Methyl salicylate

Identification

Name
Methyl salicylate
Accession Number
DB09543
Type
Small Molecule
Groups
Approved, Vet approved
Description

Methyl salicylate (oil of wintergreen or wintergreen oil) is an organic ester naturally produced by many species of plants, particularly wintergreens. The compound was first extracted and isolated from plant species Gaultheria procumbens in 1843. It is also synthetically produced, used as a fragrance, in foods and beverages, and in liniments. It forms a colorless to yellow or reddish liquid and exhibits a characteristic odor and taste of wintergreen. For acute joint and muscular pain, methyl salicylate is used as a rubefacient and analgesic in deep heating liniments. It is used as a flavoring agent in chewing gums and mints in small concentrations and added as antiseptic in mouthwash solutions.

Structure
Thumb
Synonyms
  • 2-(Methoxycarbonyl)phenol
  • 2-Carbomethoxyphenol
  • 2-Hydroxybenzoic acid methyl ester
  • Betula oil
  • Gaultheria oil
  • Methyl 2-hydroxybenzoate
  • Methyl o-hydroxybenzoate
  • Natural wintergreen oil
  • Oil of wintergreen
  • Spicewood Oil
  • Sweet birch oil
  • Teaberry oil
Active Moieties
NameKindUNIICASInChI Key
Salicylic acidunknownO414PZ4LPZ69-72-7YGSDEFSMJLZEOE-UHFFFAOYSA-N
Prescription Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
SportgelEmulsion10 %TopicalMeyer Zall Laboratories Pty Ltd.Not applicableNot applicableCanada
Over the Counter Products
NameDosageStrengthRouteLabellerMarketing StartMarketing End
Aspi-Rub Pain RelieverSpray23 g/100gTopicalAspiRub Enterprises LLC2014-08-29Not applicableUs
Balsamo de Ubre MascuraOintment10.5 g/90gTopicalPharmalab Enterprises Inc.2011-05-102011-05-11Us
Balsamo de Ubre MascuraOintment10.5 g/90gTopicalMenper Distributors2011-05-10Not applicableUs
Bumooly-SSolution3 g/100mLTransdermalScott Holdings Co., Ltd.2014-05-16Not applicableUs
Bumooly-SSolution3 g/100mLTransdermalScott Holdings Co., Ltd.2014-09-25Not applicableUs
Coats Aloe AnalgesicLotion10 g/1gTopicalTychasis Corporation2015-09-29Not applicableUs
Coats Aloe AnalgesicLotion10 g/100mLTopicalTychasis Corporation2015-11-02Not applicableUs
Foot Works Arthritis Achy Foot and MuscleCream250 mg/1mLTopicalNew Avon Llc2012-05-30Not applicableUs
Humco Wintergreen OilLiquid980 mg/1mLTopicalHumco Holding Group. Inc.1998-03-252021-10-31Us
Hyundai Moolpas FSolution3 g/100mLTransdermalScott Holdings Co., Ltd.2014-09-25Not applicableUs
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
1st Medxpatch With Lidocaine 4%Methyl salicylate (20 1/1) + Capsaicin (0.0375 1/1) + Levomenthol (5 1/1) + Lidocaine (4 1/1)PatchTopical1ST MEDX LLC2018-03-15Not applicableUs
701 Dieda Zhengtong Yaogao Medicated PlasterMethyl salicylate (10 g/1) + Levomenthol (8 g/1) + Synthetic Camphor (3.1 g/1)PlasterTopical; TransdermalGUANGZHOU BAIYUNSHAN PHARMACEUTICAL CO., LTD. BAIYUNSHAN HEJIGONG PHARMACEUTICAL FACTORY2001-10-15Not applicableUs
AA Top MedicatedMethyl salicylate (0.05 g/1mL) + Levomenthol (0.1 g/1mL)OilTopicalAlbert Max, Inc.2018-02-01Not applicableUs
Advanced AntisepticMethyl salicylate (.060 kg/100L) + Eucalyptol (.092 kg/100L) + Levomenthol (.042 kg/100L) + Thymol (.064 kg/100L)MouthwashOralDemoulas Supermarkets, Inc.2010-07-22Not applicableUs
Advanced AntisepticMethyl salicylate (.060 mL/100L) + Eucalyptol (.042 mL/100L) + Levomenthol (.042 mL/100L) + Thymol (.064 mL/100L)MouthwashOralWakfern Food Corporation2010-11-24Not applicableUs
