j. Cosmet.

Sci., 50, 315-325 (September/October

1999)

Determinationof phenol, resorcinol,salicylic acid and

-hydroxy acids in cosmeticproductsand
salon preparations
RONALD L. YATES and DONALD C. HAVERY,

U,S, Foodand

Drug Administration,
Officeof Cosmetics
and Colors,
200 C St. SW,
Washington
DC 20204.
Accepted
for publication
August31, 1999.

Synopsis

A methodis describedfor the determinationof glycolicacid, lactic acid, citric acid, phenol, resorcinol,
salicyclicacid, tx-hydroxyoctanoic
acid, and tx-hydroxydecanoic
acid in commercialcreamsand lotins. A
mixtureof the productanda filter aid wasextractedwith an appropriatesolvent.The extractswerecleaned
up by eithersolid-phase
extractionchromatography
or ion-exchange
chromatography.
The resultingextracts
wereanalyzedby HPLC usinga C8 column.Recoveries
of citric acid,lacticacid,phenol,resorcinol,
and
salicylicacid addedto a simpleemulsionrangedfrom 99% to 102%, while recoveries
of glycolicacid
averaged93%. tx-Hydroxyoctanoic
acid and tx-hydroxydecanoic
acid recoveries
from a commerciallotion
rangedfrom 90% to 101%. The resultsof surveys
of commercial
productsobtaineddirectlyfrom manufacturers,andpurchased
from salons,retail stores,and throughthe mail, from 1992 to 1996, arepresented.

INTRODUCTION

To improvethe appearance
of facialskin, dermatologists
havedevelopedtechniquesto
removethe skin'supper layers.Mechanicaltechniquessuchas dermabrasionand dermaplaninghavebeenusedfor the treatmentof acnescarringand skin wrinkling (1,2).
Sincethe 1960s chemicalmethodsof skin peeling using keratolyticagentssuch as
trichloroacetic
acid,phenol,resorcinol,
and salicyclicacidhavebeenused(3-6). Chemicalpeelingis typicallyperformedby a dermatologistor trainedsaloncosmetologist
and
hasbeenusedto treat skin wrinkling, pigmentationdisorders,photoaging,acnescarring, and premalignantlesions(3,8-10). Since1992 there has been a proliferationof
productsdesignedto exfoliatethe skin marketedas cosmeticsto the generalpublic
(11,12). Theseproductsmostoftencontainglycolicand lacticacids,which aregenerally
referredto as ot-hydroxyacids(AHAs). Market claims for productscontainingAHAs
have included diminishing of skin wrinkling, eveningof skin tones, skin softening/
smoothing,repairof sundamage,repairof skin imperfectionssuchasminor scarringand
sun damage,and increasedskin elasticity/firmness
(10,13-16).
315

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JOURNAL OF COSMETIC SCIENCE

AHAs reportedlyfunctionas exfoliantsby reducingintercorneocyte

cohesionand interferingwith intercellularionicbonding,whichcauses
an acceleration
of cell turnover
in the stratumcorneum(17-20). AHAs are most effectiveat promotingcell turnover
only in the un-ionizedform (21,22). Maximum cell turnoveris obtainedat pH 3 (23).
Therefore,productscontainingAHAs stimulatethe highestrate of cell turnoverat a pH
rangingfrom 2.8 to 4.8 (18).
In 1989 the Food and Drug Administration(FDA) receivedseveralcomplaintsfrom
consumers
who sustainedfacial burnsfrom the use of a chemicalskin-peelproduct
obtainedthroughthe mail. Laboratory
analysisof the productindicatedthe presence
of
phenol,resorcinol,
andsalicylicacid.As AHA-containingproductsbecameincreasingly

availableto the generalpublic, the FDA receivedincreasingnumbersof consumer

complaintsrelatingto the useof theseproducts.Since1989 the FDA hasreceivedmore
than 100 complaintsrelating to productscontainingAHAs purchasedat retail stores.
Typicalcomplaintsincludedfacialredness,
swelling(especially
in the eyearea),burning,
blistering,bleeding,scarring,rashformation,itching, contactdermatitis,skin discoloration(reportedlypermanent),andadverseneurological
responses.
Because
of the numberof severityof someof the complaints,
an analyticalmethodwasneededto determine
the concentration
of AHAs and otherkeratolyticagentsin productsavailableto both
salonprofessionals
and the generalpublic.
No analyticalmethodsfor the determinationof AHAs and other keratolyticchemicals
in an emulsionmatrix havebeenpublished.High-performance
liquid chromatographic

