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J. Soc. Cosmet.Chem.

29 185-200 (1978)

compoundswith the menthol coolingeffect


WilkinsonMatch ResearchDivision,PoyleRoad, Coinbrook,Buckinghamshire

Presentedat the AnnualScientificMeeting,Societyof CosmeticChemists,

1-2 December 1977, New York


The coolingsensationof menthol on the skin resultsfrom a physiologicalaction on the nerveendings.

Structure/activityanalysisas usedin pharmacologyhas allowedpredictionand subsequent synthesisof
a large number of compoundswhich have the cooling action of menthol.The compoundsrange in
chemicaltype, e.g. carboxamides to ureasto phosphine oxides.Many are as effectiveas menthol,and yet
do not havethe disadvantages associatedwith its volatility; they are non-odorousand remain longer on
the skin.To be effectivethe compounds needto penetratethe skin,and asexpected,the degreeof cooling
sensationfor an area of the body correlatesinversely with the thicknessof the stratum corncure.
The range of coolingeffects(e.g. subjects'descriptions,duration of effect) which has been noted,
and the influenceof vehicles,is described.Somepostulatesrelatingto the easeof skinpenetration,and the
physicalparametersof the moleculeare discussed. Future potentialapplicationsare briefly described.


The effectwhich/-menthol imparts to the skin and oral cavity is well known and is
usuallydescribedas 'cooling'or 'fresh'.The compoundhaslong beenaddedto toiletdes
in order to give a freshsensationand to pharmaceuticals
to alleviatethe sensationsof
inflammation or itch. Becausementhol is volatile, its effect on the skin is somewhat
transient.In someuses,especiallyshavingfoams,the vapourcangiveriseto an unwanted
coolingsensationin the eyes.In all uses,the dominant odour is almostimpossibleto
mask when mentholis presentin a proportion sufficientto give an appreciablecooling
This paper describescompoundswhich give a cooling effect, but do not have the
which resultfrom the volatility of menthol.The compounds
were synthesised by us between1971 and 1976, during a searchbasedon conceptsof
correlationbetweenstructureand biologicalactivity.Over 1200coolingcompoundswere
found; the purposeof this paperis to give a generalaccountof the molecularrequire-
mentsof cooling,and of the action of coolingcompoundson the skin. Details of the
syntheticwork and other aspectsof the studywill be publishedelsewhere,but further
descriptionof the compoundsis availablein publishedpatents(1).

* Present address: Footscray Institute of Technology, Ballarat Road, Footscray, Victoria 3011,

0037-9832/78/0400-0185$02.00¸ 1978 Societyof CosmeticChemistsof Great Britain

186 H.R. Watson et al.



Mentholdoesnot coolby volatilisation.

The coolingeffectalmostcertainlyresultsfrom
chemicalaction at or near thosenerveendingswhich are associatedwith the sensation
of cold. When mentholis placedon the lingual nerve of the cat the cold fibresof that
nerveare eitherprovokedinto firing or, if alreadyfiring, respondwith a higherrate of
firing(2). Sincethe neurophysiological
basesof the response
to coldare essentiallythe
samein all mammals(3-15), includingman (16), and sincethere are many common
featuresin the actionof mentholandsyntheticcoolingagents,asrelatedin thispaper,it
seemsreasonableto assumethat all suchcoolantsact by a commonmechanism,which is
that of a drug-receptor


We haveestablishedthat four importantcriterianeedto be satisfiedfor a compoundto

(i) a hydrogenbondinggroup;
(ii) a compacthydrocarbonskeleton;
(iii) a correcthydrophilic/hydrophobicbalance;
(iv) a molecularweightin the range 150-350.

(i) HydrogenBonding
A hydrogenbondingfunctionis essentialfor coolingaction.We believethat the function
must containan oxygenatom capableof acting as a hydrogenbond acceptor.For
greatestcoolingactivity,stronghydrogenbondacceptingcapabilityis necessary. Thereis
no indicationthat the provisionof morethan onehydrogenbondaccepting groupin the
moleculeenhancesthe coolingeffect;somep-menthane-diolsare active,but none is as
active as/-menthol.
Functionalgroupsare listedin TableI, togetherwith commentson the groups,and
on the compoundswhich incorporatethem.

