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Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The mutagenic potential of the test substance has been evaluated in a weight of evidence approach using three different tools for QSAR prediction, namely OASIS TIMES, Derek Nexus, and CASE Ultra. The outcome for bacterial reverse mutagenicity was negative in all models.

Link to relevant study records

Referenceopen allclose all

Endpoint:
genetic toxicity in vitro, other
Remarks:
calculation
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Sep 2018
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 : CASE Ultra v1.6.2.3

2. MODEL: GT_EXPERT 1.6.0.2.11461.500 Expert Rules for Bacterial Mutagenicity

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL: CC(C)C(C)[n]1ncc(C(O)=O)c1C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Bacterial Mutagenicity

5. APPLICABILITY DOMAIN
- Other considerations (as appropriate): Overall negative outcome because no alerts were identified in the test chemical and all the unknown fragments (fragments not covered by the training set of models) were dismissed.
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Version / remarks:
May / July 2008
GLP compliance:
no
Type of assay:
bacterial reverse mutation assay
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

Table 1: Prediction Summary of Individual Models

Model

Outcome

Positive Alerts

Deactivating Features

Unknown Fragments

GT1_AT_ECOLI

1.6.0.0.1199.500

E.coli/Salmonella TA 102 (A-T-Base Pair Mutation)

Out of Domain

0

0

1

GT1_A7B

1.6.0.0.3979.450

Salmonella t 7-strains (RCA)

Negative

0

0

0

GT_EXPERT

1.6.0.2.11461.500

Expert Rules for Bacterial Mutagenicity

Negative

0

0

0

Conclusions:
Overall negative outcome because no alerts were identified in the test chemical and all the unknown fragments (fragments not covered by the training set of models) were dismissed.
Endpoint:
genetic toxicity in vitro, other
Remarks:
calculation
Type of information:
(Q)SAR
Adequacy of study:
other information
Study period:
Sep 2018
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 6.0.1, Nexus 2.2.1

2. MODEL: Mutagenicity in vitro in bacterium (from KB: Derek KB 2018 1.1)

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL : CC(C)C(C)n1ncc(C(=O)O)c1C

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Mutagenicity in vitro in bacterium

5. APPLICABILITY DOMAIN
- Other considerations (as appropriate): No misclassified or unclassified features
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Version / remarks:
May / July 2008
GLP compliance:
no
Type of assay:
bacterial reverse mutation assay
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)

The query structure does not match any structural alerts or examples for (bacterial in vitro) mutagenicity in Derek. Additionally, the query structure does not contain any unclassified or misclassified featues and is consequently predicted to be inactive in the bacterial in vitro (Ames) mutagenicity test.

Conclusions:
The query structure does not match any structural alerts or examples for (bacterial in vitro) mutagenicity in Derek. Additionally, the query structure does not contain any unclassified or misclassified featues and is consequently predicted to be inactive in the bacterial in vitro (Ames) mutagenicity test.
Endpoint:
genetic toxicity in vitro, other
Remarks:
calculation
Type of information:
(Q)SAR
Adequacy of study:
other information
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 : OASIS TIMES v2.27.19.13

2. MODEL: Ames mutagenicity S9 activated v.12.12

3. SMILES OR OTHER IDENTIFIERS USED AS INPUT FOR THE MODEL : CC(C)C(C)N1C(C)=C(C(O)=O)C=N1

4. SCIENTIFIC VALIDITY OF THE (Q)SAR MODEL
- Defined endpoint: Bacterial Reverse Mutation Test
- Unambiguous algorithm: Ames mutagenicity S9 activated
- Defined domain of applicability: The LMC stepwise approach was used to define the applicability domain. It contains two layers: General properties requirements (log Kow, MW) and Structural domain (Atom Centered Fragments (ACFs)).
- Appropriate measures of goodness-of-fit and robustness and predictivity:
Sensitivity = (predicted positive / observed positive) = 79 %
Specificity = (predicted negative / observed negative) = 82 %
Concordance = (correct predicted positive and negative chemicals in respect to all training set chemicals) = 81 %
- Mechanistic interpretation: The chemical fulfils the general properties requirements.

5. APPLICABILITY DOMAIN
- Structural and mechanistic domains:
Parameter domain: The chemical fulfills the general properties requirements.
Structural fragments domain: The chemical is out of the interpolation structural space (fragments in correctly predicted training chemicals: 42.86 %; fragnments in non-correctly predicted training chemicals: 0.00 %; fragments not present in the training chemicals: 57.14 %)
- Similarity with analogues in the training set: no structural analogues in the training set reported
Qualifier:
according to
Guideline:
other: REACH Guidance on QSARs R.6
Version / remarks:
May / July 2008
Principles of method if other than guideline:
- Software tool(s) used including version: OASIS TIMES v2.27.19.13
- Model(s) used: Ames mutagenicity S9 activated (v.12.12)
- Model description: see field 'Justification for non-standard information'
- Justification of QSAR prediction: see field 'Justification for type of information'
GLP compliance:
no
Target gene:
his
Species / strain / cell type:
S. typhimurium, other: no further specification
Metabolic activation:
with
Metabolic activation system:
S9 mix
Species / strain:
S. typhimurium, other: no further specification
Metabolic activation:
with
Genotoxicity:
negative
Cytotoxicity / choice of top concentrations:
not determined
Remarks on result:
no mutagenic potential (based on QSAR/QSPR prediction)
Conclusions:
Based on the OASIS TIMES prediction the test substance is not considered to be mutagenic.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (negative)

Genetic toxicity in vivo

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

OASIS TIMES

The chemical fulfills the general properties requirements for the parametric domain but it is out of the interpolation structural space (fragments in correctly predicted training chemicals: 42.86 %; fragnments in non-correctly predicted training chemicals: 0.00 %; fragments not present in the training chemicals: 57.14 %). However, the substance was predicted to be negative in the model for bacterial reverse mutation potential with metabolic activation.

Derek Nexus

The query structure does not match any structural alerts or examples for (bacterial in vitro) mutagenicity in Derek. Additionally, the query structure does not contain any unclassified or misclassified featues and is consequently predicted to be inactive in the bacterial in vitro (Ames) mutagenicity test.

CASE Ultra

Overall negative outcome because no alerts were identified in the test chemical and all the unknown fragments (fragments not covered by the training set of models) were dismissed.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No. 1272/2008

The available QSAR predictions are reliable and suitable for classification purposes under Regulation 1272/2008. No adverse outcome for Ames mutagenicity were predicted. As a result, the substance is not considered to be classified for mutagenicity under Regulation (EC) No. 1272/2008, as amended for the thirteenth time in Regulation (EC) No. 2018/1480.