Existing regulation of substances as groups based on structural similarity and/or intrinsic properties has been successful, as demonstrated in the Montreal Protocol of ODSs and the Stockholm Convention of POPs. Meanwhile, regrettable substitution with increasing production of PMT/vPvM substances such as TFA and GenX has been noted as a side-effect. This shows a limitation of the grouping approach under the Montreal Protocol and the Stockholm Convention: limiting the scope of intrinsic properties during grouping may lead to burden shifting to other hazards. This calls for a grouping strategy that can prevent regrettable substitution and improve the efficiency and effectiveness of chemical regulatory processes.