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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

Gene mutation (Bacterial Reverse Mutation Assay/Ames test): Negative (QSAR; Weight of evidence)

Link to relevant study records

Referenceopen allclose all

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
Ferrari T, Gini G (2010) An open source multistep model to predict mutagenicity from statistical analysis and relevant structural alerts. Chemistry Central Journal , 4(Suppl 1):S2. http://www.journal.chemistrycentral.com/content/4/S1/S2

The software is and is freely available through the portal of the CAESAR project.
Specific details on test material used for the study:
C(=C\F)\C(F)(F)F
Species / strain:
other: Salmonella typhimurium; strains not specified
Metabolic activation:
not specified
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not determined
Vehicle controls validity:
not applicable
Untreated negative controls validity:
not applicable
True negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)
Conclusions:
Mutagenicity (Ames test) model (CAESAR) version 2.1.13 predicts the substance is NON-MUTAGENIC.
Executive summary:

The prediction of Mutagenicity (Ames test) model (CAESAR;version 2.1.13) on the target compound may be considered adequate. The main reason for the low ADI value is that the target compounds has a fragment defined by the SMILES: FC=C that is an uncommon fragment not present in the compounds of the training set of the model.

Despite the Applicability Domain tool within VEGA identifies some issues to be verified, using a weight of evidence approach combining several VEGA models and read-across, it allows to support a non mutagenic assessment for the target compound. Indeed, there is agreement between the prediction and all similar compounds containing Fluorine atoms, which are experimentally non mutagenic.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
The model provides a qualitative prediction of mutagenicity on Salmonella typhimurium (Ames test), applying a consensus approach based on the four QSAR models currently available in VEGA

Evaluation of QSAR models for the prediction of Ames genotoxicity: a retrospective exercise on the chemical substances registered under the EU REACH regulation. Antonio Cassano, Giuseppa Raitano, Enrico Mombelli, Alberto Fernández, Josep Cester, Alessandra Roncaglioni, Emilio Benfenati. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2014; 32(3): 273–298. doi: 10.1080/10590501.2014.938955

- www.vegahub.eu
Specific details on test material used for the study:
C(=C\F)\C(F)(F)F
Species / strain:
other: Salmonella typhimurium (strain not specified)
Metabolic activation:
not specified
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not determined
Vehicle controls validity:
not applicable
Untreated negative controls validity:
not applicable
True negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)
Conclusions:
VEGA Mutagenicity (Ames test) CONSENSUS model (version 1.0.2) predicts the substance is NON-MUTAGENIC
Executive summary:

The prediction of Mutagenicity (Ames test) CONSENSUS model, version 1.0.2)) on the target compound may be considered adequate. The low value for the Consensus score depends on the low ADI values of the individual models.

Despite the Applicability Domain tool within VEGA identifies some issues to be verified, using a weight of evidence approach combining several VEGA models and read-across, it allows to support a non mutagenic assessment for the target compound. Indeed, there is agreement between the prediction and all similar compounds containing Fluorine atoms, which are experimentally non mutagenic.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
The Benigni / Bossa rulebase for mutagenicity and carcinogenicity - a module of Toxtree, (2008) by R. Benigni, C. Bossa, N. Jeliazkova, T. Netzeva, and A. Worth. European Commission report EUR 23241 EN.

R. Benigni, C. Bossa, T. Netzeva, A. Rodomonte, and I. Tsakovska (2007) Mechanistic QSAR of aromatic amines: new models for discriminating between mutagens and nonmutagens, and validation of models for carcinogens. Environ mol mutag 48:754-771

VEGA platform available at www.vegahub.eu
Specific details on test material used for the study:
C(=C\F)\C(F)(F)F
Species / strain:
other: Salmonella typhimurium (no strain specified)
Metabolic activation:
not specified
Genotoxicity:
positive
Cytotoxicity / choice of top concentrations:
not determined
Vehicle controls validity:
not applicable
Untreated negative controls validity:
not applicable
True negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
mutagenic potential (based on QSAR/QSPR prediction)
Conclusions:
The prediction of the ISS model (version 1.0.2) is Mutagenic but the result presents some issues. The SA identified in the target compound demonstrated to be relevant when the halogen atom is a Chlorine while in the target compound there is a Fluorine atom. In this specific dataset there are no similar compounds containing Fluorine. From the analysis with the read-across approach of the compounds containing Fluorine atoms it appears that all of them are not mutagenic in Ames test.
Executive summary:

The prediction of Mutagenicity (Ames test) model (ISS; version 1.0.2) on the target compound is not adequate on its own because:

- its low ADI value

- the low similarity of the analogues (considering also those with the same fragment in their structure),

- the piece of information related to SA4 structural alert seems to be not relevant in this case, since it is often associated to Chlorine halogen atom and not to a Fluorine

- The following Atom Centered Fragments have been found in the molecule, but they are not found or rarely found in the model's training set:

  • Fragment defined by the SMILES: FC(F)(F)C; The fragment has less than 3 occurrences in the model's training set
  • Fragment defined by the SMILES: FC=C; The fragment has never been found in the model's training set

Combination of other more reliable QSAR models and read-across allows to support a non mutagenic assessment for the target compound.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
VEGA platform available at www.vegahub.eu

The dataset include 5770 compounds collected from:

