1-{4-[2-(benzyloxy)ethoxy]phenyl}-1,2-diphenylbutane-1,4-diol

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:

supporting study

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction: migrated from IUCLID 5.6

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:
1. 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)
2. 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.
3. Toxtree for the prediction of skin and eye irritation, skin sensitization, gene mutation (Ames test), micronucleus in vivo (rodent) and biodegradation (ready)

GLP compliance:

no

Type of assay:

micronucleus assay

Test animals

Species:

other: rodent

Strain:

not specified

Sex:

not specified

Results and discussion

Test results

Sex:

not specified

Genotoxicity:

positive

Remarks:

worst case scenarius

Toxicity:

not specified

Any other information on results incl. tables

ACD/Percepta

ACD/Percepta micronucleus in vivo rodent prediction for 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol resulted to be undefined. In fact, the prediction is borderline reliable, being the reliability index equal to 0.40.

Together with the prediction, Percepta displays up to 5 most structurally similar structures from the training set along with experimental micronucleus in vivo rodent 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. 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol, is represented in the training set. This analysis can also help to better understand the reliability index value.

The five most similar structures from the training set were identified along with their micronucleus in vivo rodent data, as illustrated in below. It has to be noted that they exhibit moderate similarity, with a similarity index lower than 0.7.

Salmeterol

RN: 89365-50-4

Result: Negative

Similarity: 0.67

Bisphenol A diglycidyl

ether diacrylate

RN: 4687-94-9

Result: Negative

Similarity: 0.62

Bisopropol

RN: 66722-44-9

Result: Negative

Similarity: 0.62

Propafenone

RN: 64063-53-5

Result: Negative

Similarity: 0.60

Troxerutin

RN: 7085-55-4

Result: Negative

Similarity: 0.59

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 0.12 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, 7 fragments were found, and

only one similar structure was identified in the training set as analog to 1-(4-(2-(benzyloxy)ethoxy)phenyl)-

1,2-diphenylbutane-1,4-diol. The similar training structure, i.e. Bisoprolol, is characterized by a little

similarity with 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol; its experimental data is

consistent with the prediction, being negative. Thus it was concluded that 1-(4-(2-

(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol is predicted negative but the prediction has little

reliability, since only one training structure was identified as similar to 1-(4-(2-(benzyloxy)ethoxy)phenyl)-

1,2-diphenylbutane-1,4-diol and its similarity is little.

Toxtree

Toxtree predicts the positive or negative to micronucleus in vivo rodent according to decision rules based on

the identification of Structural Alerts (SA) for to micronucleus in vivo rodent, 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 identified in 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol the

Hacceptor-path3-Hacceptor micronucleous structural alert, leading to the conclusion that it is positive to

micronucleus in vivo roden. The Hacceptor-path3-Hacceptor alert explores the possibility that a chemical

interacts with DNA and/or proteins via non-covalent binding, such as DNA intercalation or groove-binding

(Snyder et al. 2006. Mutat. Res. 609, 47-59). Among the descriptors potentially accounting for non-covalent

interactions, the present molecular framework representing two bonded atoms connecting two H bond

acceptors (calculated with software Leadscope Enteprise 2.4.15-6) resulted in an increased

sensitivity/specificity for what concerns the Micronucleus training set.

In silico tool	Prediction	PositivePrediction probability	Applicability domain	Reliability assessment
ACD/Percepta	Undefined	0.17	Reliability index (RI) = 0.40	BORDERLINE
Leadscope ModelApplier	NEGATIVE	0.12	Model Fragments Count = 730% Sim Training Neighbors Count = 1	LITTLERELIABLE
Toxtree	POSITIVE		Hacceptor-path3-Hacceptor
CONSENSUS	POSITIVE (worst case scenario)

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): positive
The micronucleus in vivo rodent of 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol was predicted employing three in silico predictors: QSAR model as provided by ACD/Percepta and Leadscope Model applier 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 and the worst case scenario was envisaged: thus, based on Toxtree identification of the Hacceptor-path3-Hacceptor structural alert for micronucleus in vivo rodent, it was concluded that 1-(4-(2-(benzyloxy)ethoxy)phenyl)-1,2-diphenylbutane-1,4-diol is positive on micronucleus in vivo rodent.