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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The available data for this endpoint include one Ames assay, an European Food Safety Authority (EFSA) review and QSARs conducted using VEGA and ToxTree software.

Link to relevant study records

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Endpoint:
genetic toxicity in vitro, other
Remarks:
in silico prediciton
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Not applicable
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 : ToxTree (Estimation of Toxic Hazard- A Decision Tree Approach)

2. MODEL: v.2.6.13

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL
: O(c1ccc(cc1)CCC)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint:
In vitro mutagenicity (Ames test) alerts by ISS decsion tree method. A decision tree for estimating in vitro mutagenicity (Ames test). Developed by Istituto Superiore di Sanita for JRC IHCP Computational Toxicology and Modelling and IdeaConsult Ltd., (Sofia, Bulgaria)


5. APPLICABILITY DOMAIN
No details on how the substance falls within the applicability domain of the model was provided by the software.


6. ADEQUACY OF THE RESULT
No details on how the prediction fits the purpose of classification and labelling and/or risk assessment was provided by the software.

This endpoint study record is part of a weight of evidence approach comprising of QSAR predictions using ToxTree and OECDToolbox. Both data sources agree with the prediction that the test substance is a mutagen.
Qualifier:
no guideline required

A QSAR using ToxTree software and applying the 'In vitro mutagenicity (Ames test)' decsion tree results in ' No alerts for S. tymphimurium mutagenicity'.

Conclusions:
A QSAR using ToxTree software and applying the 'In vitro mutagenicity (Ames test)' decsion tree results in ' No alerts for S. tymphimurium mutagenicity'.
Executive summary:

A QSAR using ToxTree software and applying the 'In vitro mutagenicity (Ames test)' decsion tree results in ' No alerts for S. tymphimurium mutagenicity'.

Endpoint:
genetic toxicity in vitro, other
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Not applicable
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 limited documentation / justification
Justification for type of information:
1. SOFTWARE : VEGA QSAR MODEL Core version 1.2.4

2. MODEL: Mutagenicity (Ames test) model (CAESAR) 2.1.13

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :O(c1ccc(cc1)CCC)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Mutagenicity
- Unambiguous algorithm:
- Defined domain of applicability: Compound is into the Applicability Domain of the model
- Appropriate measures of goodness-of-fit and robustness and predictivity: Good reliabilility


5. APPLICABILITY DOMAIN
- Descriptor domain: Global AD Index = 0.96
- Similarity with analogues in the training set: Strongly similar


6. ADEQUACY OF THE RESULT
The model is considered reliable.

This endpoint study record is part of a weight of evidence approach comprising of experimental data and supporting QSAR predictions using ToxTree and VEGA. Both experimental data and QSARs predict that the compound is not mutagenic.
Qualifier:
no guideline required

A QSAR conducted using VEGA software and applying the CAESAR model results in a 'non-mutagenic' prediction.

Conclusions:
A QSAR conducted using VEGA software and applying the CAESAR model results in a 'non-mutagenic' prediction.
Executive summary:

A QSAR conducted using VEGA software and applying the CAESAR model results in a 'non-mutagenic' prediction.

Endpoint:
genetic toxicity in vitro, other
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Not applicable
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
Justification for type of information:
1. SOFTWARE : VEGA QSAR MODEL Core version 1.2.4

2. MODEL: Mutagenicity (Ames test) model (ISS) 1.0.2

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :O(c1ccc(cc1)CCC)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Mutagenicity
- Defined domain of applicability: Compound could be out of the Applicability Domain (AD)of the model
- Appropriate measures of goodness-of-fit and robustness and predictivity:Not optimal

5. APPLICABILITY DOMAIN
- Descriptor domain: Global AD Index = 0.665
- Similarity with analogues in the training set: Not adequate


6. ADEQUACY OF THE RESULT
The model is considered reliable, however, the accuracy of prediciton for similar molecules found in the data set is not adequate and the predicted compound could be out of the AD of the model.

This endpoint study record is part of a weight of evidence approach comprising of experimental data and supporting QSAR predictions using ToxTree and VEGA. Both experimental data and QSARs predict that the compound is not mutagenic.
Qualifier:
no guideline required

A QSAR conducted using VEGA software and applying the ISS model results in a 'non-mutagenic' prediction. However, the accuracy of prediction for similar molecules in the training set is not adequate.

