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Record Information
Version2.0
Creation Date2009-07-30 17:56:33 UTC
Update Date2014-12-24 20:26:01 UTC
Accession NumberT3D3224
Identification
Common NameMenthol
ClassSmall Molecule
DescriptionMenthol is an alcohol produced from mint oils or prepared synthetically. Menthol is a covalent organic compound made synthetically or obtained from peppermint or other mint oils. It is a waxy, crystalline substance, clear or white in color, which is solid at room temperature and melts slightly above. The main form of menthol occurring in nature is (-)-menthol, which is assigned the (1R,2S,5R) configuration. Menthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation.
Compound Type
  • Antipruritic
  • Drug
  • Food Toxin
  • Fragrance Toxin
  • Household Toxin
  • Metabolite
  • Natural Compound
  • Organic Compound
  • Plant Toxin
Chemical Structure
Thumb
Synonyms
Synonym
(-)-(1R,3R,4S)-Menthol
(-)-menthol
(-)-Menthyl alcohol
(-)-trans-p-Menthan-cis-ol
(1alpha,2beta,5alpha)-5-Methyl-2(1-methylethyl)cyclohexanol
(1R)-(-)-Menthol
(1R,2S,5R)-(-)-menthol
(1R,3R,4S)-(-)-Menthol
(1R-(1-alpha,2-beta,5-alpha))-5-Methyl-2-(1-methylethyl)cyclohexanol
(R)-(-)-Menthol
1-Menthol
2-Isopropyl-5-methylcyclohexanol
5-Methyl-2-(1-methylethyl)cyclohexanol
5-methyl-2-propan-2-ylcyclohexan-1-ol
D-(-)-Menthol
Hexahydrothymol
L-(-)-Menthol
L-Menthol
Levomenthol
Levomentholum
Levomentol
Menthacamphor
Menthomenthol
p-Menthan-3-ol
Peppermint camphor
U.S.p. Menthol
Chemical FormulaC10H20O
Average Molecular Mass156.265 g/mol
Monoisotopic Mass156.151 g/mol
CAS Registry Number2216-51-5
IUPAC Name(1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol
Traditional Namementhol
SMILES[H][C@@]1(C)CC[C@@]([H])(C(C)C)[C@]([H])(O)C1
InChI IdentifierInChI=1S/C10H20O/c1-7(2)9-5-4-8(3)6-10(9)11/h7-11H,4-6H2,1-3H3/t8-,9+,10-/m1/s1
InChI KeyInChIKey=NOOLISFMXDJSKH-KXUCPTDWSA-N
Chemical Taxonomy
Description belongs to the class of organic compounds known as menthane monoterpenoids. These are monoterpenoids with a structure based on the o-, m-, or p-menthane backbone. P-menthane consists of the cyclohexane ring with a methyl group and a (2-methyl)-propyl group at the 1 and 4 ring position, respectively. The o- and m- menthanes are much rarer, and presumably arise by alkyl migration of p-menthanes.
KingdomOrganic compounds
Super ClassLipids and lipid-like molecules
ClassPrenol lipids
Sub ClassMonoterpenoids
Direct ParentMenthane monoterpenoids
Alternative Parents
Substituents
  • P-menthane monoterpenoid
  • Monocyclic monoterpenoid
  • Cyclohexanol
  • Cyclic alcohol
  • Secondary alcohol
  • Organic oxygen compound
  • Hydrocarbon derivative
  • Organooxygen compound
  • Alcohol
  • Aliphatic homomonocyclic compound
Molecular FrameworkAliphatic homomonocyclic compounds
External Descriptors
Biological Properties
StatusDetected and Not Quantified
OriginExogenous
Cellular Locations
  • Extracellular
  • Membrane
Biofluid LocationsNot Available
Tissue Locations
  • Bladder
  • Mouth
  • Nerve Cells
  • Neuron
  • Skeletal Muscle
  • Stratum Corneum
PathwaysNot Available
Applications
Biological RolesNot Available
Chemical RolesNot Available
Physical Properties
StateSolid
AppearanceWhite crystals (20).
Experimental Properties
PropertyValue
Melting Point43°C
Boiling Point212°C
Solubility490 mg/L (at 25°C)
LogP3.4
Predicted Properties
PropertyValueSource
Water Solubility0.56 g/LALOGPS
logP2.68ALOGPS
logP2.66ChemAxon
logS-2.4ALOGPS
pKa (Strongest Acidic)19.55ChemAxon
pKa (Strongest Basic)-0.81ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count1ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area20.23 ŲChemAxon
Rotatable Bond Count1ChemAxon
Refractivity47.45 m³·mol⁻¹ChemAxon
Polarizability19.69 ųChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleYesChemAxon
Spectra
Spectra
Spectrum TypeDescriptionSplash KeyView
GC-MSGC-MS Spectrum - GC-MS (1 TMS)splash10-0006-1900000000-cc06fe70d7649d059f92JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-00ea-9100000000-0be605183591bf5f33a0JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - EI-B (Non-derivatized)splash10-00ea-9100000000-977cf0c036d597693bebJSpectraViewer | MoNA
GC-MSGC-MS Spectrum - GC-MS (Non-derivatized)splash10-0006-1900000000-cc06fe70d7649d059f92JSpectraViewer | MoNA
GC-MSGC-MS Spectrum - GC-EI-Q (Non-derivatized)splash10-00ym-9100000000-ff2f7ebe48769147a112JSpectraViewer | MoNA
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, Positivesplash10-0a4l-9600000000-fcf4b2a96455b111f889JSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (1 TMS) - 70eV, Positivesplash10-01w0-9520000000-26cc8cab97979ec9fb4dJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
Predicted GC-MSPredicted GC-MS Spectrum - GC-MS (Non-derivatized) - 70eV, PositiveNot AvailableJSpectraViewer
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 10V, Positive (Annotated)splash10-053r-9300000000-d9c35833e73c8655fb23JSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 25V, Positive (Annotated)splash10-0ldl-9000000000-abf2f837df49fbedc53cJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - Quattro_QQQ 40V, Positive (Annotated)splash10-0007-9000000000-adee6385265c6606326dJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (JEOL JMS-D-3000) , Positivesplash10-00ea-9100000000-e3f1b7b69a021063fabbJSpectraViewer | MoNA
LC-MS/MSLC-MS/MS Spectrum - EI-B (JEOL JMS-DX-300) , Positivesplash10-00ea-9100000000-d69777874c9615b7e751JSpectraViewer | MoNA
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-052r-0900000000-39d327015211bdc2b4e8JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-052r-6900000000-67e6c41c2a8d759d6cafJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0aor-9200000000-88888989ba15a9dc0269JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0900000000-3a700dc611fb070e6b45JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0900000000-86ed17c709dc4636ad41JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0bti-6900000000-fc116bf41f068d3f6f75JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Positivesplash10-05mk-9800000000-bb8a9e58bdc61e2654e6JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Positivesplash10-053e-9100000000-6405f7fe35f6f6bdc8c5JSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Positivesplash10-0006-9000000000-fee5c7d55bf523973cbfJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 10V, Negativesplash10-0a4i-0900000000-f6034c6a8245c68a37acJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 20V, Negativesplash10-0a4i-0900000000-7efa42d43b7858e2c2ceJSpectraViewer
Predicted LC-MS/MSPredicted LC-MS/MS Spectrum - 40V, Negativesplash10-0zfr-0900000000-b6eef0a7f66ac7e97e78JSpectraViewer
MSMass Spectrum (Electron Ionization)splash10-00ea-9100000000-602436010653202a4da9JSpectraViewer | MoNA
1D NMR1H NMR SpectrumNot AvailableJSpectraViewer
1D NMR13C NMR SpectrumNot AvailableJSpectraViewer
2D NMR[1H,13C] 2D NMR SpectrumNot AvailableJSpectraViewer
Toxicity Profile
Route of ExposureOral (20) ; inhalation (20) ; dermal (20) ; eye exposure (20).
Mechanism of ToxicityMenthol acts as a weak Kappa Opioid Receptor Agonist.
MetabolismL-Menthol conjugates rapidly, forming L-Methyl-beta-Glucuronide. About half of the menthol absorbed is excreted combined with glucuronic acid (1).
Toxicity ValuesORAL (LD50): Acute: 2900 mg/kg [Rat], 3100 mg/kg [Mouse] DERMAL (LD50): Acute: 5001 mg/kg [Rabbit] LD50: 10001 mg/kg (oral, rat)
Lethal DoseNot Available
Carcinogenicity (IARC Classification)No indication of carcinogenicity to humans (not listed by IARC).
