The application of acute oral toxicity computational models in dangerous goods classification.

Acute oral toxicity (AOT) data inform the acute toxicity potential of a compound and guides occupational safety and transportation practices. AOT data enable the categorization of a chemical into the appropriate AOT Globally Harmonized System (GHS) category based on the severity of the hazard. AOT data are also utilized to identify compounds that are Dangerous Goods (DGs) and subsequent transportation guidance for shipping of these hazardous materials. Proper identification of DGs is challenging for novel compounds that lack data. It is not feasible to err on the side of caution for all compounds lacking AOT data and to designate them as DGs, as shipping a compound as a DG has cost, resource, and time implications. With the wealth of available historical AOT data, AOT testing approaches are evolving, and in silico AOT models are emerging as tools that can be utilized with confidence to assess the acute toxicity potential of de novo molecules. Such approaches align with the 3R principles, offering a reduction or even replacement of traditional in vivo testing methods and can also be leveraged for product stewardship purposes. Utilizing proprietary historical in vivo AOT data for 210 pharmaceutical compounds (PCs), we evaluated the performance of two established in silico AOT programs: the Leadscope AOT Model Suite and the Collaborative Acute Toxicity Modeling Suite. These models accurately identified 94% and 97% compounds that were not DGs (GHS categories 4, 5, and not classified (NC)) suggesting that the models are fit-for-purpose in identifying PCs with low acute oral toxicity potential (LD50 >300 mg/kg). Utilization of these models to identify compounds that are not DGs can enable them to be de-prioritized for in vivo testing. This manuscript provides a detailed evaluation and assessment of the two models and recommends the most suitable applications of such models.