Chemical Space Covered by Applicability Domains of Quantitative Structure–Property Relationships and Semiempirical Relationships in Chemical Assessments

Abstract

A significant number of chemicals registered in national and regional chemical inventories require assessments of their potential "hazard" concerns posed to humans and ecological receptors. This warrants knowledge of their partitioning and reactivity properties, which are often predicted by quantitative structure−property relationships (QSPRs) and other semiempirical relationships. It is imperative to evaluate the applicability domain (AD) of these tools to ensure their suitability for assessment purpose. Here, we investigate the extent to which the ADs of commonly used QSPRs and semiempirical relationships cover seven partitioning and reactivity properties of a chemical "space" comprising 81,000+ organic chemicals registered in regulatory and academic chemical inventories. Our findings show that around or more than half of the chemicals studied are covered by at least one of the commonly used QSPRs. The investigated QSPRs demonstrate adequate AD coverage for organochlorides and organobromines but limited AD coverage for chemicals containing fluorine and phosphorus. These QSPRs exhibit limited AD coverage for atmospheric reactivity, biodegradation, and octanol−air partitioning, particularly for ionizable organic chemicals compared to nonionizable ones, challenging assessments of environmental persistence, bioaccumulation capability, and long-range transport potential. We also find that a predictive tool's AD coverage of chemicals depends on how the AD is defined, for example, by the distance of a predicted chemical from the centroid of the training chemicals or by the presence or absence of structural features.

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