(ii) HydrocarbonSkeleton
It is assumed that thefunctionalgrouptakespart in hydrogenbondingat a receptorsite,
and that for coolingthehydrocarbon portionor portionsof the moleculemustprovidea
compacthydrophobicregionnear to the site of hydrogenbonding.
The relationshipbetweenthe structureof the hydrocarbonskeletonand cooling
activity has been most thoroughly examinedwith N-alkyl carboxamides.Figure 1
indicatesthe variety of hydrocarbonstructureswhich, in conjunctionwith suitableN-
alkyl carboxamidegroups(-X), givecompoundsof strongcoolingactivity.It is note-
worthy that the hydrocarbonskeletonsare highly branched;this forcesa compact
and for manyskeletons,
allowsan apparentrequirement
that for strong
coolingactivity the functionalgroup shouldbe attachedto a carbonatom which itself
is a branchingsite,or is adjacentto a branchedcarbonatom.If the functionalgroupis
separatedfrom the branchingby a -CH•- group,coolingactivityis muchreduced,and
when separatedby a -CH•CH•- group,activity is almostlost.
New compounds
with mentholcoolingeffects 187

Table I. Hydrogen bonding groups: cooling

High Activity
Hydroxyl, -OH The hydrogen bonding group of menthol. Strong
hydrogenbonding,which givessomecompoundsof high
activity.Compoundsare normallyvolatile and odorous.
N-Alkylcarboxamide, -CONHR Probably the most useful group. Compoundsare of low
volatility, and the many possiblevariationsof the R
allow the hydrophilic/hydrol•hobicbalanceof the
moleculeto be tuned finely.
N,N-Dialkyl carboxamide,-CONRa Compoundsreasonablystrong but many are volatile.
Sulphoxido,-S(O) R Gives effectivecompounds,but their use is limited
owing to problemsof stability.
Phosphineoxide, =P(O)R Strong hydrogenbondinggroupswhich give effective,
usefulcompounds.(Although organo-phosphoms
compoundsin generalare suspecton ground• of
toxicity, we are not aware of a toxicologicaleffect
attributable to the phosphineoxide group; the
compoundsare thermodynamicallyvery stableand are
of low chemical reactivity.)
Medium or Low •lctivity
Carboxyl, -COOH Compoundsrelativelyweak; activity is reducedin
alkaline vehicles.
Carboxamide, -CONHa Compoundsrelatively weak.
Hydroxyalkyl ester,-COOCnH2n0H If the hydroxyl group is in the 2-position,moderate-
strongactivity can result.
Urea, -NCONRa Somecompoundsreasonablyactive.
Sulphone,-SOAR Medium hydrogen bonding, but compoundsof low
Sulphonamide,-SOaNRa Medium hydrogenbonding, but compoundsweak and
have very bitter taste.
Sulphinamide,-SONR2 Weak compounds,many of which are of limited
Ether, -OR These hydrogen bonding groupsappear not to give
Ketone carbonyl, -C(O)R activity,either becausethey are not capableof hydrogen
Ester (simple), -COOR bond acceptance,
or, if capable,giveonly relatively
Chloro, -C1 weak bonds.
Amine, -NHa
Thioamide, --C(S)NRa

apply to other functionalgroups,althoughit shouldbe noted
that owingto difficulties
of synthesis,
we did not explorefully systems
with sulphuror
phosphorusas the hetero-atomof a cyclicskeleton,and the most activephosphine
oxidesand sulphoxides preparedhaveopenchainstructures.

(iii) Hydrophilic/Hydrophobic
For strongcoolingactivity,a compoundmusthavethe correcthydrophilic/hydrophobic
balance.This balanceis of recognisedimportancein drug-receptorinteractions.The
most commonmeasureof hydrophilic/hydrophobic balanceis the Hanschlog P value,
whereP is the partitionfunctionof the compoundbetweenn-octanoland water (18).
The logP valueis wellestablished
asan importantfactorof thepharmacological
188 H.R. Watson et al.

Figure1. Hydrocarbonskeletonswhich give strongcoolingcompoundswhen -X is a suitable

N-alkyl carboxamidegroup.

Io.3) 1o.2•

Figure2. Somestructures
of coolingcompounds.
The figurein parentheses
value in micrograms.
New compounds
with mentholcoolingeffects 189

of seriesof relatedcompounds(19-22). It is alsorecognised

as one of the factorswhich
determinesthe rate of transportof compoundsthrough biologicalmembranes,especially
the skin (23).
The log P valuesof coolingcompoundswere calculatedfrom publishedtablesof the
substituentx-values(24). Strongcoolingcompoundshavelog P valuesin the relatively
narrowrange1.5-4.0 and valuesfor nearlyall coolingcompoundslie in the range 1.0-5.0.
The log P value of menthol is 3' 1.

