One systemic acquired resistance signal in tobacco is methyl salicylate. It (0–1 mg/L) possesses the esterase activity of salicylic acid binding protein 2 (SABP2), which is necessary for systemic tissues to perceive SAR signals and changes MeSA into salicylic acid (SA) [2].

Absorption, Distribution and Excretion
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%.
Excreted by kidneys as free salicylic acid (10%), salicyluric acid (75%), salicylic phenolic (10%) and acyl glucuronide (5%), and gentisic acid (less than 1%).
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.
MAY BE ABSORBED RAPIDLY THROUGH INTACT SKIN. BOWEL ABSORPTION IS SOMEWHAT ERRATIC ... ABSORBED AT LEAST IN PART AS THE INTACT ESTER AND SMALL AMT ARE EVEN EXCRETED AS SUCH BY THE KIDNEYS ... .
HUMAN SUBJECTS WERE GIVEN 7 MG/KG OF METHYL SALICYLATE BY MOUTH. AFTER 0.25 HOURS THE BLOOD CONCN WAS 1.28 MG%. AFTER 1.5 HOURS THE BLOOD CONCN WAS 1.33 MG%. /FROM TABLE/
At therapeutic doses, conjugation accounts for most salicylic elimination, whereas renal elimination becomes more important with large or multiple doses. A substantial first-pass effect occurs at therapeutic doses. /Salicylates/
Orally ingested salicylates are absorbed rapidly, partly from the stomach but mostly from the upper small intestine. Appreciable conc are found in plasma in less than 30 min; after a single dose, a peak value is reached in about 2 hr and then gradually declines. /Salicylates/
For more Absorption, Distribution and Excretion (Complete) data for METHYL SALICYLATE (6 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.
...EVIDENCE THAT CONSIDERABLE HYDROLYSIS OF ESTER OCCURS IN INTESTINAL TRACT... IN SOME SPECIES, SUCH AS RABBIT, MAY BE PARTLY EXCRETED AS SULFATE OR GLUCURONIC ACID CONJUGATE ON THE FREE HYDROXYL GROUP. CONJUGATION APPEARS TO TAKE PLACE BEFORE HYDROLYSIS OF THE METHYL ESTER.
For small doses 80% of the hepatic metabolism results from conjugation with glycine to form salicyluric acid and with glucuronic acid to form salicyl acyl and phenolic glucuronide. The two parallel pathways (glycine, glucuronide conjugation) have limited capacity and saturate easily above therapeutic doses. /Salicylates/
The biotransformation of salicylates takes place in many tissues, but particularly in the hepatic endoplasmic reticulum and mitochondria. The three chief metabolic products are salicyluric acid (the glycine conjugate), the ether or phenolic glucuronide, and the ester or acyl glucuronide. In addition, a small fraction is oxidized to gentisic acid (2,5-dihydroxybenzoic acid) and to 2,3-dihydroxybenzoic and 2,3,5-trihydroxybenzoic acids; gentisuric acid, the glycine conjugate of gentisic acid, is also formed. /Salicylates/

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

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

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Interactions
... The prolonged and excessive ingestion of analgesic mixtures containing salicylates in combination with acetaminophen or salicylamide can produce papillary necrosis and interstitial nephritis. /Salicylates/

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Non-Human Toxicity Values
LD50 Rat oral 0.887 g/kg
LD50 Rabbit oral 2.8 g/kg
LD50 Guinea pig oral 1.060 g/kg
LD50 Dog oral 2.1 g/kg
LD50 Guinea pig dermal 0.70 ml/kg

[1]. A critical review of the literature to conduct a toxicity assessment for oral exposure to methyl salicylate. Crit Rev Toxicol. 2017 Feb;47(2):98-120.

[2]. Methyl salicylate is a critical mobile signal for plant systemic acquired resistance. Science. 2007 Oct 5;318(5847):113-6.

[3]. Fragrance material review on methyl salicylate. Food Chem Toxicol. 2007;45 Suppl 1:S428-52.

[4]. 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.

