishedresultson actualcosmetic
lines
andon ingredients,andproposed
the development
of noncomedogenic
cosmetics
using
ingredients
that werenonoffenders
in the rabbitearassay(2,3). Severalmajorcosmetic
manufacturers
have now producedthesetypesof products.However, our screening
indicatesthat work is still neededon manyskin careformulations.
It becameapparentduringour research
into potentialnoncomedogenic
ingredientsthat
several
hypotheses
couldbedeveloped:
(1) In orderforan ingredientto becomedogenic,
it must penetrateinto the follicle, and (2) once in the follicle, the chemicalmust
producethe follicularreactionof "retentionhyperkeratosis"
(8). In addition, the overall
penetratibilityof the moleculemayberelatedto (1) the water/oilpartitioncoefficient
of
the compound(HLB balance)and (2) the relativemolecularweight of the ingredient.
The ingredientappearsto havethe mostpotentialif it is fairly solublein bothwaterand
oil (HLB around10 to 12) and hasa rangeof molecularweight between200 and 300.
The comedogenicity
of 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/lipidsolubilityandmolecularweightsareapparentin
eachclassof chemicals
examined(TableI). Amongthe lanolins,the classicanhydrous
lanolinsare not as comedogenic
as the moderatelyethoxylatedderivatives(laneth 10).
324
JOURNAL OF THE SOCIETYOF COSMETICCHEMISTS
Table
I
IngredientsandTheir Comedogenicity
and Irritancy
Grade (0- 5)
Grade (0- 5)
Ingredient
Comedo.
?
Irrit. ½
Ingredient
Comedo.? Irrit.½
Myristylalcohol
2
Acetylatedlanolin
Acetylatedlanolinalcohol
Anhydrouslanolin
0
4
0-1'
0
2
0
Cetyl alcohol
2
2
Isocetylalcohol
4
4
Cetearylalcohol
2
1
Lanolin alcohol
0-2*
0
Oleylalcohol
4
2
Stearylalcohol
Cetearylalcoholq-
2
2
I. Lanolins and derivatives
Lanolin
0-1'
0
PEG 16 lanolin (Solulan 16)
oil
4
3
ceteareth 20
4
4
PEG 75 lanolin
0
0
Laneth- 10
2
1
Ceteareth-20
2
3
PPG 12 PEG 65 lanolin oil
2
0
Propyleneglycol
Butyleneglycol
Hexyleneglycol
PG caprylate/caprate
PG dicaprylate/caprate
PG dipelargonate
0
1
0-2*
2
1
2
0
0
02
0
2
PG laurate
0
PG monostearate
0- 3
3
0-
II. Fattyacidsandtheir derivatives
Caprylicacid
1
Capricacid
2
Lauric acid
3
2
4
Myristic acid
3
0
Palmitic
2
0
Stearic acid
Eicosanoic acid
Behenic acid
2 - 3'
2
0
0
0
0
Ascorbylpalmitate
Behenylerucate
Butyl stearate
Cetyl acetate
Cetyl esterNF
Cetyl palmitate
Decyl oleate
Di (2 ethylhexyl)succinate
Dioctyl malate
Dioctyl succinate
Diisopropyladipate
Diisopropyldimerate
2
0
3
4
1
0
3
2
3
3
0
0
0
0
0
2
1
0
0
0
1
2
0
0
Ethylhexylpalmitate
4
0
Ethylhexylpelargonate
Isodecyloleate
Isopropylisostearate
Isopropyllinolate
Isopropyl myristate
Isopropylpalmitate
Isostearylneopentanoate
Isostearylisostearate
Myristyl lactate
Myristyl myristate
Octyldodecylstearate
Octyldodecylstearoyl
2
2- 3'
5
4
5
4
3
4
4
5
0
3
1- 2
0
2
3
1
3
1
2
2
0
0
0
4
0
0
3
acid
stearate
Stearylheptanoate
Tridectyl neopentanoate
Ethyleneglycol
0
0
Glucoseglutamate
monostearate
0
0
Sorbitol
0
0
Sorbitan laurate
1- 2'
!- 2
Sorbitansesquinoleate
0- !*
0
Sorbitan oleate
Sorbitan stearate
3
0
PEG 40 sorbitan laurate
0
1-2'
0
0
Polysorbate20
Polysorbate80
Glycerin
0
0
0
0
0
0
Glycereth-26
Glyceryl-3-diisostearate
GlycerylstearateNSE
GlycerylstearateSE
Glyceryltricapylo/caprate
Behenyltriglyceride
0
4
1
3
1
0
0
0
0
2
1
0
2
0
Pentaerythrital
tetracapra/
caprylate
0
Wheat germglyceride
3
Polyglyceryl3-diisostearate 4
Polyethylene
glycol(PEG
0
2
0
Sorbitan isostearate
Pentaerythritaltetra
isostearate
400)
Sucrose distearate
Sucrose stearate
!
