Significance of Chemical Grouping in E&L Risk Assessment 

Excerpt from our presentation titled Applications of Chemical Grouping in Extractables and Leachables (E&L) Risk Assessments at Extractables & Leachables US 2025.

In toxicology, chemical grouping supported by clustering approaches offers a science-based framework for organizing structurally or functionally related substances, facilitating more efficient evaluations, uncovering mechanistic insights, and strengthening the overall weight of evidence in risk assessments. At the recent Extractables and Leachables USA conference, we explored how grouping strategies combined with in silico profiling and tiered classification, can inform decision-making throughout the product lifecycle. 

Chemical grouping allows the classification of newly identified E&L compounds by shared structural features and toxicological profiles. This approach is especially valuable in regulatory submissions, where grouping can support a read-across strategy for data-poor substances by establishing biological similarity with data-rich analogues, thereby providing a robust scientific justification.  

Previous studies have examined classification/grouping of chemicals in the E&L space, both at a structural¹ and functional level². Recently, we investigated a two-tiered clustering based on a broad class-level (Tier 1) and a more granular subclass distinctions (Tier 2)³.  While further justification of similarity is required to establish applying these clusters to support read-across assessments, they can be used to develop triaging strategies to rapidly categorize and identify compounds that pose critical risk. In silico profiles are especially powerful when integrated within a clustering strategy and applied to well-characterized chemical classes. By analyzing predicted toxicological endpoints across a cluster (such as mutagenicity and potent dermal sensitization) chemical groups of potential concern can be identified, along with newly associated substances that share the cluster chemical features as well as the concerning properties. In some cases, a category-based approach may be used to derive class-based exposure limits that inform safe use. 

Chemical grouping not only support toxicological assessments through justified read-across assessments but can be used to highlight patterns in leachables associated with hazardous materials and supports material selection and change. Embedding grouping and predictive toxicology into decision making workflows, provides an evidence-based, efficient risk management approach.