(HPLC) methodshavebeendescribed
for the determinationof phenolin urine(24-26),
water (27), rain (28), serum(29), honey(30), and polyvinylchloride(31). HPLC methods
havebeenreportedfor the determinationof salicylicacidasa metabolitein plasma(32)
and urine (33). An HPLC methodfor the determinationof resorcinolin erythrosinehas
beenreported(34). Reversed-phase
HPLC wasusedfor the determinationof wine acids
(35). The determinationof glycolicacid in urine by HPLC and gaschromatography-

massspectrometry
wasusedto estimatecanineexposure
to ethyleneglycol(36). The
HPLC determinationof urinaryglycolicacid wasusedasan indicatorof possiblelevels
of oxalicacid in the body(37).
This reportdescribes
an HPLC methodfor the determination
of glycolicacid,lacticacid,
citric acid, o-hydroxyoctanoic
acid, o-hydroxydecanoic
acid, phenol, resorcinol,and
salicylicacid.Surveysof salonproductsandretail productsavailableto consumers
in the
U.S. wereconducted.The pH of eachproductwasalsodetermined.The resultsof these
surveysare reported.

EXPERIMENTAL
MATERIALS

HPLC-gradeacetonitrile,water, and methanolwere obtainedfrom BaxterHealthcare

Corp.(Muskegon,MI). Vacuum-extraction
manifoldandsolid-phase
extractionadapters
wereobtainedfrom Supelco(Bellefonte,PA). Celite 545, Dowex 1-X10 ion exchange
resin(200-400 mesh),filtrationcolumns(3 and 6 ml), C-18 solidphaseextractiontubes
(6 ml, 500 mg packing),ACS-gradesulfuricacid, 85% phosphoricacid, ammonium
hydroxide,and sodiumhydroxidewere obtainedfrom J. T. Baker (Phillipsburg,NJ).

ACID

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317

Glycolic acid (99%), lactic acid (85%) in water, citric acid (99%), phenol (99%),
resorcinol(99%), and salicylicacid (99%) were obtainedfrom Aldrich Chemical Co.
(Milwaukee,WI). ot-Hydroxyoctanoic
acid and ot-hydroxydecanoic
acid were obtained
from SigmaChemicalCo. (Morton Grove, IL). Cosmetic-grade
DEG stearatewas obtained from StepanChemicalCo. (Northfield, IL).

LIQUID CHROMATOGRAPHY

HPLC analyses
wereperformedon a systemconsisting
of two Model 510 HPLC pumps
(WatersAssociates,
Milford, MA), solventprogrammerModel 660 (WatersAssociates),
anda programmablevariableabsorbance
UV-VIS detector(Hitachi L-3000, EM Science,
Cherry Hill, NJ). Product extracts and standard solutionswere introduced into the
HPLC by a Rheodyneinjector(Cotati,CA) equippedwith eithera 20- or 100-pl loop

into a C8 HPLC column(4.6 x 250 mm, ProdigyC8, Phenomenex,

Torrance,CA).
Chromatographic
data were processed
with a D-2000 chromatographic
integrator(Hitachi).HPLC solventA waspreparedby dissolving11.5 g of phosphoric
acidin 950 ml
of HPLC-gradewater, addingammoniumhydroxideuntil the pH was 2.5, and then
diluting to one liter with water. HPLC solventB waspreparedby diluting 200 ml of
HPLC solventA to oneliter with water. HPLC solventC waspreparedby mixing 250

ml of solventA with methanolto a volumeof oneliter. HPLC solventD wasprepared

by addingwater to 900 ml of acetonitrileto make one liter. All HPLC solventswere
filtered through a 0.5-pm filter beforeuse.

pH MEASUREMENTS

All pH measurements
weredonewith an EA ExpandableIon Analyzer(Orion Research
Inc., Cambridge,MA). One gram of productwas addedto 9 ml of water and mixed
thoroughlybeforemeasurement
of pH.
STANDARD

SOLUTIONS

Stockstandardsolutionsof glycolicacid, citric acid, and lactic acid werepreparedby

accuratelyweighing approximately250 mg of eachinto 25-ml volumetricflasksand
filling to the markwith HPLC solventA. Working standardsolutionsof approximately

