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EC number: 601-489-9 | CAS number: 1176-81-4
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
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- Density
- Particle size distribution (Granulometry)
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- 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
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
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- Genetic toxicity
- Carcinogenicity
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- Specific investigations
- Exposure related observations in humans
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- Additional toxicological data
Endpoint summary
Administrative data
Key value for chemical safety assessment
Genetic toxicity in vitro
Description of key information
Fluocortolone-A-acetate is negative with and without metabolic activation in a bacterial reverse mutation assay with the S. typhimurium strains TA 98, TA 100, TA1535, TA1537 and TA1538 (Reimann and Görke, 2000). Additionally, the mutagenic potential of Fluocortolone-A-Acetate was determined using the two QSAR models Leadscope and DEREK. There was no indication for a mutagnic potential in these QSAR predictions.
Link to relevant study records
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- (Q)SAR
- Adequacy of study:
- supporting study
- Study period:
- 2021
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
- Justification for type of information:
- 1. SOFTWARE
Leadscope model applier (v3.0.2)
2. MODEL (incl. version number)
Leadscope model applier (v3.0.2)
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS: 1176-81-4 ; Chemical name: Fluocortolon-A-Acetat
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: QMRF 4.10. Mutagenicity OECD 471 Bacterial Reverse Mutation Test
- Unambiguous algorithm:
A new ICH M7 compliant expert alert system to predict the mutagenic potential of impurities (white paper) http://www.leadscope.com/white_papers/ICHM7-WhitePaper-0314.pdf
The logic for matching alerts is detailed in "A new ICH M7 compliant expert alert system to predict the mutagenic potential of impurities" (white paper): http://www.leadscope.com/white_papers/ICHM7-WhitePaper-0314.pdf
- Defined domain of applicability: The applicability domain is defined as having at least one chemical in a reference set with at least 30% global similarity to the test structure (using the Leadscope 27,000 chemical fragments as descriptors and the Tanimoto similarity score).
- Appropriate measures of goodness-of-fit and robustness and predictivity: Chemicals/descriptor ratio: 241 alerts for 11,528 reference chemicals (ratio = 48); Alerts are run within the Leadscope model applier that provides the capability to specify one or more compounds (using SMILES, Mol files, SD files, or copying from the clipboard), select and run the alerts, assess the applicability domain, and view the results including an explanation for any prediction (such as a full description of any matched alerts). The performance was assessed using the Hansen dataset comprised of 3,700 chemicals (47% positive).
Concordance = 83%, Sensitivity = 92%, Specificity = 70%, Positive
Predictivity = 81%, Negative Predictivity = 86% , coverage = 95% were
obtained.
- Mechanistic interpretation: Accompanying any positive prediction, any alert(s) that match the test compounds are described including a description of the mechanistic basis from the literature reference that cites the alert.
5. APPLICABILITY DOMAIN
- Descriptor domain: The applicability domain is defined as having at least one chemical in a reference set with at least 30% global similarity to the test structure (using the Leadscope 27,000 chemical fragments as descriptors and the Tanimoto similarity score).
- Structural domain: Leadscope Predictive Data Miner is a software program for systematic sub‐structural analysis of a chemical using predefined structural features stored in a template library, training set‐dependent generated structural features (scaffolds) and calculated molecular descriptors. The feature library contains approximately 27,000 pre‐defined structural features and the structural features chosen for the library are motivated by those typically found in small molecules: aromatics, heterocycles, spacer groups, simple substituents. Leadscope allows for the generation of training set‐dependent structural features (scaffold generation), and these features can be added to the pre‐defined structural features from the library and be included in the descriptor selection process.
- Mechanistic domain: The global model identifies structural features and molecular descriptors which in the model development was found to be statistically significant associated with effect. Many predictions may indicate modes of action that are obvious for persons with expert knowledge for the endpoint
- Similarity with analogues in the training set: The original data set from Kazius et al. (2005) consisted of 4337 molecular structures with corresponding Ames test data.
The structural similarity of the test compound with respect to the training set compounds was analysed and quantified in terms of Tanimoto distance, which provides a quantitative measure of structural relatedness between the test compound and each training set compound. The 25 training set compounds found to be mostly similar to the test compound.
