dinotefuran (ISO); 1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

Genetic toxicity: in vivo

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 guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

other: JMAFF 59 NohSan no. 4200 (1985)

Deviations:

no

GLP compliance:

yes

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

EC Number:

605-399-0

Cas Number:

165252-70-0

Molecular formula:

C7H14N4O3

IUPAC Name:

(RS)-1-methyl-2-nitro-3-(tetrahydro-3-furylmethyl)guanidine

Test material form:

solid: crystalline

Test animals

Species:

mouse

Strain:

other: BDF1 (C57BL/6 x DBA/2)

Sex:

male

Details on test animals or test system 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.