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EC number: 228-408-6
CAS number: 6259-76-3
The 17 salicylate substances assessed in the RIFM review indicate
consistent metabolism by hydrolysis to form salicylic acid and the
alcohol of the corresponding side chain. This pattern
of metabolism is consistent with information on other esters which are
hydrolysedin vivoby carboxylesterases or esterases, especially
In vivo metabolic data are available for methyl salicylate and
one human metabolism study is available on phenyl salicylate. Carboxylesterases
show extensive tissue distribution with respect to hydrolysis of methyl
salicylate. In vitr ostudies demonstrate
greatest activity in the liver, but also extensive activity in the
intestines, kidney, pancreas and spleen. Both the
liver and intestines can contribute to the pre-systemic hydrolysis of
Oral consumption of 0.42 mL methyl salicylate by human volunteers
resulted in the rapid appearance of salicylic acid in the plasma. At
15 and 90 minutes post administration, salicylic acid concentrations
were 2-4 times higher in plasma than the parent methyl salicylate. The
hydrolysis of methyl salicylate was also demonstrated following oral
administration to dogs at a dose level of 300 mg/kg bw; metabolism was
almost complete within 1 hour of administration. Gavage
dosing of rats with methyl salicylate (300 mg/kg bw) resulted in the
appearance of free salicylate in plasma and tissues within 20 minutes. Salicylic
acid was also found in the plasma of pregnant rats exposed dermally to
2000 mg/kg bw/d methyl salicylate.
Results from a study in a single human volunteer show that ingestion
phenyl salicylate resulted in a rapid increase in free urinary phenol
concentration, indicating rapid hydrolysis.
In vitro metabolism studies using mouse skin absorption models
have shown variable results with respect to the degree of hydrolysis,
from <5% for methyl salicylate to 25-30% for ethyl
salicylate and total absorption of 100% of butyl salicylate. In
an in vitro guinea pig skin preparation, 38% of the absorbed
methyl salicylate was metabolized to salicylic acid in non-viable skin.
In viable skin, 57% of methyl salicylate metabolised to 21% salicyluric
acid and 36% salicylic acid.
Metabolism of salicylic acid
Based on numerous metabolic studies in both humans and experimental
animals, salicylic acid undergoes metabolism primarily in the liver. At
low, non-toxic doses, approximately 80% of salicylic acid is further
metabolised in the liver via conjugation with glycine and subsequent
formation of salicyluric acid. Salicylic acid also
undergoes glucuronide conjugation. The metabolism of
salicylic acid is characterized by first order kinetics at low doses and
zero order kinetics at doses that saturate conjugation capacity. A
small amount of salicylic acid is oxidized to gentisic acid, a product
that in turn may be subject to glucuronide conjugation.
The activity of salicylic acid metabolic pathways (i.e., extensive
glycine and/or glucuronide conjugation followed by partial degradation
of the conjugates) is evidenced by the finding of glucuronide, glycine,
or sulphate conjugates as the major urinary metabolites of several
alkyl-and alkoxy-benzyl derivatives. These compounds are close
structural analogues of the salicylates, in rats, rabbits, dogs, and
humans. The consistency of the degradation pathway is
such that it can be assumed for hexyl salicylate to follow a similar
Metabolism of hexanol
For salicylates, following hydrolysis to salicylic acid, the resulting
side chain could be expected to be further metabolised. In
the case of the alcohol formed following hydrolysis (i.e. hexanol),
further metabolism would result in the formation of the corresponding
aldehydes and acids, with eventual degradation to carbon dioxide by the
fatty acid pathway and the tricarboxylic acid cycle.
Data from structurally-related salicyclic acid esters indicate rapid
metabolism by hydrolysis to liberate free salicylic acid. In the case of
hexyl salicylate, metabolism will produce the initial metabolites
salicylic acid and hexanol.
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