6. ADEQUACY OF THE RESULT
As can be seen from Annex A and B of the QPRF the result is considered adequate due to the presence of almost all structural features of the parent compound which can also be found in the training/validation dataset. Furthermore the prediction substantiate the experimental result for the substance of interest. - Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Software tool(s) used including version: Leadscope model applier (v3.0.2)
- Model(s) used: Leadscope model applier (v3.0.2)
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification' - GLP compliance:
- no
- Type of assay:
- bacterial reverse mutation assay
- Species / strain / cell type:
- other: Combination of results from the S. typhimurium histidine reversion gene mutation test using tester strains TA97, TA97a, TA1537, TA98, TA100, TA1535, TA102, E.coli (any variant)
- Additional strain / cell type characteristics:
- other: The QSAR prediction is based on results from all tester strains recommended by the OECD Test guideline
- Evaluation criteria:
- The model used was the Leadscope Applier which is a statistical model using structural fragments to set an alert. Only descrete organic compounds can be predicted. The model searches for structural fragments and combines them with eight molecular descriptors. Thus, a probability of either a negative or positive result is calculated. If experimental data are available the prediction of the statistical model may be overruled.
- Key result
- Species / strain:
- bacteria, other: Not applicable for in silico study
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- other: Not applicable for in silico study
- Vehicle controls validity:
- not applicable
- Untreated negative controls validity:
- not applicable
- True negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Conclusions:
- Based on the predictions performed with the statistical QSAR model Leadscope Applier Fluocortolone-A-Acetate is not mutagenic in a bacterial reverse mutation assay.
- Executive summary:
In a QSAR prediction using Leadscope Model Applier (v3.0.2) the potential of Fluocortolone-A-Acetate to induce mutagenicity was assessed. Leadscope uses two parameters to guide the applicability of model domain: 1) having at least one structural feature defined in the model in addition to all the property descriptors; 2) having at least one chemical in a training neighbourhood with at least 30% global similarity to the test structure. In this case the prediction is within the applicability domain, since 37 training compounds were identified in the model training set being structurally similar to the test compound.
The query structure does not match structural alerts or examples for (bacterial in vitro) mutagenicity in Leadscope.
Based on these results Fluocortolone-A-Acetate is considered not mutagenic as predicted by Leadscope.
This study is classified as acceptable for assessment based on methodology and documentation. This study satisfy the requirement for Test Guideline OECD 471 for in vitro mutagenicity (bacterial reverse gene mutation) and the data is part of an overall assessment.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- (Q)SAR
- Adequacy of study:
- supporting study
- Study period:
- 2021
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- results derived from a valid (Q)SAR model and falling into its applicability domain, with adequate and reliable documentation / justification
- Justification for type of information:
- 1. SOFTWARE
DEREK Nexus 6.1
2. MODEL (incl. version number)
DEREK Nexus 6.1
3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
CAS 1176-81-4
4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: TOX 7.6.1. Genetic toxicity in vitro
- Unambiguous algorithm: logic of argumentation. Derek Nexus makes qualitative predictions for and against toxicity through reasoning. For the endpoint of mutagenicity, predictions for toxicity decrease in confidence in the following order: certain>probable>plausible>equivocal. Predictions against toxicity increase in confidence in the following order: inactive (with unclassified and/or misclassified features) inactive
- Defined domain of applicability: The scopes of the structure-activity relationships describing the mutagenicity endpoint are defined by the developer to be the applicability domain for the model. Therefore, if a chemical activates an alert describing a structure-activity for mutagenicity it can be considered to be within the applicability domain. If a compound does not activate an alert or reasoning rule then Derek makes a negative prediction. The applicability of the negative prediction to the query compounds can be determined by an expert, if required, by investigating the presence (or absence) of misclassified and/or unclassified features. The applicability domain of each alert is defined by the alert developer on the basis of the training set data and expert judgement on the chemical and biological factors which affect the mechanism of action for each alert. For non-alerting compounds, users should determine the applicability of negative predictions by evaluating the information supplied by Derek (i.e. the presence or absence of misclassified and/or unclassified features).
- Appropriate measures of goodness-of-fit and robustness and predictivity: n/a
- Mechanistic interpretation: All alerts describing structure-activity relationships for the mutagenicity endpoint have a mechanistic basis wherever possible.
Mechanistic information is detailed in the comments associated with an alert and can include information on both the mechanism of action and biological target. The mechanistic basis of the model was developed a priori by examining the toxicological and mechanistic evidence before developing the structure-activity relationship.
5. APPLICABILITY DOMAIN
- Descriptor domain:
[1]Markush structures encoding activating and deactivating features (known as patterns in the Derek Nexus knowledge base)
[2]count of non-hydrogen atoms
[3]ClogP
[4]2D structural fragments
There is an a priori assumption that patterns and associated reasoning will be used to model toxicity within Derek Nexus. Further, experts identified that misclassified and unclassified features were useful descriptors for determining the reliability of negative predictions for non-alerting compounds.
