2026-09-06T21:04:09Zhttps://riubu.ubu.es/oai/request

oai:riubu.ubu.es:10259/119872026-09-04T00:05:21Zcom_10259_6168com_10259_5086com_10259_2604com_10259_4323col_10259_6169col_10259_4330

A three-tier in silico toxicology framework for formulated essential-oil nanocapsules: integrating molecular hazard, release kinetics and nano-bioavailability for safe-and-sustainable-by-design assessment Huerta Sainz, Sergio de la Diez Cabanes, Valentin Gutiérrez Vega, Alberto Martel Martín, Sonia Fernández Pampín, Natalia Rumbo Lorenzo, Carlos Marcos Villa, Pedro A. Bol Arreba, Alfredo Marson, Domenico Laurini, Erik Aparicio Martínez, Santiago Essential oil nanocapsules Systems toxicology Integrated hazard prediction Korsmeyer Peppas release kinetics Safe and sustainable by design Human and environmental health Essential-oil nanocapsules are bio-based antimicrobial formulations central to agri-food sustainability, yet their human and environmental hazard as formulated products cannot be assessed by conventional molecular QSAR, which ignores controlled release kinetics, nano-specific bio-interactions, and shell-material contributions. We apply a systems toxicology approach — integrating molecular QSAR (Tier 1), Korsmeyer–Peppas release kinetics (Tier 2), and a nano-specific bioavailability correction layer (Tier 3) — to produce the first quantitative integrated hazard prediction for two clove-oil advanced-material (AdMa) nanocapsule formulations: AdMa EO@PEC-GEL (pectin–gelatin shell, CaCl₂ crosslinker) and AdMa EO@Chi (chitosan shell, formaldehyde crosslinker).Eugenol (∼90 wt% core) is the principal toxicophore. Release parameters were scaled from published eugenol–chitosan kinetic data to the 1 μm target particle size; nano-correction factors were calibrated from published surface-charge and uptake relationships. The integrated model predicts AdMa EO@PEC-GEL to be 9.1× safer than free eugenol (IC₅₀ ∼3.5 mM vs. 0.38 mM), driven by anionic surface charge and 80% encapsulation efficiency. AdMa EO@Chi retains toxicity close to the free molecule (IC₅₀ ∼0.91 mM; 2.4×) because cationic surface charge offsets the encapsulation benefit. The formaldehyde crosslinker introduces independent sensitisation, genotoxicity, and IARC Group 1 carcinogenicity flags — quantified via the concentration-addition mixture model — entirely absent from PEC-GEL.Sensitivity analysis identifies zeta potential as the dominant model uncertainty driver. Tier 2 is retrospectively validated against published release kinetics (R2 = 0.997). The Korsmeyer–Peppas tier applies directly to environmental fate scenarios — pH-dependent shell dissolution in soil and aquatic compartments — providing a unified architecture for human–environment integrated hazard assessment aligned with planetary health priorities. An interactive, browser-based digital twin is provided as Supplementary Information: it recomputes all integrated predictions in real time as the user adjusts the model inputs (zeta potential, particle size, encapsulation efficiency, eugenol fraction, release time and pH/enzyme condition), enabling transparent scenario analysis and progressive refinement as experimental data become available, in line with the iterative Safe-and-Sustainable-by-Design (SSbD) workflow. 2026-09-02T07:37:25Z 2026-09-02T07:37:25Z 2026-09 info:eu-repo/semantics/article 2468-1113 https://hdl.handle.net/10259/11987 10.1016/J.COMTOX.2026.100440 eng Computational Toxicology. 2026, V. 39, art. 100440 https://doi.org/10.1016/j.comtox.2026.100440 http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess Attribution-NonCommercial-NoDerivatives 4.0 Internacional Elsevier