Advanced Antiseptic CitrusMethyl salicylate (.060 mL/100L) + Eucalyptol (.092 mL/100L) + Levomenthol (.042 mL/100L) + Thymol (.042 mL/100L)MouthwashOralDrug Mart1991-06-15Not applicableUs
Advanced Antiseptic CitrusMethyl salicylate (.060 mL/100L) + Eucalyptol (.092 mL/100L) + Levomenthol (.042 mL/100L) + Thymol (.042 mL/100L)MouthwashOralH.E.B.2010-10-15Not applicableUs
Advanced CitrusMethyl salicylate (.060 kg/100L) + Eucalyptol (.092 kg/100L) + Levomenthol (.042 kg/100L) + Thymol (.064 kg/100L)MouthwashOralWalmart Stores2010-07-22Not applicableUs
Advanced Citrus AntisepticMethyl salicylate (.060 mL/100L) + Eucalyptol (.092 mL/100L) + Levomenthol (.042 mL/100L) + Thymol (.064 mL/100L)MouthwashOralPublix Supermarkets, Inc.2001-05-03Not applicableUs
Ageless Pain ReliefMethyl salicylate (140 mg/1mL) + Levomenthol (70 mg/1mL)CreamTopicalIsagenix International, Llc2011-04-23Not applicableUs
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
1st Medxpatch With Lidocaine 4%-rxMethyl salicylate (20 1/1) + Capsaicin (0.0375 1/1) + Levomenthol (5 1/1) + Lidocaine (4 1/1)PatchTopical1ST MEDX LLC2018-03-15Not applicableUs
AdazinMethyl salicylate (1.0 g/100g) + Benzocaine (2 g/100g) + Capsaicin (0.035 g/100g) + Lidocaine (2 g/100g)CreamTopicalSterling Knight Pharmaceuticals, Llc2014-12-03Not applicableUs
Comfort EZ Extra Strength Pain Relief PatchMethyl salicylate (20 g/100g) + Levomenthol (1 g/100g) + Lidocaine (4 g/100g)PatchTopicalSimple Diagnostics. Inc.2015-03-172015-03-17Us
Comfort EZ Extra StrengthTransdermal PatchMethyl salicylate (2 g/100g) + Levomenthol (1 g/100g) + Lidocaine hydrochloride (4 g/100g)PatchTopicalSimple Diagnostics. Inc.2015-03-232015-03-24Us
Comfort EZ Pain Relief PatchMethyl salicylate (16 g/100g) + Levomenthol (2 g/100g) + Lidocaine (4 g/100g)PatchTopicalSimple Diagnostics. Inc.2015-03-092015-03-09Us
Dolor-parche With Lidocaine-RXMethyl salicylate (20 g/1) + Capsaicin (0.035 g/1) + Levomenthol (5 g/1) + Lidocaine (0.5 g/1)PatchTopicalTwo Hip Consulting, Llc2013-07-312016-05-31Us
Doloracin RxMethyl salicylate (20 g/100mL) + Capsaicin (0.035 g/100mL) + Levomenthol (5 g/100mL)CreamTopicalTwo Hip Consulting, Llc2013-08-112016-04-11Us
Doloracin/l Rx With LidocaineMethyl salicylate (20 g/100mL) + Capsaicin (0.035 g/100mL) + Levomenthol (5 g/100mL) + Lidocaine (4 g/100mL)CreamTopicalTwo Hip Consulting, Llc2013-07-312016-06-02Us
Medi-derm / L With Lidocaine RxMethyl salicylate (20 g/100mL) + Capsaicin (.0355 g/100mL) + Levomenthol (5 g/100mL) + Lidocaine (4 g/100mL)CreamTopicalTwo Hip Consulting, Llc2012-08-18Not applicableUs
Medi-derm RxMethyl salicylate (20 g/100mL) + Capsaicin (0.035 g/100mL) + Levomenthol (5 g/100mL)CreamTopicalTwo Hip Consulting, Llc2012-08-18Not applicableUs
Categories
UNII
LAV5U5022Y
CAS number
119-36-8
Weight
Average: 152.1473
Monoisotopic: 152.047344122
Chemical Formula
C8H8O3
InChI Key
OSWPMRLSEDHDFF-UHFFFAOYSA-N
InChI
InChI=1S/C8H8O3/c1-11-8(10)6-4-2-3-5-7(6)9/h2-5,9H,1H3
IUPAC Name
methyl 2-hydroxybenzoate
SMILES
COC(=O)C1=CC=CC=C1O

Pharmacology

Indication

Ointments or liniments containing methyl salicylate are applied topically as counter irritant for relief of acute pain associated with lumbago,sciatica and rheumatic conditions. Local analgesics for human and veterinary medicine.

