Registration Dossier

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:
18/11/1994 - 15/03/1995
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP, Guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1995
Report Date:
1995

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
Qualifier:
according to
Guideline:
other: JMAFF 59 NohSan no. 4200 (1985)
Deviations:
no
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: crystalline

Test animals

Species:
mouse
Strain:
other: BDF1 (C57BL/6 x DBA/2)
Sex:
male
Details on test animals and environmental conditions:
Sex: Male
Age/weight at study initiation: Weighing 24.8 – 27.1g
Number of animals per group: 6 males per group

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
0.5% aqueous carboxymethyl cellulose solution
Details on exposure:
2 applications
Duration of treatment / exposure:
2 days
Frequency of treatment:
Daily dosing for 2 days (24 hour interval between applications)
Post exposure period:
24 hours after final treatment
Doses / concentrations
Remarks:
Doses / Concentrations:
0 (vehicle), 270, 540 and 1080 mg/kg/day on 2 consecutive days, 24 hours apart (total doses: 540, 1080 or 2160 mg/kg).
Basis:
nominal conc.
No. of animals per sex per dose:
6 males per group
Control animals:
yes, concurrent vehicle
Positive control(s):
Single intraperitoneal injection of 2 mg/kg Mitomycin C(MMC), 24 hours before necropsy, as a positive control group.

Examinations

Tissues and cell types examined:
Bone marrow
Details of tissue and slide preparation:
Clinical signs: Yes, after treatment and before sacrifice.

Body weight: Yes, first day of treatment and on the day of sacrifice.

Tissue: Bone marrow:
Number of animals: all animals
Number of cells: 2000
Time points: 24 h after final treatment
Type of cells: Micronucleated polychromatic erythrocytes in bone marrow

Evaluation criteria:
Parameters: Polychromatic/normochromatic erythrocytes ratio
Statistics:
The incidence of MNPCE was subjected to the shochastic method by Kastenbaum and Bowman, and the ratio of PCE was subjected to the Dunnett's t-test for the analysis of significant differences.

Results and discussion

Test results
Sex:
male
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
There were no deaths during the treatment period and no signs of toxicity including body weight change were evident at any dose level. The MNPCE frequencies and PCE/total erythrocyte ratios of all dinotefuran-treated groups were comparable to and not significantly different from control values.
In contrast, mitomycin C produced a statistically significant increase in the MNPCE frequency and a statistically significant decrease in the PCE/total erythrocyte ratio.
Since the incidences of MNPCE and the ratios of PCE/total erythrocytes in both the vehicle control and positive control groups were within the laboratory historical control ranges, the test was considered to be valid.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
Dinotefuran at dose levels approaching the maximum tolerated dose does not induce the formation of micronuclei and does not inhibit spindle formation in the bone marrow of mice.