Registration Dossier

Administrative data

Endpoint:
in vitro gene mutation study in bacteria
Remarks:
Type of genotoxicity: gene mutation
Type of information:
(Q)SAR
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Report Date:
2015

Materials and methods

Principles of method if other than guideline:
Gene mutation as microbial in vitro Salmonella was estimated by using four predictors: Leadscope, ACD/Percepta, Vega and Toxtree decision rule system.
GLP compliance:
no
Type of assay:
bacterial reverse mutation assay

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Any other information on results incl. tables

 Leadscope  ACD/Percepta  Vega  Toxtree  Consensus prediction

 NEGATIVE

Moderate reliable

 NEGATIVE

Borderline reliable

 NEGATIVE

Borderline reliable

 NEGATIVE

Not Reliable

 NEGATIVE

Moderate Reliable

Leadscope Model Applier

 LeadscopePredictioncall  LeadscopePositivePrediction probability  Model FeaturesCount  30% Sim. Training Neighbors Count  Reliabilityassessment
 NEGATIVE  0.12  12  4  MODERATE RELIABLE

Model Features Count. Parameter used to verify that the target compound, i.e.2-phenyl-2-piperidin-2-ylacetamide, contains a significant number of features that are present in the prediction model. The structural features used to make the prediction provide information on the reliability of the prediction: a prediction provided by a low number of features means that the model is not able to fully describe the test compound, while a prediction supported by a high number of features reveals that the test compound is well described by the model. Since 12 features were found, it was concluded that 2-phenyl-2-piperidin-2-ylacetamide is well represented by the model.

30% Similarity Training Neighbours Count. Number of compounds structurally similar to the target, i.e.2-phenyl-2-piperidin-2-ylacetamide, in the model's training set of compounds. Another way to assess the reliability of the prediction is looking at the analogues, i.e. the compounds structurally similar to the target in the model's training set of compounds. While this information does not take part to the prediction, it provides the user a complementary means to see how similar compounds were predicted and what the experimental values of similar compounds are. Look at analogues is also an initial, less-sophisticated easy way to understand estimate of toxicity. Four structures were identified in the training set as analogues to 2-phenyl-2-piperidin-2-ylacetamide, illustrated in the Table. It has to be noted that the identified analogues have little to moderate similarity with respect to the target (similarity index ranging from 0.32 to 0.58) and inconsistent experimental data, being two negative and two positive. However, since the mostly similar analogue has moderate similarity with respect to the target (similarity = 0.58) and consistent experimental data, being negative, the prediction was considered of moderate reliability.

 Methylphenidate Result: negative Similarity: 0.58
  phenyl-2-ethylmalondiamide, 2- Result: positive Similarity: 0.43
 naphthyl)acetamide, 2-(1- Result: positive Similarity: 0.35
 Atenolol Result: negative Similarity: 0.32

ACD/Percepta genotoxicity prediction

ACD/Percepta genotoxicity prediction is illustrated in Table 11. The prediction is provided together with a reliability index, which assesses the degree of confidence of the prediction. The reliability index (RI)takes into account the similarity of the target with the training set compounds and the consistency of experimental values for similar compounds. Itranges from0 to 1: if the RI is less than 0.3 the prediction has to be considered not reliable while if RI is more than 0.5 the prediction is considered reliable. ACD/Percepta prediction resulted to be negative, and the prediction is of borderline reliability being the reliability index equal to 0.32.

ACD/Percepta prediction call  ACD/Percepta positive probability ACD/Percepta RI  Reliability assessment
 NEGATIVE 0.12  0.32  BORDERLINE

No hazardous fragment was identified.

Together with the prediction, ACD/Percepta displays up to 5 most structurally similar structures from the training set along with experimental Ames test results for the corresponding compounds. The structural similarity is evaluated by a fragmental approach. The information on the structurally similar compounds in the training set is used to further assess the reliability of the prediction, since it illustrates how the test compound, i.e.2-phenyl-2-piperidin-2-ylacetamide, is represented in the training set. The five mostly similar compounds from the training set, illustrated in the Table, exhibit little similarity with respect to the target 2-phenyl-2-piperidin-2-ylacetamide, only one with similarity greater than 0.5. Despite their little similarity, the five mostly similar training compounds exhibit consistent experimental data, being all of them negative and one inconclusive. Because of the little similarity of the training compounds with respect to the target, the prediction was considered of borderline reliability.

