July 9, 2015

Identification by Mandom of the mechanism by which
hypo-osmotic solutions such as water cause irritation in thenasal cavity and eyes-Adopting TRP channels to develop cosmetics that do not cause eye irritationMandom Corporation (Head Office: Osaka, President Executive Officer: Motonobu Nishimura, hereafter“Mandom”), through joint research with Professor Makoto Tominaga of the Okazaki Institute for Integrative
Bioscience, has developed an evaluation method for cosmetics focusing on TRP (Transient Receptor Potential)channels as sensors of skin sensations, and applied it in product evaluations.
Here, we report the discovery of TRPA1 (an irritation sensor), one of TRP channels, that is activated by cells
responding to low osmotic pressure, and the identification of a functional sensory irritation mechanism for water orother low osmotic solvents as they enter the nasal cavity or eyes.
We have presented these results at “The 76th Workshop of the Society of Cosmetic Chemists of Japan (SCCJ)”
held on July 9, 2015.
1. Hypo-osmotic solutions like water cause pain when they enter the nasal cavity and eyes
People experience pain when rinsing their eyes with water or aspirating water up their nose. This pain is caused
because water has low osmotic pressure compared to cellular or bodily fluids; such that the concentration of thedissolved ingredients becomes diluted.
The pain is partly due to the semipermeable nature of the cell membranes (membranes encompassing cells).
A semipermeable membrane allows the transfer of water and hypo-osmotic solutions, but does not easily allow thepassage of salts. When cells encompassed by semipermeable cell membranes are placed in water (or hypo-osmoticsolution), the large concentration difference between the “fluid in the cells” and “water”, allows movement of watercontent from the low concentration to the inside. This results in expansion of cells, and if extreme, results in
rupturing. To avoid this, the human body is protected by defense such as the skin. However, in areas with lessprotection such as the nasal cavity and eye mucosa, ass the cells come in contact with a hypo-osmotic solution,
signal is transmitted from such cells to the brain, and “pain” is experienced.
2. Identifying the mechanism of pain in hypo-osmotic conditions
TRPA1 receptor reacts to various pains, and this receptor’s role has been reported by Mandom in various cases.
On one hand, TRPA1 is said to receive physical (hitting or pulling) stimulation, but despite the many previous
reports, the validity of this is unclear. We concluded that TRPA1 activation is amplified under hypo-osmotic
conditions, and discovered that hypo-osmotic solutions play a direct role in the activation of TRPA1 (Fig. 1). Inaddition, we observed consistent correlation between the magnitude of cell expansion in hypo-osmotic solution andTRPA1 activation. We discovered that physical irritation in the form of cell expansion contributes to TRPA1
activation under hypo-osmotic conditions (Fig. 2). This discovery clarifies the unknown fact that TRPA1 functions
as a mechano-sensitive receptor.
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-1-3. TRPA1 as an alternative to evaluating eye irritation in human and animal subjects
Based on the results of this research, we concluded that TRPA1 is involved in pain due to hypo-osmotic
solutions occurring in the nasal cavity and eyes. We thereby, enabled the evaluation of eye irritation using TRPA1for the purpose of cosmetics development.
We confirmed that the pain occurring in case of hypo-osmotic model lotions enters the eyes and loses pressurenecessitating osmotic pressure adjustment (Fig. 3).
This evaluation for eye irritation using TRPA1 is gradually being applied to the development of safe andreliable cosmetics. In addition, at Mandom we are already applying TRP channels for raw material screen and atdevelopment stages to evaluate skin irritability.
Furthermore, Mandom is keen to explore this area to develop newer products for customers to use themreliably and safely.
<Reference material>
TRPA1
TRPA1activation
activationlevel→Highlevel→High

TRPA1 activation level→HighTRPA
1

activation
Osmoticpressure(normal)→Low
Osmoticpressure(normal)→Low

Cell(normal)→High
Cellexpansion
expansion (normal)→HighFig. 2 Relationship of cell expansion and TRPA1activation

Fig. 1 Activation level of TRPA1 due to low osmoticpressure

No feeling←Intensity of eye irritation→StrongNofeeling←Int

ensityLow
osmoticpressureLowosmotic

Iso-osmoticpressure
Iso-osmotic

Fig. 3 Differences in eye irritation from lotion based on
osmotic pressure-2-