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EC number: 613-915-0 | CAS number: 66233-43-0
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- 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
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Genetic toxicity: in vivo
Administrative data
- Endpoint:
- in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration
- Type of information:
- experimental study
- Adequacy of study:
- other information
- Study period:
- Sep 1995
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 997
- Report date:
- 1997
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 474 (Mammalian Erythrocyte Micronucleus Test)
- Version / remarks:
- 26 May 1983
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Type of assay:
- micronucleus assay
Test material
- Reference substance name:
- Fluocortolone
- EC Number:
- 205-811-5
- EC Name:
- Fluocortolone
- Cas Number:
- 152-97-6
- Molecular formula:
- C22H29FO4
- IUPAC Name:
- 6-fluoro-11,21-dihydroxy-16-methylpregna-1,4-diene-3,20-dione
- Details on test material:
- - Name of test material (as cited in study report): fluocortolone (ZK 10445)
- Lot/batch No.: 25058890
- Expiration date of the lot/batch: Jul 98
Constituent 1
Test animals
- Species:
- mouse
- Strain:
- NMRI
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River GmbH, Sulzfeld, Germany
- Age at study initiation: ca. 9 to 10 weeks old
- Weight at study initiation: males: ca. 29 - 36 g; females: ca. 25 - 29 g
- Assigned to test groups randomly: yes
- Fasting period before study: ca. 17-21 h
- Housing: individually, in Makrolon® type II cages containing wood-chip bedding
- Diet (e.g. ad libitum): Altromin ® R; Lage; Germany, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 13 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 60-62
- Photoperiod (hrs dark / hrs light): 12/12
Administration / exposure
- Route of administration:
- intraperitoneal
- Vehicle:
- - Vehicle(s)/solvent(s) used: 0.9% NaCI; 0.085% MyrjC8i 53 in bidist. water
- Concentration of test material in vehicle: 7.5; 15 or 30 mg fluocortolone/ml (pH 3.4-4.0)
- Amount of vehicle: 10 mL/kg i.p. - Details on exposure:
- TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg i.p.
- Concentration (if solution): 7.5, 15, 30, 3 mg/mL
- Constant volume or concentration used: yes - Duration of treatment / exposure:
- single
- Frequency of treatment:
- once
- Post exposure period:
- 24 and 48 hours
Doses / concentrationsopen allclose all
- Dose / conc.:
- 75 mg/kg bw/day (nominal)
- Dose / conc.:
- 150 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 10/sex/dose (test substance and negative control)
Positive control animals: 5/sex - Control animals:
- yes, concurrent vehicle
- Positive control(s):
- cyclophosphamide
- Route of administration: gavage
- Doses / concentrations: 30 mg/kg
Examinations
- Tissues and cell types examined:
- bone marrow of femur
- Details of tissue and slide preparation:
- CRITERIA FOR DOSE SELECTION: It was known from acute toxicity studies in male and female mice after single i.p. application that the LD50 of fluocortolone was 395-510 mg/kg. Therefore, in order to achieve toxic effects while avoiding mortality, 300 mg/kg was chosen as highest dose in the micronucleus test.
TREATMENT AND SAMPLING TIMES ( in addition to information in specific fields): All animals were treated once in the morning. The animals of the negative control group and the three dose groups were treated intraperitoneally with the vehicle or the test substance. The positive contral substance cyclophosphamide was administered by gavage. Furthermore, in the highest dose group 3 reserve animals of each sex were also treated in order to replace moribund or dead animals, if necessary. 5 males and 5 females from the negative control and the fluocortolone groups were killed by carbon dioxide asphyxiation at 24 or 48 hours after treatment (the positive control animals were killed 24 hours after treatment) and both femurs were dissected out from each animal.
DETAILS OF SLIDE PREPARATION: The bone marrow was flushed/aspirated into fetal calf serum. The resulting cell suspensions
were centrifuged and smears were prepared from drops of the cell pellets which had been resuspended in a few drops of serum. The slides were air-dried and stained using May-Gruenwald and Giemsa solutions. The slides were coded and analysed "blind" in random order.
METHOD OF ANALYSIS: The stained smears were examined using oi! immersion high power magnification in regions where cells were weil spread and stained. The slides were examined for the incidence of micronucleated cells per 2000 polychromatic (PCE) and 1000 normochromatic (NCE) erythrocytes per anima!. The ratio of polychromatic to normochromatic erythrocytes was calculated on the basis of 1000 NCE scored.
- Statistics:
- The statistical analysis was conducted for each of the following variables:
P1: proportion of micronucleated PCE
P2: proportion of micronucleated NCE
P3: ratio of PCE/NCE
For investigation of treatment differences of the variables P1 and P2 were arc sin √pi transformed. The analyses were conducted separately for the sampie times. Regarding the first sampie time one-sided t-tests were performed to assess the difference between positive and negative controls with pooled values for both sexes; the positive control group was then excluded from further analysis. Thereafter in a two-factorial analysis of variance (factors "sex", "treatment") for each sampie time it was investigated as to whether treatment effect was present. In case of significant interactions, comparisons between the control and each of the treatment groups were conducted separately for each sex. Where no significant interactions
occurred but a global treatment effect, comparisons were performed with values pooled for both sexes. The pair-wise comparisons were performed with one-sided t-tests (increase of P1 and P2, decrease of P3), using the error estimate of the analysis of variance table. The test levels were always α = 0.05 (least significant differences test-LSD).