- Similarity with analogues in the training set: Non-proprietary elements of the training set are available through the references, and illustrated by the examples, within Derek Nexus. The illustrative examples are not available, due to the proprietary nature of Derek Nexus.
6. ADEQUACY OF THE RESULT
Based on the common structure of the substance, the result is considered reliable. - Qualifier:
- no guideline followed
- Principles of method if other than guideline:
- - Software tool(s) used including version: DEREK Nexus 6.1
- Model(s) used: DEREK Nexus 6.1
- Model description: see field 'Attached justification'
- Justification of QSAR prediction: see field 'Attached justification' - GLP compliance:
- no
- Type of assay:
- bacterial reverse mutation assay
- Species / strain / cell type:
- bacteria, other: Predictions are made for the domain of bacteria and can be broken down into species (e.g. Salmonella typhimurium and Escherichia coli)
- Additional strain / cell type characteristics:
- other: The prediction is based on results from all tester strains recommended by the OECD Test Guideline
- Evaluation criteria:
- Two types of models were used to predict the mutagenic potential of the test item.
The DEREK Nexus model was used as a rule-based model which is based on the training set data and expert judgement on the chemical and biological factors which affect the mechanism of action for each alert. The second model used was the Leadscope Applier which is a statistical model using structural fragments to set an alert. If experimental data are available the prediction of the statistical model may be overruled. - Key result
- Species / strain:
- bacteria, other: Not applicable for in silico study
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- other: Not applicable for in silico study
- Vehicle controls validity:
- not applicable
- Untreated negative controls validity:
- not applicable
- True negative controls validity:
- not applicable
- Positive controls validity:
- not applicable
- Conclusions:
- Based on the predictions performed with the statistical QSAR model Leadscope Applier and the rule-based model DEREK Nexus Fluocortolone-A-Acetate is not mutagenic in a bacterial reverse mutation assay.
- Executive summary:
In a QSAR prediction using DEREK Nexus v6.1 the potential of Fluocortolone-A-Acetate to induce mutagenicity was assessed. Derek Nexus makes qualitative predictions for and against toxicity through reasoning. For the endpoint of mutagenicity, predictions for toxicity decrease in confidence in the following order: certain>probable>plausible>equivocal. Predictions against toxicity increase in confidence in the following order: inactive (with unclassified and/or misclassified features)<inactive<improbable. Likelihood levels have been shown to correlate with predictivity [Judson et al, 2013]. Multiple data sources (e.g. toxicity data from multiple assays and mechanistic evidence) are synthesised into the structure-activity relationships that underpins Derek Nexus predictions. An appreciation of the assay units applied by alert writers when building the alert training set. However, predictions are not quantitative and, as a result, do not include units.
The query structure does not match a structural alert or examples for (bacterial in vitro) mutagenicity in Derek.
Based on these results Fluocortolone-A-Acetate is not considered mutagenic as predicted by DEREK Nexus.
This study is classified as acceptable for assessment based on methodology and documentation. This study satisfy the requirement for Test Guideline OECD 471 for in vitro mutagenicity (bacterial reverse gene mutation) and the data is part of an overall assessment.
- Endpoint:
- in vitro gene mutation study in bacteria
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- Mar to Apr 1999
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- comparable to guideline study with acceptable restrictions
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 471 (Bacterial Reverse Mutation Assay)
- Version / remarks:
- 21 July 1997
- Deviations:
- yes
- Remarks:
- no E. coli WP2 or S. typhimurium TA102 strain tested; only one experiment (direct plate incorporation procedure) was performed
- GLP compliance:
- yes
- Type of assay:
- bacterial reverse mutation assay
- Target gene:
- Histidine gene locus
- Species / strain / cell type:
- S. typhimurium TA 1538
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 1537
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 1535
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 100
- Additional strain / cell type characteristics:
- not applicable
- Species / strain / cell type:
- S. typhimurium TA 98
- Additional strain / cell type characteristics:
- not applicable
- Metabolic activation:
- with and without
- Metabolic activation system:
- Aroclor 1254 induced male rat liver S9 mix
Type and composition of metabolic activation system:
- source of S9: Liver homogenates (S9:9000xg fraction), derived from male Sprague-Dawley rats pre-treated with Aroclor 1254, was obtained from CN/Cappel Pharmaceuticals, Inc., Aurora, Ohio, USA, [S9 batch no. 99554; protein content 37.3 mg/mL; EROD activity: 2627.3 pmoles 7-hydroxyresorufin/min/mg S9 protein].
