Characteristics and safety assessment of intractable proteins in genetically modified crops

•“Intractable proteins” in GM crops cannot be isolated or studied by existing methods.•Intractability results from low expression, membrane association, or other factors.•The established tiered weight-of-evidence approach can be used for safety assessment.•No protein is needed for history of safe use (HOSU) and bioinformatics analyses.•Enriched or substitute proteins may offer alternatives to pure protein dose testing.