1, 3, and 6 mg/ml werepreparedfrom the stocksolutionsby addingthe appropriate

aliquotto a 10-ml volumetricflaskandfilling to the mark with HPLC solventA. Stock
solutionsof phenol,resorcinol,
and salicylicacidwerepreparedby accuratelyweighing
approximately75 mg of eachinto separate25-ml volumetricflasksand filling to the
mark with HPLC solventC. Working solutionsof approximately
0.3, 1, and 2 mg/ml
werepreparedby addingthe appropriatealiquotto a 10-ml volumetricflaskand filling
to the mark with HPLC solventC. Stock solutionsof ot-hydroxyoctanoic
acid and
ot-hydroxydecanoic
acid werepreparedby accuratelyweighing(five-placebalance)approximately3 mg of eachinto 10-ml volumetricflasks.Three milliliters of acetonitrile
was added to each, the standardswere dissolved,and the flasks filled to the mark with

HPLC solventB. Working solutionsof 0.03, 0.06, and0.12 mg/ml werepreparedusing

HPLC

solvent B.

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JOURNAL OF COSMETIC SCIENCE

ISOLATION

OF ANALYTES

G/yco/ic,lactic,analdtric adds.Approximately300 mg of a product was accurately

weighedinto a 30-ml beaker.Approximately1.5 g of Celite was addedand mixed
thoroughlywith a spatulauntil the mixture wasuniform.The mixture wastransferred
to a C8 (6 ml, 500 mg) solid-phase
extractiontube, and a filter disc from a 6-ml
filtration columnwas placedon top of the mixture and pusheddown firmly with a
stirring rod to pack the mixture. The preparedcolumnwas placedonto the vacuum
manifold and eluted with 0.1 M NH4H2PO 4 (HPLC solventA). The vacuumwas
adjustedto obtaina flow of 3-4 drops/sec.
The eluatewascollectedin a 10-ml volumetric flask to the mark. The collected eluate was mixed well and reserved for HPLC

analysis.

Resorcinol'
phenol'andsalicylicacid.The productwasmixed with Celite and packedin a
C-18 solid-phase
extractiontube describedabove.The preparedtube wasplacedon the
vacuummanifold and eluted with a mixture of methanol:water:0.1M NH4H2PO 4
(HPLC solventA), 75:15:10.The vacuumwasadjustedto obtaina flow of 3-4 drops/sec.
The eluate was collected in a 25-ml volumetric flask to the mark, mixed well, and

reservedfor HPLC analysis.

tx-Hydroxyoctanoic
acidandtx-hydroxydecanoic
acid.An ion exchange
columnwasprepared
by firstpushingout the two filter discson a 3-ml filtrationcolumnusinga straightened
paperclip. One of the discswas replaced,and 250 mg of the ion exchangeresinwas
addedfollowedby the secondfilter disc.The resinwasthen washedwith 2 ml of 1.0 N
NaOH to convertthe resinto the free-baseform, followedby 5 ml of water and 3 ml
of 70% methanol.Approximately300 mg of a productor an amountknown to contain
at least 2 mg of the tx-hydroxyacid(s)was accuratelyweighed into a 30-ml beaker.
Approximately1.5 g of Celite was addedand mixed thoroughlywith a spatula.The
mixturewastransferredto a 6-ml filtration columnand tappedon the laboratorybench
to settleand compactthe mixture. A filter disk wasplacedon top of the mixture and
pusheddown firmly with a stirring rod. The filtration columnwasmountedon the ion
exchange
columnwith an adapter.The filtrationcolumnwaselutedwith 20 ml of 70%
methanol.The vacuumwasadjustedto obtaina flow of 4-5 drops/sec.
The eluatewas
discarded.The filtration column containingthe product-Celitemixture was removed,
and3 ml of 1N sulfuricacidwaspassed
throughthe ion exchange
columnanddiscarded.
The ion exchangecolumnwaselutedwith 70% methanol,and the eluatewascollected
in a 25-ml flaskto the mark. The eluatewasmixed thoroughlyand reservedfor HPLC
analysis.

