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6.1.3 - CLUSTER 3

Justifications and discussions

Category definition:
The structure of the two clustered targets justifies the adoption of a category approach many to many on the basis of their intrinsic similarity (0.956), which it is mirrored by the similarity scores with the same source molecules. The cluster analysis includes in the category also other similar chemicals, but they were discarded due to lack of reliable data or for the presence of relevant differences in the molecular structures, as well as the presence of a lower similarity index than the other members.
The two targets of the cluster are reactive dyes and structural isomers, which differ only on a conformational level, for a rotation of the naphthalene group around the diazo bond and for the position of the single bond with the acetamide on this group. Both are disodium salts.
In detail:
• the target 355 is a disodium; 6-acetamido-4-hydroxy-3-[[4-(2-sulphonatooxyethylsulphonyl)phenyl] diazenyl]naphthalene-2-sulphonate;
• the target 356 is a disodium;7-acetamido-4-hydroxy-3-[[4-(2-sulphonatooxyethylsulphonyl)phenyl] diazenyl]naphthalene-2-sulphonate;
For the targets, the available information about the composition of the dyes is reported in the section “1.2 – Composition” of the registration dossier.
According to the cluster analysis, conducted for every single target chemical, the source chemicals that present good similarity index and reliable experimental data for the endpoint considered are reported below. In particular it should be noted that the clustering analysis shows for the two targets several similar source chemicals, and this should also justify the category hypothesis.
Based on similarities, data quality and reliability of the sources, it is possible to include in the category the chemicals 177, 69 and 193. The other sources have structural characteristics and other differences that lead to not include them in this category approach, as explained below; therefore, they are not considered in the general reasoning for the endpoint assessment.
Category description:
Source 177, despite no good information about the test protocol followed, was selected for the category justification due to a similarity index of 1 (i.e., identity) with target 355 and, consequently, a very high similarity with target 356 (0.956).
Category rationale:
The choice of the target and the potential source substances that compose the category was based on a clustering method described in “6.1.3 – Cluster 3 - ClusteringMethod.pdf”. This method allows to calculate the similarity of each potential source with the targets and the similarity among the targets. The comparison between two molecules is based on the Tanimoto Coefficient that compares the Daylight fingerprints (as calculated in Python by RDKit) of the two molecules.
In this case, among the pool of potential sources (the ones with a reliable value for the endpoint of interest) the sources 177, 69 and 193 were selected based on their similarity with the targets (data reported in the data matrix) and the quality of the available data. Data on water solubility were also considered.
The target and the source substances can be considered in the applicability domain of the category due to their high structural similarity (higher than 0.75) and their similar physicochemical properties (the water solubility ranges between 210000 and 500000 mg/L, with the exception ofsource 193 where it is lower due probably of the metal complex).