Conclusions:
A QSAR conducted using VEGA software and applying the ISS model results in a 'non-mutagenic' prediction. However, the accuracy of prediction for similar molecules in the training set is not adequate.
Executive summary:

A QSAR conducted using VEGA software and applying the ISS model results in a 'non-mutagenic' prediction. However, the accuracy of prediction for similar molecules in the training set is not adequate.

Endpoint:
genetic toxicity in vitro, other
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Not applicable
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
Justification for type of information:
1. SOFTWARE : VEGA QSAR MODEL Core version 1.2.4

2. MODEL: Mutagenicity (Ames test) model (KNN/ReadAcross) 1.0.0

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL :O(c1ccc(cc1)CCC)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Mutagenicity
- Defined domain of applicability: Compound could be out of the Applicability Domain of the model
- Appropriate measures of goodness-of-fit and robustness and predictivity: Moderate reliability


5. APPLICABILITY DOMAIN
- Descriptor domain: Global AD Index = 0.891
- Similarity with analogues in the training set: Strongly similar


6. ADEQUACY OF THE RESULT
The model is considered reliable (experimental data)

This endpoint study record is part of a weight of evidence approach comprising of experimental data and supporting QSAR predictions using ToxTree and VEGA. Both experimental data and QSARs predict that the compound is not mutagenic.
Qualifier:
no guideline required

A QSAR using  VEGA software and applying the KNN/Read Across model results in a 'non mutagen' prediction. However, the accuracy of prediction for similar models found in the training set is not optimal.

Conclusions:
A QSAR using VEGA software and applying the KNN/Read Across model results in a 'non mutagen' prediction. However, the accuracy of prediction for similar models found in the training set is not optimal.
Executive summary:

A QSAR using VEGA software and applying the KNN/Read Across model results in a 'non mutagen' prediction. However, the accuracy of prediction for similar models found in the training set is not optimal.

Endpoint:
genetic toxicity in vitro, other
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Not applicable
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 limited documentation / justification
Justification for type of information:
1. SOFTWARE: VEGA QSAR MODEL Core version 1.2.4

2. MODEL: Mutagenicity (Ames test) model (SarPy/IRFMN) 1.0.7

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL:O(c1ccc(cc1)CCC)C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Mutagenicity
- Defined domain of applicability: the predicted compound is iwithin the Applicability Domain of the model
- Appropriate measures of goodness-of-fit and robustness and predictivity: Good reliability


5. APPLICABILITY DOMAIN
- Descriptor domain:Global AD Index = 0.96
- Similarity with analogues in the training set: Strongly similar


6. ADEQUACY OF THE RESULT
The model is considered to be of good reliability; the predicted compound is within the AD of the model, the accuracy of prediction for similar molecules found in the training set is good and similar molecules found in the training set have experimental values in the training set have been found.

This endpoint study record is part of a weight of evidence approach comprising of experimental data and supporting QSAR predictions using ToxTree and VEGA. Both experimental data and QSARs predict that the compound is not mutagenic.
Qualifier:
no guideline required

A QSAR using the VEGA software and applying the SarPy/IRFMN model results in a 'possible non-mutagenic' prediction.

Conclusions:
A QSAR using the VEGA software and applying the SarPy/IRFMN model results in a 'possible non-mutagenic' prediction.
Executive summary:

A QSAR using the VEGA software and applying the SarPy/IRFMN model results in a 'possible non-mutagenic' prediction.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
other information
Study period:
2011
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
not specified
GLP compliance:
not specified
Remarks:
EFSA review of available mutagenicity data; details on methodology are not reported.
Type of assay:
bacterial reverse mutation assay
Specific details on test material used for the study:
No details reported.
Target gene:
No details reported
Species / strain / cell type:
other: Salmonella typhimurium (TA98, TA100, TA1535, TA1537, TA1538)
Additional strain / cell type characteristics:
not applicable
Metabolic activation:
with and without
Metabolic activation system:
S9
Test concentrations with justification for top dose:
Concentrations up to 750 micrograms/plate were tested (no further details reported).
Vehicle / solvent:
No details reported.
Details on test system and experimental conditions:
No details reported.
Rationale for test conditions:
No details reported.
Evaluation criteria:
No details reported.
Statistics:
No details reported.
Key result
Species / strain:
other: TA98, TA100, TA1535, TA1537, TA1538
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
not specified
Conclusions:
The test item was found to be negative in the Ames test (with or without metabolic activation). EFSA concluded that there was "no safety concern" regarding the test item, at the estimated level of intake as a flavouring substance.
Executive summary:

This review summarises the results of an Ames assasy conducted by Wild, et al. (1989). The original data reported by Wild et al. (1989) is included in this registration as part of the weight of evidence approach.