HPLC

ANALYSIS

Product extractswere analyzedby HPLC with the conditionslisted below for each
specificgroup of compounds.
The eluted components
were identifiedby comparing
retentiontimes of productcomponentswith thoseof standards.A standardcalibration
curvewaspreparedfor eachcompoundidentifiedby analyzingthe corresponding
standard solutionsand then plotting mg/ml vs. peak area. If the concentrationof the
compoundbeing determinedfell abovethat of the higheststandard,an appropriate
dilution of the product extract was made and reanalyzed.The concentrationin the
extract was determined

from the standard calibration

curve.

ACID DETERMINATION

IN COSMETIC

PREPARATIONS

319

Glycolic,lactic,andcitricacids.Productscontainingglycolic,lactic,and citric acidswere

separatedon a C8 columnwith HPLC solventA. The injectorwasequippedwith a 20-pl
loop, and the UV detectorwasset at a wavelengthof 210 nm.
Resorcinol,
phenol,and salicylicacid.Productscontainingresorcinol,phenol,and salicylic
acid were separatedon a C8 columnwith a linear gradientusing HPLC solventsB and
C. The solventprogramwas0% C to 100% C in 10 minutes.Initially the UV detector
was set at 270 nm. After the elution of phenol,it was changedto 305 nm to detect
salicylicacid. The volumeof the injectionloopwas20 pl.

tx-Hydroxyoctanoic
acid and tx-hydroxydecanoic
acid.Productscontainingot-hydroxyoctanoic acid and ot-hydroxydecanoic
acid were separatedon a C8 column with a linear
gradientelution usingsolventsB and D. The solventprogramwas 20% D to 90% D
in 25 minutes.The UV detectorwassetat 210 nm.. The volumeof the injectionloop
was 100 pl.
CALCULATIONS

The amountof the analytein the productwasdeterminedusingthe followingequation:

Csx V sx DF x SP
Ws

whereCs is the concentration

of the componentof interestfrom the standardcurve
(mg/ml), V s is the volumeof the productextract(ml), DF is the dilution factoror
aliquot, SP is the standardpurity (%) (someot-hydroxyacidssuchas lactic acid are
suppliedas aqueoussolutions),and Ws is the weight of the product(mg).

RESULTS
HPLC

AND

DISCUSSION

CONDITIONS

The HPLC mobile phasewas developedto separatethe compoundsof interestand to

give good peak symmetryof the ot-hydroxyacids.It was necessary
to suppressthe
ionizationof the ot-hydroxyacidsduring chromatographic
separation,
and soan acidic
bufferwasused.A mobile-phase
pH from 2.3 to 2.5 gavesatisfactory
chromatography
and completelyresolvedthe ot-hydroxyacids.Typical chromatograms
of the separation
of the ot-hydroxyacids,resorcinol,phenol,and salicylicacid are shownin Figure 1.
Becausethe separationbetweenphenol and salicylicacid was only 1.8 minutes, the
wavelengthwas changedfrom 270 nm to 305 nm immediatelyafter the elution of
phenol.
INTERFERENCES

No chromatographic
interferences
wereobservedduring the analysisof more than 100
commercialproductsfor AHAs, as evidencedby consistentchromatographic
retention
timesandpeakwidths,andpeakswith no shoulders.
To assurethat no interferences
were
present,numerousproductextractswerepassedthrougha basicion-exchange
column.
HPLC analysisof the eluatedemonstratedthat there were no chromatographic
inter-

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JOURNAL OF COSMETIC SCIENCE

10

15

20

25

30

Time (Min.)
Figure 1. HPLCchromatograms
of standards
of A (glycoliclactic,andcitricacids),B (resorcinol,
phenol,
andsalicylicacid),andC (o-hydroxyoctanoic
acidando-hydroxydecanoic
acid).

ACID

DETERMINATION

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321

ferences
present.No interferences
wereobserved
duringthe analysisof productsfor
resorcinol,phenol,and salicylicacid.