0
0
0
0
0
0
2
PEG 120 methyl glucose
dioleate
PEG 8 stearate
III. Alcohols•sugarsand their derivatives
0
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)
Ingredient
Comedo.•-
Grade (0 - 5)
Irrit. :•
Ingredient
Comedo.•-
Irrit.:•
PEG 100 distearate
2
0
Sesame oil
3(1)**
PEG 150 distearate
2
0
Corn oil
3
0
PEG 200 dilaurate
Laureth-4
Laureth-23
3
5
3
2
4
0
Avocado oil
3(2)
0
Eveningprimroseoil
3
2
Mink
3(2)
Steareth-2
2
2
Soybeanoil
Steareth- 10
4
3
Shark liver oil
Cotton seed oil
oil
0
3
3
3
0
2
2
0
Steareth-20
2
1
Steareth- 100
0
0
Peanut oil
2
Oleth-3
Oleth-5
5
3
2
2
Olive oil
2(1)
0
Sandalwood seed oil
2
0
Oleth- 10
2
1
Almond
Oleth-20
1
0
Apricot kernel oil
Hydrogenated
polyisobutane
2(I)
2(1)
0
0
1
2
Oleth-3 phosphate
2
2
Triacetin
0
0
PPG 5 Ceteth 10 phosphate
PPG 2 myristyl propionate
PPG 10 cetyl ether
PPG 30 cetyl ester
PPG 50 cetyl ester
PEG 78 glyceryl
4
3
3
0
0
2
2
1
0
0
oil
Castor oil
1
0
Hydrogenatedcastoroil
Chaulmoograoil
1
0
1
0
Babassu oil
1
0
Squalane
Maleatedsoybeanoil
1
0
0
0
monococoate
0
1
Safflower oil
0
0
PEG 8 castor oil
1
1
Sunflower oil
0
0
PEG 40 castor oil
0
0
Mineral
0-2
0
0
0
VII. Pigments
Polypentaerythrital
tetralaurate
IV.
Waxes
Candelilla wax
1
0
Carnuba wax
Ceresin wax
Beeswax
Lanolin wax
1
0
0- 2 *
1
0
0
0
0
Jojobaoil
Sulfatedjojobaoil
Emulsifyingwax NF
0-2*
3
0
0
2
0- 2'
0
1
1
0
0
0
0
0
V.
Thickeners
Carboxymethylcellulose
Carboxypropylcellulose
Hydroxypropylcellulose
Magnesiumaluminum
silicate
oil
D & C red #3
D & C red #4
D & C red #6
D & C red #7
D & C red #9
D & C red # 17
D & C red # 19
D & C red #21
D & C red #27
D & C red #30
D & C red #33
D & C red #36
D & C red #40
Ultamarine
violet
Iron oxides
Carmine
Titanium
dioxide
Carbomer 940
1
0
Bentonite
0
0
VIII.
Kaolin
Talc
0
1
0
0
Dimethicone
PVP
0
0
Cyclomethicone
Cocoa butter
Coconut butter
4
4
0
0
Hydrogenatedvegetableoil
3
0
VI.
