Feature Article

The refreshing sensation left in the mouth by toothpaste or chewing gum, and the freezing feeling on the skin from applying body wash, come from a series of chemical substances known as "cooling agents (also called coolant)." These types of personal care products often feature designs with mint leaves, ice cubes, and other elements on their packaging, suggesting to consumers that they can provide a cooling relief in the hot summer. The credit for this cooling sensation goes to the cooling agents. Figure1. WS-3 sample, shooted by Foreverrest In nature, pure natural cooling agents include essential oils like eucalyptus oil, camphor oil, and peppermint oil, with peppermint leaves being a prime example. Peppermint has a cooling sensory characteristic because it contains menthol. Menthol selectively stimulates the TRPM8 receptors (CMR1)1 in human skin or mucous membranes. TRPM8 receptors are molecular transducers of cold somatosensation, cold-activated receptors that stimulate the human spinal cord and brain in low-temperature environments, making us feel cold2. When we suffer minor injuries, such as twisting an ankle during exercise, we often use cold items like ice to relieve pain3. Research and application of TRPM8 have confirmed the analgesic effect of menthol4. Thus, natural menthol is used not only in cooling agents but also in medical applications. Table 1. Important cooling compounds added to the FEMA GRAS lists (by year) © John Leffingwell, Leffingwell & Associates, and David Rowsell, Chromatography Resources CAS WS# Flavis# FEMA# Material Year 89-79-2 NAa 02.067 2962 Coolact P; isopulegol; (-)-isopulegolb 1965 39711-79-0 WS-3 16.013 3455 N-Ethyl-p-menthane-3-carboxamide 1975 59259-38-0 NA 09.551 3748 Frescolat ML; L-menthyl lactatec 1985 87061-04-9 NA 02.224 3784 Coolact 10; Coolant 10; 3-(L-menthoxy)propane-1,2-diol 1993 51115-67-4 WS-23 16.053 3804 2-Isopropyl-N,2,3-trimethylbutyramide 1996 156324-78-6 NA 09.842 3805 Frescolat MGC; L-menthol ethylene glycol carbonate 1996 30304-82-6 NA 09.843 3806 Frescolat MPC; L-menthol 1&2-propylene glycol carbonate 1996 563187-91-7 NA 06.133 3807 Frescolat MGA; L-menthone 1,2-glycerol ketal 1996 63187-91-7 NA 06.120 3806 Frescolat MGA (racemic); DL-menthone 1,2-glycerol ketal 1996 77341-67-4 NA 09.616 3810 Monomenthyl succinate 1996 195863-84-4 NA 02.254 3849 3-(L-Menthoxy)-2-methylpropan-1,2-diol 1998 156324-82-2 NA - 3992 Frescolat Type MPC (racemic); DL-menthol propylene glycol carbonate 2001 220621-22-7 NA 09.929 4006 (-)-Menthyl glutarate 2001 42822-86-6 NA 02.246 4053 Coolact 38D; PMD 38; (+)-cis & (-)-trans p-menthane-3,8-diol 2003 38618-23-4 NA 02.247 4154 Coolact 5; 2-(L-menthoxy)ethanol 2005 68127-22-0 NA - 4155 Questice;d (-)-menthyl pyrrolidone carboxylate 2005 544714-08-1 NA 16.092 4230 (±)-N,N-Dimethyl menthyl succinamidee 2005 115869-76-6 NA 09.949 4308 L-Menthyl (S)-3-hydroxybutyratef 2007 68489-14-5 WS-5 16.111 4309 (1R,2S,5R)-N-((Ethoxycarbonyl)methyl)-p-menthane-3-carboxamide 2007 59557-05-0 NA - 4327 Ultracool 7; (-)-menthyl acetoacetateg 2007 852379-28-3 NA 16.117 4496 G-180; N-(4-cyanomethylphenyl)-p-menthanecarboxamide 2009 23445-02-5 NA - 4497 (-)-Cubebol 2009 51115-77-6 WS-116 - 4603 2,2-Diethyl-N-(2-hydroxy-1,1-dimethylethyl)butanamide 2009 406179-71-3 NA 09.935 4604 Dimenthyl glutarate 2009 51115-70-9 WS-27 - 4557 N-Ethyl-2,2-diisopropylbutanamide 2009 883215-02-9 NA 4602 N-(2-Hydroxyethyl)-2,3-dimethyl-2-isopropylbutanamide 2009 847565-09-7 NA 16.118 4549 G-190; (lR,2S,5R)-N-(2-pyridin-2-ylethyl)menthylcarboxamide 2009 1119711-29-3 NA 16.125 4684 (2S,5R)-N--p-menthanecarboxamide 2011 73435-61-7 WS-NA 16.124 4693 (1R,2S,5R)-N-Cyclopropyl-p-menthanecarboxamid 2011 28804-53-7 NA - 4718 2-ethanol 2011 68489-09-8 WS-12 16.123 4681 (1R,2S,5R)-N-(4-Methoxyphenyl)-p-menthanecarboxamide 2011 The abundance of cooling agent products today originates from the research achievements of Wilkinson Sword Ltd5. in the 1970s. They proposed a low-volatility substance that could replace menthol (with a logP value of 3.0±0.35) while providing the same cooling sensation6. Natural menthol's drawbacks are its volatility and overly strong cooling strength. Researchers like Hugh R. Watson and David G. Rowsell developed over a thousand synthetic substances, represented by WS-3. These synthetic substances have a cooling sensation and feature electron-donating oxygen atoms that can act as hydrogen bond acceptors. The optimal hydrogen bond groups are hydroxy, N-alkylcarboxamides, sulfoxides, and phosphine oxides. The WS series of cooling agents also overcame the volatility issue of natural menthol. According to the development requirements at that time, the common characteristics of these cooling agents were6: a) hydrogen bond groups; b) compact hydrocarbon skeletons; c) good hydrophilic/hydrophobic balance; d) molecular weight in the range of 150-350. During the 1970s and 1980s, R.J. Reynolds and Philip Morris studies confirmed that WS-14 (N-tert-butyl-p-menthane-3carboxamide) was the best cooling agent choice for cigarettes. By the 1990s, in addition to WS-3 and WS-23 cooling agents, Haarmann & Reimer’s (now Symrise) introduced Frescolat MGA (menthone glycerin acetal), Frescolat ML (menthyl lactate), and Japan's Takasago introduced Coolact 10 (menthoxy propanediol) and l-Menthyl Acetate. The market was flourishing at that time. Entering the 2000s, TRPM8 receptors were confirmed. WS series cooling agents such as WS-5, WS-116, WS-27, WS-NA, and WS-12 entered the market successively. Table 2 Approximate Relative Cooling Strengths vs Menthol (as 100) © John C. LeffingwellCenters for Disease Control and Prevention, 2014 Cooling Agent Cooling Strengths WS-5 400 WS-3 150 WS-12 125 (-)-menthol 100 WS-23 75 WS-14 75 N-Cyclopropyl-p-menthane-3-carboxamide 60 Menthyl 3-hydroxybutyrate 45 Frescolat ML 43 Frescolat MGA 41 (2S)-3-(I-menthoxy)propane-1,2-diol 39.5 (+)-Neomenthol 32 (+)-Menthol 27 Coolact P (-)-isopulegol 25 WS-4 23 WS-30 22.5 TK-10 22.5 WS-27 18 (-)-Neoisomenthol 13 (+)-lsomenthol 11 PMD 38 11 (-)-lsomenthol 3 (-)-NeomenthoL 3 (+)-Neoisomenthol 3 According to the financial report of Kunshan Asia Aroma Corp Ltd, the global demand for WS-23 cooling agents in 2019 was approximately 350 tons. The trade volume of menthol in 2022 was $669 million, and the production value is expected to reach $1.2 billion by 2030. Major consumers included Mars Wrigley and Kraft for chewing gum production, and Vaporesso, JUUL, and Puff Bar for e-cigarette production. Reference Lizhen Xu al., Molecular mechanisms underlying menthol binding and activation of TRPM8 ion channel, Natural, 2020. David D. McKemy al., Identification of a cold receptor reveals a general role for TRP channels in thermosensation, Natural, 2002. Raymond W. Colburn al., Attenuated Cold Sensitivity in TRPM8 Null Mice, Neuron, 2007. John C, Cool without Menthol & Cooler than Menthol and Cooling Compounds as Insect Repellents, Leffingwell, 2018. Shafaq Sikandar al., Genes, molecules and patients—Emerging topics to guide clinical pain research, European Journal of Pharmacology, 2013. John Leffingwell, Wilkinson Sword Cooling Compounds: From the Beginning to Now, Perfumer & Flavorist, 2014.