A numberof chromatographic
interferences
wereobserved
whenproductswereanalyzed
for o-hydroxyoctanoic
ando-hydroxydecanoic
acids.It wasthereforenecessary
to isolate
the acidsfrom productsby ion-exchange
chromatography
prior to HPLC analysis.
LIMIT OF QUANTITATION

The quantitationlimits for the compounds

of interestwereestimatedbasedon HPLC
responses
of approximately
ten timesbaselinenoise.For glycolicacidthe quantitation
limit wasapproximately
0.5 lag(0.025 mg/ml whenusinga 20-lalinjectionloop).The
quantitation
limitsfor citricandlacticacidswereestimated
to be of the sameorderof
magnitudeasthatforglycolicacid.o-Hydroxyoctanoic
acidando-hydroxydecanoic
had
quantitationlimits of approximately1 lag(0.01 mg/ml usinga 100-lalinjectionloop).
The quantitationlimits of phenol,resorcinol,
and salicylicacidwereall approximately
0.2 lag(0.01 mg/ml for a 20-lal injectionloop).
METHODS

VALIDATION

The analyticalmethodswerevalidatedby performingrecovery

studiesof the AHAs and
other keratolyticagentsfrom a commercialproductor a simple emulsionof DEG
stearateandwaterpreparedin the laboratory.A mixtureof glycolicacid(1.23%), lactic
acid (1.15%), citric acid (1.43%), phenol(7.34%), resorcinol(31.45%), and salicylic
acid (1.59%) in 2.2 ml of waterwasaddedto 1.7 g of DEG stearate.The mixture was
warmed on a steam bath until the DEG stearatemelted. The resulting emulsion was

cooledwith stirringuntil a homogeneous

pastewasobtained.Aliquotsof the emulsion
wereanalyzedin triplicatefor the keratolyticagents.The resultsareshownin TableI.
Averagerecoveries
rangedfrom93% to 102%. The analyticalmethodfor the determinationof o-hydroxyoctanoic
ando-hydroxydecanoic
acidswasvalidatedby fortifyinga
commercialcosmeticproductat approximately1%. Portionsof the fortifiedproduct
wereanalyzedin triplicate.The resultsareshownin TableII. Recoveries
of o-hydroxyoctanoicand o-hydroxydecanoic
acidsrangedfrom 90% to 101%.
MARKET

SURVEY

Surveys
of productscontainingkeratolyticagentswereconducted
to determinethe levels
Table

Recoveryof KeratolyticAgentsFrom a LaboratoryPreparation

Found (%)

Keratolyticagent
Resorcinol
Phenol

Added(%)

Mean

Recovery(%)

31.45
7.34

29.88
7.11

31.20
7.37

31.92
7.89

31.00
7.46

99
102

Salicylicacid

1.59

1.56

1.57

1.62

1.58

100

Citric acid
Lactic acid

1.43
1.15

1.28
1.10

1.57
1.24

1.50
1.17

1.45
1.17

101
102

Glycolicacid

1.23

1.23

1.18

1.01

1.14

93

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JOURNAL OF COSMETIC SCIENCE

Table

II

Recoveryof tx-Hydroxyoctanoic
Acid and tx-Hydroxydecanoic
Acid From a CommercialSkinLotion
SampleNo.

Added (mg)

Found (mg)

Recovery(%)

4.37
3.54
4.50
3.00

4.29
3.51
4.08
3.02

98
99
91
101

3.67
3.54
2.86
2.74

3.37
3.20
2.85
2.50

92
90
100
91

o-Hydroxyoctanoic
acid
1
2
3
4

tx-Hydroxydecanoic
acid
i
2
3
4

of thesecompounds
andthe pH of commercial
products.Productswereobtaineddirectly
from manufacturers,
andwerepurchased
from salons,retail stores,andthroughthe mail,
from 1992 to 1996. Productswereanalyzedand keratolyticagentswereidentifiedby
HPLC retentiontime but were not confirmedby massspectrometry.The resultsof the
surveysare summarizedin Table III. Twenty productsobtainedfrom salonswereanalyzed. Glycolicacid wasthe most commonkeratolyticagent and wasfound in 95% of
the productsat concentrations
rangingfrom 3% to 67%. The pH of salonproducts
rangedfrom 0.2 to 4.38, with an averageof 2.95. Forty-fiveproductsobtainedfrom
retailstoresandthroughthe mail wereanalyzedfor keratolyticagents.Glycolicacidwas
the most commonkeratolyticagent,and wasfound in 67% of the productsat levels
rangingfrom 1% to 26%. The pH of commercialproductsrangedfrom 2.42 to 7.40,
with an averageof 3.92.
COSMETIC