Associated Conditions
Pharmacodynamics

Methyl salicylate relieve musculoskeletal pain in the muscles, joints, and tendons by causing irritation and reddening of the skin due to dilated capillaries and increased blood flow. It is pharmacologically similar to aspirin and other NSAIDs but as a topical agent it primarily acts as a rubefacient and skin irritant. Counter-irritation is believed to cause a soothing sensation of warmth.

Mechanism of action

Counter-irritation is thought to be effective at alleviating musculoskeletal pain as the irritation of the sensory nerve endings is thought to alter or offset pain in the underlying muscle or joints that are served by the same nerves [5]. This is thought to mask the underlying musculoskeletal pain and discomfort. When applied topically, methyl salicylate is thought to penetrate the skin and underlying tissues where it reversibly inhibits cyclooxygenase enzyme and locally and peripherally prevents the production of inflammatory mediators such as prostaglandin and thromboxane A2.

Absorption

Approximately 12-20% of topically applied methyl salicylate may be systemically absorbed through intact skin within 10 hours of application, and absorption varies with different conditions such as surface area and pH. Dermal bioavailability is in the range of 11.8 – 30.7%. For the assessment of potential oral exposure to salicylates, bioavailability is assumed to be 100% [9].

Volume of distribution

After absorption, methyl salicylate is distributed throughout most body tissues and most transcellular fluids, primarily by pH dependent passive processes. Salicylate is actively transported by a low-capacity, saturable system out of the CSF across the choroid plexus. The drug readily crosses the placental barrier.

Protein binding

Degree of albumin binding depends on the plasma concentration of the compound

Metabolism

Minor metabolism may occur in various tissues but hepatic metabolism constitutes the majority of metabolic processes of absorbed methyl salicylate. It is mainly hydrolyzed to salicylic acid via hepatic esterase enzymes. Conjugation with glycine forms salicyluric acid and conjugation with glucuronic forms ester or acyl and ether or phenolic glucuronide, which are the three main metabolites.

Route of elimination

Excreted by kidneys as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl glucuronide (5%), and gentisic acid (less than 1%).

Half life

The plasma half-life for salicylate is 2 to 3 hr in low doses and about 12 hr at usual anti-inflammatory doses. The half-life of salicylate may be as long as 15 to 30 hr at high therapeutic doses or when there is intoxication.

Clearance
Not Available
Toxicity

Oral LD50 values (mg/kg) for mouse, rat and rabbit are 1110, 887 and 1300, respectively. Oral LD50 values for child and adult human (mg/kg) are 228 and 506, respectively. Although systemic toxicity from topical administration is rare, methyl salicylate can be absorbed in intract skin to cause stimulation of the central nervous system respiratory center, disturbance of lipid and carbohydrate metabolism, and disturbance of intracellular respiration. Severe toxicity can result in acute lung injury, lethargy, coma, seizures, cerebral edema, and death. In case of salicylate poisoning, the treatment consists of general supportive care, gastrointestinal decontamination with activated charcoal in cases of salicylate ingestion, and monitoring of serum salicylate concentrations. Bicarbonate infusions or hemodialysis can be used to achieve enhanced salicylate elimination [7].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
(R)-warfarinThe risk or severity of bleeding can be increased when Methyl salicylate is combined with (R)-warfarin.
(S)-WarfarinThe risk or severity of bleeding can be increased when Methyl salicylate is combined with (S)-Warfarin.
1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic AcidThe risk or severity of renal failure can be increased when Methyl salicylate is combined with 1-(3-Mercapto-2-Methyl-Propionyl)-Pyrrolidine-2-Carboxylic Acid.
2,4-thiazolidinedioneMethyl salicylate may increase the hypoglycemic activities of 2,4-thiazolidinedione.
4-hydroxycoumarinThe risk or severity of bleeding can be increased when Methyl salicylate is combined with 4-hydroxycoumarin.
AbciximabThe risk or severity of bleeding can be increased when Methyl salicylate is combined with Abciximab.
AcarboseMethyl salicylate may increase the hypoglycemic activities of Acarbose.
AceclofenacThe therapeutic efficacy of Methyl salicylate can be decreased when used in combination with Aceclofenac.
AcenocoumarolThe risk or severity of bleeding can be increased when Methyl salicylate is combined with Acenocoumarol.
AcetazolamideThe risk or severity of adverse effects can be increased when Methyl salicylate is combined with Acetazolamide.
Food Interactions
Not Available

