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Categories

Category name:
Diisocyanates

Justifications and discussions

Category definition:
Diisocyanates
Category order description:
Category approach – Scenario 4 of RAAF
Category rationale:
REPORTING FORMAT FOR THE CATEGORY APPROACH

1. CATEGORY HYPOTHESIS
[Describe why the category can be formed (e.g. common functional group(s), common precursor(s)/breakdown product(s), common mechanism(s) of action, trends in properties and/or activities)]

Referring to chemical structures of the diisocyanate category members, the read-across hypothesis, which is proposed for toxicological endpoints, follows rather Scenario 4 of the RAAF document (ECHA, 2017) presuming that different compounds, i.e. diisocyanates, show qualitatively similar biological effects. This scenario generally implies that properties investigated in studies conducted with different source substances of the chemical category are used to predict the properties that would be observed in a study with the target substance if it were to be conducted. In this case, quantitative variations in the biological effects observed among members of the chemical category can occur and they may form a regular pattern because of presence of isocyanate groups. The prediction can be based either on this regular pattern or on a worst-case approach.
The diisocyanate members of the category share isocyanate NCO group, which is known to be reactive to biomolecules i.e. proteins, and determines their common mechanism of action namely respiratory sensitization and irritation (citation):
“Studies generally report very similar diisocyanate-induced hazardous effects in humans and test animals, namely irritation and sensitization” (ECHA, 2019).
Exposure to structurally different diisocyanates causes thus qualitatively similar effects through the common mechanism (reactivity with proteins), while the strength of these effects can vary and may potentially be associated with differing steric hindrance of the reactive diisocyanate groups, dependent on the relative position of the aliphatic side-chains on the benzene ring.


2. CATEGORY JUSTIFICATION
[Summarise here based on available experimental data how these results verify that the category is robust]

Structural similarity and differences within the category
As can be seen from the chemical structure of the source substances, the chemical category consists of structurally rather different diisocyanates because two isocyanate groups are localized either on one or two benzene rings, or even they can be attached to the aliphatic side chains. Further, isocyanate groups can be localized also on two different benzene rings of phenyl moieties or on a naphthalene moiety. Therefore, no incremental and constant increase in aliphatic chain length of the aromatic diisocyanate members can be established.
The three supporting compounds show a higher extend of structural variation in relation to the target compound TRIDI, with aliphatic core to which two isocyanate groups are attached.
The structural similarity of the diisocyanate category members is displayed thus only by the presence of the two reactive isocyanate groups, which position on aromatic or aliphatic moieties and the position of the aliphatic side-chains on aromatic moieties does result in their different reactivity.
Therefore, a prediction for the endpoint of interest cannot be based on an inter- or extrapolation of qualitative or quantitative toxicological data from a neighbor chemical. Rather the strengths of toxicological activity of diisocyanates is considered to be entirely governed by the reactivity of their isocyanate groups, which is dependent on their localization and the localization and the length of their aliphatic side chains.
Therefore, a prediction of the reactivity of isocyanate groups of the target substance TRIDI is the goal in the prediction of skin and respiratory sensitization, systemic toxicity effects by long-term exposure and reproductive/developmental toxicity effects.

Link of structural similarities and structural differences with the biological effects of the diisocyanate compounds
As outlined above, variation in toxicological properties among diisocyanate members of the chemical category may depend on accessibility of the reactive isocyanate groups of the respective diisocyanate compounds in the exposed organism to biomolecules, e.g. proteins and DNA.
As the consequence of structural differences in aromatic and (cyclo)aliphatic moieties of diisocyanate members, their toxicological properties do vary but a regular pattern in potency of predicted properties can hardly be established for this category. No variable defining order within the category really exists, since for example the lengths of aliphatic side chains and their branching on the benzene ring do not form a regular pattern. This variation may potentially be associated with differing steric hindrance of the reactive isocyanate group, dependent on their position and the position of aliphatic side-chains on aromatic or aliphatic moieties as well as direct electronic effects from the aromatic or aliphatic backbone, respectively.

For details please refer to read-across statement in section 13.

3. APPLICABILITY DOMAIN OF THE CATEGORY
[Describe the set of inclusion and/or exclusion rules that identify the ranges of values within which reliable estimations can be made for category members]

For details please refer to read-across statement in section 13.