Potassium 2-hydroxy-5-nitrobenzoate

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 rat (male, female and composite) 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:

Potassium 2-hydroxy-5-nitrobenzoate

EC Number:

807-692-0

Cas Number:

54234-73-0

Molecular formula:

C7 H4 O5 N K

IUPAC Name:

Potassium 2-hydroxy-5-nitrobenzoate

Details on test material:

In silico predictions for salt substances, require the removal of the counter ion and the subsequent neutralization. This procedure is needed to calculate the descriptors used to make the predictions. The procedure of removing the counter ion and subsequent neutralization was discussed and confirmed by several experts, both academic and regulators (European Agency for chemicals, ECHA) and is therefore the procedure commonly used for the in silico predictions of salt substances. Thus, for modelling purposes, the chemical structures of benzoic acid, 2-hydroxy-5-nitro-,potassium salt (1:1) has been processed by removal of the counter ion and subsequent neutralization.

Test animals

Species:

rat

Sex:

male/female

Results and discussion

Effect levels

Dose descriptor:

other: alert

Sex:

male/female

Basis for effect level:

other: Negative prediction, little reliable

Remarks on result:

other: Effect type: carcinogenicity (migrated information)

Any other information on results incl. tables

The prediction results are illustrated in Table:

Model	Leadscope	ACD/Percepta	Consensus
Rat male	NEGATIVELittle reliable	UNDEFINEDBorderline reliable	NEGATIVELittle reliable
Rat female	NEGATIVELittle reliable	UNDEFINEDBorderline reliable	NEGATIVELittle reliable
Rat composite	NEGATIVELittle reliable	UNDEFINEDBorderline reliable	NEGATIVELittle reliable

Leadscope Model Applier

The table shows the result of Leadscope model which includes a prediction (positive, negative or not in domain), a positive prediction probability and two parameters which assess the reliability of the prediction.

Model	LeadscopePredictioncall	LeadscopePositivePrediction probability	Model FeaturesCount	30% Sim. Training Neighbors Count	Reliabilityassessment
Rat male	NEGATIVE	0.39	6	9	LITTLE RELIABLE
Rat female	NEGATIVE	0.27	14	9	LITTLE RELIABLE
Rat composite	NEGATIVE	0.40	10	9	LITTLE RELIABLE

Model Features Count. Parameter used to verify that the target compound, i.e. 2-hydroxy-5-nitrobenzoic acid, 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 6, 14 and 10 features were found for carcinogenicity on rat male, female and composite, respectively, it was concluded that 2-hydroxy-5-nitrobenzoic acid is well represented by the models.

30% Similarity Training Neighbours Count. Number of compounds structurally similar to the target, i.e. 22-hydroxy-5-nitrobenzoic acid, 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. Nine compounds (in common in the rat male, female and composite models) were identified in the training set as analogues to 2-hydroxy-5-nitrobenzoic acid. The five mostly similar analogues are illustrated in Table 40. It has to be noted that the identified analogues exhibit little to moderate similarity with respect to the target 2-hydroxy-5-nitrobenzoic acid and inconsistent experimental test results, therefore, the predictions were considered of little reliability.

OlsalazineResult: POSITIVESimilarity: 0.62

SulfasalazineResult: POSITIVESimilarity: 0.49

MesalamineResult: NEGATIVESimilarity: 0.45

DiflunisalResult: NEGATIVESimilarity: 0.44

BalsalazideResult: NEGATIVESimilarity: 0.42

 ACD/Percepta

The ACD/Percepta carcinogenicity on rat prediction reliability is estimated with the reliability index (RI), which takes into account the similarity of the tested compound with the training set compounds and the consistency of experimental values for similar compounds. It ranges from 0 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 results of carcinogenicity on rat are illustrated in Table:

Model	ACD/Perceptaprediction call	ACD/Perceptapositiveprobability	ACD/PerceptaRI	Reliabilityassessment
Rat male	UNDEFINED	0.50	0.37	BORDERLINE
Rat female	UNDEFINED	0.54	0.39	BORDERLINE
Rat composite	UNDEFINED	0.50	0.47	BORDERLINE

ACD/Percepta predictions of carcinogenicity on rat male, female and composite for 2-hydroxy-5-

nitrobenzoic acid resulted to be undefined, meaning that it cannot be can be reliably classified on the basis of

the positive probability (0.50, 0.54 and 0.50 for rat male, female and composite, respectively) and the

reliability index value (0.37, 0.39 and 0.47 for rat male and composite, respectively).

Together with the prediction, ACD/Percepta displays up to 5 most structurally similar structures from the

training set along with their experimental 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. -phenyl-2-piperidin-2-ylacetamide, is represented in the training set. The five mostly similar

compounds from the training set of the carcinogenicity on rat male, female and composite, illustrated in

Table, exhibit good similarity with respect to -phenyl-2-piperidin-2-ylacetamide meaning that the target

compound is well represented in the training set of the model. It has also to be noted that the five training set

chemicals mostly similar to -phenyl-2-piperidin-2-ylacetamide exhibit inconsistent experimental test results,

being the mostly similar, i.e. Tolcapone, positive while the other four negative. Thus, it was concluded that

the predictions of carcinogenicity on rat male, female and composite are undefined.

TOLCAPONEResult: positiveSimilarity: 0.83

BIFENOXResult: negativeSimilarity: 0.81

4-NITROBENZOIC ACIDResult: negativeSimilarity: 0.80

4-NITROANTHRANILICACIDResult: negativeSimilarity: 0.80

DNOCResult: negativeSimilarity: 0.80

Applicant's summary and conclusion

Conclusions:

Based on the only reliable prediction (Leadscope) of carcinogenicity on rat male, female and composite, it was concluded that the target 2-hydroxy-5-nitrobenzoic acid is NEGATIVE, although the predictions were assessed as little reliable.

Executive summary:

Carcinogenicity on rat male, female and composite of the target 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. Thus, based on Leadscope predictions of carcinogenicity on rat

male, female and composite, it was concluded that the target 2-hydroxy-5-nitrobenzoic acid is NEGATIVE,

although the predictions were assessed as little reliable.