(iv) Molecular Weight

If a hydrocarbonskeletoncapableof givingstrongcoolingcompoundsis combinedwith a
stronghydrogen-bond acceptingfunctionalgroup,and if the log P valueof the resultant
moleculeis in the correctrange,then coolingwill be observedif the molecularweight is
in the range150-350.The criterionof molecularweightis moreflexiblethan criteria(i),
(ii) and (iii) but it is certainlynot possibleindefinitelyto add balancedhydrophobicand
hydrophilicportionsto the moleculeand to retain a coolingeffect.
The observations on the four criteriaaccordwith a drug-receptorinteraction(17).


The varietyof typesof moleculewhichgiveriseto coolingis shownin Fig. 2. All of these

we have rated as medium-strongto strongcoolingagents;their averageoral threshold,
recordedin [tg (determinedas describedbelow), is givenin parentheses.Compound
I is, of course,menthol.CompoundII hasreceivedparticularattentionas beingof merit
for oral and topical use; it is FEMA GRAS listed.
The variety of effectiveN-alkyl- or substitutedN-alkyl-carboxamidefunctional
groupsis worthy of note. TableH givesoral thresholdsof compoundswherean N-alkyl-
carboxamidegroup is substitutedfor the hydroxylgroup in/-menthol.
TableH showsexamplesof moleculeswherea large hydrophobicN-alkyl group is
balancedby the presenceof a further hydrophilicgroup.Note alsoan indicationthat the
hydrogenbond acceptingfunctionof the carboxamidegroupis influencedby the presence
of otherelectronwithdrawingatoms.All thep-menthane-3-carboxamides listedin TableII
have the samestereochemical configurationas natural/-menthol.

Table II. N-alkyl carboxamidefunctional groups

N-Alkylcarboxamide Oral threshold,gg

-CONHCH, 1.1
-CONHCH(CH,): 0.45
-CONHC(CHa)a 0' 4
-CONHC6H4OCHa(p) 0' 2
-CONH(CH•)aOH 2' 7
190 H.R. Watson et al.

Justas bmentholhasthe greatestcoolingactivity of the eight stereoisomeric

we believethat carboxamides suchas II (Fig. 2) with the samestereochemistry also
possesshigheractivitythan any of their isomers.Thus, d-mentholis 45 timeslessactive
thanitsnaturalenantiomer/-menthol (asdetermined by the oral thresholdmethod),and
the d-enantiomerof CompoundII is 70 timeslessactive than II. Theseobservationsare
consistentwith mentholand the syntheticcoolantsactingat commonreceptorsites,the
sitesbeingassociatedwith the nervesresponsiblefor the sensationof cold. We believe
that wharestereoisomerism is possiblein a moleculeit is a determinantof activity.


Apart from the coolingeffect,and a degreeof flavourpotentiationand odour modi-

fication,*thereis no commonpropertyof coolingcompounds.For instance,thereis no
associationbetweenminty smelland cooling.
There being such a wide range of chemicaltype, the physicalpropertiesof the
compounds are varied.Most are solids,althoughliquidsare not uncommonwhenthe
functionalgroup is hydroxyl,N,N-dialkylcarboxamide,or phosphineoxide.Most are
readilysolublein commonorganicsolvents,but owingto the requirementsof the log P
value,all are of verylimitedsolubilityin water(althoughit shouldbenotedthatsaturated
aqueoussolutionshave readily perceptiblecooling effects).The alcoholsand N,N-
dialkylcarboxamides are in generalvolatile,and are odorous,the odour typesranging
from minty to fruity to earthyto camphoraceous. Compoundsof otherclasses havelow
or very low volatilityand are non-odorous.
Many of theN-alkylcarboxamides, phosphineoxidesand ureasarevirtuallyinvolatile,
and are odoudessand tasteless.Chemical and thermodynamicstability follow the
known characteristics of the constituentgroups.The simplealcohols,acids,amidesand
phosphineoxidesare of very high stability.This includesthe long-termstabilityin
aqueousenvironments whichis essential
for mostprojectedenduses.Sulphurcompounds
and ureas are less stable and careful considerationis needed when matching these
compoundswith usagecompositions.



IntrinsicActivity- Oral Thresholds

A reliabletestof the intrinsiccoolingeffectof a compoundwasessentialfor development
of any theoryof relationshipof structureto activity.The tongueis very sensitive
to the
coolingeffect,it offersa convenienttest siteand, in particular,appearsto presentre-
lativelylittle physicalbarrier to the compounds.Althoughthere are a few exceptions,
coolingcompounds appliedto the tongueappearto penetraterapidlyto the coldnerve
* It appearsthat whencoldreceptorsare chemicallyexcited,thereis an associated
mild response
adjacentodour and tastereceptors,and modificationof thesetwo sensesis almostcertainlya general
of coolingcompounds(25). (David Kendall of Arthur D. Little, Boston,has testedover
100 compoundsof our series;all modifiedflavour.)The propertyis in accordwith that of pungentor
'warming' compounds;pungent componentsof peppers,chilliesetc. are well establishedas flavour
New compounds
with mentholcoolingeffects 191

