Homosalate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

no data available

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: This study is performed before guidelines and GLP establishment. This is sufficiently documented and is acceptable for evaluation of methyl salicylate hydrolysis.

Data source

Reference

Reference Type:

publication

Title:

On the metabolism and toxicity of methyl salicylate

Author:

Davison C, Zimmerman EF, Smith PK

Year:

1961

Bibliographic source:

J Pharmacol Expt Therap 132: 207-211

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

method: other:
- Plasma analyses in rats after oral administration of methyl salicylate, sodium salicylate and acetylsalicylic acid.

Test material

Test material information

Constituent 1

Reference substance name:

Methyl salicylate

EC Number:

204-317-7

EC Name:

Methyl salicylate

Cas Number:

119-36-8

Molecular formula:

C8H8O3

IUPAC Name:

Methyl 2-hydroxybenzoate

Radiolabelling:

no

Test animals

Species:

rat

Strain:

Wistar

Sex:

male

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: methyl cellulose

Details on exposure:

no data

Duration and frequency of treatment / exposure:

single dose

Doses / concentrations

Remarks:

Doses / Concentrations:
500 mg/kg, calculated as free salicylic acid.

No. of animals per sex per dose / concentration:

10/males/500 mg/kg as salicylic acid

Control animals:

no

Positive control reference chemical:

none

Details on study design:

no data

Details on dosing and sampling:

Pharmacokinetic study:

- Tissues and body fluids sampled: plasma (2mL) and 4 mL of brain homogenate (one part tissue and three parts water)
- time and frequency of sampling: the blood was removed by intracardiac puncture at 20 or at 60 min after administration
- From how many animals: samples pooled from 10 animals

Statistics:

An analysis of variance of the Plasma and brain concentrations of total salicylate in rats after the oral administration of methyl salicylate, sodium salicylate and acetyl salicylic acid.

Results and discussion

Preliminary studies:

no data are available

Toxicokinetic / pharmacokinetic studies

Details on absorption:

- MeS, NaS, and ASA are all rapidly absorbed; with NaS being the most rapid.
- a significantly lower absorption of MeS than ASA was observed.

Details on distribution in tissues:

Not performed

Details on excretion:

not performed

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

The results (see table 1) showed that MeS does not produce any higher plasma or brain concentrations than NaS and ASA, and is completely
hydrolyzed to free salicylate in as little as 20 minutes.

Any other information on results incl. tables

Table 1 presents the mean values obtained for total salicylate in groups of 10 animals. MeS values are not given because they were negligible.

Tissue Analyzed	Minutes after Administration	After MeS (500 mg/kg*)	After NaS (500 mg/kg*)	After ASA (500 mg/kg*)
Plasma	20	217 +/- 16.1(x)	296 +/- 22.3	209 +/- 18.6
Brain	20	8 +/- 2.7	38 +/- 5.9	22 +/- 4.4
Plasma	60	278 +/- 16.7	316 +/- 24.8	274 +/- 23.5
Brain	60	42 +/- 7.3	52 +/- 7.4	38 +/- 5.5

Table 1: Plasma and brain concentrations of total salicylate in mg/l* in rats after the oral administration of theree salicylates.

MeS: methyl salicylate

NaS: Sodium salicylate

ASA: acetysalicylic acid

*: calculated as free salicylic acid

(x): Mean +/- standard error. Each figure is an average of determinations in ten animals.

Applicant's summary and conclusion

Conclusions:

Under the test conditions, MeS, NaS and ASA are all rapidly absorbed even at high concentrations, with NaS absorpton being the most rapid. Also
plasma analysis showed rapid hydrolysis to free salicylate for all three compounds.

Executive summary:

Davison et al. (1961) reported that gavage of MeS to10 Wistar rats at doses equivalent to 500 mg/kg as SA resulted in the appearance of hydrolyzed free salicylate in both the plasma and brain tissue within 20 min.This study showed rapid hydrolysis to free salicylate for MeS, NaS and ASA, with comparable plasma concentrations of salicylate at 60 minutes post dosing. In the same study, the authors demonstrated that the major site of hydrolysis of methyl salicylate in the rat, rabbit, dog and monkey is the liver.