References

General References
  1. He YY, Yan Y, Zhang HF, Lin YH, Chen YC, Yan Y, Wu P, Fang JS, Yang SH, Du GH: Methyl salicylate 2-O-beta-d-lactoside alleviates the pathological progression of pristane-induced systemic lupus erythematosus-like disease in mice via suppression of inflammatory response and signal transduction. Drug Des Devel Ther. 2016 Sep 29;10:3183-3196. eCollection 2016. [PubMed:27729775]
  2. Xin W, Huang C, Zhang X, Xin S, Zhou Y, Ma X, Zhang D, Li Y, Zhou S, Zhang D, Zhang T, Du G: Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice. Br J Pharmacol. 2014 Jul;171(14):3526-38. doi: 10.1111/bph.12715. [PubMed:24712652]
  3. Mason L, Moore RA, Edwards JE, McQuay HJ, Derry S, Wiffen PJ: Systematic review of efficacy of topical rubefacients containing salicylates for the treatment of acute and chronic pain. BMJ. 2004 Apr 24;328(7446):995. Epub 2004 Mar 19. [PubMed:15033879]
  4. Higashi Y, Kiuchi T, Furuta K: Efficacy and safety profile of a topical methyl salicylate and menthol patch in adult patients with mild to moderate muscle strain: a randomized, double-blind, parallel-group, placebo-controlled, multicenter study. Clin Ther. 2010 Jan;32(1):34-43. doi: 10.1016/j.clinthera.2010.01.016. [PubMed:20171409]
  5. Derry S, Matthews PR, Wiffen PJ, Moore RA: Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults. Cochrane Database Syst Rev. 2014 Nov 26;(11):CD007403. doi: 10.1002/14651858.CD007403.pub3. [PubMed:25425092]
  6. Moore RA, Derry S, McQuay HJ: Topical analgesics for acute and chronic pain in adults. Cochrane Database Syst Rev. 2010;(7). pii: CD008609. [PubMed:25411557]
  7. Thompson TM, Toerne T, Erickson TB: Salicylate Toxicity from Genital Exposure to a Methylsalicylate-Containing Rubefacient. West J Emerg Med. 2016 Mar;17(2):181-3. doi: 10.5811/westjem.2016.1.29262. Epub 2016 Mar 2. [PubMed:26973745]
  8. FDA SALONPAS® Pain Relief Patch Clinical Review [Link]
  9. Norwegian Food Safety Authority: Methyl salicylate risk review [Link]
External Links
Human Metabolome Database
HMDB0034172
KEGG Drug
D01087
KEGG Compound
C12305
PubChem Compound
4133
PubChem Substance
347827876
ChemSpider
13848808
ChEBI
31832
ChEMBL
CHEMBL108545
Drugs.com
Drugs.com Drug Page
Wikipedia
Methyl_salicylate
AHFS Codes
  • 28:08.04.24 — Salicylates
MSDS
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Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2Not Yet RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL) / Large B-cell Lymphoma / Refractory CD19+ B-cell Pediatric ALL / Refractory Diffuse Large B Cell Lymphoma / Refractory Large B-cell Lymphoma / Relapsed CD19+ B-cell Pediatric ALL / Relapsed Large B-cell Lymphoma1
2WithdrawnTreatmentPain, Acute1
2, 3WithdrawnTreatmentHuman Immunodeficiency Virus Infection(HIV)/Acquired Immunodeficiency Syndrome (AIDS) / Immune Reconstitution Inflammatory Syndrome / Immune Reconstitution Syndrome / Tuberculosis Infection1
3Not Yet RecruitingTreatmentAcute Lymphoblastic Leukaemias (ALL)1
4CompletedPreventionNeonatal Infections1
4CompletedTreatmentPeriodontitis, Aggressive1
4CompletedTreatmentSub-acute Back Pain1
4RecruitingTreatmentBack Pain Lower Back Chronic2
Not AvailableRecruitingTreatmentPeriodontitis / Type 2 Diabetes Mellitus1
Not AvailableUnknown StatusTreatmentPain NOS1

