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A cheminformatics workflow to select representative TSCA chemicals for NAM screening
Citation:
Patlewicz, G., K. Paul-Friedman, AND A. Williams. A cheminformatics workflow to select representative TSCA chemicals for NAM screening. QSAR, Copenhagen, DENMARK, June 05 - 09, 2023. https://doi.org/10.23645/epacomptox.22710220
Impact/Purpose:
N/A
Description:
The Toxic Substances Control Act (TSCA) requires the US EPA to evaluate the hazard and exposure to new and existing chemicals. New chemical notifications are typically data poor and EPA’s Office of Pollution Prevention and Toxics (OPPT) has historically relied upon the use of tools including chemical categories and read-across approaches to fill data gaps. As part of a multi-year, New Chemicals Collaborative Research Program between OPPT and EPA’s Office of Research & Development, opportunities will be explored to leverage New Approach Methods (NAMs). In vitro NAMs will be used to generate mechanistic, hazard, and toxicokinetic data that will be evaluated for their applicability to new chemical assessments. Herein, we describe the cheminformatics workflow developed to identify a set of 200-300 representative candidate case study chemicals for screening from the TSCA non-confidential active inventory. Chemicals were first categorised using EPA’s New Chemicals Categories (NCC) to evaluate their scope, coverage, and potential gaps. Approximately half of the non-confidential active inventory with discrete structure representations could be assigned at least one NCC. Chemical classification information generated from the freely available web application ClassyFire was used to categorise all discrete organic structures from the TSCA inventory into one of 68 primary categories. The inventory was then profiled in a number of different ways to create filters that would aid in the selection of candidate substances from each primary category. Informative physicochemical property predictions from OPERA QSAR models, such as melting point, boiling point, and vapour pressure, were used to indicate likely physical form and volatility. PubChem was queried to identify the feasibility of finding a vendor from which a given substance could be procured. Analytical method detection amenability predictions for liquid-chromatography mass spectrometry were generated to provide an indication of which chemicals lent themselves to aqueous based-screening. Structural alerts were also used to identify potential explosive or highly reactive substances. The centroid of each primary category was taken as the nominal representative substance. Potential candidate substances were selected on the basis of being structurally similar to the centroid and meeting the other screenability conditions. The final set of 200-300 chemicals amenable to aqueous screening will undergo analytical quality control and screening in a range of broad and targeted biological technologies for human health relevant endpoints.
URLs/Downloads:
DOI: A cheminformatics workflow to select representative TSCA chemicals for NAM screening
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