Registration Dossier

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Micronucleus assay
Type of information:
other: hydrolysis product
Adequacy of study:
other information
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
review article or handbook
Title:
Unnamed
Year:
2003

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
99,5%

Test animals

Species:
mouse
Strain:
NMRI
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
olive oil
Duration of treatment / exposure:
24h/48h
Frequency of treatment:
single dose
No. of animals per sex per dose:
5

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative

Any other information on results incl. tables

Range finding study:

During pretests deaths were observed down to a dose of 2250 mg/kg bw whereas 2000 mg/kg bw was survived by all animals but led to signs of toxicity including irregular

respiration, piloerection, squatting posture in some cases, closed eyelids, and saltatory convulsions.

Main Study:

Analytical examination of olive oil samples revealed concentrations of 52.9, 100.4, and 198.0 g/l, i.e. 99-106% of the theoretical values. Substance stability was verified.

Clinical signs:

none after vehicle or after positive control substances. Signs following TS at 500 mg/kg bw: irregular respiration and piloerection 15-30 min after dosing; at 1000 mg/kg bw additionally closed eyelids in some cases within 15-30 min; at 2000 mg/kg bw: additionally squatting posture in some animals; one high dose animals was found dead within 1 h after dosing. No signs were noted in positive control animals.

Mean micronuclei counts at 24 hr after dosing, expressed as 0/oo in polychromatic (=pe) and total number of normochromatic (=ne) erythrocytes containing micronuclei:

Solvent control:   pe=2.6    ne= 0.3

cyclophosphamide:  pe=8.6    ne= 1.6

vincristine:       pe= 15.4   ne= 3.0

TS, 500 mg/kg bw:  pe=2.2    ne= 0.4

TS, 1000 mg/kg bw: pe=1.7    ne= 0.4

TS, 2000 mg/kg bw: pe=2.3    ne= 0.3

Other time intervals

TS, 2000 mg/kg bw, 16 h; pe= 1.9 ne= 1.1

TS, 2000 mg/kg bw, 48 h; pe= 1.4 ne= 0.9

Compared to control animals imidazole did not change the incidence of micronuclei in polychromatic or normochromatic erythrocytes at any time or dose. The ratio of polycromatic to normochromatic erythrocytes was unchanged.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
No significant or biologically relevant differences were
noted between treated and solvent control group animals.
Thus, imidazole showed no clastogenic (DNA-damaging)
property, nor did it impair chromosome distribution due to a spindle poison effect.