receptors.For this reason,we believethat the oral activitiesare a reasonablyclose

approximationto the intrinsicactivitiesof the compounds.Oral equipotencytests,in
whichtrainedpanelistswould deriveequivalentcoolingeffectsby balancingdifferent
concentrations of test and control solutionswould have been the most scientifically
satisfying,but suchtestsare very time-consuming and in view of the large number of
compoundsinvolved,were not consideredfor our own studies.(Trained panelistsat
Arthur D. Little, Boston,derivedthe sameorder of ranking of effectiveness which results
from the thresholdmethoddescribedbelow when testing20 of the compoundsby an
A thresholdmethodwasusedfor all determinationof oral activity,and the valuesof
oral thresholdderivedfrom it are treatedas (reciprocal)measures of intrinsiccooling
activity.Filter paper(1 x 1 cm) wasimpregnated with a knownamountof compoundby
applicationof a measuredvolume(1-5 pl) of a solutionin redistilledpetroleumether
(40-60ø).After 30 sec,the paper was placedon the tongueof the subject,who was
required only to report presenceor absenceof a cooling effect.After an interval, the
procedurewas repeated,adjustingthe amount of compoundas required, until the
thresholdwas ascertained.Usually, a sufficientlyaccurateestimatecould be obtained
with asfew asfiveto ten measurements, and althoughtherewasa variationof + 30•o on
repeat tests,this was acceptablebecausedifferencesbetweencompoundswere usually
quite considerable.
Individualsdifferin their sensitivityto the coolingeffect,and the personalthresholds
of a groupof subjects are likelyto covera considerable range.For example,the menthol
thresholdsof 23 subjects,chosenat random, were in the range of 0.02-10 lsg.Also it is a
generalfeaturethat the distributionisnot simpleGaussian.Most panelistshad thresholds
reasonablynear the minimum,there beinga long tail to the value representinglowest
Eventhoughthe individualmembersof a panelmay havehad a widevariationin their
mentholthreshold,theyrankeda seriesof compoundsin the sameorder.Thus, although
the basicsensitivity
to a coolingeffectvariedfrom subjectto subject,the relativeeffectsof
a seriesof compounds wereequivalent for all panelists.
All strongcompoundsappeared
relativelystrongto all subjects,and all weak compoundsappearedrelativelyweak. In
the absenceof this feature, ranking of intrinsic effect would have been much more
In view of the wide variation betweenpanelists,arithmeticmeansof thresholdresults
wereobviouslyof no value.Geometricmeansgaveusefulranking,but it is believedthat a
more accuratecomparisonof compoundswas achievedby comparing a panelist's
thresholdfor a test compoundwith his personalthresholdfor a standardcompound.
The averageratio for the whole panel was then derivedas the arithmeticmean of the
individualratios,and the meanthresholdwascalculatedby referenceto the known mean
threshold(geometricmean of 23 subjects)of the standardsubstance.Menthol was not
chosenas the standardsubstance becauseit givesoccasionalinaccuratevaluesowingto
its volatility;N-ethyl-p-menthane-3-carboxamide (II, Fig. 2) is our standard.
The above method appearsto be reliable. Panelistswere routinely checkedfor
standardresponse by normalcross-check methods,and it is noteworthythat their thres-
hold for a givencoolingcompounddoesnot changeevenafter severalyearsof practice.
Oral thresholds recordedduringthe work spannedthe range0-08-50 pg.A compound
with a thresholdof lessthan 0.5 [tgis regardedas 'strong'.Thresholdsof greaterthan 50
[tg were not quantified;at that level a compoundshowsexceedingly weak activity, and
192 H.R. Watson et al.

undesirablesideeffectssuchas an unpleasanttaste,tinglingand burningusuallypre-

dominate.Large numbersof compoundswereexaminedin our study.When the method
describedabove had becomewell established,a small panel of four to six subjects,
chosenfrom the largerpanelfor their near averagesensitivitywasusedfor rapid initial
screeningof compounds.