Uses/SourcesMenthol has local anesthetic and counterirritant qualities, and it is widely used to relieve minor throat irritation. Menthol is also used to prepare menthyl esters to emphasize floral notes (especially rose) (19). Used to treat occasional minor irritation, pain, sore mouth, and sore throat as well as cough associated with a cold or inhaled irritants.
Minimum Risk LevelNot Available
Health EffectsDeath from respiratory failure can result in cases of severe poisoning. Persons with pre-existing skin disorders or eye problems or impaired respiratory function may be more susceptible to the effects of the substance. Menthol may give rise to hypersensitivity reactions including contact dermatitis. Hyspomia can result from poisoning too. Moreover, jaundice may occur in infants with G6PD deficiency (17, 20).
SymptomsVapors or dust can be irritating in large amounts due to the phenolic character of the compound. The normal sensation is that of a pleasant odor. May cause allergic reaction in sensitive individuals. Toxic. Estimated fatal dose, average human, is 2 g. General gastrointestinal upset can occur with pain, vomiting, vertigo, drowsiness and coma. Mild irritant but may cause pain or inflammation on sensitive areas of the skin. Irritant due to its phenolic character. Can cause reddening and tearing (20).
TreatmentNot Available
Normal Concentrations
Not Available
Abnormal Concentrations
Not Available
DrugBank IDDB00825
HMDB IDHMDB03352
PubChem Compound ID16666
ChEMBL IDCHEMBL256087
ChemSpider ID15803
KEGG IDC00400
UniProt IDNot Available
OMIM ID
ChEBI ID15409
BioCyc IDCPD-4944
CTD IDNot Available
Stitch ID1-Menthol
PDB IDNot Available
ACToR ID2067
Wikipedia LinkMenthol
References
Synthesis Reference

Tatsuo Higashiyama, Isao Sakata, “Menthol glycoside, process for preparing the same and method for releasing menthol therefrom.” U.S. Patent US4038270, issued December, 1972.

MSDSLink
General References
  1. Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D, Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L, Adler LE, Soti F, Kem WR, Freedman R: Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry. 2006 Jun;63(6):630-8. [16754836 ]
  2. Stich HF, Stich W: Chromosome-damaging activity of saliva of betel nut and tobacco chewers. Cancer Lett. 1982 Mar-Apr;15(3):193-202. [7116324 ]
  3. Haahr AM, Bardow A, Thomsen CE, Jensen SB, Nauntofte B, Bakke M, Adler-Nissen J, Bredie WL: Release of peppermint flavour compounds from chewing gum: effect of oral functions. Physiol Behav. 2004 Sep 15;82(2-3):531-40. [15276819 ]
  4. Mukerji G, Yiangou Y, Corcoran SL, Selmer IS, Smith GD, Benham CD, Bountra C, Agarwal SK, Anand P: Cool and menthol receptor TRPM8 in human urinary bladder disorders and clinical correlations. BMC Urol. 2006 Mar 6;6:6. [16519806 ]
  5. Rohacs T, Lopes CM, Michailidis I, Logothetis DE: PI(4,5)P2 regulates the activation and desensitization of TRPM8 channels through the TRP domain. Nat Neurosci. 2005 May;8(5):626-34. Epub 2005 Apr 24. [15852009 ]
  6. Valdez JS, Martin DK, Mayersohn M: Sensitive and selective gas chromatographic methods for the quantitation of camphor, menthol and methyl salicylate from human plasma. J Chromatogr B Biomed Sci Appl. 1999 Jun 11;729(1-2):163-71. [10410939 ]
