The focus of the Read-Across Assessment Framework (RAAF) published in May 2015 is on mono-constituent substances. Although the assessment framework may also be applied in an analogous manner to multi-constituent substances and ‘substances of unknown or variable composition, complex reaction products or biological materials (UVCBs)’, ECHA considered that additional issues need to be addressed when read-across cases involving such substances have to be assessed. The first step towards a future extension of the RAAF is to identify such additional issues emerging in readacross cases involving multi-constituent substances and/or UVBCs. This document describes the additional key issues for the ECHA experts assessing such cases. Such considerations may also be relevant for registrants in the justification of read-across cases. However, due to the case-specific nature of read-across cases for multi-constituent substances and/or UVCBs, the document does not provide considerations on how to deal with the identified issues when adaptations using readacross are developed.