Benzyl benzoate

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vitro / ex vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: published data in peer reviewed journal providing some information related to test substance toxicokinetics.

Data source

Reference

Reference Type:

publication

Title:

Prodrugs as delivery systems. 68. Chemical and plasma-catalyzed hydrolysis of various esters of benzoic acid: a reference system for designing prodrug esters of carboxylic acid agents

Author:

Nielsen NM & Bundgaard H

Year:

1987

Bibliographic source:

International Journal of Pharmaceutics 39: 75-85

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The enzymatic lability of carboxylic acid prodrugs and their potential for enzymatic hydrolysis in human blood or plasma was investigated using a series of esters of benzoic acid.

A range of esters from the same acid were used to allow enzymatic lability to be observed. Human blood plasma was used as source of various specific enzymes, to ensure results were suitable for use in vivo.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Benzoic acid

EC Number:

200-618-2

EC Name:

Benzoic acid

Cas Number:

65-85-0

Molecular formula:

C7H6O2

IUPAC Name:

benzoic acid

Constituent 2

Reference substance name:

various substances identified

IUPAC Name:

various substances identified

Constituent 3

Reference substance name:

Benzyl benzoate

EC Number:

204-402-9

EC Name:

Benzyl benzoate

Cas Number:

120-51-4

Molecular formula:

C14H12O2

IUPAC Name:

benzyl benzoate

Test material form:

not specified

Details on test material:

benzyl benzoate was tested as one of the homologous series of benzoic acid esters. methyl-, ethyl-, propyl-, butyl-, amyl-, benzyl and phenyl-ethyl benzoates were all tested for pro-drug potential

No further details provided for any of the test substances

Radiolabelling:

no

Test animals

Species:

other: human

Strain:

other: not applicable

Sex:

not specified

Administration / exposure

Route of administration:

other: not applicable

Vehicle:

other: not applicable

Details on exposure:

All studies were done at 37°C, the alkaline hydrolysis of the esters, including benzyl benzoate, was investigated in aqueous sodium hydroxide buffer solution over a concentration range of 0.001-0.22 M NaOH. The progress of the reactions was followed by UV-spectrophotometry. The rate of hydrolysis was monitored by measuring decrease in absorbance at 235 nm.

Duration and frequency of treatment / exposure:

No data

Doses / concentrations

Remarks:

Doses / Concentrations:
No data

No. of animals per sex per dose / concentration:

not applicable

Control animals:

no

Positive control reference chemical:

No data

Details on study design:

All studies were done at 37°C, the alkaline hydrolysis of the esters, including benzyl benzoate, was investigated in aqueous sodium hydroxide buffer solution over a concentration range of 0.001-0.22 M NaOH. The progress of the reactions was followed by UV-spectrophotometry. The rate of hydrolysis was monitored by measuring decrease in absorbance at 235 nm.

Details on dosing and sampling:

No information available

Statistics:

no data

Results and discussion

Preliminary studies:

not applicable

Toxicokinetic / pharmacokinetic studies

Details on absorption:

not applicable

Details on distribution in tissues:

not applicable

Details on excretion:

not applicable

Metabolite characterisation studies

Metabolites identified:

no

Details on metabolites:

not applicable

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

no data

Any other information on results incl. tables

Under the experimental conditions, all the kinetics of hydrolysis for benzoic acid esters, including benzyl benzoate, followed first order kinetics over several half lives and rates of hydrolysis were proportional to the hydroxde ion concentration in the range investigated (0.001 -0.22 M NaOH).

The rate of hydrolysis for benzyl benzoate in human plasma was k= 3.7 x 10E -2 /min and the half life was 19 minutes.

The rates of enzymatic hydrolysis determined in human plasma for benzoic acid and its esters also followed first order kinetics over several half lives. Hydrolysis of the esters is strongly catalysed by plasma enzymes but to varying extents depending on the ester.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: no bioaccumulation potential based on study results.
Benzyl benzoate was shown to be hydrolysed relatively rapidly in human plasma in vitro; a half-life of 19 minutes was shown. This hydrolysis rate indicates rapid metabolism in vivo and suggests that bioaccumulation is unlikely.

Executive summary:

The enzymic hydrolysis of a series of substances including benzyl benzoate was investigated in human plasma in vitro. Benzyl benzoate was shown to be hydrolysed relatively rapidly in human plasma in vitro; a half-life of 19 minutes was shown. This hydrolysis rate indicates rapid metabolism in vivo and suggests that bioaccumulation of benzyl benzoate is unlikely.