Professional Documents
Culture Documents
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
INTRODUCTION
322
METHODS
Grade
0.009 in or less
0.010 in-.014
in
0.015 in-.019
0.020 in-.025
in
in
2
3
0.025 in-.029
in
0.030
in or more
No significantincreasein follicularkeratosis
No irritation
2
3
4
5
Diffusescaling,no erythema
Generalizedscalingwith erythema
Scaling,erythema,andedema
Epidermalnecrosisand slough
COMEDOGENICITY
323
acids are dissolvedin either a volatile solvent or sunflower oil. The D&C red #36
RESULTS
AND
DISCUSSION
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.
324
IngredientsandTheir Comedogenicity
and Irritancy
Grade (0- 5)
Grade (0- 5)
Ingredient
Comedo.
?
Irrit.
Ingredient
Comedo.? Irrit.
Myristylalcohol
Acetylatedlanolin
Acetylatedlanolinalcohol
Anhydrouslanolin
0
4
0-1'
0
2
0
Cetyl alcohol
Isocetylalcohol
Cetearylalcohol
Lanolin alcohol
0-2*
Oleylalcohol
Stearylalcohol
Cetearylalcoholq-
Lanolin
0-1'
oil
ceteareth 20
PEG 75 lanolin
Laneth- 10
Ceteareth-20
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
PG monostearate
0- 3
3
0-
3
2
Myristic acid
Palmitic
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
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
4
0
0
3
acid
stearate
Stearylheptanoate
Tridectyl neopentanoate
Ethyleneglycol
0
Glucoseglutamate
monostearate
Sorbitol
Sorbitan laurate
1- 2'
!- 2
Sorbitansesquinoleate
0- !*
Sorbitan oleate
Sorbitan stearate
0
1-2'
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
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
SD alcohol 40
PEG 20 stearate
Isopropylalcohol
COMEDOGENICITY
325
Table I (continued)
Grade (0-5)
Ingredient
Comedo.-
Grade (0 - 5)
Irrit. :
Ingredient
Comedo.-
Irrit.:
Sesame oil
3(1)**
Corn oil
3
5
3
2
4
0
Avocado oil
3(2)
Eveningprimroseoil
Mink
3(2)
Steareth-2
Soybeanoil
Steareth- 10
oil
3
3
3
0
2
2
0
Steareth-20
Steareth- 100
Peanut oil
Oleth-3
Oleth-5
5
3
2
2
Olive oil
2(1)
Oleth- 10
Almond
Oleth-20
2(I)
2(1)
0
0
Oleth-3 phosphate
Triacetin
4
3
3
0
0
2
2
1
0
0
oil
Castor oil
Hydrogenatedcastoroil
Chaulmoograoil
Babassu oil
Squalane
Maleatedsoybeanoil
monococoate
Safflower oil
Sunflower oil
Mineral
0-2
VII. Pigments
Polypentaerythrital
tetralaurate
IV.
Waxes
Candelilla wax
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
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
violet
Iron oxides
Carmine
Titanium
dioxide
Carbomer 940
Bentonite
VIII.
Kaolin
Talc
0
0
Dimethicone
PVP
Cyclomethicone
Cocoa butter
Coconut butter
4
4
0
0
Hydrogenatedvegetableoil
VI.
Oils*
Silicones
Simethicone
IX.
SteroIs
Cholesterol
Soyasterol
Peg 5 soyasterol
0
0
(continued)
326
Grade (0-5)
Ingredient
Comedo.
?
Irrit.$
Ingredient
Comedo.?
Irrit.
Peg 10 soyasterol
XlI. Miscellaneous
Choleth24
Sterolesters
0
0
0
0
Octyl dimethylPABA
Oxybenzone
Octylmethoxycinnamate
Octyl salicylate
Phytantriol
X. Vitamins
andherbs
A & D additive
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
Acetone
Ethyl
ether
Diethylene
glycol
monoethyl
ether
Ethylene
glycol
monomethyl
ether
(EGME)
Xylene
Lithium stearate
Magnesium stearate
Methylparaben
Propylparaben
Phenoxyethyl
paraben
0
0
0
0
0
0
Zinc oxide
Zinc stearate
Triethanolamine
Allantoin
Hydantoin
Sodium
hyaluronate
Amoniomethylpropinate
Sodium
PCA
Chondroitinsulfate
Precipitatedsulfur
0
0
0
0
Hydrolyzedanimalprotein
Water-soluble sulfur
? 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
COMEDOGENICITY
327
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.
Clinically,naturaloilssuchascocoabutterandcoconutbutterhavelongbeenknownto
causeproblemswith pomadeacne.This is confirmedin the rabbit ear assay.Also,
328
- OCTYLDODECYL
ISOPROPYLMYRISTATE
STEAROYL
STEARATE
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
..
.,
;,
.'-".
, rtl'.,.,'/'
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
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.
SUMMARY
332
III
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
Myristicacid
Palrnitic
Stearic acid
acid
Archidic acid
Behenic acid
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
COMEDOGENICITY
333
(4) W. R. Markland,Acneandcosmetic
comedogenicity,
NordaBriefi,481, 1-6 (1977).
(5) G. W. Hambrick
andH. Blank,A microanatomical
studyoftheresponse
ofthepilosebaceous
apparatusof the rabbits'earcanal.J. Invest.Dermatol.,26, 185-200 (1956).
(6) H. Gougerot,
A. Carteaud,
andE. Grupper,Epidermie
decoedons
parlesbrillantines,
crSmes
etc.de
gerer, Bull. Soc.Franc.Derm.Syph.,52, 124-125 (1945).
(11) M. Lanzet,Comedogenic
effectsof cosmeticraw materials,Cosmet.
Toiletr.101, 63-72 (1986).
(12) J. S. Strauss
andE. M. Jackson,
AmericanAcademy
of Dermatology
InvitationalSymposium
on
Comedogenicity,
J Am. Acad. Dermatol.
, 20, 272-277 (1989).