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Toxicological information

Genetic toxicity: in vitro

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Administrative data

Endpoint:
genetic toxicity in vitro
Remarks:
Type of genotoxicity: gene mutation
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

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: ACD/Percepta: Impurity Profiling - Microbial in vitro Salmonella composite.
Model version: ACD labs/Percepta (2015 Release).
Type of assay:
other: (Q)SAR prediction

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)

Results and discussion

Any other information on results incl. tables

Predicted value (model result): Positive Prediction Probability = 0.13; Negative.

Endpoint: Mutagenicity - microbial in vitro Salmonella

Dependent variable: Mutagenicity as microbial in vitro Salmonella (composite) 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 output of the probabilistic QSAR model consists of: the probability that a compound will result in a positive test in this mutagenicity assay (“p-value”); an indication of whether the compound belongs to the model applicability domain according to the calculated RI value; and a “positive” or “negative” call if the compound can be reliably classified on the basis of p and RI values (“Undefined” otherwise).

Model or submodel name: ACD/Percepta: Impurity Profiling - Microbial in vitro Salmonella composite.

Model version: ACD labs/Percepta (2015 Release).

Domains: ACD/Percepta provides an estimation of the reliability of the prediction, by a reliability index (RI). This index provides values in a range from 0 to 1 and gives an evaluation of whether a submitted compound falls within the model applicability domain. In particular: RI < 0.3 (Not Reliable), RI in range 0.3-0.5 (Borderline Reliability), RI in range 0.5-0.75 (Moderate Reliability), RI >= 0.75 (High Reliability). Estimation of the RI takes into account the following two aspects: similarity of the tested compound to the training set and the consistency of experimental values for similar compounds. In this case the prediction is considered as moderate reliable since RI is equal to 0.74.

i. descriptor domain: not applicable.

ii. structural fragment domain: not applicable.

iii. mechanism domain: one structural alert for genotoxicity, namely the aromatic amine alert, was identified. Aromatic amines exhibit genotoxic activity after metabolic transformation to hydroxylamines.

The z-score associated to this alert is equal to 12.74, meaning that the presence of the alert leads to a statistically significant increase in proportion of compounds with a positive test result. However, analysing the five mostly similar compounds from the training set possessing this alert it was noted that they exhibit moderate to high similarity with respect to the target, but not consistent experimental Ames test results (three negative and two positive). Thus, the positive expert-rule based prediction provided by this alert was assessed as borderline reliable for the target 6-chloropyrimidine-2,4-diamine.

iv. metabolic domain, if relevant: not applicable.

Considerations on structural analogues: The five mostly similar compounds from the training set exhibit moderate to high similarity with respect to 6-chloropyrimidine-2,4-diamine (similarity index ranging from 0.81 to 0.97), meaning that the target compound is well represented in the training set of the model, and experimental negative Ames test results (except for acenaphtho(1,2 -d)pyrimidin-8,10-diamine, which is positive). This information supports the reliable negative prediction obtained by the probabilistic QSAR model.

The uncertainty of the prediction is evaluated by ACD/Percepta by means of the reliability index (RI). This index provides values in a range from 0 to 1 and gives an evaluation of whether a submitted compound falls within the model applicability domain. In particular: RI < 0.3 (Not Reliable), RI in range 0.3-0.5 (Borderline Reliability), RI in range 0.5-0.75 (Moderate Reliability), RI >= 0.75 (High Reliability).

Estimation of the RI takes into account the following two aspects: similarity of the tested compound to the training set and the consistency of experimental values for similar compounds. In this case the statistical-based prediction is considered as moderate reliable since RI is equal to 0.74. However, the identification of the aromatic amine alert decreased the reliability of the negative prediction provided by the statistical-based approach, leading to a negative prediction of borderline reliability.

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information):
negative

6-chloropyrimidine-2,4-diamine is predicted negative for microbial in vitro Salmonella gene mutation assay and the prediction is borderline 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. ACD/Percepta predicted 6-chloropyrimidine-2,4-diamine as negative for microbial in vitro Salmonella Assay. The prediction is considered borderline reliable