Clustering a Chemical Inventory for Safety Assessment of Fragrance Ingredients: Identifying Read-Across Analogs to Address Data Gaps

Abstract

A valuable approach to chemical safety assessment is the use of read-across chemicals to provide safety data to support the assessment of structurally similar chemicals. An inventory of over 6000 discrete organic chemicals used as fragrance materials in consumer products has been clustered into chemical class-based groups for efficient search of read-across sources. We developed a robust, tiered system for chemical classification based on (1) organic functional group, (2) structural similarity and reactivity features of the hydrocarbon skeletons, (3) predicted or experimentally verified Phase I and Phase II metabolism, and (4) expert pruning to consider these variables in the context of specific toxicity end points. The systematic combination of these data yielded clusters, which may be visualized as a top-down hierarchical clustering tree. In this tree, chemical classes are formed at the highest level according to organic functional groups. Each subsequent subcluster stemming from classes in this hierarchy of the cluster is a chemical cluster defined by common organic functional groups and close similarity in the hydrocarbon skeleton. By examining the available experimental data for a toxicological endpoint within each cluster, users can better identify potential read-across chemicals to support safety assessments.

Synthesis of Cyclic Fragrances via Transformations of Alkenes, Alkynes and Enynes: Strategies and Recent Progress

“…The utilization of machine learning, artificial intelligence and brain–computer interfaces for fragrance design, synthesis and quantitative olfactory studies is expected to show rapid growth [ 165 , 166 , 167 , 168 , 169 , 170 , 171 , 172 , 173 ]. The safety, therapeutic efficacy, allergic effect and biodegradability of these new fragrances should also be investigated further, especially in the case of fragrances containing new scaffolds [ 174 , 175 , 176 , 177 , 178 , 179 , 180 ].…”

Toxicological Assessment of Flavor Ingredients in E-Vapor Products

“…1565/2000 ( European Commission, 2000 ). Similarly, Date et al (2020) developed a tiered system for chemical classification of fragrances on the basis of (a) organic functional group, (b) structural similarity and reactivity features of the hydrocarbon skeletons, (c) predicted or experimentally verified phase I and phase II metabolism, and (d) expert screening to consider these variables in the context of specific toxicity endpoints ( Date et al, 2020 ).…”

Incorporating lines of evidence from New Approach Methodologies (NAMs) to reduce uncertainties in a category based read-across: A case study for repeated dose toxicity

“…Tetraconazole (the target for read-across) and an initial set of 14 triazole compounds (the source molecules for read-across) were selected on the basis of a common triazole functionality, and grouped as a category to read-across repeated dose toxicity. Whilst a simplistic concept, structural similarity is at the heart of read-across and is highly useful to cluster similar compounds to initiate analyses (Date et al, 2020). The read-across was analysed utilising both the AE from the ECHA RAAF and the scheme proposed by Schultz et al (2019) to identify uncertainties.…”