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Carcinogenicity

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Administrative data

Endpoint:
carcinogenicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Other: read across from a Qsar prediction
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

Referenceopen allclose all

Reference Type:
other: QMRF
Title:
Unnamed
Year:
2015
Report date:
2015
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 female
Model version: Leadscope model applier (v2.0.3, 2015)

Test material

Constituent 1
Chemical structure
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:
female

Results and discussion

Any other information on results incl. tables

Positive Prediction Probability = 0.07; Negative.

Endpoint: Carcinogenicity (rat female)

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 female

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

Descriptor values:

Property Descriptors: Rotatable Bonds = 0.002; Hydrogen Bond Acceptors =7.13E-4; Polar Surface Area = 7.26E-5; Parent Molecular Weight = -0.001; Parent Atom Count = -0.002; Hydrogen Bond Donors = -0.002; ALogP = -0.004.

Model Feature(s): aromatic amine(NH2) = 0.009; pyrimidine, 4-amino- = -0.011; pyrimidine, 4-amino(NH2)- = -0.051; Scaffold 667-amine-amine = -0.057.

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) four model fragments were found in the target, which are characterized by an higher frequency in negative training compounds; 2) 13 training compounds structurally similar to the target were identified.

i. descriptor domain: not applicable.

ii. structural fragment domain: four 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 13 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), and experimental negative results. This information supports the 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, four 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 consistent negative experimental results. Thus, the prediction is considered as moderate reliable.

Applicant's summary and conclusion

Conclusions:
Read across from 6-chloropyrimidine-2,4-diamine predicted the substance 2,4-Diamino-6-chloropyrimidine-3-oxide as negative for in vivo carcinogenicity (rat female). The prediction is assessed as moderate reliable.
Executive summary:

Regulatory purpose: This study was designed to generate estimated in silico (nontesting) carcinogenicity data, as in vivo carcinogenicity in rat female, 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 female). 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.