Results and discussion
Test results
- Key result
- Sex:
- male/female
- Genotoxicity:
- negative
- Toxicity:
- yes
- Vehicle controls validity:
- valid
- Negative controls validity:
- valid
- Positive controls validity:
- valid
- Additional information on results:
RESULTS OF DEFINITIVE STUDY
- Induction of micronuclei (for Micronucleus assay): In male animals 48 hours post application a significant decrease in the ratio of PCE and NCE was observed for all three dose groups as compared to the control, indicating a bone marrow depression induced by the test compound. Regarding micronucleated PCE counts there were neither biologically relevant nor statistically significant differences (p > 0.05) at any sampling time. However, a significant increase in the number of micronucleated NCE was observed for all three dose groups as compared to the negative control at the early sampling time 24 hours post application. Since this statistically significant increase is obviously due to an unusually low NCE rate (0.4‰) , in the vehicle control in comparison to the historical control (0.7-1.1‰, MV 0.89‰ ± 0.17), this effect is considered to be of no biological relevance. This assessment is strongly supported by the fact that micronuclei first appear in PCE at 15 hours after treatment and only the NCE will have micronuclei induced by a recent treatment within 2-3 days of sampling. Consequently, 24 hours after treatment test substance-related micronuclei cannot be expected in the mature normochromatic erythrocytes (NCE). And anyway for the micronucleus assay in the bone marrow, it is essential to base the conclusion primarily upon micronuclei in polychromatic erythrocytes, i.e. the frequency of micronucleated immature erythrocytes is the principal end-point. However, these were not increased by the test substance in this study.
- Ratio of PCE/NCE (for Micronucleus assay): see 'Any other information on results incl. tables'
Any other information on results incl. tables
Slight to moderate apathy was seen as a sign of systemic toxicity dose dependently in all treated groups. In male animals 48 hours after exposure a significant decrease in the ratio of PCE and NCE was observed for all three dose groups, indicating bone marrow suppression.
Summary of results -
Frequency of micronucleated polychromatic erythrocytes (in ‰) from 2000 cells scored per animal and ratio PCE/NCE in mouse bone marrow after a single i.p. administration of the test item
Sampling times, 24 h and 48 h after treatment
Treatment | Dosage (mg/kg) | Number of animals | 24 h post application | |||
Male | Female | Male and Female | ||||
PCE (M) (MV ± SD) | PCE (M) (MV ± SD) | PCE (M) (MV ± SD) | Ratioa) PCE/NCE | |||
Negative control (vehicle) |
| 5M +5 F | 0.70 ± 0.27 | 0.60 ± 0.42 | 0.65 ± 0.34 | 0.99 ± 0.06 |
Test item | 75 | 5M +5 F | 1.10±0.74 | 0.90 ± 0.42 | 1.00 ± 0.58 | 0.97 ± 0.07 |
| 150 | 5M +5 F | 1.00 ± 0.50 | 0.90 ± 0.55 | 0.95 ± 0.50 | 0.98 ± 0.09 |
| 300 | 5M +5 F | 1.50 ± 0.94 | 0.60 ± 0.22 | 1.05 ± 0.80 | 0.93 ± 0.07 |
Cyclophosphamide | 30 | 5M +5 F | 10.20 ± 4.72 | 12.50 ± 1.46 | 11.35*± 3.51 | 0.85*± 0.08 |
| ||||||
Treatment | Dosage (mg/kg) | Number of animals | 48 h post application | |||
Male | Female | Male and Female | ||||
PCE (M) (MV ± SD) | PCE (M) (MV ± SD) | PCE (M) (MV ± SD) | Ratioa) PCE/NCE | |||
Negative control (vehicle) |
| 5M +5 F | 0.60 ± 0.42 | 0.70 ± 0.57 | 0.65 ± 0.47 | 0.94 ± 0.07 |
Test item | 75 | 5M +5 F | 0.50 ± 0.50 | 1.00 ± 0.61 | 0.75 ± 0.59 | 0.90 ± 0.06 |
| 150 | 5M +5 F | 0.90 ± 0.55 | 0.80 ± 0.27 | 0.85 ± 0.41 | 0.89 ± 0.05 |
| 300 | 5M +5 F | 0.70 ± 0.57 | 0.50 ± 0.50 | 0.60 ± 0.52 | 0.88 ± 0.05 |
Cyclophosphamide | 30 | -- | -- | -- | -- | -- |
| ||||||
PCE = polychromatic erythrocytes NCE = normochromatic erythrocytes PCE(M) = micronucleated polychromatic erythrocytes SD = standard deviation MV = mean value a) = calculated on the basis of 1000 NCE's scored per animal * p < 0.05, compared to negative control |
Applicant's summary and conclusion
- Conclusions:
Fluocortolone did not show any mutagenic/clastogenic potential under the test conditions. Classification is not reqiured.- Executive summary:
In a NMRI mouse bone marrow micronucleus assay according to OECD test guideline 474 (1983), (10/sex/dose) mice were treated i.p. with Fluocortolone (100% a.i.) at doses of 0, 75, 150, 300 mg/kg bw. Bone marrow cells were harvested at 24 and 48 h post-treatment. The vehicle was 0.9% NaCI; 0.085% MyrjC8i 53 in bidist. water.
Slight to moderate apathy was seen as a sign of systemic toxicity dose dependently in all treated groups. In male animals 48 hours after exposure a significant decrease in the ratio of PCE and NCE was observed for all three dose groups, indicating bone marrow suppression. Fluocortolone was tested at an adequate dose based on preliminary tests. The positive control induced the appropriate response. There was not a significant increase in the frequency of micronucleated polychromatic erythrocytes in bone marrow after any treatment time.
Fluocortolone did not show any mutagenic/clastogenic potential under the test conditions.
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