Oils*
Silicones
Simethicone
IX.
SteroIs
Cholesterol
0
Soyasterol
Peg 5 soyasterol
0
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
Sterolesters
0
0
0
0
Octyl dimethylPABA
Oxybenzone
0
0
0
0
Octylmethoxycinnamate
0
0
Octyl salicylate
0
0
0
0
0
0
0
0
0
0
Phytantriol
X. Vitamins
andherbs
2
2
A & D additive
2
0
Tocopherol*
Tocopheryl
acetate
Black
walnut
extract
Papain
Chamomile
extract
Vitamin
Apalmitate
0-3'
0
0
0
0
1-3'
0-3'
0
0
0
0
1-3'
Panthenol
0
0
Acetone
Ethyl
ether
Diethylene
glycol
monoethyl
ether
Ethylene
glycol
monomethyl
ether
(EGME)
Xylene
Lithium stearate
4
3
1
0
Magnesium stearate
1
0
Methylparaben
Propylparaben
Phenoxyethyl
paraben
0
0
0
0
0
0
Zinc oxide
Zinc stearate
Triethanolamine
1
0
0
0
2
0
Allantoin
0
0
Stearic acid: TEA
3
2
Hydantoin
Sodium
hyaluronate
0
0
Amoniomethylpropinate
Sodium
PCA
0
0
0
0
Chondroitinsulfate
Precipitatedsulfur
0
0
0
0
Hydrolyzedanimalprotein
0
0
Water-soluble sulfur
3
0
XI. Preservativesand additives
? Comedogenicity
or abilityof testsubstance
to produce
follicular
hyperkeratosis.
$ Irritancyor abilityof testsubstance
to produce
surface
epithelial
irritation.
* Resultsdependon sourceof raw material.
** Parentheses
indicateresultsusing"reftned"oil.
The higherethoxylated
derivatives
with HLBsabove12 aremorewater-soluble
and
noncomedogenic
andnonirritating
(PEG 75 lanolin).Two of the lanolinderivatives
studiedrequirespecial
comments:
(1) Theacetylated
lanolinalcohols
arebothcomedogenicandirritating,not because
of the acetylated
lanolinbut because
of the cetyl
acetateadditive(Figure1), and(2) PEG 16 lanolin(Solulan16) is quitecomedogenic
andirritating,perhaps
secondary
to thecombination
ofnonlanolin
additives:
ceteth-16,
oleth-16, and steareth-16.
Amongthefattyacidsandesters
a similaranalogy
isfound.Themid-chain-length
fatty
acids,suchaslauricacidandmyristicacidanditsanalogs
cause
folliclehyperkeratosis.
Asthemolecular
weightof thefattyacidbecomes
largerandtheeffective
charge
of the
overallmoleculeis reduced,lessfollicularreactionis produced.When the fatty acidis
esterifiedwith a small- to mid-sizealcohol,the combinationbecomesmorepotent than
the fatty aciditself.The cousins
of isopropyl
myristate,suchasmyristylmyristate,
isopropyl
isostearate,
isostearyl
neopentanoate,
butylstearate,
anddecyloleate,areall
comedogenic
(Figure2). Also,whenbranched-chain
fattyacidsareused,thederivatives
maybemorecomedogenic.
Largemolecular
weightesters,
suchasbehenyl
erucate
and
cetylpalmitate,arenot a problem.
COMEDOGENICITY
327
Figure 1. The key ingredientis acetylated
lanolinalcohol
-- cetylacetate--is not onlycomedogenic,
but
it is also an irritant.
Similar analogiesare apparentwith the alcohols,ethers,glycols,and sugars.Shortchainalcoholsdo not causea reaction.The mid-chain-lengthalcoholsare comedogenic
and moreirritating than their fatty acidanalogs(Figure3). In the glycolseries,as the
hydrocarbon
component
becomes
moredominant,the compoundis moreeffectiveat
producingcomedones.