- concentration or volume of S9 mix and S9 in the final culture medium: 0.5 mL of S9 mix were added to each bacterial culture with a volume of approx. 2.55 mL - Test concentrations with justification for top dose:
- 0.1, 0.25, 0.5, 1.0, 2.5, 5.0 mg/plate
- Vehicle / solvent:
- DMSO
- Untreated negative controls:
- yes
- Negative solvent / vehicle controls:
- yes
- True negative controls:
- no
- Positive controls:
- yes
- Positive control substance:
- 2-nitrofluorene
- sodium azide
- benzo(a)pyrene
- cyclophosphamide
- other: 4-nitro-o-phenylenediamine (only TA 1537) 10 µg/plate without S9, 2-aminoanthracene (all strains) 5 µg/plate with S9
- Details on test system and experimental conditions:
- NUMBER OF REPLICATIONS:
- Number of cultures per concentration triplicate
- Number of independent experiments one
METHOD OF TREATMENT/ EXPOSURE:
- Cell density at seeding (if applicable): Aliquots of a E-06 dilution of the overnight culture were spread onto complete agar to measure the viability and cell densityof each culture.
- Test substance added in agar (plate incorporation)
METHODS FOR MEASUREMENT OF CYTOTOXICITY
- Method, e.g.: background growth inhibition
METHODS FOR MEASUREMENTS OF GENOTOXICITY
The plates were scored for the number of mutant colonies with an automated colony counter (Artek M 982B, Artek Systems Corporation, Farmingdale, NY, USA). In exceptional cases, where reliable automatic counting is not possible, e.g. due to distinct precipitates of the test compound, the colonies are scored manually. - Evaluation criteria:
- The arithmetic means of the number of mutant colonies of the 3 parallel plates in the negative control groups were compared with those of the compound groups. A positive. response was considered if the number of revertants of the compound groups compared to the number of revertants of the negative group was reproducibly higher than 2-fold. A dose-dependent increase in the number of revertants was also considered to indicate a mutagenic effect.
- Key result
- Species / strain:
- S. typhimurium TA 1538
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- growth inhibition at 5.0 mg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1537
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- growth inhibition at 5.0 mg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 1535
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- growth inhibition at 5.0 mg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 100
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- growth inhibition at 5.0 mg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Key result
- Species / strain:
- S. typhimurium TA 98
- Metabolic activation:
- with and without
- Genotoxicity:
- negative
- Cytotoxicity / choice of top concentrations:
- cytotoxicity
- Remarks:
- growth inhibition at 5.0 mg/plate
- Vehicle controls validity:
- valid
- Untreated negative controls validity:
- not examined
- Positive controls validity:
- valid
- Conclusions:
- The mutagenic potential of the test substance was evaluated in a Salmonella/microsome test with the S. typhimurium strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 in the presence and absence of S9 mix according to OECD TG 471. Evidence of mutagenic activity was not seen up to the maximum recommended dose level of 5.0 mg/plate. No substantial increases in revertant colony numbers of any of the five tester strains were observed at any dose level in the presence and absence of metabolic activation. Therefore, ZK 47525 (fluocortolone-A-acetate) was considered to be non-mutagenic in the Salmonella typhimurium reverse mutation assay.
- Executive summary:
In a reverse gene mutation assay in bacteria according to OECD test guideline 471, strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of S. typhimurium were exposed to Fluocortolone acetate (100% a.i.), in DMSO at concentrations of 0.1, 0.25, 0.5, 1.0, 2.5, 5.0 mg/plate in the presence and absence of mammalian metabolic activation with the plate co-incubation method.
Fluocortolone acetate was tested up to cytotoxic and insoluble concentrations. None of the five tester strains TA 1535, TA 100, TA 1537, TA 1538 and TA98 showed increased reversion to prototrophy in assays with ZK 47525 at the doses tested between 0.1 and·5.0 mg/plate, either in the absence or presence of S9 mix. In the present study ZK 47525 was tested up to the highest recommended dose of 5 mg/plate. Precipitates in the agar were found starting at 1.0 mg/plate onwards. Growth inhibition of the background lawn was observed at the highest dose tested. The positive controls induced the appropriate responses in the corresponding strains. There was no evidence of induced mutant colonies over background.
This study satisfies the requirement for Test Guideline OECD 471 for in vitro mutagenicity (bacterial reverse gene mutation) data.
Referenceopen allclose all
The total colony counts of the 10 -6 dilution of bacterial suspension culture confirmed the viability and high cell density of the cultures of the individual strains.The colony counts recorded on appropriate negative control plates confirmed the characteristically spontaneous reversion rates of the tester strains. Appropriate positive control chemicals induced marked increases in revertant colony numbers with all strains.
