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

Toxicity to reproduction

Administrative data

Endpoint:

toxicity to reproduction

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

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 – Reproductive Toxicity Suite - repro rat female
b. 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:

female

Results and discussion

Overall reproductive toxicity

Reproductive effects observed:

not specified

Any other information on results incl. tables

Positive Prediction Probability = 0.15; Negative.

Endpoint: In vivo pre-, peri-, post natal development and/or fertility – Reproductive toxicity (rat female)

Dependent variable: Reproductive toxicity, based on in vivo reproductive toxicity studies in rat females, including adverse effects to female reproductive organs (cervix, fallopian tube, ovary, uterus, and vagina) and fertility.

Reproductive toxicity 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.

Descriptor values: Property Descriptors: Rotatable Bonds = 0.008; Hydrogen Bond Acceptors =0.006; Hydrogen Bond Donors = 4.49E-4; Polar Surface Area = -7.91E-4; Lipinski Score = -0.003; Parent Atom Count = -0.003; Parent Molecular Weight = -0.008; ALogP = -0.016. Model Features: Pyrimidine = -0.01

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 fragment was

found in 6-chloropyrimidine-2,4-diamine, which is characterized by an higher frequency in negative training compounds; 2) six 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: 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 six identified training neighborhood with

at least 30% similarity to 6-chloropyrimidine-2,4 -diamine, two compounds were 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 consistent negative 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, one model fragment was found in 6-chloropyrimidine-2,4-diamine and two training compounds moderately similar to the target were identified, characterized by consistent negative experimental

results. Overall, the prediction is assessed 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 reproductive toxicity (rat female). The prediction is considered moderate reliable.

Executive summary:

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