 Methylphenidate

Result: negative

Similarity: 0.52

 Amphetamine

Result: inconclusive

Similarity: 0.31

 Methamphetamine

Result: negative

Similarity: 0.31

 Dicyclohexylamine

Result: positive

Similarity: 0.83

 2-METHYL-5-NITROBENZOIC ACID

Result: negative

Similarity: 0.23

 HexahydroazepineResult: negativeSimilarity: 0.23

CAESAR QSAR model for mutagenicity implemented in Vegais an integrated model arranged cascading two models, a trained Support Vector Machine (SVM) classifier, and an additional for false negatives (FNs) removal based on Structural Alerts (SAs) matching. It assesses the reliability of the mutagenicity prediction according to a global applicability domain index, which ranges from 0 (not reliable) to 1 (fully reliable) taking into account many parameters, e.g. descriptor ranges, chemical similarity index, fragments similarity, etc… An ADI value greater than 0.9 means that the predicted substance is into the applicability domain of the model; ADI value lower than 0.7 means that the predicted substance is out of the applicability domain of the model, while an ADI value between 0.7 and 0.9, means that the predicted substance could be out of the Applicability Domain of the model.

 Vega Prediction call  Vega prediction reliability  Reliability assessment
NEGATIVE  AD Index = 0.85   BORDERLINE RELIABLE

Vega predicted the target substance as negative and the prediction is of borderline reliability, being the ADI equal to 0.85, since some similar molecules found in the training set have experimental values that disagree with the predicted value. The six compounds most similar to 2-phenyl-2-piperidin-2-ylacetamide are illustrated in the Table. It can be noted that the identified analogues exhibit good similarity with respect to the target (similarity ranging from 0.82 to 0.92) and five out of the six exhibit negative experimental test results.

The five compounds most similar are:

 CAS: 113-45-1 (Training set) Similarity: 0.92 Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 34798-80-6 (Test set) Similarity: 0.85 Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 87625-62-5 (Training set) Similarity: 0.84 Experimental value: POSITIVE Predicted value: POSITIVE
CAS: 2431-96-1 (Training set) Similarity: 0.84Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 134-72-5 (Training set) Similarity: 0.82 Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 92071-51-7 (Training set) Similarity: 0.82 Experimental value: NEGATIVE Predicted value: NEGATIVE

Toxtree predicts the positive or negative mutagenicity according to decision rules based on the identification of Structural Alerts (SA) for mutagenicity, i.e. molecular functional groups or substructures known to be linked to the mutagenicity activity of chemicals. As one or more SAs embedded in a molecular structure are recognised, the system flags the potential mutagenicity of the chemical.The reliability of Toxtree mutagenicity prediction was evaluated by theApplicability Domain Index (ADI)implemented in VEGA platform (ADI > 0.9: into the domain; 0.9 > ADI ≥ 0.7: could be out of the domain; ADI < 0.7: out of the domain). Toxtree did not identify any structural alert in the target 2-phenyl-2-piperidin-2-ylacetamide, butthe prediction is not reliable being the ADI (global Applicability Domain Index) equal to 0.00.In fact, the following issues were addressed:only moderately similar compounds with known experimental value in the training set have been found; similar compounds found in the training set have experimental values that disagree with the predicted value and the accuracy of prediction for similar compounds found in the training set is not adequate.

The six compounds mostly similar are:

 CAS: 125-33-7 (Training set) Similarity: 0.84 Experimental value: POSITIVE Predicted value: NEGATIVE
 CAS: 50 -06 -6 (Training set) Similarity: 0.81 Experimental value: POSITIVE Predicted value: NEGATIVE
 CAS: 54 -80 -8 (Training set) Similarity: 0.81Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 55268-74-1 (Training set) Similarity: 0.79 Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 136-77-6 (Training set) Similarity: 0.78 Experimental value: NEGATIVE Predicted value: NEGATIVE
 CAS: 77191-36-7 (Training set)Similarity: 0.77 Experimental value: NEGATIVE Predicted value: NEGATIVE

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information):
negative Moderate Reliable

Gene mutation of the target 2-phenyl-2-piperidin-2-ylacetamide was estimated by using four predictors: Leadscope, ACD/Percepta, Vega and Toxtree decision rule system. The four predictors were employed in order to apply a consensus approach to enhance the reliability of the prediction. In the consensus assessment only reliable predictions are to be taken into account. Thus, in the case of 2-phenyl-2-piperidin-2-ylacetamide, Toxtree prediction was not taken into account due to the fact that its prediction resulted to be not reliable. The other three predictors, i.e. Leadscope, ACD/Percepta and Vega, were all in agreement providing a negative prediction although with a different level of confidence. Therefore, it was concluded that the target 2-phenyl-2-piperidin-2-ylacetamide is NEGATIVE for microbial in vitro Salmonella, and the prediction is of moderate reliability.