Topical Testing
Like oral thresholddetermination,measurementof topicalthresholdsis complicatedby
the fact that individual sensitivitiesto cooling compoundsdiffer considerably.Skin
thresholdswere measuredas follows: 0.2 ml of a solutionin petroleumether (40-60ø)
wasmeasured on to a circularareael0 cm•) of skinsurfaceon theinsideof theforearm,
midwaybetweenthe wristand elbow.After 30 min, the subjectwasrequiredto respond
whetheror not a coolingeffecthad beennoticedduringthe period. CSomecompounds
were slowto act, but the main reasonfor the delaybetweendoseand questionwas to
allow the panelistto differentiatethe chemicalcoolingeffectfrom the inevitablebut
transient physical effect of the solvent evaporation.) Since degreasingthe skin with
solventbeforeapplicationof the coolingcompounddid not changethe threshold,and
washingmay have causedhydration,the skin was not treatedbefore a thresholdtest.
A panel of 50 subjects,testedby the abovemethod, had thresholdsfor menthol of
between0.5 and 100 mg. As an example of the non-Gaussiangrouping towards the
sensitiveend,the thresholdsof 32 of the subjects
lay between2.0 and 10 mg, and only six
subjectshad thresholdsof greaterthan 25 mg.
It shouldbe recalledthat the oral thresholdmethod was usedextensivelybecauseit
appearedto givethe bestmeasureof intrinsiccoolingactivity.Skin thresholdlevelswere
not of value for that purpose,and in addition they were confoundedby the mannerin
which the compounddepositedon the skin followingevaporationof the solvent.Some
compoundseven crystallised,and thereforeclearly gave spuriouslyhigh 'threshold'
results.For thesereasons,our topicaltestingdid not rely on thresholdmethods.
The aim of the topicaltestingwas Ca) to find, in generalterms,thosecompounds
whichweremostsuitablefor applicationin topicalproductsandCb)to matchcompounds
with producttypessothat the overalleffectof the additionof a particularcoolingcom-
poundto a productcouldbejudged.In view of the difficultiesimplicitin skin threshold
testing,and the inevitablerelationshipbetweencompoundeffectiveness and the medium
in whichit is applied,we concentratedon testsbasedon applicationin the producttype.
Thereby (b) above, for a particular composition,was satisfieddirectly, and Ca), the
relative generalcharacteristicsof the compounds,graduallyemergedas the number of
testsin differentmedia increased.This part of the studyis on-going.The pattern of
productorientedtestsis exemplified by thefollowing,whichwasusedfor aerosolshaving
foams. The panel consistedof five men who were experienced in the effectsof cooling
compounds.The subjectsappliedapproximately0.5 g* of the shavingfoam acrossthe
trigeminal/cheek area,wipedthe areaafter 5 rain, and a trainedobserverrecordedtheir
commentsduring(normally)the first 10 min followingapplication.The observertook

* Unlike thresholdtesting,direct effectiveness

testingis lessinfluencedby the quantity of material
applied. The concentrationof the cooling compoundin the medium is important, but compositions
suchas shavefoams,whichare appliedin excess,are besttestedin excess, it beingimplicit that theydo
not dry out during the period of observation.
New compounds
with mentholcoolingeffects 193

particularnote of time of onset,degreeof cooling,and 'quality'(the meaningof the term

'quality' in this contextis describedbelow).
The degreeof coolingeffectwasscoredon an 8-pointscale(no effect,threshold,weak,
weak-moderate, moderate, moderate-strong,strong, very strong). Repeat tests on
differentdaysweredesirable;a subject'srepeatscorescould vary by as much as 3 points
on the scale.It wasimportantthat, asmuchas possible,the subject'sskin was in the same
stateof hydrationon repeattests.(As an extremeexample,thefaceis considerably more
sensitiveimmediatelyfollowing shavingthan at other times of the day.) It was also
desirablefrequentlyto includeas a controlthe basecompositionwith no coolingcom-
pound; this actedas a test on the panelists,and alsopermittedweightingof the scores
sincethe basecompositioninvariablycausedthe subjectsto recordsensations. Similarly,
compositionsof known very strongcoolingeffectwere includedas positivecontrols.


