5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol

Genetic toxicity: in vivo

Administrative data

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / erythrocyte micronucleus

Remarks:

Type of genotoxicity: chromosome aberration

Type of information:

(Q)SAR

Adequacy of study:

key 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:

2014

Materials and methods

Principles of method if other than guideline:

Micronucleus in vivo on mouse predictions were generated employing Leadscope Model Applier.
Micronucleus in vivo on rodent predictions were generated employing three predictors: Leadscope Model Applier, ACD/Percepta and Toxtree decision rule system.

GLP compliance:

no

Type of assay:

micronucleus assay

Test material

Test material information

Constituent 1

Reference substance name:

2-(1-methylpiperidin-4-yl)tricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,9,12,14-heptaen-2-ol

EC Number:

609-737-8

Cas Number:

3967-32-6

Molecular formula:

C21H23NO

IUPAC Name:

2-(1-methylpiperidin-4-yl)tricyclo[9.4.0.0^{3,8}]pentadeca-1(11),3,5,7,9,12,14-heptaen-2-ol

Test animals

Species:

other: mouse and rodent

Results and discussion

Any other information on results incl. tables

Micronucleus in vivo on mouse predictions:

Leadscope prediction call (RI)	LeadscopePositivePrediction probability	Model FeaturesCount	30% Sim. Training Neighbors Count
NEGATIVE (Little reliable)	0.11	18	3

                 

Model Features Count. Parameter used to verify that the target compound, i.e. 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol, 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 18 features were found, it was concluded that 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol is represented by the model.

30% Similarity Training Neighbours Count. Number of compounds structurally similar to the target, i.e. 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol, 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. Three compounds, illustrated in Table 18, were identified in the training set as analogue to 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol characterized by little similarity with respect to the target 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol. Therefore, the prediction was considered of little reliability.

TerfenadineResult: negativeSimilarity: 0.42

AzatadineResult: negativeSimilarity: 0.37

FexofenadineResult: negativeSimilarity: 0.32

Micronucleus in vivo on rodent predictions:

Leadscope	ACD/Percepta	Toxtree	Consensus prediction
NEGATIVELittle reliable	-	NEGATIVE	NEGATIVELittle reliable

Leadscope Model Applier

Leadscope prediction call (RI)	LeadscopePositivePrediction probability	Model FeaturesCount	30% Sim. Training Neighbors Count
NEGATIVE (Little reliable)	0.08	9	3

Model Features Count. Parameter used to verify that the target compound, i.e. 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol, 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 9 features were found, it was concluded that 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol is represented by the model.

30% Similarity Training Neighbours Count. Number of compounds structurally similar to the target, i.e. 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol, 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. Three compounds, illustrated in Table 21, were identified in the training set as analogue to 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol characterized by little similarity with respect to the target 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol. Therefore, the prediction was considered of little reliability.

TerfenadineResult: negativeSimilarity: 0.42

AzatadineResult: negativeSimilarity: 0.37

FexofenadineResult: negativeSimilarity: 0.32

ACD/Percepta did not provide any prediction for the target 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol since it resulted to be out of the model applicability domain.

Toxtree predicts the positive or negative micronucleus activity according to decision rules based on the identification of Structural Alerts (SA) for based on the rules, published in the document “Development of structural alerts for the in vivo micronucleus assay in rodents”, by Romualdo Benigni, Cecilia Bossa, Olga Tcheremenskaia and Andrew Worth, European Commission report EUR 23844 EN. As one or more SAs embedded in a molecular structure are recognised, the system flags the potential micronucleus activity of the chemical. Toxtree did not identify any structural alert in the target 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol. An assessment of the reliability of the prediction is not provided.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): negative
The consensus assessment was based only on Leadscope (for mouse) and on Leadscope and Toxtree (for rodent) predictions which were in agreement concluding that the target 5-(1-methylpiperidin-4-yl)-5H-dibenzo[a,d][7]annulen-5-ol is NEGATIVE, although the prediction is of little reliability since Leadscope prediction is of little reliability and Toxtree does not provide an assessment of its reliability.

Executive summary:

Micronucleus in vivo on rodent of the target was estimated by using three predictors: Leadscope Model

Applier, ACD/Percepta and Toxtree decision rule system. The three 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. In the case of the target, the consensus assessment was

based only on ACD/Percepta prediction, concluding that the target 2-Thiophenecarboxylic acid, 3-[[(2-

methoxy-2-oxoethyl)amino]sulfonyl]-, methyl ester is LIKELY NEGATIVE, although the prediction is of

borderline reliability.