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
Aerosol, sprayPercutaneous; Topical; Transdermal
Aerosol, sprayCutaneous; Topical; Transdermal
OintmentEnteral
RinseOral
MouthwashOral
SprayTopical23 g/100g
LiquidTopical
MouthwashBuccal
OintmentTopical10.5 g/90g
SolutionTopical
OilPercutaneous; Topical; Transdermal
PowderTopical
SolutionTransdermal3 g/100mL
LotionTopical10 g/1g
LotionTopical10 g/100mL
GelTopical
MouthwashDental
SalveTopical
CreamTopical250 mg/1mL
PatchCutaneous; Topical; Transdermal
PasteTopical
SprayTopical
LiquidTopical980 mg/1mL
OilTopical60 g/100mL
OintmentTopical13.5 g/100g
KitOral; Topical
StickTopical
OintmentTopical10.5 g/100g
OilTopical105 mg/1mL
Kit
CreamTopical
OintmentTopical
JellyNasal
GelTopical105 mg/1g
LotionTopical20 g/100g
KitOral
LinimentTopical
LiquidOral
LiquidTopical40 g/100mL
GelPercutaneous; Topical; Transdermal
PatchPercutaneous; Topical; Transdermal
Aerosol, foamPercutaneous; Topical; Transdermal
OintmentPercutaneous; Topical; Transdermal
LiquidCutaneous; Topical; Transdermal
LiquidTopical10 g/100g
PatchTopical10 mg/100mg
PatchTopical10 g/100g
EmulsionTopical10 %
CreamTopical100 mg/1g
LotionTopical
PatchTopical
PlasterTransdermal
PlasterTopical
PatchTransdermal
GelTopical100 mg/1g
OintmentTopical15.75 g/150g
OilTransdermal
OilTopical
LiquidTopical
PlasterTopical; Transdermal
CreamTopical10 g/100mL
PoulticeTransdermal160 mg/17g
PoulticeTransdermal105 mg/17.5g
LiquidTopical200 mg/1g
Prices
Not Available
Patents
Patent NumberPediatric ExtensionApprovedExpires (estimated)
US8809615No2014-08-192030-01-03Us
US9233184No2016-01-122027-08-01Us

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)-8.6MSDS
boiling point (°C)220-224MSDS
water solubilitySlightly solubleMSDS
logP2.5MSDS
Predicted Properties
PropertyValueSource
Water Solubility5.73 mg/mLALOGPS
logP2.07ALOGPS
logP2.32ChemAxon
logS-1.4ALOGPS
pKa (Strongest Acidic)9.72ChemAxon
pKa (Strongest Basic)-4.3ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area46.53 Å2ChemAxon
Rotatable Bond Count2ChemAxon
Refractivity40.06 m3·mol-1ChemAxon
Polarizability14.98 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-00dl-9800000000-4c121b87ee97a30f4150
GC-MS Spectrum - EI-BGC-MSsplash10-00dl-9800000000-aeff759175e190d33827
GC-MS Spectrum - EI-BGC-MSsplash10-00dl-9700000000-8449a003796d4c61d429
Mass Spectrum (Electron Ionization)MSsplash10-00dl-9800000000-1d56d6cf07db519b50e2
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0udi-0900000000-eba52e49290e16ea60c0
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-0uk9-0900000000-684f1c8a3cf324183257
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-0uk9-9300000000-a594ffaab84fc15a2edc
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0900000000-76d5fc81bafad7c2222c
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0udi-0900000000-dae7a80af6333acd66fc
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-0gb9-9600000000-09304803bc773495c704
LC-MS/MS Spectrum - LC-ESI-QTOF , negativeLC-MS/MSsplash10-0fk9-3900000000-e2029bf3c75775175ff3
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

Taxonomy

Description
This compound belongs to the class of organic compounds known as o-hydroxybenzoic acid esters. These are benzoic acid esters where the benzene ring is ortho-substituted with a hydroxy group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Benzoic acids and derivatives
Direct Parent
o-Hydroxybenzoic acid esters
Alternative Parents
Salicylic acid and derivatives / Benzoyl derivatives / 1-hydroxy-4-unsubstituted benzenoids / 1-hydroxy-2-unsubstituted benzenoids / Vinylogous acids / Methyl esters / Monocarboxylic acids and derivatives / Organooxygen compounds / Organic oxides / Hydrocarbon derivatives
Substituents
O-hydroxybenzoic acid ester / Salicylic acid or derivatives / Benzoyl / 1-hydroxy-4-unsubstituted benzenoid / 1-hydroxy-2-unsubstituted benzenoid / Phenol / Vinylogous acid / Methyl ester / Carboxylic acid ester / Carboxylic acid derivative
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
salicylates, benzoate ester (CHEBI:31832) / a small molecule (CPD-6442)

Drug created on November 30, 2015 12:10 / Updated on December 16, 2018 06:57