Methyl N-benzyl-N-(3-methoxy-3-oxopropyl)-β-alaninate

Genetic toxicity: in vivo

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:

supporting study

Study period:

no data to 2004-10-26

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study performed similar to OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test) and EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test); Only male mice are studied.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2004

Report date:

2004

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)

Deviations:

yes

Remarks:

Only male mice studied.

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)

Deviations:

yes

Remarks:

Only male mice studied.

GLP compliance:

not specified

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

Methyl N-benzyl-N-(3-methoxy-3-oxopropyl)-β-alaninate

EC Number:

212-343-5

EC Name:

Methyl N-benzyl-N-(3-methoxy-3-oxopropyl)-β-alaninate

Cas Number:

793-19-1

Molecular formula:

C15H21NO4

IUPAC Name:

methyl 3-[benzyl(3-methoxy-3-oxopropyl)amino]propanoate

Details on test material:

- Name of test material (as cited in study report): T000723
- Substance type: no data
- Physical state: pale yellow liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: no data
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: at room temperature in the dark
- Other: no data

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: no data
- Concentration of test material in vehicle: no data
- Amount of vehicle: 10 mL/kg
- Type and concentration of dispersant aid (if powder): not applicable
- Lot/batch no. (if required): no data
- Purity: no data

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
- no data

DIET PREPARATION
- Rate of preparation of diet (frequency): no data
- Mixing appropriate amounts with (Type of food): no data
- Storage temperature of food: no data

Duration of treatment / exposure:

single oral treatment

Frequency of treatment:

once

Post exposure period:

24 or 48 hours for the highest dose group but 24 hours for the low and mid dose group.

Doses / concentrations

Remarks:

Doses / Concentrations:
20, 40 and 80 mg/kg bw
Basis:
nominal conc.

No. of animals per sex per dose:

7

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

Examinations

Tissues and cell types examined:

bone marrow erythrocytes

Details of tissue and slide preparation:

CRITERIA FOR DOSE SELECTION:
- Clinical signs were observed at and above 100 mg/kg in a range finding test.

TREATMENT AND SAMPLING TIMES (in addition to information in specific fields):
- no data

DETAILS OF SLIDE PREPARATION:
- Two-thousand PCEs were scored per concentration.

METHOD OF ANALYSIS:
- no data

OTHER:
- no data

Evaluation criteria:

no data

Statistics:

Results were judged for statistical significance at p<0.05, p<0.01 and p<0.001.

Results and discussion

Test results

Sex:

male

Genotoxicity:

negative

Toxicity:

yes

Remarks:

Hunched posture was observed in animals dosed at 80 mg/kg in both the 24- and 48- hour groups.

Vehicle controls validity:

valid

Negative controls validity:

not specified

Positive controls validity:

valid

Additional information on results:

RESULTS OF RANGE-FINDING STUDY
- Dose range: 40-800 mg/kg bw
- Solubility: no data
- Clinical signs of toxicity in test animals: The maximum dose level investigated, 800 mg/kg, was limited by supplied toxicity data. Premature deaths occurred at 800 mg/kg, and the severity of the clinical signs observed at and above 100 mg/kg resulted in animals being killed in extremis. The clinical signs that were observed at and above 100 mg/kg were as follows: hunched posture, lethargy, ataxia, ptosis, splayed gait, decreased respiratory rate, labored respiration, dehydration, emaciation, hypothermia, pilo-erection and pallor of the extremities. Animals dosed with test material at dose levels below 100 mg/kg only exhibited one clinical sign, i.e., hunched posture.
- Evidence of cytotoxicity in tissue analyzed: not applicable
- Rationale for exposure: no data
- Harvest times: not applicable
- High dose with and without activation: not applicable
- Other: no data


RESULTS OF DEFINITIVE STUDY
- Types of structural aberrations for significant dose levels (for Cytogenetic or SCE assay): not applicable
- 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.
- 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.
- Appropriateness of dose levels and route: In the micronucleus test there were no premature deaths seen in any of the dose groups. One clinical sign (hunched posture) was observed in animals dosed with the test material at 80 mg/kg, in both the 24 and 48-hour groups.
- Statistical evaluation: The positive control elicited a statistically significant (p<0.001) increase in the mean number of mPCE/2000 NCE compared to the vehicle control.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): negative
The test substance was considered to be non-genotoxic under the conditions of the test.