Predicting the Toxicity In Silico of the Aqueous Extract of Chiranthodendron pentadactylon Flowers. Experimental Evaluation In Vivo

Chiranthodendron pentadactylon Larreat (“flor de manita”) is traditionally used for gastrointestinal, cardiovascular, and neurological disorders. Objective: This study comprehensively integrated phytochemical characterization, in silico toxicological profiling, an exposure-informed Integrative Toxicity Prediction Model (ITPM), uncertainty analysis, and acute testing of a fresh flower aqueous extract (FFAE). Methods: Thirty-six phytochemicals were screened for hepatotoxicity, nephrotoxicity, Ames mutagenicity, carcinogenicity, hERG inhibition, reproductive-effects alerts, and acute oral toxicity. Five organ- or effect-specific endpoints were integrated into an exploratory Toxicological Alert Score (TAS), whereas reproductive alerts and predicted LD50 were reported separately. Seventeen compounds quantified in the FFAE were compared with a 20-compound literature-informed profile through 50,000 Monte Carlo iterations. Male CD-1 mice received a single FFAE dose of 300–5000 mg/kg and were observed for 14 days. Results: Positive predictions occurred for hERG inhibition in 33 compounds (91.7%), hepatotoxicity in 29 (80.6%), nephrotoxicity and carcinogenicity in 28 each (77.8%), and mutagenicity in 21 (58.3%). Six compounds had predicted LD50 values ≤ 1000 mg/kg. The proportional ITPM toxicity-evidence index was 6.91% for the experimental profile and 19.34% for the literature-informed profile. Monte Carlo means were 6.98% (95% uncertainty interval, 5.65–8.44%) and 19.32% (16.76–22.37%), respectively. No mortality, overt clinical signs, or treatment-related body weight differences occurred up to 5000 mg/kg. Conclusions: Compound-level predictions identified priorities for confirmatory testing, while the extract-specific model yielded a lower comparative toxicity-evidence proportion, and the animal study showed low overall acute toxicity under the evaluated conditions. These findings do not establish general or long-term safety, calibrated risk probabilities, or biological neutralization of toxicological liabilities.