1. Freely available Benchmark dataset for in silico prediction of Ames mutagenicity (Hansen, K., Mika, S., Schroeter, T., Sutter, A., Ter Laak, A., Steger-Hartmann, T., Heinrich N., and Müller, K.-R. (2009). Benchmark data set for in silico prediction of Ames mutagenicity. J. Chem. Inf. Model. 49, 2077-2081)

2. Japan’s Health Ministry (data produced within the Ames QSAR project organized by National Institute of Health Sciences of Japan). The Ames assays were conducted under GLP according to Industrial Safety and Health Act in Japan.
Specific details on test material used for the study:
C(=C\F)\C(F)(F)F
Species / strain:
other: Salmonella typhimurium and or Escherichia coli test strains
Metabolic activation:
not specified
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not determined
Vehicle controls validity:
not applicable
Untreated negative controls validity:
not applicable
True negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)
Conclusions:
VEGA k-NN / read-across model to predict Ames mutagenicity, version 1.0.0 predicts the substance is NON-MUTAGENIC
Executive summary:

The prediction of Mutagenicity (Ames test) model (KNN/Read-Across) on the target compound may be considered adequate. The main reason for the low ADI value is that the target compounds has a fragment defined by the SMILES: FC=C that is an uncommon fragment not present in the compounds of the training set of the model.

Despite the Applicability Domain tool within VEGA identifies some issues to be verified, using a weight of evidence approach combining several VEGA models and read-across, it allows to support a non mutagenic assessment for the target compound. Indeed, there is agreement between the prediction and all similar compounds containing Fluorine atoms, which are experimentally non mutagenic.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model, but not (completely) falling into its applicability domain, with adequate and reliable documentation / justification
Guideline:
other: REACH Guidance on QSARs R.6
Principles of method if other than guideline:
- T. Ferrari, D. Cattaneo, G. Gini, N. Golbamaki Bakhtyari, A. Manganaro, E. Benfenati, “Automatic knowledge extraction from chemical structures: the case of mutagenicity prediction”, SAR and QSAR in Environmental Research (2013), vol. 24 issue 5, 365-83.

- Ferrari T, Gini G (2010) An open source multistep model to predict mutagenicity from statistical analysis and relevant structural alerts. Chemistry Central Journal, 4(Suppl 1):S2
http://www.journal.chemistrycentral.com/content/4/S1/S2

- http://www.vegahub.eu/

- http://sarpy.sourceforge.net/
Specific details on test material used for the study:
C(=C\F)\C(F)(F)F
Species / strain:
other: Histidine-dependent strains of Salmonella typhimurium
Metabolic activation:
not specified
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not determined
Vehicle controls validity:
not applicable
Untreated negative controls validity:
not applicable
True negative controls validity:
not applicable
Positive controls validity:
not applicable
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)
Conclusions:
VEGA Mutagenicity (Ames test) SARpy/IRFMN Model (v. 1.0.7) predicts the substance is NON-MUTAGENIC


Executive summary:

The prediction of Mutagenicity (Ames test) model (SarPy/IRFMN, v. 1.0.7)) on the target compound may be considered adequate. The main reason for the low ADI value is that the target compounds has a fragment defined by the SMILES: FC=C that is an uncommon fragment not present in the compounds of the training set of the model.

Despite the Applicability Domain tool within VEGA identifies some issues to be verified, using a weight of evidence approach combining several VEGA models and read-across, it allows to support a non mutagenic assessment for the target compound. Indeed, there is agreement between the prediction and all similar compounds containing Fluorine atoms, which are experimentally non mutagenic.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Additional information

Gene mutation (Bacterial Reverse Mutation Assay/Ames test)

Five VEGA QSAR models (VEGA Mutagenicity (Ames test) CONSENSUS model (version 1.0.2), Caesar hybrid model for bacterial reverse mutation (Ames test) (version 2.1.13), VEGA k-NN/read-across model to predict Ames mutagenicity (version 1.0.0), VEGA Mutagenicity (Ames test) SARpy/IRFMN Model (v. 1.0.7) and VEGA implementation of Mutagenicity ISS Model (version 1.0.2)) were available and were used in a weight of evidence approach. All models used in VEGA except one predicted the target compound as a Non-Mutagen, but all with a low score of applicability domain index (ADI). The models Consensus, KNN/Read Across, SarPy/IRFMN and CAESAR predict the compound as non-mutagenic, Consensus with a score of 0.15 (where 1 is the max) and the others three models with a ADI of 0.54 (where 1 is the max); however the ADI of the ISS model, predicting the target as mutagenic, is even lower (0.3). The mutagenic prediction is due to the match with the structural alert (SA) 4 monohaloalkene, but this SA is often associated to Chlorine halogen atoms and not to Fluorine. If we look at the most similar compounds of all models, we can see that the fluorinated compounds are always not mutagens. The reason why the ADI is low is that the target compound has an ethene fluoride structure that is an uncommon fragment not recognized by any model. In conclusion, despite the fact that the compound does not fall into the applicability domain of all models, using a weight of evidence approach, we can assess that probably the compound is not a mutagen.

Justification for classification or non-classification

Based on the available information in the dossier, the substance (1Z)-1,3,3,3-Tetrafluoroprop-1-ene (CAS No. 29118-25-0) does not need to be classified for germ cell mutagenicity, when the criteria outlined in Annex I of 1272/2008/EC are applied.