None of the five tester strains showed increased reversion to prototrophy with ZK 47525 (fluocortolone-A-acetate) at the concentrations tested between 0.1 and 5.0 mg/plate, either in the absence or presence of S9 mix.
Precipitates in the agar were found starting at 1.0 mg/plate onwards. Growth inhibition of the background lawn was observed at the highest concentration tested.
TA 1535 |
| Revertants per plate | Quotient | ||||||
Dose/Plate | -S9 | M | SD | +S9 | M | SD | -S9 | +S9 | |
DMSO | 50µL | 35 | 41 | 6 | 15 | 15 | 1 | 1.0 | 1.0 |
|
| 46 |
|
| 15 |
|
|
|
|
|
| 41 |
|
| 14 |
|
|
|
|
Phosphate Buffer | 50µL | 52 | 55 | 8 | 16 | 15 | 1 | 1.4 | 1.0 |
|
| 64 |
|
| 15 |
|
|
|
|
|
| 49 |
|
| 14 |
|
|
|
|
Test item | 0.10mg | 52 | 52 | 10 | 14 | 13 | 1 | 1.3 | 0.9 |
|
| 42 |
|
| 13 |
|
|
|
|
|
| 61 |
|
| 13 |
|
|
|
|
| 0.25mg | 62 | 60 | 2 | 17 | 19 | 2 | 1.5 | 1.3 |
|
| 60 |
|
| 18 |
|
|
|
|
|
| 59 |
|
| 21 |
|
|
|
|
| 0.50mg | 42 | 49 | 6 | 18 | 19 | 2 | 1.2 | 1.3 |
|
| 51 |
|
| 21 |
|
|
|
|
|
| 54 |
|
| 17 |
|
|
|
|
| 1.0mg | 41P | 45 | 3 | 21P | 20 | 1 | 1.1 | 1.3 |
|
| 46P |
|
| 19P |
|
|
|
|
|
| 47P |
|
| 19P |
|
|
|
|
| 2.5mg | 40 mP | 37 | 3 | 17 mP | 17 | 2 | 0.9 | 1.1 |
|
| 35 mP |
|
| 18mP |
|
|
|
|
|
| 37 mP |
|
| 15 mP |
|
|
|
|
| 5.0mg | 30 mPB | 31 | 2 | 18 mPB | 17 | 2 | 0.8 | 1.1 |
|
| 33 mPB |
|
| 15 mPB |
|
|
|
|
|
| 30 mPB |
|
| 17 mPB |
|
|
|
|
2-AA | 5µg | 55 | 58 | 2 | 113 | 129 | 20 | 1.4 | 8.8 |
|
| 59 |
|
| 151 |
|
|
|
|
|
| 59 |
|
| 124 |
|
|
|
|
CP | 400µg | 101 | 96 | 8 | 195 | 205 | 9 | 2.4 | 14.0 |
|
| 101 |
|
| 207 |
|
|
|
|
|
| 87 |
|
| 212 |
|
|
|
|
NaN3 | 5µg | 361 | 365 | 7 | 39 | 46 | 8 | 9.0 | 3.1 |
|
| 373 |
|
| 55 |
|
|
|
|
|
| 360 |
|
| 44 |
|
|
|
|
| |||||||||
TA 100 |
| Revertants per plate | Quotient | ||||||
Dose/Plate | -S9 | M | SD | +S9 | M | SD | -S9 | +S9 | |
DMSO | 50µL | 128 | 144 | 14 | 111 | 105 | 5 | 1.0 | 1.0 |
|
| 147 |
|
| 103 |
|
|
|
|
|
| 156 |
|
| 101 |
|
|
|
|
Phosphate Buffer | 50µL | 135 | 139 | 12 | 110 | 113 | 16 | 1.0 | 1.1 |
|
| 129 |
|
| 131 |
|
|
|
|
|
| 153 |
|
| 99 |
|
|
|
|
Test item | 0.10mg | 147 | 148 | 14 | 113 | 112 | 6 | 1.0 | 1.1 |
|
| 135 |
|
| 118 |
|
|
|
|
|
| 162 |
|
| 106 |
|
|
|
|
| 0.25mg | 113 | 131 | 15 | 103 | 107 | 5 | 0.9 | 1.0 |
|
| 138 |
|
| 112 |
|
|
|
|
|
| 141 |
|
| 107 |
|
|
|
|
| 0.50mg | 145 | 147 | 2 | 100 | 105 | 5 | 1.0 | 1.0 |
|
| 147 |
|
| 109 |
|
|
|
|
|
| 149 |
|
| 107 |
|
|
|
|
| 1.0mg | 147P | 138 | 12 | 117P | 115 | 10 | 1.0 | 1.1 |
|
| 142P |
|
| 104P |
|
|
|
|
|
| 125P |
|
| 123P |
|
|
|
|
| 2.5mg | 145 mP | 145 | 6 | 111 mP | 124 | 13 | 1.0 | 1.2 |
|
| 139 mP |
|
| 123 mP |
|
|
|
|
|
| 150 mP |
|
| 137 mP |
|
|
|
|
| 5.0mg | 150 mPB | 137 | 12 | 109 mPB | 105 | 5 | 1.0 | 1.0 |
|
| 129 mPB |
|
| 100 mPB |
|
|
|
|
|
| 131 mPB |
|
| 106 mPB |
|
|
|
|
2-AA | 5µg | 229 | 220 | 16 | 1554 | 1602 | 56 | 1.5 | 15.3 |
