Utility of generational developmental and reproductive toxicity and juvenile animal study protocols for the infant safety assessment of food contact materials

Abstract

The US Food and Drug Administration (FDA) Division of Food Contact Notifications (DFCN) performs infant lifestage-specific exposure and safety assessments during the premarket review of FCNs proposed for use with infant formula or human milk. DFCN previously identified two protocols that may be best suited to support infant safety: the multigenerational developmental and reproductive toxicology (Gen-DART) protocol and the juvenile animal study (JAS) protocol. The Gen-DART protocol tests chemical exposure from prior to mating through one or two generations in rodents, while JAS protocols test a chemical during a specific developmental window. At FDA, Gen-DART studies are currently recommended to support the safety of food additives (FAs), including food contact substances, across lifestages (from conception through adulthood). JAS protocols are recommended in the nonclinical safety assessment of drugs seeking pediatric indications. To improve our recommendations regarding the use of either Gen-DART or JAS protocols for the infant safety assessment of food contact materials, we created a database of FDA-reviewed Gen-DART or JAS. Our database contains information from 41 Gen-DART studies (38 FAs) and 51 JAS (29 drugs). Both protocols can detect toxicity relevant to infant safety assessment, such as developmental toxicity in neurological, endocrine, reproductive, immunological, or skeletal systems. Selection of either protocol will depend on the amount of information available for the chemical under study. The Gen-DART protocol may be preferred when limited data on the mode of action or target organ of the chemical are available. However, if these data are available, a JAS may provide the best assessment of potential juvenile toxicity.