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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:
2005-12-15 (date test material was received) to 2006-12-14
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:
2006
Report date:
2006

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
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
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
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
GLP compliance:
no
Type of assay:
micronucleus assay

Test material

Constituent 1
Chemical structure
Reference substance name:
1'-(phenylmethyl)-[1,4'-bipiperidine]-4'-carbonitrile
EC Number:
282-544-0
EC Name:
1'-(phenylmethyl)-[1,4'-bipiperidine]-4'-carbonitrile
Cas Number:
84254-97-7
Molecular formula:
C18H25N3
IUPAC Name:
1'-benzyl-[1,4'-bipiperidine]-4'-carbonitrile
Test material form:
solid: particulate/powder
Specific details on test material used for the study:
Description: cream coloured powder
Batch number: 00470548RT000745G1B521
Date received: 2005-12-15
Storage conditions: Room temperature in the dark

Test animals

Species:
mouse
Strain:
not specified
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: no data
- Age at study initiation: no data
- Weight at study initiation: no data
- Assigned to test groups randomly: no data
- Fasting period before study: no data
- Housing: no data
- Diet: no data
- Water: no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (deg C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: From: no data To: 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 treatmen
t at the high dose group and 24 hours for the two lower dose groups were sacrificed at 24 hours. P
ositive control animals were sacrificed at 24 hours.
Doses / concentrationsopen allclose all
Dose / conc.:
75 other: mg/kg bw
Remarks:
24-hour and 48-Hour Sampling Time
Dose / conc.:
37.5 other: mg/kg bw
Remarks:
24-hour Sampling Time
Dose / conc.:
18.75 other: mg/kg bw
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(s): no data
- Route of administration: oral (unspecified)
- Doses / concentrations: 50 mg/kg bw

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: A range-finding test showed marked that the maximum tolerated dose was 75 mg/kg.

TREATMENT AND SAMPLING TIMES (in addition to information in specific fields): 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 conside red in the study to be statistically significant.

Results and discussion

Test results
Key result
Sex:
male
Genotoxicity:
negative
Toxicity:
yes
Remarks:
Lethargy, decreased respiratory rate, laboured respiration and ptosis were observed in the 75 mg/kg animals 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 100 mg/kg produced toxicity and premature deaths. No further data were provided on the other dose levels were used.
- Solubility: no data
- Clinical signs of toxicity in test animals: Premature deaths occurred at and above 100 mg/kg, and clinical signs were observed at and above 100 mg/kg as follows: prostration, decreased respiratory rate, laboured respiration, fasciculations, clonic convulsions, tonic convulsions, elevated tail, ptosis, lethargy, ataxia, body tremors and splayed gait.
- Evidence of cytotoxicity in tissue analyzed: not applicable
- 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 (for Micronucleus assay): 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.
- 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 cyclophosphamide under the conditions of the test.
- Ratio of PCE/NCE (for Micronucleus assay): There were no statistically significant decreases in the PCE/NCE ratio in the 24 or 48-hour test substance groups when compared to their concurrent vehicle control groups. However, the observation of clinical signs was taken to indicate that systemic absorption had occurred.
- Appropriateness of dose levels and route: The dose levels were chosen based on the results of the range-finding study: 75 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 75 mg/kg in both the 24 and 48-hour groups, these were as follows: Lethargy, decreased respiratory rate, laboured respiration, ptosis and lethargy.

Applicant's summary and conclusion

Conclusions:
Interpretation of results: negative
The test substance was considered to be non-genotoxic under the conditions of the test.