|
| 202 |
|
| 1589 |
|
|
|
|
|
| 230 |
|
| 1664 |
|
|
|
|
B[a]P | 2.5µg | 135 | 130 | 7 | 1153 | 1007 | 165 | 0.9 | 9.6 |
|
| 122 |
|
| 1040 |
|
|
|
|
|
| 134 |
|
| 828 |
|
|
|
|
NaN3 | 5µg | 1109 | 1023 | 77 | 294 | 348 | 49 | 7.1 | 3.3 |
|
| 960 |
|
| 360 |
|
|
|
|
|
| 999 |
|
| 389 |
|
|
|
|
| |||||||||
TA 1537 |
| Revertants per plate | Quotient | ||||||
Dose/Plate | -S9 | M | SD | +S9 | M | SD | -S9 | +S9 | |
DMSO | 50µL | 13 | 20 | 6 | 18 | 19 | 4 | 1.0 | 1.0 |
|
| 23 |
|
| 23 |
|
|
|
|
|
| 24 |
|
| 16 |
|
|
|
|
Phosphate Buffer | 50µL | 28 | 24 | 4 | 15 | 17 | 4 | 1.2 | 0.9 |
|
| 21 |
|
| 14 |
|
|
|
|
|
| 23 |
|
| 21 |
|
|
|
|
Test item | 0.10mg | 25 | 21 | 9 | 16 | 15 | 1 | 1.1 | 0.8 |
|
| 11 |
|
| 15 |
|
|
|
|
|
| 27 |
|
| 15 |
|
|
|
|
| 0.25mg | 19 | 23 | 4 | 7 | 15 | 8 | 1.1 | 0.8 |
|
| 23 |
|
| 17 |
|
|
|
|
|
| 26 |
|
| 22 |
|
|
|
|
| 0.50mg | 19 | 19 | 1 | 14 | 13 | 3 | 1.0 | 0.7 |
|
| 20 |
|
| 10 |
|
|
|
|
|
| 18 |
|
| 15 |
|
|
|
|
| 1.0mg | 22P | 21 | 3 | 12P | 13 | 1 | 1.1 | 0.7 |
|
| 24P |
|
| 14P |
|
|
|
|
|
| 18P |
|
| 13P |
|
|
|
|
| 2.5mg | 19P | 19 | 5 | 10 mP | 11 | 2 | 1.0 | 0.6 |
|
| 15 mP |
|
| 9 mP |
|
|
|
|
|
| 24 mP |
|
| 13 mP |
|
|
|
|
| 5.0mg | 25 mPB | 17 | 7 | 9 mPB | 13 | 4 | 0.9 | 0.7 |
|
| 13 mPB |
|
| 15 mPB |
|
|
|
|
|
| 14 mPB |
|
| 16 mPB |
|
|
|
|
2-AA | 5.0 µg | 24 | 29 | 6 | 155 | 137 | 16 | 1.5 | 7.2 |
|
| 35 |
|
| 127 |
|
|
|
|
|
| 28 |
|
| 128 |
|
|
|
|
4-NPDA | 10.0 µg | 71 | 72 | 1 | 33 | 32 | 2 | 3.6 | 1.7 |
|
| 73 |
|
| 33 |
|
|
|
|
|
| 73 |
|
| 30 |
|
|
|
|
| |||||||||
TA 1538 |
| Revertants per plate | Quotient | ||||||
Dose/Plate | -S9 | M | SD | +S9 | M | SD | -S9 | +S9 | |
DMSO | 50µL | 11 | 12 | 1 | 19 | 17 | 3 | 1.0 | 1.0 |
|
| 12 |
|
| 13 |
|
|
|
|
|
| 12 |
|
| 19 |
|
|
|
|
Phosphate Buffer | 50µL | 9 | 12 | 3 | 31 | 28 | 3 | 1.1 | 1.7 |
|
| 14 |
|
| 28 |
|
|
|
|
|
| 14 |
|
| 26 |
|
|
|
|
Test item | 0.10mg | 11 | 16 | 5 | 23 | 23 | 1 | 1.4 | 1.3 |
|
| 16 |
|
| 23 |
|
|
|
|
|
| 21 |
|
| 22 |
|
|
|
|
| 0.25mg | 13 | 10 | 3 | 20 | 20 | 9 | 0.9 | 1.2 |
|
| 7 |
|
| 12 |
|
|
|
|
|
| 11 |
|
| 29 |
|
|
|
|
| 0.50mg | 14 | 15 | 2 | 19 | 21 | 2 | 1.3 | 1.3 |
|
| 14 |
|
| 22 |
|
|
|
|
|
| 18 |
|
| 23 |
|
|
|
|
| 1.0mg | 14 mP | 13 | 1 | 26P | 19 | 6 | 1.1 | 1.1 |
|
| 13 mP |
|
| 15 mP |
|
|
|
|
|
| 12 mP |
|
| 16 mP |
|
|
|
|
| 2.5mg | 10 mP | 11 | 3 | 18 mP | 16 | 3 | 0.9 | 1.0 |
|
| 14 mP |
|
| 13 mP |
|
|
|
|
|
| 9 mP |
|
| 18 mP |
|
|
|
|
| 5.0mg | 9 mPB | 12 | 3 | 17 mPB | 16 | 3 | 1.0 | 1.0 |
|
| 12 mPB |
|
| 13 mPB |
|
|
|
|
|
| 14 mPB |
|
| 19 mPB |
|
|
|
|
2-NF | 10µg | 23 | 24 | 2 | 959 | 1114 | 150 | 2.1 | 65.5 |
|
| 26 |
|
| 1123 |
|
|
|
|
|
| 23 |
|
| 1259 |
|
|
|
|
2-AA | 5µg | 1303 | 1326 | 75 | 598 | 530 | 67 | 113.7 | 31.2 |
|
| 1266 |
|
| 465 |
|
|
|
|
|
| 1410 |
|
| 526 |
|
|
|
|
| |||||||||
TA 98 |
| Revertants per plate | Quotient | ||||||
