2,4-Pyrimidinediamine, 6-chloro-, 3-oxide

Genetic toxicity: in vitro

Administrative data

Endpoint:

genetic toxicity in vitro

Remarks:

Type of genotoxicity: gene mutation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

other information

Study period:

November 2015

Reliability:

2 (reliable with restrictions)

Justification for type of information:

Read across from a (Q)SAR prediction for the substance 6-chloropyrimidine-2,4-diamine CAS 156-83-2: QSAR migrated from IUCLID 5.6

Data source

Reference

Reference 1

Reference Type:

other: QMRF

Title:

Unnamed

Year:

2015

Report date:

2015

Reference 2

Reference Type:

other: QPRF

Title:

Unnamed

Year:

2015

Report date:

2015

Materials and methods

Test guideline

Guideline:

other: guideline REACH guidance on QSARs R.6, May/July 2008

Principles of method if other than guideline:

Model or submodel name: Leadscope Model Applier - Genetic Toxicity Suite - Microbial in vitro - Salmonella
Model version: Leadscope model applier (v2.0.3, 2015)

Type of assay:

other: (Q)SAR prediction

Test material

Test material information

Constituent 1

Reference substance name:

4-chloro-2,6-diaminopyrimidine

EC Number:

205-863-9

EC Name:

4-chloro-2,6-diaminopyrimidine

Cas Number:

156-83-2

Molecular formula:

C4H5ClN4

IUPAC Name:

6-chloropyrimidine-2,4-diamine

Details on test material:

SMILES: Clc1cc(N)nc(N)n1
InChI: InChI=1S/C4H5ClN4/c5-2-1-3(6)9-4(7)8-2/h1H,(H4,6,7,8,9)

Results and discussion

Any other information on results incl. tables

Predicted value (model result): Positive Prediction Probability = 0.16; Negative.

Endpoint: Mutagenicity - microbial in vitro Salmonella

Dependent variable: Mutagenicity as microbial in vitro Salmonella gene mutation assay (Ames test) is modelled for study calls, where the positive calls are trained as binary 1 and negative calls as binary 0. The outcome of the QSAR prediction is given as the probability of being positive on a scale of 0 to 1. The Leadscope FDA Model Applier considers a Positive Prediction Probability under 0.5 to be negative and a probability of greater than or equal to 0.5 to be positive.

Model or submodel name: Leadscope Model Applier - Genetic Toxicity Suite - Microbial in vitro - Salmonella

Model version: Leadscope model applier (v2.0.3, 2015)

Descriptor values: Property Descriptors: ALogP = 0.006; Parent Molecular Weight = 0.004; Polar Surface Area = 0.002; Parent Atom Count = 0.002; Hydrogen Bond Donors =0.001; Hydrogen Bond Acceptors = 0.001; Rotatable Bonds = -1.35E-4

Model Feature(s): Pyrimidine scaffold = -0.07

Domains: Leadscope uses two parameters to guide the applicability of model domain:

1) having at least one structural feature defined in the model in addition to all the property descriptors;

2) having at least one chemical in a training neighborhood with at least 30% global similarity to the test structure. In this case the prediction is assessed as moderate reliable since: 1) one model fragments was found in the target, which is characterized by an higher frequency in negative training compounds; 2) 28 training compounds structurally similar to the target were identified.

i. descriptor domain: not applicable.

ii. structural fragment domain: One model fragment was found in 6 -chloropyrimidine-2,4-diamine, which is characterized by an higher

frequency in negative training compounds.

iii. mechanism domain: no structural alerts related to mutagenicity have been found in the target compound.

iv. metabolic domain, if relevant: not applicable.

Structural analogues: The similarity of 6-chloropyrimidine-2,4-diamine with respect to the training set compounds was analysed and quantified in terms of Tanimoto distance (using structural features), which provides a quantitative measure of structural relatedness between 6-chloropyrimidine-2,4-diamine and each training set compound. Among the 28 identified training neighborhood with at least 30% similarity to 6-chloropyrimidine-2,4-diamine, six compounds are characterised by a similarity higher that 0.5.

Considerations on structural analogues: The six mostly similar compounds from the training set exhibit moderate similarity with respect to 6-chloropyrimidine-2,4-diamine (similarity index ranging from 0.52 to 0.66), and experimental negative Ames test results (except for Acenaphtho(1,2-d)pyrimidin-8,10-diamine). This information supports the moderate reliable negative prediction

obtained by the probabilistic QSAR model.

The uncertainty of the prediction is evaluated by Leadscope with the two parameters which guide the applicability of model domain: 1) the number of structural feature defined in the model in addition to all the property descriptors; 2) the analogues with at least 30% global similarity to the test structure. In this case, one model fragment was found in 6 -chloropyrimidine-2,4 -diamine and six training compounds moderately similar to the target were identified (structural similarity > 0.5), the majority of them characterized by consistent negative experimental results. Thus, the prediction is considered as moderate reliable.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information):negative

6-chloropyrimidine-2,4-diamine is predicted by Leadscope Model Applier as negative for microbial in vitro Salmonella gene mutation assay. The prediction is considered moderate reliable.
Read across from 6-chloropyrimidine-2,4-diamine predicted the substance 2,4-Diamino-6-chloropyrimidine-3-oxide as negative for microbial in vitro Salmonella gene mutation assay. The prediction is considered moderate reliable.

Executive summary:

Regulatory purpose: This study was designed to generate estimated in silico (nontesting) mutagenicity data, as microbial in vitro Salmonella, for 6-chloropyrimidine-2,4-diamine to be used in the regulatory framework of REACH.

Approach for regulatory interpretation of the model result: Leadscope Model Applier predicted 6-chloropyrimidine-2,4-diamine as negative for microbial in vitro Salmonella Assay. The prediction is considered moderate reliable.

Read across from 6-chloropyrimidine-2,4-diamine as supporting substance (structural analogue or surrogate) of the substance 4-Diamino-6-chloropyrimidine-3-oxide is considered moderate reliable.