Benzonitrile, 4-bromo-2-chloro-

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity

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:

Carcinogenicity on mouse and rat (male, female) was estimated by using two predictors: Leadscope
Model Applier and ACD/Percepta.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

4-bromo-2-chlorobenzonitrile

EC Number:

679-039-6

Cas Number:

154607-01-9

Molecular formula:

C7H3BrClN

IUPAC Name:

4-bromo-2-chlorobenzonitrile

Test animals

Species:

other: rat and mouse

Sex:

male/female

Results and discussion

Any other information on results incl. tables

Model	Leadscope	ACD/Percepta	Consensus prediction
Rat male	NEGATIVE (moderate reliable)	UNDEFINED (moderate reliable)	NEGATIVE(borderline reliable)
Rat female	POSITIVE (borderline reliable)	UNDEFINEDBorderline reliable	LIKELY NEGATIVE Borderline reliable

 

Name	Model	ACD/Percepta	Leadscope	Consensus prediction
4-bromo-2-chlorobenzonitrile	Mouse male	UNDEFINED (borderline reliable)	NEGATIVE (moderate reliable)	NEGATIVE (moderate reliable)
	Mouse female	UNDEFINED (borderline reliable)	NEGATIVE (moderate reliable)	NEGATIVE (moderate reliable)

ACD/Percepta models for carcinogenicity in rat/mouse estimate probability (“p-value”) that a compound will result positive in the carcinogenicity tests. The reliability of prediction is assessed in terms of reliability index (RI), which ranges from0 to 1 and takes into account the similarity of the target with the training set compounds and the consistency of experimental values for similar compounds. A “positive” or “negative” call is provided if the compound can be reliably classified on the basis of p and RI values (“Undefined” otherwise).

Predictions of carcinogenicity on rat/mouse male and femaleresulted to be undefined, meaning that it cannot be reliably classified on the basis of the positive probability (0.26 for rat male and 0.23 for rat female) (0.25 for mouse male and 0.23 for mouse female) and the reliability index value (0.51 for rat male and 0.43 for rat female; 0.45 for mouse male and 0.49 for mouse female).

The predictions for carcinogenicity on rat male and female were assessed as moderate and borderline reliable, respectively, being the reliability indices equal to 0.51 (rat male) and 0.43 (rat female).

The predictions on mouse were assessed as borderline reliable being the reliability indices equal to 0.45 (mouse male) and 0.49 (mouse female).ACD/Percepta displays up to 5 most structurally similar structures from the training set along with their experimental test results. The information on the structurally similar compounds in the training set was used to further assess the reliability of the prediction. Five compounds for rat/mouse male and female, respectively, were identified as analogues of 4-bromo-2-chlorobenzonitrile. These training compounds exhibit moderate to high similarity with respect to 4-bromo-2-chlorobenzonitrile (similarity index ranging from 0.71 to 0.94), meaning that the target compound is well represented in the training set of the model, and experimental not consistent test results.

Based on the outcome of the two ACD/Percepta models and the analysis of structural analogues, the prediction of carcinogenicity on rat/mouse for the target 4-bromo-2-chlorobenzonitrile resulted to be undefined and this prediction was assessed as borderline reliable.

Leadscope Model Applier

Carcinogenicity on rat/mouse was predicted by combining two Leadscope models. Leadscope models estimate the probability that a compound will result positive in the two carcinogenicity tests.

For each model, Leadscope results include the prediction call forcarcinogenicity on rat/mouse (positive, negative or not in domain), a positive prediction probability and two parameters which assess the reliability of the prediction: 1) Model Features Count, i.e., containing structural model features that are present in the prediction model; 2) 30% Similarity Training Neighbours Count, i.e. number of training compounds with at least 30 % similarity.

Leadscope FDA Model Applier prediction for carcinogenicity on rat/mouse male and female resulted to be NEGATIVE and POSITIVE, respectively since the positive prediction probability was equal to 0.32 (rat male) and 0.75 (rat female) and to to 0.42 (mouse male) and 0.49 (mouse female). Since at least 7 features were found, it was concluded that 4-bromo-2-chlorobenzonitrile is well represented by the models. The robustness of the prediction was further evaluated by examining compounds similar to the 4-bromo-2-chlorobenzonitrile from the training set.While this information does not take part to the prediction, it provides the complementary means to see how similar compounds were predicted and what the experimental values of similar compounds are.

Seven structures from the training set of Car Rat Malemodel andCar Rat Female model were identified as analogues to 4-bromo-2-chlorobenzonitrile (similarity > 30%), although only one of them characterized by similarity greater than 0.5. It has to be noted that in the case ofCar Rat Malethe mostly similar analogue has consistent negative experimental test results, while in the case ofCar Rat Femalethe mostly similar analogue has not consistent experimental test results. Therefore, Leadscope prediction of carcinogenicity on rat male and female were assessed as moderate and borderline reliable, respectively.

Six structures from the training set of Car Mouse Male model and Car Mouse Female model were identified as analogues to 4-bromo-2-chlorobenzonitrile (similarity > 30%), and among them one with similarity greater than 0.5 and consistent negative test results.Based on that, Leadscope predictions were assessed as moderate reliable.

Applicant's summary and conclusion

Conclusions:

Carcinogenicity on rat/mouse male and female of the 4-bromo-2-chlorobenzonitrile was estimated by using two predictors: Leadscope Model Applier and ACD/Percepta. The two 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. Since ACD/Percepta did not provide any prediction, based on Leadscope predictions of carcinogenicity on rat/mouse male and female and considering their level of confidence it was concluded that the target 4-bromo-2-chlorobenzonitrile is predicted as NEGATIVE on rat/mouse and the prediction was assessed as moderate reliable.