Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
other: Literature review
Adequacy of study:
supporting study
Study period:
Review published in 2007
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
secondary literature

Data source

Reference
Reference Type:
review article or handbook
Title:
A toxicologic and dermatologic assessment of salicylates when used as fragrance ingredients
Author:
Belsito D, Bickers D, Bruze M, Calow P, Greim H, Hanifin J, Rogers A, Saurat J, Sipes I & Tagami H
Year:
2007
Bibliographic source:
Food and Chemical Toxicology Volume 45, Issue 1, Supplement 1,2007, Pages S318-S361
Report Date:
2007

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Review of the available toxicokinetic literature for hexyl salicylate and related salicylic acid esters
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Hexyl salicylate
- Analytical purity: One sample was 50% solution in DEP and the other was 100% pure

Test animals

Details on test animals and environmental conditions:
No further data

Results and discussion

Metabolite characterisation studies

Metabolites identified:
yes

Any other information on results incl. tables

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 the A-esterases.

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 salicylates.

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 path.

 

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.

Applicant's summary and conclusion

Conclusions:
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.
Executive summary:

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.