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Toxicological information

Basic toxicokinetics

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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

Reference
Name:
Unnamed
Type:
Constituent
Type:
impurity
Type:
impurity
Type:
impurity
Type:
impurity
Type:
impurity
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 / concentrationsopen allclose all
Dose / conc.:
145 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
No. of animals per sex per dose:
First experiment: two animals, sex not specified;
Second experiment: eight animals, female
Control animals:
no

Results and discussion

Main ADME resultsopen allclose all
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
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.