The use of computational chemistry to predict toxicity of antioxidants food additives and its metabolites as a reference for food safety regulation

Publication: Der Pharma Chemica
Software: ADMET Predictor®


Antioxidant food additives are used to prevent or slowing down the oxidation process in foods. European Food Safety Authority (EFSA) by EC257/2010 regulation set up a program for reevaluation approved antioxidant food additives. Safety of the food additive was one of its concerns. The aim of this research was to predict antioxidant food additives toxicity using in silico toxicity prediction as preliminary evaluation of safety antioxidant food additives evaluation. The in silico prediction was conducted for acute toxicity (LD50), mutagenicity, carcinogenicity, reproduction toxicity, chronic toxicity (NOEL), Acceptable Daily Intake (ADI) value and toxicity of Metabolites. The applied softwares were Toxtree, TEST, Admet Predictor and OECD QSAR Toolbox. Among 42 antioxidant food additives as chemicals test, the prediction methods predict that 6 compounds as carcinogen (carnosic acid, citric acid, ethylene diamine tetra acetate, isopropyl citrate, octyl gallate, and stearyl citrate); 2 compounds as mutagen (ascorbyl palmitate and 2,4,5-trihydroxybutyrophenone); 8 compounds as reproduction toxic (4 hexyl resorcinol, alpha tocopherol, butylated hydroxy anisole, delta tocopherol, ethoxyquine, gamma tocopherol, tertiary butyl hydroquinone); and 1 compound as mutagen and reproduction toxic, that is norhydroguairetic acid. Acute toxicity prediction was conducted by LD50 prediction. The lowest LD50 value was ethoxyquine, 937.84 mg/kg and the highest LD50value was dilauryl thiodipropionate, 13367.79 mg/kg. The comparison between LD50 prediction and LD50 experimental was using paired t-test method. It is concluded that there is no significantly difference between LD50 prediction and LD50 experimental. Chronic toxicity prediction was conducted by NOEL value prediction, and ADI value was calculated from NOEL value. The lowest ADI value was carnosic acid (0.38 mg/kg bw/day) and the highest ADI value are calcium ascorbic and calcium disodium ethylen diamine tetraacetate (1.35 mg/kg bw/day). The comparison between ADI prediction and ADI experimental was using paired t-test method concluded that there is no significant difference between ADI prediction and ADI experimental. Metabolitee prediction was conducted using two softwares that are Toxtree and Admet Predictor. The Metabolitee prediction showed change in prediction result. The in silico toxicity prediction method can be used as one supportive method to perform food additive safety evaluation by prediction of carcinogen, genotoxicity, reproduction toxicity, LD50 value and ADI value.