Registration Dossier

Administrative data

in vitro gene mutation study in bacteria
Type of genotoxicity: gene mutation
Type of information:
Adequacy of study:
key study
2 (reliable with restrictions)
Justification for type of information:
QSAR prediction: migrated from IUCLID 5.6

Data source

Reference Type:
study report
Report Date:

Materials and methods

Principles of method if other than guideline:
Several computational tools are nowadays available for applying in silico approaches. Among them, for QSAR predictions the following were selected and used:
- ACD/Percepta for the prediction of acute oral toxicity, skin and eye irritation, gene mutation (Ames test), micronucleus in vivo (rodent), carcinogenicity rat and mouse composite, acute aquatic toxicity (Daphnia), octanol-water partition coefficient (logKow)
- Leadscope for the prediction of gene mutation (Ames test), chromosome aberration in vivo (rat and other rodent), micronucleus in vivo (mouse and rodent), carcinogenicity mouse and rat composite.
- Toxtree for the prediction of skin and eye irritation, skin sensitization, gene mutation (Ames test), micronucleus in vivo (rodent) and biodegradation (ready)
- Vega for the prediction of skin sensitization

GLP compliance:
Type of assay:
bacterial reverse mutation assay

Test material



Species / strain
Species / strain / cell type:
not specified
Additional strain / cell type characteristics:
not specified
Metabolic activation:
not specified

Results and discussion

Test results
Species / strain:
not specified
Metabolic activation:
not specified
Cytotoxicity / choice of top concentrations:
not determined

Any other information on results incl. tables


ACD/Percepta genotoxicity predicted 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol negative, being its probability of being positive for the Ames test equal to 0.13. The prediction is provided together with a reliability index ranging from 0 to 1, which serves as an evaluation of whether a submitted compound falls within the Model Applicability Domain. Estimation of the RI takes into account the following two aspects: similarity of the tested compound to the training set and the consistency of experimental values for similar compounds. If the RI is less than 0.3 the prediction has to be considered not reliable while if RI is equal to or more than 0.5 the prediction results reliable. In this case, the reliability index takes value equal to 0.17 and therefore the prediction has to be considered not reliable.

Leadscope Model Applier

Leadscope FDA Model Applier predicted 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol negative, being the positive prediction probability equal to 0.05 and therefore under 0.5. The reliability of the prediction is evaluated by two parameters:

 Model Fragment Count. Parameter used to verify that the test compound contains a significant number of fragments that are present in the prediction model. The prediction is reliable if at least one model fragment is present in the test compound.

 30% Similarity Training Neighbours Count. Number of compound structurally similar to the test compound.

In the case of 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol, the prediction is reliable since the model fragment count is equal to 21, meaning that 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2 -diphenylbutane-1,4-diol is well described by the model, and 5 training structures were identified being similar to 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol. The similar training structures exhibit a little similarity with 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol, being the reason of the moderate reliability of the prediction. Among the similar training structures, the mostly similar ones, i.e. Bisoprolol and Bosentan, are characterized by consistent experimental data, being all of them negative to Ames test.


Vega assess the reliability of the gene mutation prediction according to many parameters, e.g. descriptor ranges, chemical similarity index, fragments similarity, ...Vega predicted 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol as negative. The prediction is considered reliable, since, despite only moderately similar compounds are found in the training, their experimental values agree with the predicted value; the accuracy of prediction for similar molecules found in the training set is good; all atom centered fragment of the compound have been found in the compounds of the training set and 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol has values inside the descriptor range of the compounds of the training set.


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. Toxtree did not identify any structural alert for genotoxicity for 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol, concluding that 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol is negative on Ames test.

Applicant's summary and conclusion

Interpretation of results (migrated information):

The gene mutation of 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol was predicted employing four in silico approaches: QSAR model as provided by ACD/Percepta, Leadscope Model applier and Vega and a decision rule system as provided by Toxtree. The different predictors were employed in order to apply a consensus analysis to enhance the reliability of the prediction. In the consensus assessment only reliable predictions were taken into account. The two reliable QSAR predictions, i.e. Leadscope Model Applier and Vega, both agreed predicting 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol negative for Ames test gene mutation. In addition, Toxtree decision rule system did not identify any structural alert. Thus, it is concluded that 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol is NEGATIVE on Ames test.