Methyl salicylate appears as colorless yellowish or reddish liquid with odor of wintergreen. (USCG, 1999)
Methyl salicylate is a benzoate ester that is the methyl ester of salicylic acid. It has a role as a flavouring agent, a metabolite and an insect attractant. It is a benzoate ester, a member of salicylates and a methyl ester. It is functionally related to a salicylic acid.
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 can be manufactured synthetically and it used as a fragrance, in foods, beverages, and 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.
Methyl Salicylate has been reported in Camellia sinensis, Phellinus tremulae, and other organisms with data available.
Methyl 2-hydroxybenzoate is found in beverages. Methyl 2-hydroxybenzoate is present in white wine, tea, porcini mushroom Boletus edulis, Bourbon vanilla, clary sage, red sage and fruits including cherry, apple, raspberry, papaya and plum. Methyl 2-hydroxybenzoate is found in leaves of Gaultheria procumbens (wintergreen). Methyl 2-hydroxybenzoate is a flavouring agent.
Methyl 2-hydroxy benzoate is a metabolite found in or produced by Saccharomyces cerevisiae.
See also: Salicylic Acid (has active moiety); Clove Oil (part of); Levomenthol; methyl salicylate (component of) ... View More ...

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Drug 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.

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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. 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.

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Therapeutic Uses
OINTMENTS OR LINIMENTS CONTAINING METHYL SALICYLATE ARE APPLIED TOPICALLY AS COUNTERIRRITANTS FOR RELIEF OF PAIN ASSOCIATED WITH LUMBAGO, SCIATICA, AND RHEUMATIC CONDITIONS. FORMERLY USED INTERNALLY IN SMALL DOSES AS A CARMINATIVE.
MEDICATION (VET): ORALLY, PRIMARILY AS FLAVORING AGENT OR AS CARMINATIVE; TOPICALLY, AS IRRITANT OR COUNTERIRRITANT AIDED BY MASSAGE OR RUBBING AS IN UDDER OINTMENTS (1-3% CONCN), POULTICES & COUNTERIRRITANT MIXT (@ LEAST 5-10%) OVER SORE JOINT, MUSCLE, & BONE AREAS.
LOCAL ANALGESIC FOR HUMAN AND VETERINARY MEDICINE

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Drug Warnings
OINTMENTS OR LINIMENTS ... . SHOULD NOT BE APPLIED TO BURNED AREAS OR TO OTHERWISE DAMAGED SKIN...USUALLY IN CONCN FROM 10-25% ... .
ABSORPTION OF METHYL SALICYLATE CAN OCCUR THROUGH THE SKIN, & DEATH HAS RESULTED FROM SYSTEMIC POISONING FROM THE LOCAL MISAPPLICATION OF THE DRUG. IT IS A COMMON PEDIATRIC POISON, & ITS USE SHOULD BE STRONGLY DISCOURAGED.
Children with fever and dehydration are particularly prone to intoxication from relatively small doses of salicylate. ... The use of aspirin is contraindicated in children and adolescents with febrile viral illnesses because of the risk of Reye's syndrome. /Salicylates/

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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.

C8H8O3

152.14

152.047

119-36-8

Methyl Salicylate-d4;1219802-12-6

4133

Colorless to light yellow liquid

1.2±0.1 g/cm3

222.0±0.0 °C at 760 mmHg

-8 °C

86.8±12.6 °C

0.1±0.4 mmHg at 25°C

1.547

2.23

1

3

2

11

144

0

O(C([H])([H])[H])C(C1=C([H])C([H])=C([H])C([H])=C1O[H])=O

OSWPMRLSEDHDFF-UHFFFAOYSA-N

InChI=1S/C8H8O3/c1-11-8(10)6-4-2-3-5-7(6)9/h2-5,9H,1H3

methyl 2-hydroxybenzoate

Gaultheria oil; Betula; Methyl salicylate

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Ethanol : ~25 mg/mL (~164.31 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (16.43 mM) (saturation unknown) in 10% EtOH + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (16.43 mM) (saturation unknown) in 10% EtOH + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear EtOH stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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 (Please use freshly prepared in vivo formulations for optimal results.)