4-chloro-2,6-diaminopyrimidine

Carcinogenicity

Administrative data

Endpoint:

carcinogenicity

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Study period:

November 2015

Reliability:

3 (not reliable)

Justification for type of information:

QSAR prediction: 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 - Rodent Carcinogenicity Suite - carc rat male
Model version: Leadscope model applier (v2.0.3, 2015)

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)

Test animals

Species:

rat

Sex:

male

Results and discussion

Any other information on results incl. tables

Predicted value (model result): Positive Prediction Probability = 0.25;

Negative.

Endpoint: Carcinogenicity (rat male)

Dependent variable: Carcinogenicity, based on in vivo carcinogenicity studies in rat males, 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 - Rodent Carcinogenicity Suite - carc rat male

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

Descriptor values: Property Descriptors: Rotatable Bonds = 0.007; Hydrogen Bond Acceptors = 0.003; Parent Molecular Weight = 0.001; Parent Atom Count = 8.83E-5; Polar Surface Area = -7.791E-4; Hydrogen Bond Donors = -0.005; ALogP = -0.009.

Model Feature(s): pyrimidine, 2-amino- = -0.057; pyrimidine, 4-amino(NH2)- = -0.094.

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) two model fragments were found in the target, which are characterized by an higher frequency in negative training compounds; 2) 15 training compounds structurally similar to the target were identified.

i. descriptor domain: not applicable.

ii. structural fragment domain: two model fragments were found in 6-chloropyrimidine-2,4-diamine, which are characterized by an higher frequency in negative training compounds.

iii. mechanism domain: not applicable.

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 15 identified training neighborhood with at least 30% similarity to 6-chloropyrimidine-2,4-diamine, two compounds are characterised by a similarity higher that 0.5.

Considerations on structural analogues: The two mostly similar compounds from the training set exhibit moderate similarity with respect to 6- chloropyrimidine-2,4-diamine (similarity indices equal to 0.66 and 0.57), but not consistent experimental results.

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, two model fragments were found in 6-chloropyrimidine-2,4-diamine and two training compounds moderately similar to the target were identified (structural similarity > 0.5) characterized by not consistent experimental results. Thus, the prediction is considered as borderline reliable.

Applicant's summary and conclusion

Conclusions:

6-chloropyrimidine-2,4-diamine is predicted by Leadscope Model Applier as negative for in vivo carcinogenicity (rat male). The prediction is assessed as borderline reliable.

Executive summary:

Regulatory purpose: This study was designed to generate estimated in silico (nontesting) carcinogenicity data, as in vivo carcinogenicity in rat male, 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 in vivo carcinogenicity (rat male). The prediction is considered borderline reliable