Acrylonitrile

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian cell study: DNA damage and/or repair

Remarks:

Type of genotoxicity: DNA damage and/or repair

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

significant methodological deficiencies

Remarks:

UDS was measured using liquid scintillation counting (LSC)

Data source

Reference

Reference Type:

publication

Title:

Pulmonary Toxicity of Acrylonitrile: Covalent Interaction and Effect on Replicative and Unscheduled DNA Synthesis in the Lung

Author:

Ahmed, A.E., Abdel-Aziz, A.H., Abdel-Rahman, S.Z., Haque, A.K., Nouraldeen, A.M., Shouman, S.A.

Year:

1992

Bibliographic source:

Toxicology 76(1): 1-14

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

In vivo UDS in the lung

GLP compliance:

no

Type of assay:

unscheduled DNA synthesis

Test material

Test material information

Constituent 1

Reference substance name:

Acrylonitrile

EC Number:

203-466-5

EC Name:

Acrylonitrile

Cas Number:

107-13-1

Molecular formula:

C3H3N

IUPAC Name:

prop-2-enenitrile

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male

Details on test animals or test system and environmental conditions:

Young male Sprague-Dawley rats

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

No vehicle reported

Details on exposure:

A single oral dose of 46.5 mg/kg was administered

Duration of treatment / exposure:

A single oral dose of 46.5 mg/kg was administered; the lungs were examined 0.5, 3, 6, 12, or 72 hours after administration

Frequency of treatment:

Single dose

Post exposure period:

Lungs were examined 0.5, 3, 6, 12, or 72 hours after administration

Doses / concentrations

Dose / conc.:

46.5 mg/kg bw (total dose)

Remarks:

Single oral dose

No. of animals per sex per dose:

No information available

Control animals:

yes

Positive control(s):

Not examined

Examinations

Tissues and cell types examined:

Lung tissue

Details of tissue and slide preparation:

No information available

Evaluation criteria:

Replicative DNA synthesis and UDS in lung DNA was measured by the ratio of ³H–thymidine incorporated following hydroxyurea suppression.

Statistics:

No information available

Results and discussion

Test results

Key result

Sex:

male

Genotoxicity:

positive

Toxicity:

yes

Remarks:

Hyperplasia of Clara cells and occasional focal perivascular edema were seen 24 hours after acrylonitrile administration.

Vehicle controls validity:

valid

Negative controls validity:

not examined

Positive controls validity:

not examined

Additional information on results:

There was a 1.5-fold increase in thymidine incorporation into lung DNA 30 minutes after dosing, rising to a 3.3-fold increase after 24 hours. At all time points, a significant decrease in lung DNA synthesis was observed in acrylonitrile treated animals compared to controls. Covalent binding of acrylonitrile was detected in lung DNA.
Hyperplasia of Clara cells and occasional focal perivascular oedema were seen 24 hours after acrylonitrile administration.

Any other information on results incl. tables

The DNA replicative index, calculated as the amount of ³H-thymidine incorporated in DNA of acrylonitrile-treated animal/control, was significantly lower than 1.0 at all time points, thus implying a significant decrease in lung DNA replication resulting from a single oral dose of acrylonitrile. As replicative DNA synthesis is blocked by hydroxyurea, the authors attributed the thymidine incorporation to DNA repair.

Applicant's summary and conclusion

Conclusions:

Interpretation of results: positive
The authors conclude that acrylonitrile demonstrates genotoxic effects in the lung following a single oral dose in rats

Executive summary:

Acrylonitrile was administered to Sprague-Dawley rats in a single oral dose of 46.5 mg/kg bw. Replicative DNA synthesis and UDS in lung DNA was measured by the ratio of tritiated thymidine incorporated following hydroxyurea suppression at 0.5, 3, 6, 12, or 72 hours after administration. The authors reported decreases in replicative DNA synthesis of more than 50% at 0.5, 6 and 24 hours after acrylonitrile administration, and an increased rate of DNA repair at 0.5 and 6 hours; they conclude that acrylonitrile demonstrates genotoxic effects following a single oral dose. The EU RAR (2004) advises that results of studies employing these methods must be interpreted with caution, as there is no validated UDS assay using lung as a target tissue.