Different parts of the body differ greatlyin their sensitivityto the coolingcompounds.
No attempt has been made to determinethe relative sensitivitiesin absoluteterms, but
the order of sensitivityis:
eye> > tongue> interior buccal region> ano-genital area> lip > trigeminal area>
other face areas> axilla > inside forearm, breast> other arm areas, thigh, back >
hands,feet> > palms,* soles.
The eye is extremelysensitive,with thresholdsprobably measurablein nanograms,
and to an extentthat a simpletestfor coolingeffectin a vol•tile compoundis to hold the
openedbottle near the eye. This test with menthol givesa sharp and very obvious
sensation,which accordswith consumerscommentson the effectof mentholatedshaving
foam on the eye.
Like menthol,syntheticcoolingcompoundsalsogivea coolingsensationin the lungs
(when added to cigarettesor inhaled as an aerosolspray) and to the gastrointestinal
tract (wheningested).
The order of sensitivityclearly follows a generalorder of increasingthicknessof
stratumcorneum(26), andit seems
probablethat the sensitivity
of an areais determined
mainly by the easewith which the compoundcan penetratethis barrier. Further in-
dicationis providedby the fact that abradedor hydratedforearmskin has a reduced
thresholdcomparedto intact skin. Although the barrier role of the stratumcorneumis
probablydominant(27), it is likelyalsothat the numberof cold-sensitive nerveendings
per unit area, and the efficiencywith which the centralnervoussystemprocesses nerve
signals,vary with the locationon the skin (3, 28). (During a searchfor an equipotency
methodbasedon mirror imagedbody areas,the menthol thresholdsof sixteensubjects
weremeasuredon the left and right forearm. Six were more sensitiveon the right, and
six on the left forearm. Four had no difference of threshold. There was no correlation
with the sideof the dominanthand of the subjects.Similardifferences betweenleft and
right sidesof the facehavebeennotedin thresholdtests.The studyhasnot beentaken
further, but it seemspossiblethat thesedifferencesare related to the efficiencyof neural
signalprocessing. At suprathresholdlevelsthesebilateraldifferences are not detectable).

* Some subjectshave recordeda responsewhen strongsolutionsare applied to the palms but our
currentview is that the effectis insufficientlydistinctto be recordedpositively.
194 H.R. Watson et al.

All subjectsin this study were Caucasians.Using 50 subjects,we soughtto relate

forearmthresholdvaluesto age,gender,hair colourand skintype(aspaleor dark, greasy
or dry), but on this smallpopulationno relationshiphas beennoted.


In compositions designedfor usagethe concentration

of coolingcompoundis manytimes
the thresholdconcentration,and althoughthresholdmeasurements are a usefulguideto
relativeactivitiesa studyof the relationship
betweendoseandthe subjects'responseis of
more relevanceto practical formulations.
Ideally, we wouldhavepreferredto usethe well established
of magnitudeestimationand crossmodalitymatching(29) to evaluatethe form of the
powerlaw (30) whichwould relatethe sensationproducedby the coolingcompounds
to the degreeof stimulus(that is, the dose)applied.The numberof formulations andthe
variety of compoundswhich we wishedto cover necessitated a more rapid technique,
that of the magnituderating describedearlier.This gaveresultswhich affordedvaluable
informationon the relationshipbetweendoseand response,and which allowed com-
parisonbetweendifferentcompounds whenusedin the sameformulation.Figure3 shows
typicalresponse patternsfor two compounds in a shavingfoam formulation.
It is important to note that at suprathresholdlevelsof coolingcompoundsin com-
positionsthe variation of responsefrom one individualto anotheris muchlessthan the



V V o o
V • V o o o
• o o


0 0.02 0,04 0'06 0.08 0.10 0,12 0.14


Figure 3. Plots, for two compounds,of subjects'descriptionof degreeof cooling againstcon-

centration of compound in a shaving foam formulation.
New compounds
with mentholcoolingeffects 195

variation of thresholdlevels.(If this were not the case,then it is unlikelythat menthol

would be usedso widelyin toilet preparations.)
The duration of the cooling effect on the skin is related to the dose, higher doses
resultingin a more prolongedeffect.Also, at a givenconcentration,the more activethe
compoundthenthemoreprolongedthe effect;thispertainsregardless of compoundtype.
Obviously,volatility is an important factor in determiningduration. The coolingeffect
of volatile compounds,includingmenthol,is relativelytransientand is rarely recorded
for more than 15 min. The duration of involatile compoundsis considerablylonger;
someproducecoolingfor morethan 4 h.
After the initial perceptionof coolingeffecthas ceased,it is frequentlyobservedthat
the coolingsensationis further perceived,but for shorterperiods.This effectis more
noticeablewith strong compoundsat high doses,and normally follows washingor
sweating.The long durationof involatilecompounds,and the repetitionof the cooling
effect,is consistentwith the findingthat compoundscan still be detectedin the stratum
corneum24 h after application.Thus,whenCompoundII (Fig. 2) wasappliedas a 10•o
solutionin ethanolto a 5 x 5 cm area of the forearm, half of the areabeingstrippedwith
pressure-sensitive tape after 30 rain, and the other half after 24 h, 1-5 mg of compound
was detectedin strippings3-6 after 30 min and 0.3 mg in stripping3-6 after 24 h.