The puresugarsarenoncomedogenic.
However,if theyarecombinedwith penetratingfatty acids,they may becomefollicularirritants.Also, if they
are combinedwith anotherirritant, as in glycerylstearate(SE), which containsadded
sodiumor potassiumstearate,the combinationbecomes
morecomedogenic.
The increasing
additionof polyethylene
glycolsto the fatty acidsincreases
the HLB balance,
reducesthe follicularirritancy,and appearsto preventhyperkeratosis.
An exampleis
the oleth3, 5, 10, 20 series(Figure4).
Among the waxes,the hydrocarbon
chainsappeartoo long to penetrateunlessthe wax
is modified,suchasin sulfatedjojobaoil. In the caseof beeswaxes
and jojobaoils, some
commercialpreparations
are more comedogenic
than others.This suggests
more contaminantsor irritants in someof the preparations.Emulsifyingwax NF may be irritating, dependingon the concentration
of longer-chainalcoholssuchas cetearylalcohol.
Chemicalssuchas cellulosicpolymers,the silicates,and the carbomersusedin the
pharmaceutical
and cosmeticindustryto thickenlotionsand creamsare not usuallya
problem.The clays,bentonite,and kaolinarealsonot a problem.Neither is talc.
Clinically,naturaloilssuchascocoabutterandcoconutbutterhavelongbeenknownto
causeproblemswith pomadeacne.This is confirmedin the rabbit ear assay.Also,
328
JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
- OCTYLDODECYL
ISOPROPYLMYRISTATE
STEAROYL
STEARATE
Figure 2. Ingredienttesting in the rabbit ear assay--the macroscopic
view of the resultsfrom testing
isopropylmyristate.Microscopic
examination
confirmedthe comedogenicity
seenvisually.Note that the
ingredientis alsoan irritant compared
to a potentialsubstitute,octyldodecylstearoylstearate.
hydrogenated
vegetableoil (Crisco
©) appearsto containresidualirritating lipids.
Among the naturaloils suchas sesameoil, avocadooil, and mink oil, the resultsare
improvedwhena morerefinedoil is used.However,it seemseasierto usesaffloweroil
and sunfloweroils, which are naturallylesscomedogenic.
Mineral oil presentsa complex problem:somesources
are acceptable;
othersare not.
D&C red colorsrepresenta perplexingmixture of differenttypesof red dyesand pigments. Someare mildly comedogenic;
othersare not. The commonpigmentsusedin
powderblushers
(D&C red #6, bariumlake;D&C red #7, calciumlake;andD&C red
#9, bariumlake)arerelativelynoncomedogenic.
However,the vehicleis alsoparticularly importantfor the D&C red colors.A dry compressed
powderor powdersuspended
in an evaporatingvehiclesuchaspropyleneglycolmay be noncomedogenic.
The same
dyeincorporated
intoa nonevaporating
oil canbecomedogenic
(TableII, Figure5).
Carmine,whichis a red dye obtainedfrom insectwings,is noncomedogenic
andmay
be usedasa substitute.The iron oxides,chromiumhydroxide,andtitaniumdioxideare
not a problem.
The silicones
andsteroIsdo not appearto be a problem.Amongthe vitamins,tocopherol is a follicularirritant. Tocopherolhasbeenadvocated
by the laymanfor yearsto
increase
woundhealingand reducescarformation.However,it shouldnot be usedon
acne-prone
skin because
of its potentialto producefollicularhyperkeratosis.
The derivative, tocopherylacetate,is noncomedogenic,
andresearch
needsto bedoneto seeif it is
an acceptablesubstitute.
COMEDOGENICITY
329
.,.
!
&t,
Cosoz
ISOCETYL
ALCOHOL
..
.,
;,
_
.'-".
, r•tl'.,.,'/'
Figure 3. The brsnched-½h•in
•l½oholis more½ornedo•eni½
•nd moreirrit•tin• th•n the
•l½ohol.