  7. Eccles R: Menthol and related cooling compounds. J Pharm Pharmacol. 1994 Aug;46(8):618-30. [7529306 ]
  8. Haeseler G, Maue D, Grosskreutz J, Bufler J, Nentwig B, Piepenbrock S, Dengler R, Leuwer M: Voltage-dependent block of neuronal and skeletal muscle sodium channels by thymol and menthol. Eur J Anaesthesiol. 2002 Aug;19(8):571-9. [12200946 ]
  9. Gelal A, Jacob P 3rd, Yu L, Benowitz NL: Disposition kinetics and effects of menthol. Clin Pharmacol Ther. 1999 Aug;66(2):128-35. [10460066 ]
  10. Grigoleit HG, Grigoleit P: Pharmacology and preclinical pharmacokinetics of peppermint oil. Phytomedicine. 2005 Aug;12(8):612-6. [16121523 ]
  11. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A: ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003 Mar 21;112(6):819-29. [12654248 ]
  12. Xu H, Blair NT, Clapham DE: Camphor activates and strongly desensitizes the transient receptor potential vanilloid subtype 1 channel in a vanilloid-independent mechanism. J Neurosci. 2005 Sep 28;25(39):8924-37. [16192383 ]
  13. Stein RJ, Santos S, Nagatomi J, Hayashi Y, Minnery BS, Xavier M, Patel AS, Nelson JB, Futrell WJ, Yoshimura N, Chancellor MB, De Miguel F: Cool (TRPM8) and hot (TRPV1) receptors in the bladder and male genital tract. J Urol. 2004 Sep;172(3):1175-8. [15311065 ]
  14. Narishetty ST, Panchagnula R: Effect of L-menthol and 1,8-cineole on phase behavior and molecular organization of SC lipids and skin permeation of zidovudine. J Control Release. 2005 Jan 20;102(1):59-70. [15653134 ]
  15. Prescott J: The generalizability of capsaicin sensitization and desensitization. Physiol Behav. 1999 Jul;66(5):741-9. [10405101 ]
  16. Liu Y, Ye X, Feng X, Zhou G, Rong Z, Fang C, Chen H: Menthol facilitates the skin analgesic effect of tetracaine gel. Int J Pharm. 2005 Nov 23;305(1-2):31-6. Epub 2005 Oct 10. [16219435 ]
  17. Rumack BH (2009). POISINDEX(R) Information System. Englewood, CO: Micromedex, Inc. CCIS Volume 141, edition expires Aug, 2009.
  18. Opdyke DLJ (ed) (1979). Monographs on Fragrance Raw Materials. New York NY: Pergamon Press.
  19. Wikipedia. Menthol. Last Updated 9 August 2009. [Link]
  20. J. T. Baker (2008). Material Safety Data Sheet (MSDS) for Menthol. [Link]
Gene Regulation
Up-Regulated GenesNot Available
Down-Regulated GenesNot Available

Targets

General Function:
Temperature-gated cation channel activity
Specific Function:
Receptor-activated non-selective cation channel involved in detection of pain and possibly also in cold perception and inner ear function (PubMed:25389312, PubMed:25855297). Has a central role in the pain response to endogenous inflammatory mediators and to a diverse array of volatile irritants, such as mustard oil, cinnamaldehyde, garlic and acrolein, an irritant from tears gas and vehicule exhaust fumes (PubMed:25389312, PubMed:20547126). Is also activated by menthol (in vitro)(PubMed:25389312). Acts also as a ionotropic cannabinoid receptor by being activated by delta(9)-tetrahydrocannabinol (THC), the psychoactive component of marijuana (PubMed:25389312). May be a component for the mechanosensitive transduction channel of hair cells in inner ear, thereby participating in the perception of sounds. Probably operated by a phosphatidylinositol second messenger system (By similarity).
