Benzonitrile

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Data source

Reference

Reference Type:

publication

Title:

Studies in detoxication. 31. The isolation of m- and p-cyanophenols as metabolites of cyanobenzene (benzonitrile) and the problem of the orientation of hydroxyl groups formed in vivo.

Author:

Smith, J.N.; Williams, R.T.

Year:

1950

Bibliographic source:

Biochem. J., 46, 243-248

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Single oral administration of 145 mg benzonitrile per kg bw to two rabbits. Determination of metabolites in the urine after 2-4 days.
A second experiment was conducted to further investigate the excretion of benzonitrile metabolites. 200 mg/kg of the test substance was orally administered to 8 female rabbits. Urine analysis were conducted up to 6 days after benzonitrile administration.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Benzonitrile

EC Number:

202-855-7

EC Name:

Benzonitrile

Cas Number:

100-47-0

Molecular formula:

C7H5N

IUPAC Name:

benzonitrile

impurity 1

Reference substance name:

Toluene

EC Number:

203-625-9

EC Name:

Toluene

Cas Number:

108-88-3

Molecular formula:

C7H8

IUPAC Name:

toluene

impurity 2

Reference substance name:

Benzaldehyde

EC Number:

202-860-4

EC Name:

Benzaldehyde

Cas Number:

100-52-7

Molecular formula:

C7H6O

IUPAC Name:

benzaldehyde

impurity 3

Reference substance name:

Terephthalonitrile

EC Number:

210-783-2

EC Name:

Terephthalonitrile

Cas Number:

623-26-7

Molecular formula:

C8H4N2

IUPAC Name:

terephthalonitrile

impurity 4

Reference substance name:

Benzene-1,3-dicarbonitrile

EC Number:

210-933-7

EC Name:

Benzene-1,3-dicarbonitrile

Cas Number:

626-17-5

Molecular formula:

C8H4N2

IUPAC Name:

isophthalonitrile

impurity 5

Reference substance name:

Water

EC Number:

231-791-2

EC Name:

Water

Cas Number:

7732-18-5

Molecular formula:

H2O

IUPAC Name:

water

Test material form:

liquid

Radiolabelling:

no

Test animals

Species:

rabbit

Strain:

not specified

Sex:

male/female

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

unchanged (no vehicle)

Duration and frequency of treatment / exposure:

Single dosage

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

145 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose / concentration:

First experiment: two animals, sex not specified;
Second experiment: eight animals, female

Control animals:

no

Results and discussion

Main ADME results

Main ADME results 1

Type:

excretion

Results:

First exp.: 60 % of the applied amount was excreted within 2 days: sulphate conjugate (23-27 %), conjugates of glucoronic acid (38-28 %); in addition aprrox. 5 % mercapturic acid. Further metabolite: benzoic acid

Main ADME results 2

Type:

metabolism

Results:

Metabolites: metabolites sulphate conjugate, conjugates of glucoronic acid, mercapturic acid, benzoic acid; a metabolic release of thiocyanate could be excluded.

Metabolite characterisation studies

Metabolites identified:

yes

Details on metabolites:

First experiment:
- Metabolites: sulphate conjugate, conjugates of glucoronic acid, mercapturic acid, benzoic acid

Second experiment:
- Maximum of excretion of metabolites on days 2 and 3 after test substance application.
- 200 mg /kg bw benzonitrile administered to 3 female rabbits was excreted within 6 days to 5.2 - 5.7 % in form of mecapturic acid.
- 200 mg /kg bw benzonitrile administered to a second set of 5 female rabbits was excreted within 2 days to 10 % in form benzoic acid.
- In urine collected from 6 rabbits over 4 days, 4- and 3-hydroxy benzonitrile could be detected. 2-hydroxy benzonitrile couls not be detected.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: Benzonitrile is a good substrate for Phase II enzymes; additional metabolites are mercapturic acid and benzoic acid; a release of thiocyanate was not detectable
Benzonitrile metabolites detected in the urine of rabbits were sulphate conjugate, conjugates of glucoronic acid, mercapturic acid and benzoic acid. Thiocyanate is not a product of benzonitrile metabolism.

Executive summary:

Benzonitrile was orally administered at a single dose concentration of 145 mg/kg bw to two rabbits. After 2-4 days the following

benzonitrile metabolites were detected: sulphate conjugate (23-27 %), conjugates of glucoronic acid (28 -38 %), mercapturic acid (ca. 5 %), benzoic acid.

In a second experiment, mercapturic acid and benzoic acid could be verified to be benzonitrile metabolites.

A metabolic release of thiocyanate could be excluded.