All coolingcompoundsproducesensationsother than pure cooling.They are most

readilydescribedby referenceto a strongpeppermintcandy,whichproducestinglein the
mouth and, if strongenough,a burning sensation.Compoundsdiffer in the relative
degreeof coolingand sideeffects;thosethat producelittle effectotherthan coolingare,
in our terminology,of high 'quality'. The relative degreeof cooling and side effect
appearsto correlateto somedegreeto compoundtype; for instance,phosphineoxides
and hydroxyesters tendto haveparticularlylow levelsof sideeffect.The sideeffectsare
dosesensitive;at low doseswith mostcompounds, or at mediumdoseswith compounds
havinga low levelof sideeffects,theyare not apparent.In general,increasing
the doseof
the coolingcompoundbeyonda certainlimit givesno apparentincreasein cooling,but
causesan increasein sideeffects,finally to a degreewherethe sideeffectsdominatethe
Descriptionsof sideeffectsin the mouth, normallytingling,stinging,and burning,
are paralleledby descriptions of sideeffectson the skin,and compounds proneto give
oral sideeffectsgivesideeffectson the skin.In general,the moreactivethe compoundthe
lessnoticeableare the sideeffectsat a givenlevel of perceivedcooling.


Hydrationor partial strippingof the stratumcorneumaidspenetrationof the cooling

compounds considerably, thusaccordingwith the established
patternreportedby the
otherworkers(27). The briefaccountof skinpenetrationwhichfollowsis directedto the
betweenthenatureof thecompounds andtheirabilityto penetrateskin,and
refersto non-occludedapplicationwherethe skinhashad no previoustreatment,with
relativehumidityat between40 and 60•o. When a compositioncontaininga cooling
196 H.R. Watson et al.

compoundis placedon the skin, three processes

mustoccurbeforea coolingeffectis
(i) molecules
of the compoundmusttransferfrom the vehicleand mustpenetrate
the surface of the stratum corneum.
(ii) moleculesmustdiffusethroughthe skin.
(iii) moleculesmustinteractwith the receptors.
Each of the threeprocesses is influencedby the propertiesof the compounds,but the
propertiesof the vehicle,in relationto its interactionwith the compounds,are also of
considerable influenceon process(i).
Polarityis the mostimportantparameterof the vehicle.This is apparentfrom results
obtainedfrom usageformulations,and alsofrom directvehicletrials.Nine compounds
with the/-menthol stereochemistry, eithercarboxamides chosenfrom compoundslisted
in Table II or hydroxyesters, were testedas 0'25•o solutionsin eight vehicleswhich
represented a polarityrangefrom olive oil to aqueousethanol,usingthe facetestdetailed
abovefor shavingfoams.Regardless of theirintrinsicactivity,all compounds
coolingratingsin the morepolar vehicles.Indeed,no coolingwasnotedfrom solutions
in the two vehiclesof lowestpolarity, olive oil and hexyllaurate.
In a corresponding testthe CompoundIII (Fig. 2) wastestedas a 0'4•o solutionin
differentethanol-watermixtures(25; 33; 50; 67•o w/w of water). The coolingscore
increasedprogressively from 'weak-moderate'(25•o water)to 'moderate-strong' (67•o
water). Onset of cooling effect occurredin lessthan 2 min, and it is believed that skin
hydration had little or no influenceon the increaseof score.
The processof transferof compoundfrom the vehicleto the outer skin layersmay be
viewedasa partitionbetweenthe vehicleand the protein/lipidmaterialwhichrepresents
the stratumcorneum.The coolingcompoundsare relativelyhydrophobic(log P> 0)
and thereforethey will partition only little from lesspolar vehiclesinto the skin: increase
in polarity of the vehicleswill shift the equilibrium in a direction which will favour
absorptioninto stratum corneum.This effect is well established;for example,hydro-
phobicdrugsare absorbedbetterfrom hydrophilicthan from hydrophobicvehicles(31-
Once a cooling compound has been releasedfrom the vehicle into the stratum
corneum,then its ability to diffuseto receptorsitesis of prime importance.It is recog-
nised that the size of moleculeis a parameter of skin diffusion,and it is noteworthy
that of the compoundsof our series,those that give effectivetopical coolingall have
molecularweightslower than 250.
A degreeof water solubility as well as lipid solubility appearsessentialfor skin
diffusion,and it is knownthat for mostdrugsthe limitingparameteris water,ratherthan
lipid, solubility(23). This is also apparent with coolingcompounds,where in general
compoundswith lower log P valuesare more likely to be effectiveon the skin.A simple
correlationof log P value with coolingeffectis not expected,becausethe log P value
influences intrinsicactivity,but in those(short)homologousserieswhichwe havebeen
able to study,the log P valueof the compoundwith the highesttopical scoreis displaced
by approximatelyone unit, in the directionof more hydrophilic,when comparedto the
log P valueof the compoundof highestintrinsiceffect.
Oral thresholdvaluesare of limited use for predictionof topical effects.Figure 4
showsa plot of oral thresholdagainstmeanactivityscoresfor 64 compoundsin shaving
foam (0'15•o concentration).There is clearlyno well-definedcorrelation,and the only
New compounds
with mentholcoolingeffects 197




x x



x x x

I I I I , I I •
0.2 0'5 I 2 5 10 "'-


Figure 4. Plot of oral threshold of 64 compoundsagainst cooling activity rating for 0'15%
concentrationin shavingfoam on face.