As for the miscellaneous
items,the usualsunscreen
activeingredients
arenoncomedogenic. Amongchemicalsolvents,acetone,ether, and EGME are not problems,but
xyleneis comedogenic
andan irritant.Whenmetallicbases,suchaslithium, magnesium,andzincstearate,
areaddedto the fattyacids,the metalappears
to preventthe
comedogenic
reaction.Amongbases,triethanolamine
is morecomedogenic
thanaminomethylpropylamine.The classicformulation of a cold cream often involvesa salt
bridgebetweenstearicacidandtriethanolamine.
In testingdifferentratios[4:1, 1:1,
1:4] of stearicacidto triethanolamine
(stearicacid:TEA)in a coldcreambase,all combinationswerefoundto be comedogenic.
The influence
of thevehicleor solvent
onthecomedogenicity
andirritancyof a chemicalappears
quitesignificant.Forexample,theuseof rapidlyevaporating
vehicles
such
asacetoneor etherreducesthe comedogenicity
of fatty acidswhencompared
to the
resultsobtainedwith 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.Whereasthe D&C red colormay be noncomedogenic
in volatile
propyleneglycol,it may be morecomedogenic
in mineraloil. Possible
alternatives
for
mineraloil, suchaspentaerythrital
tetracapra/caprylate
andpolyethylene
glycol400,
alsoreducethe comedogenicity
of the redcolor(TableII). We havechosen
propylene
glycolasthe routinediluentfor thesestudies,asit graduallyevaporates
and leavesa
concentrate
of the rawmaterialto be tested.Also,lot afterlot of propylene
glycolhas
provento be nonirritatingand noncomedogenic.
330
JOURNAL OF THE SOCIETYOF COSMETICCHEMISTS
OLETH-iO
OLETH.
2
Figure4. Oleth-3compared
to oleicacid.Theinitialadditions
of ethylene
glycols
to potentially
comedogenicandirritatingingredients
appearto increase
thispropensity.
Furtheradditions
of ethylene
glycols,
such as oleth-10 and oleth-20, tend to reduce reactions.
Someingredientcombinations--forexample,the combination
of glycerylstearate
with
potassium
stearate
(available
commercially
asglycerylstearate
S.E.) andalsothe combination of D&C red #36 and mineral oil--appear more comedogenic
than the individual compounds
themselves.
Thesesynergistic
reactionsneedto be studiedfurther.
COMEDOGENICITY
Table
331
II
Comedogenicity
of 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 pentaerythrital
tetracaprdcaprylate
D&C #36 in propylene
glycol
2
0
1
0
D&C red #36 in PEG 400
0
0
The oppositeis alsopossible.For example,the combinationproducedby the ingredient
D&C red #36 and the vehiclepolyethylene
glycolis lesscomedogenic
than D&C red
#36 whenincorporated
into othervehicles.The cosmeticchemistmay be ableto take
advantageof thesefindingsin the future to customdesignnoncomedogenic
products.
SUMMARY
Thesestudiesindicatethat skin carepreparations
that are nonirritatingand noncomedogeniccan be made.Nonreactiveingredientscanbe usedto makeelegantproducts,
and borderlineingredientscanbe combinedwith otheringredientsto reducethe reactionsto acceptable
levels.In spiteof theseguidelines,newformulations
mustalwaysbe
examinedwith the rabbit earassaybeforethe cosmeticchemistcanbe assuredthat his
ideas work.
Figure 5. The comedogenicity
of D&C red #36 whenincorporated
into two differentvehicles.The vehiclemayincrease
or decrease
an ingredient's
ability to producefollicularhyperkeratosis.
332
JOURNAL OF THE SOCIETY OF COSMETIC CHEMISTS
Table
III
Effectsof the Solventon Comedogenicity
and/orIrritancyof FattyAcids
Organicsolvent*
Sunfloweroil
Grade (0- 5)
Grade (0- 5)
Fattyacids
Comedo.
Irrit.
Comedo.
Irrit.