INGREDIENT

REVIEW

The CosmeticIngredientReview(CIR), a panelof expertssponsored

by the CTFA that
Table

III

Levelsof KeratolyticAgentsand pH of SelectedSalonand CommercialProducts

Keratolyticagent

Frequencyof occurrence

Concentrationrange(%)

pH Range

Salonproducts

Glycolicacid

95

3-67

Lactic acid

15

5-7

10
5

11-12
8

2.48
ND b

1-26

2.42-4.26

Salicylicacid
Resorcinol
Commercialproducts
Glycolicacid

67

Lactic acid

22

Salicylicacid
tx-Hydroxyoctanoic
acid

13
11

Resorcinol

11

Phenol
Citric acid

9
4

tx-Hydroxydecanoic
Acid

0.4-9

0.1-5
0.01-0.4
1-35

1-7
0.2-4

0.04-0.3

0.2-4.38
2.48-2.81

2.67-5.65

4.00-7.40
3.47-3.65
4.00-4.78

4.00-4.78
2.67-5.38

3.47-3.86

Total frequencyof useis greaterthan 100% sinceseveralproductscontainedmorethan onekeratolytic

agent.

b Not determined.

ACID

DETERMINATION

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323

reviewsandassesses
the safetyof cosmeticingredients,hasreviewedthe safetyof glycolic
andlacticacidsand their saltsand simpleesters.In 1997 the CIR issueda final report
on thesecompounds.
The panelconcludedthat in commercialproductstheseingredients
are safefor use at 10% levelsat pH 3.5, when formulatedto avoid increasingsun
sensitivityor whendirectionsfor useincludethe daily useof sunprotection.The panel
alsoconcludedthat thesecompounds
aresafefor usein salonproductsat 30% at pH 3.0,
forproductsdesignedfor brief,discontinuous
usefollowedby thoroughrinsingfromthe
skin, when appliedby trainedprofessionals
and when applicationis accompanied
by
directionsfor the daily useof sunprotection(38).
FDA

CONCERNS

The FDA has a number of concernsrelating to the safeuse of AHAs in cosmetic

products.The safetyof long-termusehasnot beenestablished,
only limited studieshave
beenconductedon maintenance
of barrierintegrity, and the effecton the absorptionof
other cosmeticraw materialsis currentlybeing evaluated.The FDA recentlytestedthe
effectof glycolicacidon the absorption
of muskxylol, a commonfragranceingredient,
and hydroquinonein hairlessguineapigs (39). The study showedno enhancedpenetration of either musk xylol or hydroquinoneafter glycolicacid use.Recentstudieshave
alsofound no disruptionof the skin barrier function after skin treatment with a 4%
glycolicacid formulationat pH 3.8 (40).

The primaryFDA concernaboutthe prolongeduseof AHAs is their effecton the skin's

exposureto UV radiationfrom the sunbecauseof the well-established
link betweenUV
exposure
and the incidenceof skincancer(41,42). Sunexposure
hasalsobeenlinked to
prematureaging of the skin, includingthinning, dryness,lossof elasticity,and fine
wrinkling(43). Increased
exposure
of the skinto UV radiationmayaccelerate
the process
of photoaging,therebyleadingto the formationof morewrinkles.The CIR recognized
the potentialfor increased
sunexposure
followingAHA use,and includedsunscreens
in
their recommendations
for the safeuseof thesecompoundsin cosmeticproducts.
FUTURE

INVESTIGATIONS

The FDA hasinitiated clinicalstudiesto investigatethe effectsof AHA applicationto

the skin on the sensitivityof skin to UV exposure.The first study will determine
changes
in skinsensitivity
by determiningminimalerythemadoseandby measuring
the
number of sunburncells following exposureof skin to UV. The secondstudy will
determinechangesin skin sensitivityby measuringthe formationof thymine dimers(an
indicationof DNA damage)followingUV exposure.
The FDA will alsocontinuemonitoring commercialAHA productsfor AHA levelsand pH. Future studieswill include
productscontainingsalicylicacid, which are becomingincreasinglypopular in commercialcosmeticproducts.The National ToxicologyProgramhasalsorecentlyapproved
glycolicacid,lacticacid,andtheir saltsfor toxicitytesting(44). The studywill focuson
phototoxicityand chronictoxicity.

REFERENCES

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JOURNAL OF COSMETIC SCIENCE

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Saunders,
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(1996).

(16) W. P. Smith, Comparativeeffectiveness

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