Integrating New Approach Methodologies (NAMs) into Read-Across Evidence Streams for Short-Chain Nitroparaffins

Read-across is commonly used to fill data gaps for chemical registration and safety assessment. Current read-across guidelines recommend systematic approaches for evaluating suitability of analogue data for assessing target chemical data gaps. However, these frameworks still lack practical approaches for consistently integrating diverse evidence, such as data from new approach methodologies (NAMs), into final read-across determinations. Herein, we present a case study of integration of multiple lines of evidence, including NAMs, to assess the suitability of a read-across from nitromethane (NM) to nitroethane (NE) and 1-nitroproane (1NP). The three nitroparaffins are structurally similar, which historically was considered sufficient evidence for read-across. However, data from several other lines of evidence suggest that read-across is not appropriate. The nitroparaffins differ in terms of physicochemical, toxicokinetic, toxicological, and toxicodynamic properties, as well as the identity of aldehyde metabolites. Our analysis reaffirms current guidelines that grouping chemicals based on shared functional groups alone is not a sufficient read-across justification. Further, our analysis demonstrates how NAMs can serve as a critical component to the overall evidentiary basis for read-across arguments, which will be particularly impactful in cases where extant in vivo data is insufficient to make a read-across determination with high confidence.