Registration Dossier
Registration Dossier
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EC number: 203-417-8 | CAS number: 106-63-8
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 16.07.2001-13.11.2001
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 001
- Report date:
- 2001
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- Isobutyl acrylate
- EC Number:
- 203-417-8
- EC Name:
- Isobutyl acrylate
- Cas Number:
- 106-63-8
- Molecular formula:
- C7H12O2
- IUPAC Name:
- isobutyl acrylate
Constituent 1
- Specific details on test material used for the study:
- - Name of test material: Isobutyl acrylate
- Lot/batch No.: S 122-01-GA
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: RCC Ltd. Biotechnology and Animal Breeding Division; CH-4414 Fuellinsdorf
- Age at study initiation: 8-10 weeks
- Weight at study initiation: males: mean 44.9 g; females: mean 33.6 g
- Housing: single
- Diet: pelleted standard diet, ad libitum
- Water: Tap water ad libitum
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 +/- 4
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- - Vehicle/solvent used: olive oil, O1500, Sigma-Aldrich Vertriebs-GmbH
- Amount of vehicle: 10 mL/kg - Duration of treatment / exposure:
- single injection; harvesting of cells 24 and 48 hours after administration of test substance
- Frequency of treatment:
- single treatment
Doses / concentrationsopen allclose all
- Dose / conc.:
- 250 mg/kg bw/day (nominal)
- Remarks:
- males/ 24 hours harvesting
- Dose / conc.:
- 500 mg/kg bw/day (nominal)
- Remarks:
- males/ 24 hours harvesting
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- males/ 24 hours harvesting
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- Remarks:
- males/ 48 hours harvesting
- Dose / conc.:
- 312.5 mg/kg bw/day (nominal)
- Remarks:
- female/ 24 hours harvesting
- Dose / conc.:
- 625 mg/kg bw/day (nominal)
- Remarks:
- female/ 24 hours harvesting
- Dose / conc.:
- 1 250 mg/kg bw/day (nominal)
- Remarks:
- female/ 24 hours harvesting
- Dose / conc.:
- 1 250 mg/kg bw/day (nominal)
- Remarks:
- female/ 48 hours harvesting
- No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- yes, historical
- Positive control(s):
- cyclophosphamide, 40 mg/kg bw, i.p.
Examinations
- Tissues and cell types examined:
- bone marrow
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION:
Dose selection: on basis of the results from a pre-experiment.
TREATMENT:
10 animals per group were evaluated for micronuclei. At least 2000 polychromatic erythrocytes (PCE) per animal were scored. Cytotoxicity was evaluated by the ratio of polychromatic to normochromatic erythrocytes (determined in the same samples as used for micronuclei scoring).
- Evaluation criteria:
- A test substance is classified as mutagenic if it induces either a dose-related increase in the number of micronucleated polychromatic erythrocytes, which clearly exceeds the negative control range or a relevant positive response for at least one of the test points.
Statistical methods (nonparametric Mann-Whitney test) can be used as an aid in evaluating the results. However, the primary point of consideration is the biological relevance of the results.
A test substance producing neither a dose-related increase in the number of micronucleated polychromatic erythrocytes nor a positive response at any of the test points is considered non-mutagenic in this system. - Statistics:
- A non-parametric Mann-Whitney-Test was performed.
Results and discussion
Test results
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Remarks:
- Clinical signs in the high dose animals
- Vehicle controls validity:
- valid
- Negative controls validity:
- not examined
- Positive controls validity:
- valid
- Additional information on results:
- RESULTS OF RANGE-FINDING STUDY
- Dose range: male: 0, 1250 mg/kg bw; female: 0, 1500 mg/kg bw
- Clinical signs of toxicity in test animals: In the dose range-finder pre-experiment, 1250 mg/kg bw i.p. were lethal to both tested male animals. In females, 1500 mg/kg bw i.p. were lethal for 1 of 2 animals.
RESULTS OF DEFINITIVE STUDY
The test item did not induce micronuclei at any dose level or any harvesting time used in this study. It was considered non-clastogenic and non-aneugenic in this assay.
The mean number of normochromatic erythrocytes was not increased after treatment with the test substance as compared to the controls, indicating that the test item had no cytotoxic effect on the bone marrow. The positive control substance induced a distinct increase of micronuclei.
- Clinical signs of toxicity in test animals: males at 1000 mg/kg bw: reduced spontaneous activity, eyelid closure, apathy, prostrate position. females at 1250 mg/kg bw: reduced spontaneous activity, eyelid closure, apathy, prostrate position. 1000 mg/kg bw induced clear signs of toxicity in 7 male animals (reduced activity, eyelid closure, apathy, prostrate position). In females, at 1250 mg/kg bw clear signs of toxicity were observed in 7 female animals (reduced activity, eyelid closure, apathy, prostrate position).
Any other information on results incl. tables
Summary of Micronucleus Test Results
Males
Test group |
dose (mg/kg bw) |
sampling time (h) |
PCEs with micronuclei (‰) |
range |
PCE / NCE |
vehicle |
0 |
24 |
1.20 |
2 - 3 |
2000 / 1965 |
test substance |
250 |
24 |
0.60 |
0 - 3 |
2000 / 1888 |
test substance |
500 |
24 |
0.60 |
0 - 3 |
2000 / 2141 |
test substance |
1000 |
24 |
1.20 |
1 - 4 |
2000 / 2371 |
positive control |
40 |
24 |
14.90 |
17 - 36 |
2000 / 1771 |
vehicle |
0 |
48 |
0.00 |
0 - 0 |
2000 / 2022 |
test substance |
1000 |
48 |
0.40 |
0 - 2 |
2000 / 2642 |
Females:
Test group |
dose (mg/kg bw) |
sampling time (h) |
PCEs with micronuclei (‰) |
range |
PCE / NCE |
vehicle |
0 |
24 |
0.10 |
0 - 1 |
2000 / 1965 |
test substance |
312.5 |
24 |
0.50 |
0 - 3 |
2000 / 1888 |
test substance |
625 |
24 |
0.40 |
0 - 3 |
2000 / 2141 |
test substance |
1250 |
24 |
0.20 |
0 - 2 |
2000 / 2371 |
positive control |
40 |
24 |
12.10 |
11 - 43 |
2000 / 1771 |
vehicle |
0 |
48 |
0.00 |
0 - 0 |
2000 / 2022 |
test substance |
1250 |
48 |
0.10 |
0 - 21 |
2000 / 2642 |
Applicant's summary and conclusion
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