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Toxicological information

Genetic toxicity: in vivo

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Administrative data

Endpoint:
in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
2003-12-22 (date test substance was received) to 2004-11-05
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2004
Report Date:
2004

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
Remarks:
No detailed documentation is provided on test substance, animals, methods and results evaluation
Qualifier:
according to
Guideline:
EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
Deviations:
no
Remarks:
No detailed documentation is provided on test substance, animals, methods and results evaluation
Qualifier:
according to
Guideline:
other: USA EPA, TSCA and FIFRA guidelines and the Japanese METI/MHLW guidelines for testing of new chemical substances.
Deviations:
no
Remarks:
No detailed documentation is provided on test substance, animals, methods and results evaluation
Principles of method if other than guideline:
not applicable
GLP compliance:
no
Type of assay:
micronucleus assay

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid
Details on test material:
- Name of test material (as cited in study reports): JNJ-118872-AAA (T000749)
- Physical state: liquid
- Appearance: Light yellow, light brown liquid
Specific details on test material used for the study:
Description: Light yellow liquid
Date received: 2003-12-02
Storage conditions: Room temperature, in the dark

Test animals

Species:
mouse
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS: no data

ENVIRONMENTAL CONDITIONS: no data

IN-LIFE DATES: no data

Administration / exposure

Route of administration:
oral: unspecified
Vehicle:
- Vehicle(s)/solvent(s) used: arachis oil
- Justification for choice of solvent/vehicle: not indicated
- Concentration of test material in vehicle: not indicated
- Amount of vehicle (if gavage or dermal): 10 mL/kg
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:no data

DIET PREPARATION: no data
Duration of treatment / exposure:
Animals were treated once.
Frequency of treatment:
single oral dose
Post exposure period:
Test substance animals and vehicle control animals were sacrificed at 24 and 48 hours after treatment at the high dose group and 24 hours for the two lower dose groups were sacrificed at 24 hours. Positive control animals were sacrificed at 24 hours.
Doses / concentrationsopen allclose all
Dose / conc.:
2 000 other: mg/kg
Remarks:
24-hour and 48-Hour Sampling Time
Dose / conc.:
1 000 other: mg/kg
Remarks:
24-hour Sampling Time
Dose / conc.:
500 other: mg/kg
Remarks:
24-hour Sampling Time
No. of animals per sex per dose:
7 animals per group and sacrifice time point for the test substance and vehicle control groups, and 5 animals for the positive control group were used.
Control animals:
yes, concurrent vehicle
Positive control(s):
Cyclophosphamide
- Justification for choice of positive control: no data
- Route of administration: oral unspecified
- Doses / concentrations: 50 mg/kg

Examinations

Tissues and cell types examined:
bone marrow (erythrocytes): at least 2000 polychromatic erythrocytes (PCEs) per animal were scored for micronuclei.
Details of tissue and slide preparation:
CRITERIA FOR DOSE SELECTION: 2000 mg/kg is the maximum recommended dose

TREATMENT AND SAMPLING TIMES: single oral administration; sampling 24h and 48h after administration

DETAILS OF SLIDE PREPARATION: Animals were killed at appropriate times, the bone marrow was extracted, and smear preparations were made and stained.

METHOD OF ANALYSIS: Polychromatic and normochromatic erythrocytes were scored for the presence of micronuclei.
Evaluation criteria:
no data
Statistics:
Statistics were performed, but no data were provided on the tests that were run. P<0.001 was considered in the study to be statistically significant.

Results and discussion

Test results
Key result
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Remarks:
Clinical signs, including hunched posture and ptosis, were observed in animals dosed with the test material at 2000 mg/kg in both the 24 and 48-hour groups.
Vehicle controls validity:
valid
Negative controls validity:
valid
Positive controls validity:
valid
Additional information on results:
RESULTS OF RANGE-FINDING STUDY
- Dose range: The study indicated that 2000 mg/kg produced toxicity but no premautre deaths. No further data were provided on the other dose levels were used.
- Solubility: no data
- Clinical signs of toxicity in test animals: No premature deaths were observed in test animals dosed with the test substance. However, clinical signs were observed at 2000 mg/kg as follows: hunched posture and ptosis.
- Evidence of cytotoxicity in tissue analyzed: no data
- Rationale for exposure: The range-finding test was performed to find suitable dose levels of the test substance for the main study and to investigate to see if there was a marked difference in toxic responses between sexes. There was no marked difference in toxicity of the test substance between sexes; therefore the main test was performed using only male mice.

RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei: There were no statistically significant increases in the frequency of micronucleated PCEs in any of the test substance dose groups when compared to their concurrent vehicle control groups. However, the observation of clinical observations was taken to indicate that systemic absorption had occurred.
- The positive control group showed a marked increase in the incidence of micronucleated polychromatic erythrocytes, hence confirming the sensitivity of the system to the known mutagenic activity of the positive control under the conditions of the test.
- Ratio of PCE/NCE: There were no statistically significant decreases in PCE/NCE ratio in the 24- or 48-hour test substance groups when compared to their concurrent vehicle control groups.
- Appropriateness of dose levels and route: The dose levels were chosen based on the results of the range-finding study: 2000 mg/kg bw was the maximum recommended dose
- Statistical evaluation: The test material was found not to produce a significant increase in the frequency of micronuclei in polychromatic erythrocytes of mice under the conditions of the test.
- Evidence of cytotoxicity: There were no premature deaths seen in any of the dose groups. Clinical signs were observed in animals dosed with the test material at 2000 mg/kg in both the 24 and 48-hour groups, these were as follows: hunched posture and ptosis.

Applicant's summary and conclusion

Conclusions:
Interpretation of results: negative
The test substance was evaluated for the potential to produce a significant increase in the frequency of micronuclei of orally treated mice. The test substance was found to be negative for the induction of micronuclei and was therefore considered to be non-genotoxic under the conditions of the test.