deductionto be made is that a reasonableoral activity (threshold <2 gg) permits, but
doesnot guarantee,a hightopicalactivity.Poor penetrationwill considerably reducethe
topicaleffectiveness of a compoundof high intrinsiccoolingactivity,but good pene-
trationcharacteristicswill not givea strongtopicalcoolingcompoundif the compoundis
not of high intrinsicactivity.
As describedpreviously,the four molecularrequirementsfor intrinsicactivity relate
to hydrogenbonding,compacthydrocarbonskeleton,hydrophilic/hydrophobic balance,
andmolecularweight.As evolvesin thissection,for topicaluseof thecompounds thelast
two criteria named are modified by requirementsof skin penetration.The limit of
molecularweightis reducedfrom 350 to 250, and the optimumrangeof log P valueis
shifted from 3.0 + 1.0 to 2.0 + 1'0.


Many compositions
containingthe syntheticcoolingcompounds
and only an outlineis possiblein this paper,togetherwith noteson instanceswheretheir
use is contra-indicated.
As might be expectedthe compoundsare very effectivein
productsfor use in the mouth (e.g. toothpastes,mouthwashetc.) and, apart from
occasionalproblemswith absorptionon solids,matchingthe coolingeffectto the flavour
profileis more important that the effectsdue to the formulation.
For topicalproducts,
the influence
of the vehicleis important.Variouscompounds
have been examinedin compositionsfor topical use; derivativesof p-menthane-3-
carboxylicacid, acyclic carboxamidesand phosphineoxides have receivedthe most
attention.Commentson the varioustypesof formulationare presentedin TableIII.
198 H.R. Watson et al.

Table 1211.
Coolantsin compositions

Nature of composition of coolant,% w/w Comments

Alcohol solution (0.3-0' 5) Gives effectivecooling. Compoundsresidingon

the face can be transferredvia finger to lips,
giving cooling effecthours later. This is viewed as
are preferred. Note that the effectivevehicle of an
aftershave is often the mixture of non-volatile
components,i.e. the fragranceoil and emollients.
For this reasonit is better to usepolar emollients
suchas propyleneglycolthan non-polaremollients
such as isopropyl myristate.
Shavingfoam (0.1-0' 2) Very effective,with cooling noticed 10-30 sec
after application.Little residueleft on face, hence
no transferproblems.Coolingremains5-15 min
after removal.

O/W emulsioncreams, (0.2-0.5) Effective.Perceptionmay be slow, e.g. 60 sex:

lotions, balms. after application.With suitablecompounds,
duration is long.
Solid cologne (0.3-0.7) Very effective.Much recurrenceof cooling
on, e.g. the forehead.

normallyrelateto the differentsensitivities
of differentbody areas'
Aerosolsprays:if aerosols
areinhaled,the coolingeffectis likelyto be noticedin the
throatandlungs(althoughin air fresheners
a verysmallproportionof compound givesa
Shampoos: accidentalingress
of theresultingfoamto theeyesgivesan intenselevelof
Talcs:the concentrationof compoundwhichis neededto provideeffectivecoolingon
mostskinareasgivesintenseeffectsin the ano-genitalarea.
Toilet Soaps:as talcs.
Deodorants, antiperspirants:
veryeffective,but the subjectassociates
coolnessin the
axillae with the wetnessof perspiration.


In thispaperonlya generaldescription
of the work hasbeenpossible.
In thefuture,we
hopeto publishin greaterdetailaspects of structure/activity
aspects of topicaleffects.
We recognisethatthewiderangeof compounds whichis now
availableofferspossiblenewtoolsfor studyof skinpenetrationandneurophysiological
effects;weareunlikelyto extendourbriefinspection
of theseareas,andinvitespecialists
in thesefieldsto take the study further.


withthework,but special
mentionshouldbemadeof John
andRoderickThomson (all of Wilkinson
Match ResearchDivision)who carriedout mostof the skintestexperiments.
New compounds
with mentholcoolingeffects 199

We thank Dr JohnSpreadborough
for his supportfor the projectand for permission
to publishthis Paper.


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