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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study

Data source

Reference
Reference Type:
secondary source
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:
- Name of test material (as cited in study report): TP-90B
- Analytical purity: no data

Test animals

Species:
mouse
Strain:
CD-1
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: not described
- Age at study initiation: 5 weeks
- Weight at study initiation: males 23-24 g, females 21-23 g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
Corn oil
Duration of treatment / exposure:
24 and 48 hours, respectively
Frequency of treatment:
once
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 375, 750, 1500 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent no treatment
Positive control(s):
Mytomicin C (3 mg/kg bw)

Examinations

Tissues and cell types examined:
Polychromatic erythrocytes (PCE) in the bone marrow.
Details of tissue and slide preparation:
- Sampling times and number of samples: 24 hours (5 males and 5 females, each from positive control, vehicle, low, mid, and high dose); 48 hours (5 males and 5 females, each from positive control, and high dose).

- Clinical observations: ca. 0.5, 5, 24 and 48 hours after treatment.

- Organs examined at necropsy: bone marrow from femurs (mature and immature erythrocytes).
Evaluation criteria:
The test item is considered to induce micronuclei if a statistically significant increase in the micronucleus incidence in polychromatic erythrocytes (PCE) (at P<0.05) is observed in any treatment group, in the pooled data for both sexes, or for either considered separately. Where increases in the incidence of micronucleated PCE's are observed which are statistically significant, but fall within the range of negative control values within this laboratory, then concurrent and historical control data are used to demonstrate that these increases do not have biological significance.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
yes
Remarks:
375 mg/kg bw
Vehicle controls validity:
valid
Negative controls validity:
not applicable
Positive controls validity:
valid

Any other information on results incl. tables

MORTALITY: One female at the low dose was found dead 24 hours after treatment.

 

CLINICAL SIGNS: Animals from the high treatment group showed ataxia, hunched posture, ungroomed appearance, reduced activity and three female animals were found moribund approximately 20 minutes after treatment. Animals from the intermediate group showed reduced activity and hunched posture, and one male animal was found moribund approximately 25 minutes after treatment. A full recovery was observed for all animals, the day after treatment. A female animal was found dead at the low dose level 24 hours after treatment. Reduced activity and hunched posture were also observed in a female animal from the vehicle control group, 24 hours and 48 hours after treatment.

 

MITOTIC INDEX OR PCE/NCE RATIO: No increases in the numbers of micronucleated PCE's were observed in any TP-90B treatment group at any sampling time.

 

STATISTICAL RESULTS: Following treatment with TP-90B, no statistically significant increase in the incidence of micronucleated PCE's over the control value was observed at any sampling time for male and female animals combined, or considered separately at each sampling time. Statistically significant increases in the incidence of micronucleate PCE's over the control values were seen in the positive control group, indicating the correct functioning of the test system.

Applicant's summary and conclusion