Registration Dossier

Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: other:
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 December 1986 to 03 September 1987
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1987
Report Date:
1987

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
yes
Remarks:
a top dose level of 2500 mg/kg was used, 1000 PCE were examined per animal
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): CGA185072 tech.
- Purity: 91.6%
- Stability: confirmed

Test animals

Species:
hamster, Chinese
Strain:
other: random outbred strain
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 4-9 weeks (males), 6-10 weeks (females)
- Weight at study initiation: 22 to 34 g
- Assigned to test groups randomly: yes, by computer generated random numbers
- Housing: individual caging
- Diet: standard diet ad libitum
- Water: ad libitum
- Acclimation period: 4-5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 21°C
- Humidity: 52-66%
- Air changes: air conditioned room
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 22 December 1986 To: 03 September 1987

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
0.5% CMC
Details on exposure:
Tolerability test: 2500 mg/kg bw, administered to 2 males + 2 females.
Main study: 625,1250, 2500 mg/kg bw (no mortality occurred in the toxicity test at 2500 mg/kg)
Control groups were treated with 0.5% CMC and the positive controls cyclophosphamide, 64 mg/kg bw.

The mutagenicity study was conducted in 8 male and 8 female hamsters per dose group and sampling time. In addition to the treated groups, negative and positive control groups were used. They received the vehicle (0.5% CMC) or the mutagen cyclophosphamide (CPA, 64 mg/kg).
Duration of treatment / exposure:
Single dose
Frequency of treatment:
Once
Post exposure period:
16, 24 or 48 hours
Doses / concentrations
Remarks:
Doses / Concentrations:
625, 1250 and 2500 mg/kg
Basis:
nominal conc.
No. of animals per sex per dose:
8 males and 8 females
Control animals:
yes, concurrent vehicle
Positive control(s):
- cyclophosphamide
- Route of administration: oral
- Doses / concentrations: 64 mg/kg bw

Examinations

Tissues and cell types examined:
Bone marrow smears were prepared from the shafts of both femurs. After staining, coded slides of 5 animals/sex/dose were scored. 1000 polychromatic erythrocytes per animal were scored for the incidence of micronuclei. The ratio of polychromatic to normochromatic erythrocytes was determined for each animal.
Details of tissue and slide preparation:
- Bone marrow smears were prepared from the shafts of both femurs.
- After staining, coded slides of 5 animals/sex/dose were scored.
Evaluation criteria:
The test substance is considered active if a statistically significant increase in the number of polychromatic erythrocytes with micronuclei in comparison with the negative control occurs at any dose and sampling time.
Statistics:
The significance of differences was assessed by the chi square test.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
- No mortality occurred
- Micronucleus test: There was no significant increase of micronuclei. The positive control substance yielded clearly enhanced incidences of polynucleated erythrocytes.

Any other information on results incl. tables

Table 1: Percentage of micronucleated PCE's at different preparation times

Compound and concentration

Sex

16 hours

24 hours

48 hours

Test article

CGA185072 (625 mg/kg)

males

females

0.04
0.10

Test article

CGA185072 (1250 mg/kg)

males

females

0.02
0.06

Test article

CGA185072 (2500 mg/kg)

males

females

0.06

0.08

0.04

0.12

0.04

0.16

Negative control

Vehicle (0.5% CMC)

males

females

0.06

0.08

0.02

0.08

0.06

0.04

Positive control

Cyclophosphamide (64 mg/kg)

males

females

4.54

4.22

 

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative
CGA185072 tech. did not show any clastogenic or aneugenic activity in this test system in vivo.
Executive summary:

In a standard in vivo micronucleus test, dose levels of 625, 1250 and 2500 mg/kg were orally administered. Animals were killed 16, 24 or 48 hours after dosing and bone marrow smears prepared from each femur. After staining the smears slides from 5 animals/sex/dose were scored for 1000 polychromatic erythrocytes per animal. The number of micronuclei were assessed .

Under the conditions of this test there were no clastogenic or aneugenic effects.