March 8, 2012

Role of the eucalyptus-derived ingredient eucalyptol in
reducing unpleasant sensory irritation from cooling sensations –Investigations by Mandom- For a very comfortable cooling sensation -Mandom Corporation (Head Office: Osaka, President Executive Officer: Motonobu Nishimura, hereafter“Mandom”) has been studying the various factors consumers attribute to sensing comfort, and aim to improve both,usability and function of cosmetics (quasi-drugs).
As part of this initiative and through joint research with Professor Makoto Tominaga of the Okazaki Institutefor Integrative Bioscience, Mandom previously established an alternative evaluation method using TRP (TransientReceptor Potential) channels (see “Reference material <Sensory irritation mechanism>”) to study sensory irritationin skin. This discovery enabled quantitative evaluation of irritation.
Here, using TRP channels, we identified the comfortable cooling effects due to eucalyptol, the eucalyptusderived ingredient that does not cause unpleasant sensory irritation. We also discovered that it possesses the ability
to reduce the unpleasant sensory irritation caused by other freshening ingredients.
Mandom is keen to continue exploring this approach, and use the findings in the application development ofcooling sensations in future products.
Furthermore, we presented the results of this study at the “Congress of the Japan Neuroscience Society” heldfrom September 14 to 17, 2011, and “The 21st Congress of the International Federation of Societies of Cosmetic
Chemists (IFSCC)” held from December 12 to 14, 2011, Bangkok, Thailand.
1. Unpleasant sensory irritation from strong cooling sensations
In recent years, many refreshing cosmetics claim to be “refreshing” and “cool” based on assessments against
heat, intense weather, energy reduction, etc. To provide such “refreshing” and “cool” feeling, these products aresupplemented with freshening ingredients such as ℓ-menthol, or by providing cool sensation by lowering the bodytemperature based on ethanol vaporization which appears as heat loss.
The typical freshening ingredient ℓ-menthol is added to many refreshing cosmetics for this purpose. Other
alternate freshening ingredients have been developed, but ℓ-menthol is indispensable given its superior ability togenerate a stronger cooling sensation. However, if a large amount of ℓ-menthol is added, it causes a burning
sensation, eventually leading to an unpleasant sensory irritation.
Mandom has surveyed several freshening ingredients that can develop a comfortable cooling sensation withminimal discomfort to consumers.

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-1-2. The comfortable and sensory irritation-free freshening ingredient eucalyptol
Burning and cooling sensations felt at the same time due to ℓ-menthol seem to involve TRPA1, which is thesame receptor in TRP channel and involved in the spicy ingredient in wasabi and pepper. Hence, if ℓ-menthol isadded at high concentrations, TRPA1 is activated, which causes the unpleasant sensory irritation. In addition,TRPM8 is also involved in generating cooling sensations. At Mandom, we are seeking an ingredient that provides
only a cooling sensation with no or minimal sensory irritation, and employing these two channels. By doing so, theratio of TRPM8 activation and TRPA1 activation due to ℓ-menthol serves as a reference, and this ratio serves as acomfort index.
Comfort index(ℓ-menthol=1)=

TRPM8 activation
TRPA1 activation

If this ratio is high, it indicates a strong cooling sensation with little unpleasant sensory irritation. Based on this
comfort index, we screened various ingredients. Based on these results, we discovered eucalyptol, a natural,eucalyptus-derived ingredient (Fig. 1).
As we analyzed eucalyptol in detail, we found that it does not activate TRPA1, but activates only TRPM8. We
also found that apart from TRPA1, eucalyptol does not activate TRPV1 and TRPV2, which are known sensors
involved in unpleasant sensory irritation upon activation (Fig. 2). In other words, eucalyptol may be considered an
ingredient that provides only a cooling sensation and no unpleasant sensory irritation.
3. Reduction of unpleasant sensory irritation by eucalyptol
Further analysis led Mandom to report the discovery for the first time that eucalyptol can inhibit TRPA1
activity (Fig. 3). Mandom from in-house studies validated the cooling sensations due to addition of ℓ-menthol,and activation of TRPA1 resulting in an unpleasant sensory irritation. When eucalyptol is added, it appears toreduce the unpleasant sensory irritation caused by ℓ-menthol (Fig. 4). We therefore, speculate that even though theaddition of ℓ-menthol results in providing a stronger cooling sensation, it also means a proportional increase inunpleasant sensory irritation, such as a burning sensation. Adding eucalyptol may reduce such unpleasant sensory
irritation, while also providing a stronger cooling sensation.
4. Realizing comfortable coolness
Assuming that the effect of ℓ-menthol simultaneously activating TRPA1 and TRPM8 represents a “rapid”
cooling sensation. The ability of eucalyptol activating only the TRPM8 but not TRPA1 may result in a “mild”
cooling sensation. So, by adjusting the balance of ℓ-menthol and eucalyptol, it may be possible to control not only
the intensity of cooling sensations but also that of sensory irritation. Thus, we explored the possibility ofdeveloping and providing satisfactory products that address customer needs regarding cooling sensations
preferences.
In the future, we shall actively use the newly identified freshening ingredient, eucalyptol, in our productdevelopment line-up.

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Discomfort←Comfort
index→Comfort

TRPA1 activation

TRPM8 activation

Fig. 1．TRPM8 and TRPA1 activation by eucalyptol for comfortable cooling

Cooling sensation score

Fig. 3. TRPA1 inactivation by eucalyptol

Fig. 4. Cooling sensation and reduction of unpleasant sensory irritation in theneck by eucalyptol

Unpleasant irritation score

TRPA1 activation

Fig. 2． Selective activation ofeucalyptol on TRPM8*Reference material<Sensory irritation mechanism>
According to recent studies, “sensors” called “TRP channels” perceive chemical substances andtemperature to convert them into electrical signals in the skin nerve cells. These signals contribute to
the transmission of sensory irritation. The TRP channels found to be associated with the unpleasant“tingling” and “stinging” sensations felt when using cosmetics in Mandom’s researches.
TRP channels are involved in the “cooling sensation” involving refreshing cosmetics, and they
activate TRPM8, a cold sensor. Addition of menthol to many refreshing cosmetics, activates TRPM8and causes the cooling sensation. Furthermore, ℓ-menthol at excess levels cause unpleasant sensory
irritation . Though this sensory irritation involves TRP channels, it is caused by the reaction ofTRPA1, which is also activated by the main ingredient in wasabi. TRPA1 therefore, contributes to thepeculiar “tingling” and “stinging” sensation from alkali in hair coloring, and preservatives andpolyalcohols in cosmetics.

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