Registration Dossier

Toxicological information

Genetic toxicity: in vivo

Currently viewing:

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: chromosome aberration
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June-July 1991
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well conducted study according to GLP

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1992
Report Date:
1992

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Batch no: BOM pp2
Purity: 87 ± 3% (m/M); see CoA attacahed
Other: m-Xylylene bis (itaconimide): 2-5%

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Duration of treatment / exposure:
single application
Frequency of treatment:
single application
Post exposure period:
24, 48 and 72 h after treatment
No. of animals per sex per dose:
Range finding: 750, 1500, 3000 and 5000 mg/kg bw

Main study: 5 mice sex/group
0 mg/kg (vehicle control); Sacrifice time: 24, 48, 72 hours
750 mg/kg; Sacrifice time: 24 hours
1500 mg/kg; Sacrifice time: 24 hours
2500 mg/kg; Sacrifice time: 24, 48, 72 hours
3000 mg/kg; Sacrifice time: 24, 48, 72 hours
Control animals:
yes, concurrent vehicle
Positive control(s):
30 mg/kg chlorambucil

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
see below
Vehicle controls valid:
yes
Positive controls valid:
yes

Any other information on results incl. tables

One male animal treated with BCI-MX at 3000 mg/kg was killed in extremis approximately 2 hours after dosing as a result of hunched posture, piloerection, inactivity and slow respiration. Another male animal dosed with BCI-MX at 2500 mg/kg was found dead approximately 4 hours after dosing, having previously showed signs of hunched posture and inactivity. All other animals survived to scheduled termination, although some animals dosed at 1500, 2500 and 3000 mg/kg showed intermittent signs throughout the study, inclUding hunched posture, piloerection, ungroomed fur at the base of the tail, reduced activity, and redness and swelling in the anal region.

Bone marrow smears on glass slides were made from each animal; these were stained and prepared for examination. As all but one animal dosed at 3000 mg/kg survived to scheduled termination, slides from animals dosed at 2500 mg/kg were not analysed. A total of at least 2000 erythrocytes per animal was then examined for the presence of micronuclei, using the light microscope. Calculated values of micronuclei per 1000 polychromatic erythrocytes were analysed statistically using the Mann-Whitney U test. The ratio of polychromatic: mature cells was also calculated for each sex and group, as an indicator of gross toxicity.

There was some evidence of bone marrow toxicity, as evidenced by depression of bone marrow proliferation, on slides prepared from animals dosed with BCI-MX at 3000 mg/kg and sacrificed 48 or 72 hours later. Frequencies of micronucleated polychromatic erythrocytes in animals killed 24, 48 or 72 hours after administration of BCI-MX were similar to those in concurrent controls. This lack of treatment-related effect was apparent in both sexes, and was confirmed by statistical analysis. Statistically significant increases over controls were, however, seen in positive control group animals given chlorambucil at 30 mg/kg (p<0.01). It is concluded that, under the conditions of test, there was no evidence of induced chromosomal or other damage leading to micronucleus formation in polychromatic erythrocytes of treated mice 24, 48 or 72 hours after oral administration of BCI-MX. The test procedure was highly sensitive to the chromosome-damaging action of chlorambucil.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative