Publications : 2022

Mihalchik A, Wood M. Considerations for standardization and derivation of pediatric and neonatal tolerable exposure limits for extractable and leachable compounds from medical devices. Poster presented at Society of Toxicology Annual Meeting, San Diego, CA, March 2022.


The risk assessment paradigm is formally well described for extractables and leachables (E&Ls) derived from medical devices for adult patients; however, few guidance documents or literature resources are available that describe derivation of tolerable exposure (TE) limits in vulnerable patient populations such as children and neonates. Existing ISO 10993 guidance regarding special populations suggests adjusting for body weight or considering population-specific data, when available, in deriving the TE. However, guidance is not provided on a standardized method of ensuring pediatric safety in the absence of nonclinical juvenile toxicity data or pediatric clinical data associated with a clearly defined point of departure. Nor does international regulatory guidance clarify how a risk assessor should adjust ICH Q3C values used in medical device risk assessment, other than accounting for differences in patient body weight. To address this gap, this poster describes the key considerations in performing a pediatric-specific evaluation of E&Ls: 1. Search strategies to identify juvenile nonclinical and clinical toxicity data 2. Consideration of differences in adult and pediatric or neonatal metabolism 3. Use of juvenile-specific data as the point of departure 4. Use of standardized pediatric weight adjustment values 5. Accounting for route-to-route extrapolation if juvenile toxicity data are unavailable for the route of interest. Case studies describing derivation of pediatric and neonatal TE values for common E&Ls, including cyclohexanone and 2,4-di-tert-butylphenol, as well as cyclohexane and toluene listed in ICH Q3C, will be provided to highlight various scenarios in which clinical data, nonclinical juvenile data, or a mixture of data sources are available to address pediatric and neonatal safety. A discussion of selecting appropriate, scalable uncertainty factors in the presence or absence of adequate pediatric or neonatal data associated with deriving a tolerable intake (TI) will be described in the context of the case studies, as will selection of population-specific points of departure in deriving pediatric and neonatal TI and subsequent TE values.