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EC number: 603-373-3 | CAS number: 129909-90-6
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
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- Density
- Particle size distribution (Granulometry)
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- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
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- Endpoint summary
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- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
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- Carcinogenicity
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- Additional toxicological data

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:
- key study
- Study period:
- 25 February 19957 - 14 March 1997
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: Only a single test material dose group used, not applicable with current guidance
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- (1983)
- Deviations:
- yes
- Remarks:
- , only a single test material dose group used, not applicable with current guidance
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.12 (Mutagenicity - In Vivo Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- (1992)
- Deviations:
- yes
- Remarks:
- , only a single test material dose group used, not applicable with current guidance
- Qualifier:
- according to guideline
- Guideline:
- EPA OPPTS 870.5395 (In Vivo Mammalian Cytogenetics Tests: Erythrocyte Micronucleus Assay)
- Version / remarks:
- (1996)
- Deviations:
- yes
- Remarks:
- , only a single test material dose group used, not applicable with current guidance
- GLP compliance:
- yes
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- 4-amino-N-tert-butyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-1-carboxamide
- EC Number:
- 603-373-3
- Cas Number:
- 129909-90-6
- Molecular formula:
- C10H19N5O2
- IUPAC Name:
- 4-amino-N-tert-butyl-5-oxo-3-(propan-2-yl)-4,5-dihydro-1H-1,2,4-triazole-1-carboxamide
- Details on test material:
- - Name of test material (as cited in study report): MKH 3586
- Physical state: powder
- Analytical purity: 98.1%
- Impurities (identity and concentrations):
- Purity test date: 4 Dec 1996
- Lot/batch No.: 05362/0005 (mixed batch)
- Expiration date of the lot/batch:2 Jun 1997
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- other: Hsd/Win: NMRI
- Sex:
- male/female
Administration / exposure
- Route of administration:
- intraperitoneal
- Duration of treatment / exposure:
- Single administration
- Frequency of treatment:
- Single administration
- Post exposure period:
- 16, 24 and 48 hrs
Doses / concentrations
- Remarks:
- Doses / Concentrations:
0, 100 mg/kg
Basis:
nominal conc.
- No. of animals per sex per dose:
- 5 animals/sex/dose
- Control animals:
- yes, concurrent vehicle
Examinations
- Tissues and cell types examined:
- Micronuclei within polychromatic erthyrocytes (PCE) analysed for endpoint assessment and PCE and normochromatic erthyrocyte cells analysed for toxicity assessment
Results and discussion
Test results
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- no effects
- Vehicle controls validity:
- valid
- Negative controls validity:
- not applicable
- Positive controls validity:
- valid
Any other information on results incl. tables
RANGE-FINDING TEST:
Four males were dosed at 160, 200, 1000 and 5000 mg/kg. Animals were sacrificed at 3 days post the end of dosing. The following deaths were observed 0/4, 1/4, 4/4 and 4/4 respectively. The MTD was determined to be 160 mg/kg, however, in spite of the death observed a maximum dose of 200 mg/kg was selected for the micronucleus assay.
MICRONUCLEUS ASSAY
Clinical observations:
No mortalities were observed in the main experiment. Clinical signs reported were similar to those already noted in the RF.
PCE ratio:
No evidence of cytotoxicity was observed.
Micronucleated polychromatic erythrocytes (MN PCE):
Analysis of the mean MN PCE group data individually and combined indicated that there was no statistically significant increases in MN PCE frequency compared to concurrent control values for either sex (or combined). Individual animal and group mean MN PCE frequencies were consistent with both the concurrent vehicle control values and the historical control. Data from the 16hr time point has been discarded and not reported as the sampling time is too short for an affect to be observed in the proliferating bone marrow, as recognised by current guidance. Positive control treatment induced the appropriate response.
Table 7.6.2 -1: Summary of micronucleus results in male and female mice (24 and 48hr sample)
Dose |
Sex |
Harvest |
No. of PCE |
Mean %MN PCE / 1000 PCE |
Mean %PCE |
Vehicle |
Male |
24 |
5000 |
2.6 |
45.7 |
Female |
24 |
5000 |
1.8 |
36.5 |
|
|
Mean |
10000 |
2.2 ±1.4 |
41.1 |
|
MKH 3586 (100) |
Male |
24 |
5000 |
2.0 |
40.2 |
Female |
24 |
5000 |
2.2 |
41.72 |
|
|
Mean |
10000 |
2.1 ± 1.2 |
41.0 |
|
MKH 3586 (100) |
Male |
48 |
5000 |
2.2 |
40.1 |
Female |
48 |
5000 |
1.2 |
37.4 |
|
|
Mean |
10000 |
1.7 ± 1.2 |
38.8 |
|
CPA (20) |
Male |
24 |
5000 |
21.4 |
49.0 |
Female |
24 |
5000 |
13.6 |
52.4 |
|
|
Mean |
10000 |
17.5 ± 6.5 * |
50.7 |
* p<0.05
Applicant's summary and conclusion
- Conclusions:
- Interpretation of results (migrated information): negative
Based on the results from this study MKH 3586 did not exhibitin vivomammalian genotoxicity in male or female mouse bone marrow cells when tested up to a dose of 100 mg/kg (considered to exceed the MTD), despite the deficiencies in the study design (i.e. only a single test material dose group, rather than the required 3 dose levels). - Executive summary:
In a bone marrow micronucleus assay using Hsd/Win: NMRI mice, a single administeredipdose of MKH 3586 tech was administered to groups of male and female animals, employing a dose volume of 10 mL/kg. Doses were selected from a pilot toxicity study where the MTD was deemed to be 100 mg/kg.
Mice were treated MKH 3586 at a single dose of 100 mg/kg and sampled at 24 and 48 hours. A negative control group was treated with vehicle only (0.5% Cremophor), and positive control group was treated with cyclophosphamide (CPA, 20 mg/kg) and sampled at 24 hours. A further sample time of 16 hours was also utilised, however as this sample time is considered too early, data from this sample time point has not been reported. Slides of bone marrow cells were prepared from five animals/sex/time point for each group and scored for the occurrence of micronucleated polychromatic erythrocytes (MN PCE) and PCE/total erythrocyte ratios.
Whilst no mortality was observed, clinical signs of toxicity reported in the micronucleus test were similar to those observed in the dose range finding experiment (splayed hind legs, rough coat etc).
Analysis of the mean MN PCE group data from the first experiment indicated that there was no statistically significant increases MN PCE frequency compared to concurrent control values for either sex. Individual animal and group mean MN PCE frequencies were consistent with both the concurrent vehicle control values and the historical control. Positive control treatment induced the appropriate response
Based on the results from this study MKH 3586 did not exhibitin vivomammalian genotoxicity in male or female mouse bone marrow cells when tested up to a dose of 100 mg/kg (considered to exceed the MTD), despite the deficiencies in the study design (i.e. only a single test material dose group, rather than the required 3 dose levels).
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