The non-intentionally added substance (NIAS) migrated from food contact material is receiving growing concern for their potential negative impact on food safety. Since the source of NIAS is complex and most of them are unknown, it poses challenges for safety assessment of food contact material, as well as market supervision. Based on the principal of threshold of toxicological concern (TTC), combined with application of Cramer decision tree, chemical analysis and bioassay screening measures, an effective and novel approach can be established to perform screening and safety assessment of NIAS from food contact material. It is, therefore, suitable for safety assessment on NIAS which lacks of toxicology data and at low exposure level. Using tier approach, it could be identified which compounds that actually pose health concern and need to be further investigated, in practical, only those compounds that TTC value exceeds 1.5 μg/kg BW have safety concern and risk assessment need to be carried out. This new strategy allows assessing high concern substances in food contact material, making transition from traditional approach that based on detection limit to a new approach base on TTC application. That will minimize unnecessary animal experiment and save huge amounts of resources on human, time and financial expending, and accelerate the process of assessment on compounds with low exposure, as well as to enhance the efficacy of market supervision.