EFSA report that the test item was found to be negative in the Ames test (with or without metabolic activation). EFSA concluded that there was "no safety concern" regarding the test item, at the estimated level of intake as a flavouring substance.

Endpoint:
in vitro gene mutation study in bacteria
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1983
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 471 (Bacterial Reverse Mutation Assay)
Deviations:
not specified
GLP compliance:
not specified
Type of assay:
bacterial reverse mutation assay
Specific details on test material used for the study:
No details reported.
Species / strain / cell type:
other: Salmonella typhimurium (TA 1535, TA 100, TA 1537, TA 1538, TA 98)
Additional strain / cell type characteristics:
not applicable
Metabolic activation:
with and without
Metabolic activation system:
S9
Test concentrations with justification for top dose:
Five doses of the test item were tested (up to 3.6 mg/plate) in all five tester strains with and without S9 mix. No further details on dose concentrations were reported.
Vehicle / solvent:
No details on the vehicle for the test item used in this study are reported. However, it is noted that If the test item was found to be soluble, then water was used as the vehicle. Otherwise dimethylsulphoxide (DMSO) was used as a solvent for test chemcials that were poorly soluble in water.
Details on test system and experimental conditions:
METHOD OF APPLICATION: The Ames test was perfomed in Volger-Bonner medium according to a standard plate procedure.

DURATION
- Preincubation period:48 hours
- Exposure duration: No details reported
- Expression time (cells in growth medium):No details reported
- Selection time (if incubation with a selection agent):No details reported
- Fixation time (start of exposure up to fixation or harvest of cells):No details reported

SELECTION AGENT (mutation assays):No details reported

NUMBER OF REPLICATIONS: Each chemical was tested at least twice. No further details reported.

METHODS OF SLIDE PREPARATION AND STAINING TECHNIQUE USED:No details reported

NUMBER OF CELLS EVALUATED: Overnight bacterial cultures had cell titres of at least 10^9 cells/ml. No further details reported.

CRITERIA FOR MICRONUCLEUS IDENTIFICATION:

DETERMINATION OF CYTOTOXICITY
- Method: mitotic index; cloning efficiency; relative total growth; other: No details reported.
- Any supplementary information relevant to cytotoxicity: No details reported

Rationale for test conditions:
No details reported
Evaluation criteria:
No details reported.
Statistics:
Statistical significance was determined according to the methods of Kastenbaum & Bowman. Test items that produced reproducible, dose-related and at least two-fold elevation of the spontaneous revertant frequency were regarded as positive. Test items producing reproducible, dose-related and significant (P <0.01) but less than two-fold elevations were classified as marginally mutagenic under the experimental conditions.
Key result
Species / strain:
other: TA 1535, TA 100, TA 1357, TA 1358, TA 98
Metabolic activation:
with and without
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not specified
Vehicle controls validity:
not specified
Untreated negative controls validity:
not specified
Positive controls validity:
valid
Conclusions:
The test item was found to be 'genetically inactive' in the Ames test. Therefore, the test item is considered to be negative for mutagenicity.
Executive summary:

The test item was found to be 'genetically inactive' in the Ames test. Therefore, the test item is considered to be negative for mutagenicity, according to CLP criteria (EC Regulation 1272/2008).

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

Additional information

Justification for classification or non-classification

The test item was negative for genotoxicity in the Ames test. This result is supported QSARs of the test item using VEGA and ToxTree result in an overall negative result for mutagenicity. Furthermore, a recent review by the European Food Safety Authority (EFSA) based on the available genotoxicity data for the test item, states that there is 'no safety concern' for at the current estimated level of intake.

Therefore, considering all of the available data (negative Ames assay, overall negative QSAR predictions, EFSA review), the test item is not classificable for genetic toxicity according to CLP criteria (EC Regulation 1272/2008).