Dose/Plate | -S9 | M | SD | +S9 | M | SD | -S9 | +S9 | |
DMSO | 50µL | 30 | 35 | 5 | 32 | 34 | 2 | 1.0 | 1.0 |
|
| 35 |
|
| 34 |
|
|
|
|
|
| 40 |
|
| 36 |
|
|
|
|
Phosphate Buffer | 50µL | 30 | 41 | 11 | 32 | 33 | 1 | 1.2 | 1.0 |
|
| 42 |
|
| 34 |
|
|
|
|
|
| 51 |
|
| 33 |
|
|
|
|
Test item | 0.10mg | 33 | 36 | 3 | 28 | 24 | 4 | 1.0 | 0.7 |
|
| 38 |
|
| 21 |
|
|
|
|
|
| 37 |
|
| 23 |
|
|
|
|
| 0.25mg | 41 | 43 | 4 | 20 | 25 | 4 | 1.2 | 0.7 |
|
| 40 |
|
| 28 |
|
|
|
|
|
| 48 |
|
| 26 |
|
|
|
|
| 0.50mg | 30 | 37 | 6 | 25 | 27 | 8 | 1.0 | 0.8 |
|
| 40 |
|
| 20 |
|
|
|
|
|
| 40 |
|
| 35 |
|
|
|
|
| 1.0mg | 45 mP | 36 | 8 | 22 mP | 24 | 2 | 1.0 | 0.7 |
|
| 29 mP |
|
| 26 mP |
|
|
|
|
|
| 33 mP |
|
| 25 mP |
|
|
|
|
| 2.5mg | 41 mP | 38 | 5 | 25 mP | 21 | 3 | 1.1 | 0.6 |
|
| 33 mP |
|
| 19 mP |
|
|
|
|
|
| 41 mP |
|
| 20 mP |
|
|
|
|
| 5.0mg | 34 mPB | 38 | 5 | 25 mPB | 22 | 4 | 1.1 | 0.6 |
|
| 37 mPB |
|
| 17 mPB |
|
|
|
|
|
| 43 mPB |
|
| 24 mPB |
|
|
|
|
2-AA | 5.0 µg | 47 | 53 | 6 | 1770 | 1805 | 57 | 1.5 | 53.1 |
|
| 59 |
|
| 1871 |
|
|
|
|
|
| 54 |
|
| 1775 |
|
|
|
|
B[a]P | 2.5 µg | 42 | 42 | 4 | 280 | 265 | 21 | 1.2 | 7.8 |
|
| 45 |
|
| 241 |
|
|
|
|
|
| 38 |
|
| 273 |
|
|
|
|
2-NF | 10µg | 726 | 760 | 37 | 318 | 373 | 56 | 21.7 | 11.0 |
|
| 753 |
|
| 430 |
|
|
|
|
|
| 800 |
|
| 371 |
|
|
|
|
M : Mean SD : Standard-deviation Quotient = Mean revertants (test substance) p : Precipitation +S9 : With S9 mix -S9 : Without S9 mix m :-Manually scored C : Contamination / : Not tested B : Background lawn reduced R : Repeat experiment |
Endpoint conclusion
- Endpoint conclusion:
- no adverse effect observed (negative)
Genetic toxicity in vivo
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
In a reverse gene mutation assay in bacteria according to OECD test guideline 471, strains TA 98, TA 100, TA 1535, TA 1537 and TA 1538 of S. typhimurium were exposed to Fluocortolone acetate (100% a.i.), in DMSO at concentrations of 0.1, 0.25, 0.5, 1.0, 2.5, 5.0 mg/plate in the presence and absence of mammalian metabolic activation with the plate co-incubation method.
Fluocortolone acetate was tested up to cytotoxic and insoluble concentrations. None of the five tester strains TA 1535, TA 100, TA 1537, TA 1538 and TA98 showed increased reversion to prototrophy in assays with ZK 47525 at the doses tested between 0.1 and·5.0 mg/plate, either in the absence or presence of S9 mix. In the present study ZK 47525 was tested up to the highest recommended dose of 5 mg/plate. Precipitates in the agar were found starting at 1.0 mg/plate onwards. Growth inhibition of the background lawn was observed at the highest dose tested. The positive controls induced the appropriate responses in the corresponding strains. There was no evidence of induced mutant colonies over background.