Gene Name:
TRPA1
Uniprot ID:
O75762
Molecular Weight:
127499.88 Da
References
  1. Story GM, Peier AM, Reeve AJ, Eid SR, Mosbacher J, Hricik TR, Earley TJ, Hergarden AC, Andersson DA, Hwang SW, McIntyre P, Jegla T, Bevan S, Patapoutian A: ANKTM1, a TRP-like channel expressed in nociceptive neurons, is activated by cold temperatures. Cell. 2003 Mar 21;112(6):819-29. [12654248 ]
  2. Namer B, Seifert F, Handwerker HO, Maihofner C: TRPA1 and TRPM8 activation in humans: effects of cinnamaldehyde and menthol. Neuroreport. 2005 Jun 21;16(9):955-9. [15931068 ]
  3. Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM: More than cool: promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci. 2006 Aug;32(4):335-43. Epub 2006 Jul 7. [16829128 ]
  4. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. [11752352 ]
General Function:
Calcium channel activity
Specific Function:
Receptor-activated non-selective cation channel involved in detection of sensations such as coolness, by being activated by cold temperature below 25 degrees Celsius. Activated by icilin, eucalyptol, menthol, cold and modulation of intracellular pH. Involved in menthol sensation. Permeable for monovalent cations sodium, potassium, and cesium and divalent cation calcium. Temperature sensing is tightly linked to voltage-dependent gating. Activated upon depolarization, changes in temperature resulting in graded shifts of its voltage-dependent activation curves. The chemical agonist menthol functions as a gating modifier, shifting activation curves towards physiological membrane potentials. Temperature sensitivity arises from a tenfold difference in the activation energies associated with voltage-dependent opening and closing. In prostate cancer cells, shows strong inward rectification and high calcium selectivity in contrast to its behavior in normal cells which is characterized by outward rectification and poor cationic selectivity. Plays a role in prostate cancer cell migration (PubMed:25559186). Isoform 2 and isoform 3 negatively regulate menthol- and cold-induced channel activity by stabilizing the closed state of the channel.
Gene Name:
TRPM8
Uniprot ID:
Q7Z2W7
Molecular Weight:
127684.035 Da
Binding/Activity Constants
TypeValueAssay TypeAssay Source
IC5092 uMNot AvailableBindingDB 50318482
Dissociation14.4 uMNot AvailableBindingDB 50318482
References
  1. Zanotto KL, Iodi Carstens M, Carstens E: Cross-desensitization of responses of rat trigeminal subnucleus caudalis neurons to cinnamaldehyde and menthol. Neurosci Lett. 2008 Jan 3;430(1):29-33. Epub 2007 Oct 22. [18060696 ]
  2. Voets T, Owsianik G, Janssens A, Talavera K, Nilius B: TRPM8 voltage sensor mutants reveal a mechanism for integrating thermal and chemical stimuli. Nat Chem Biol. 2007 Mar;3(3):174-82. Epub 2007 Feb 11. [17293875 ]
  3. Bodding M, Wissenbach U, Flockerzi V: Characterisation of TRPM8 as a pharmacophore receptor. Cell Calcium. 2007 Dec;42(6):618-28. Epub 2007 May 22. [17517434 ]
General Function:
Opioid receptor activity
Specific Function:
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synthetic opioids and for the psychoactive diterpene salvinorin A. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors, such as adenylate cyclase. Signaling leads to the inhibition of adenylate cyclase activity. Inhibits neurotransmitter release by reducing calcium ion currents and increasing potassium ion conductance. Plays a role in the perception of pain. Plays a role in mediating reduced physical activity upon treatment with synthetic opioids. Plays a role in the regulation of salivation in response to synthetic opioids. May play a role in arousal and regulation of autonomic and neuroendocrine functions.
Gene Name:
OPRK1
Uniprot ID:
P41145
Molecular Weight:
42644.665 Da
References
  1. Galeotti N, Di Cesare Mannelli L, Mazzanti G, Bartolini A, Ghelardini C: Menthol: a natural analgesic compound. Neurosci Lett. 2002 Apr 12;322(3):145-8. [11897159 ]
  2. Taniguchi Y, Deguchi Y, Saita M, Noda K: [Antinociceptive effects of counterirritants]. Nihon Yakurigaku Zasshi. 1994 Dec;104(6):433-46. [7851817 ]
General Function:
Calcium channel activity
Specific Function:
Putative receptor-activated non-selective calcium permeant cation channel. It is activated by innocuous (warm) temperatures and shows an increased response at noxious temperatures greater than 39 degrees Celsius. Activation exhibits an outward rectification. May associate with TRPV1 and may modulate its activity. Is a negative regulator of hair growth and cycling: TRPV3-coupled signaling suppresses keratinocyte proliferation in hair follicles and induces apoptosis and premature hair follicle regression (catagen).
Gene Name:
TRPV3
Uniprot ID:
Q8NET8
Molecular Weight:
90635.115 Da
References
  1. Macpherson LJ, Hwang SW, Miyamoto T, Dubin AE, Patapoutian A, Story GM: More than cool: promiscuous relationships of menthol and other sensory compounds. Mol Cell Neurosci. 2006 Aug;32(4):335-43. Epub 2006 Jul 7. [16829128 ]