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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
Remarks:
Type of genotoxicity: other: clastogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Oct 17 1996 - Feb 19 1997
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to OECD Method and EU method in accordance with GLP. Study material is well characterized

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report date:
1997

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Version / remarks:
Genetic toxicology micronucleus test
GLP compliance:
yes
Type of assay:
micronucleus assay

Test material

Constituent 1
Chemical structure
Reference substance name:
-
EC Number:
414-490-2
EC Name:
-
Cas Number:
154212-59-6
Molecular formula:
C11H9ClN2O5S
IUPAC Name:
4-nitrophenyl 1,3-thiazol-5-ylmethylcarbonate hydrochloride

Test animals

Species:
mouse
Strain:
other: Crl:CD-1®(ICR)BR
Sex:
male/female
Details on test animals or test system and environmental conditions:
Range finding
TEST ANIMALS
- Age at study initiation: ~8 wks at the start of treatment.
- Weight at study initiation: 30 - 38g, males; 22 - 27g females.
- Assigned to test groups randomly: yes
- Fasting period before study: 30 minutes
- Housing: Individualy housed in metal hanging cages
- Diet: Certified Rodent Chow® ad libitum
- Water: tap water sd libitum
- Acclimation period: ~1 week

E NVIRONMENTAL CONDITIONS
- Temperature (°F): 70- 72
- Humidity (%): ambient
- Photoperiod (hrs dark / hrs light):12hr daily light cycle

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
Propylene glycol:Ethanol :: 95:5 v/v
Details on exposure:
Main study Doses of test material: 600, 1200 and 2400 mg/kg were selected based on an oral LD50 of >2400mg/kg
Dosages given at a volume of 8ml/kg
Duration of treatment / exposure:
The mice were dosed once. Bone marrow from 50% of the mice (and all the positive control mice) was harvested 24hrs after the treatment. Bone marrow was harvested from the remaining 50% 48hrs afteer treatment.
Post exposure period:
Individual body weights were recorded for each mouse on the day of treatment. Observations on the physical condition of all treated mice were made a minimum of twice daily during the treatment period.
Doses / concentrations
Remarks:
Doses / Concentrations:

Basis:
nominal conc.
0, 600, 1200, 2400mg/kg
No. of animals per sex per dose:
10 males and 10 females for each of the 0 (vehicle),600, 1200 and 2400mg/kg doses. 5 males and 5 females for the 50mg/kg cyclophosphamide dose.
Control animals:
yes, concurrent vehicle
Positive control(s):
A positve control group of 5 males and 5 females were dosed once with 50 mg/kg cyclophosphamide.

Examinations

Tissues and cell types examined:
Bone marrow from at least 1 femur of each animal used for smears. Cell types examined for the presence of micronuclei in Polychromatic (PCE) and normochromatic (NCE) erythrocytes.
Details of tissue and slide preparation:
Immediately following termination, bone marrow smears were prepared from sections of the femurs from each animal and stained with Giemsa. The incidence of micronucleated cells per 2000 polychromatic erythrocytes (PCE- bluish-gray cells) per animal was scored. Micronuclei are normally circular in shape, although occasionally they may be oval or half-moon shaped, and have a sharp contour with even staining. In addition, the number of normochromatic erythrocytes (NCE-pink-red stained cells) were counted; these cells were also scored for incidence of micronuclei. The ratio of polychromatic to normochromatic erythrocytes was calculated.
Evaluation criteria:
The criteria for determining a positive response included a dose-related statistically significant increase in micronucleated PCEs, or if no dose response was seen, a statistically significant increase in micronucleated PCEs for at least one level. A test article that induced neither a dose response nor a statistically significant increase for at least one dose level would be considered negative. The final decision was based on scientific judgement.
Statistics:
The data was analysed using Fischer's Exact Test.

Results and discussion

Test results
Sex:
male/female
Genotoxicity:
negative
Toxicity:
no effects
Vehicle controls validity:
valid
Positive controls validity:
valid
Additional information on results:
Abbott-87439 hydrochloride was considered non-clastogenic in this study.

Any other information on results incl. tables

Observations: Animals receiving 1200 mg/kg or more showed reduced activity and eyelids were partially closed shortly after dosing. Most mice recovered within a few hours. One female at 2400 mg/kg showed ataxia and one male at 1200 mg/kg were found dead 48 hours after dosing. For mice receiving the test substance there was no decrease in PCE/(PCE + NCE) indicating that there was no bone marrow toxicity, although there were signs of systemic toxicity. There were no statistically significant increases in the incidence of micronucleated polychromatic erythrocytes (PCEs). The frequency of micronucleated PCEs for the vehicle control group was within the historical control range. Positive controls showed a statistically significant increase in micronucleated PCEs and there were signs of bone marrow toxicity.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): negative non-clastogenic
Abbott-87439 was considered non-clastogenic in this study.