This study satisfies the requirement for Test Guideline OECD 471 for in vitro mutagenicity (bacterial reverse gene mutation) data.
In a QSAR prediction using Leadscope Model Applier (v3.0.2) the potential of Fluocortolone-A-Acetate to induce mutagenicity was assessed. Leadscope uses two parameters to guide the applicability of model domain: 1) having at least one structural feature defined in the model in addition to all the property descriptors; 2) having at least one chemical in a training neighbourhood with at least 30% global similarity to the test structure. In this case the prediction is within the applicability domain, since 37 training compounds were identified in the model training set being structurally similar to the test compound.
The query structure does not match structural alerts or examples for (bacterial in vitro) mutagenicity in Leadscope.
Based on these results Fluocortolone-A-Acetate is considered not mutagenic as predicted by Leadscope.
This study is classified as acceptable for assessment based on methodology and documentation. This study satisfy the requirement for Test Guideline OECD 471 for in vitro mutagenicity (bacterial reverse gene mutation) and the data is part of an overall assessment.
In a QSAR prediction using DEREK Nexus v6.1 the potential of Fluocortolone-A-Acetate to induce mutagenicity was assessed. Derek Nexus makes qualitative predictions for and against toxicity through reasoning. For the endpoint of mutagenicity, predictions for toxicity decrease in confidence in the following order: certain>probable>plausible>equivocal. Predictions against toxicity increase in confidence in the following order: inactive (with unclassified and/or misclassified features)<inactive<improbable. Likelihood levels have been shown to correlate with predictivity [Judson et al, 2013]. Multiple data sources (e.g. toxicity data from multiple assays and mechanistic evidence) are synthesised into the structure-activity relationships that underpins Derek Nexus predictions. An appreciation of the assay units applied by alert writers when building the alert training set. However, predictions are not quantitative and, as a result, do not include units.
The query structure does not match a structural alert or examples for (bacterial in vitro) mutagenicity in Derek.
Based on these results Fluocortolone-A-Acetate is not considered mutagenic as predicted by DEREK Nexus.
This study is classified as acceptable for assessment based on methodology and documentation. This study satisfy the requirement for Test Guideline OECD 471 for in vitro mutagenicity (bacterial reverse gene mutation) and the data is part of an overall assessment.
Justification for classification or non-classification
Based on the study results a classification according to Regulation (EC) No. 1272/2008 (CLP) is not required.
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