Establishment of Expanded Botanical Thresholds of Toxicological Concern: Enrichment of Botanical PoD Databases and New Thresholds.

The Threshold of Toxicological Concern (TTC) approach is widely used for safety assessment of chemicals with limited toxicological data, but its application to botanical extracts remains limited due to challenges in chemical constituent identification. Kawamoto et al. proposed a Botanical-TTC value of 663 μg/day (1st percentile of the DNEL/DMEL distribution) from 213 repeated-dose toxicity points of departure (PoDs), but regulatory bodies raised concerns about dataset size. This study established an Expanded Botanical-TTC by verifying the original dataset and enriching it to 518 PoDs, comprehensively collected from published literature, Cosmetic Ingredient Review reports, National Toxicology Program reports, and journal articles. DNEL/DMEL values were log-transformed and analyzed by parametric distribution fitting, with subgroup analyses by plant part, extraction solvent, animal species, and study duration. The distribution was right-skewed, approximating unimodality after log transformation, and the Weibull distribution provided the best fit (by AIC/BIC). Empirical 1st and 5th percentile TTC values were 75 μg/day and 250 μg/day, respectively. The expanded dataset showed 8-11% exceedance rates against Kawamoto et al.'s original thresholds. Subgroup analyses revealed variability in lower-tail toxicity distributions across extraction conditions and study characteristics. The Expanded Botanical-TTC may offer a more conservative basis for assessing systemic toxicity of botanical extracts.