Characterizing Extractables and Leachables Chemical Space to Support In Silico Toxicological Hazard Assessments.

Area of Science:

• Pharmaceutical analysis
• Chemical safety assessment
• Toxicology

Background:

• Extractables and leachables (E&L) are critical safety considerations in pharmaceutical product development.
• Existing datasets from the Extractables and Leachables Safety Information Exchange (ELSIE) Consortium and the Product Quality Research Institute (PQRI) provide valuable E&L information.
• A comprehensive, representative dataset is needed to understand E&L profiles and associated risks.

Purpose of the Study:

• To develop a unified, representative dataset of extractables and leachables (E&L) by combining ELSIE and PQRI data.
• To analyze the chemical diversity and identify common classes within the E&L landscape.
• To assess the prevalence of potentially hazardous chemical structures, specifically mutagens and potent dermal sensitizers, within the combined E&L dataset.

Main Methods:

• Combined published E&L datasets from ELSIE and PQRI, totaling 783 chemicals.
• Employed chemical structure-based clustering to categorize the chemicals into distinct classes.
• Utilized *in silico* toxicological tools to predict potential mutagenicity and dermal sensitization properties.

Main Results:

• Identified 142 distinct chemical classes from the combined dataset, with 105 classes containing chemicals from both ELSIE and PQRI.
• Approximately 9% of E&L chemicals were flagged as potential mutagens, and 3% as potent dermal sensitizers.
• A significant overlap was observed, with 80% of potent dermal sensitizers also predicted as mutagens. Alkyl bromides and isothiocyanates were identified as unique PQRI classes with potential hazards.

Conclusions:

• The combined ELSIE-PQRI dataset offers a robust resource for E&L assessment.
• A substantial proportion of E&L chemicals possess structural alerts for mutagenicity and/or potent dermal sensitization.
• The co-occurrence of mutagenicity and sensitization alerts highlights the need for careful risk assessment of E&L compounds.