Caproicacid
Caprylicacid
Capricacid
0
1
2
4
3
2
2
1
3
2
1
1
Lauric acid
3
1
4
1
Myristicacid
1
0
3
0
Palrnitic
0
0
1
2
Stearic acid
acid
0
1
2
0
Archidic acid
1
1
2
0
Behenic acid
1
0
1
0
* Ethyl etheror acetone.
The rabbitearassayremainsimportantto the rapidevaluationof newingredients
and
the cosmeticchemist'sformulations.Both the visualand microscopicevaluationsof the
rabbitearneedto be donesimultaneously
(9). Materialsfoundto be noncomedogenic
in
the rabbit assayappearto be noncomedogenic
in the human model (10). Whether
highly comedogenic
ingredientsin the rabbit ear assayare alwayscomedogenic
in
humansstill remainsuncertain.Currently,it is moreprudentto avoidtheseoffenders.
The majoroffenders,
suchasisopropylmyristate,acetylated
lanolinalcohol,andlauric
acid derivativessuchas laureth-4, shouldbe usedwith cautionin skin careproducts.
We are not convincedof the statementthat lower concentrations
of thesecompounds
canbe safelyusedwith no comedogenic
consequences
(11). Humanskinstudieshave
beenusedto give that statementcredence,
but the backskin of humanvolunteers
is
relativelyinsensitive
(7). However,whentherabbitearassay
is positivebut thehuman
back skin resultsare negativeafter only eight weeks'exposure,the resultsfrom the
rabbitearassay
shouldnot be dismissed.
The reaction
maytakelongeror thebackskin
may not be the idealtestingsurface.
An additional"bonus"of the rabbit ear assayis detectionof the potentialof an ingredient or finishedproductto producean epithelialirritant reaction.It is easyto keep
trackof the surface
irritancywhiledoingthe follicularstudies.The stratumcorneumof
the rabbitearis verythin andundeveloped.
This resultsin an extremesensitivity
of the
skinto exposure
to irritants.If thistestfindingis confirmed
by others,we mayfind it
unnecessary
to usethe Draizerabbitdermalirritancytest.
This paperis meantto be a surveyof the ingredients
usedin skin careand hair care
products.The surveyis not at all definitivebut simplydesignedto stimulateresearch,
sothat new noncomedogenic
productswill becomeavailablefor thoseof uswith acnepronecomplexions.
Thissubject
hasrecentlyreceived
anexcellent
reviewby theAmericanAcademyof DermatologyInvitationalSymposium
on Comedogenicity
(12).
REFERENCES
(1) A. M. KligmanandO. H. Mills:Acnecosmetica,
Arch.Dermatol.,
106, 843-850 (1972).
(2) J. E. Fulton,S. Bradley,et al, Noncomedogenic
cosmetics,
Cutis,17, 344-351 (1976).
COMEDOGENICITY
333
(3) J. E. Fulton,Jr., S. R. Pay,andJE FultonIII, Comedogenicity
of currenttherapeutic
products,
cosmetics,
and ingredientsin the rabbitear,J. Am. Acad.Dermatol.,10, 96-105 (1984).
(4) W. R. Markland,Acneandcosmetic
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(5) G. W. Hambrick
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ofthepilosebaceous
apparatusof the rabbits'earcanal.J. Invest.Dermatol.,26, 185-200 (1956).
(6) H. Gougerot,
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(7) G. Piewig,J. E. Fulton,andA.M. Kligman,Pomade
acne.Arch.Dermatol.,101, 580-584 (1970).
(8) G. Piewig,J. E. Fulton,andA.M. Kligman,Dynamics
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(9) A. ZatuloneandN. A. Konnerth,Comedogenicity
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(10) O. H. Mills and A.M. Kligman, Comedogenicity
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Arch. Dermatol.,118, 417-419
(1982).
(11) M. Lanzet,Comedogenic
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(12) J. S. Strauss
andE. M. Jackson,
AmericanAcademy
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, 20, 272-277 (1989).