Toxicological evaluation of the flavour ingredient N -(1-((4-amino-2,2-dioxido-1 H -benzo[ c ][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2,6-dimethylisonicotinamide (S2218)

• Published in: Toxicology reports Vol. 4; pp. 507 - 520
• Main Authors: Karanewsky, Donald S, Servant, Guy, Liu, Hanghui, Chi, Bert, Ida, Lily, Saganich, Michael, Werner, Sara, Fotsing, Joseph R, Patron, Andrew, Tachdjian, Catherine, Arthur, Amy
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier 01.01.2017
• Subjects: Full Length; Vss, volume of distribution at steady-state; AUC, area under the curve; Subchronic toxicological evaluation; Developmental toxicity evaluation; Cmax, peak plasma concentration; Genetic toxicological evaluation; EIC, extracted ion chromatogram; FEMA, Flavour and Extract Manufacturers Association of the United States; GMP, Good Manufacturing Practices; FL-no, FLAVIS number; S2218; PK, pharmacokinetics; FMP, flavour with modifying properties; Flavours with modifying properties; t1/2, half-life; MC, methylcellulose; CYP, cytochrome P450; CL, plasma clearance; TK, toxicokinetics; NOAEL, no-observed-adverse-effect-level; amu, atomic mass units; LC/MS, liquid chromatography with mass spectrometry; FDA, Food and Drug Administration; Tmax, time to reach Cmax; GLP, Good Laboratory Practices; CBPI, cytokinesis-blocked proliferation index; HPBL, human peripheral blood lymphocytes; OECD, Organization for Economic Cooperation and Development; FEMA GRAS
• ISSN: 2214-7500; 2214-7500
• DOI: 10.1016/j.toxrep.2017.09.004

A toxicological evaluation of -(1-((4-amino-2,2-dioxido-1 -benzo[ ][1,2,6]thiadiazin-5-yl)oxy)-2-methylpropan-2-yl)-2,6-dimethylisonicotinamide (S2218; CAS 1622458-34-7), a flavour with modifying properties, was completed for the purpose of assessing its safety for use in food and beverage applications. S2218 exhibited minimal oxidative metabolism , and in rat pharmacokinetic studies, the compound was poorly orally bioavailable and rapidly eliminated. S2218 was not found to be mutagenic in an bacterial reverse mutation assay, and was found to be neither clastogenic nor aneugenic in an mammalian cell micronucleus assay. In subchronic oral toxicity studies in male and female rats, the NOAEL was 140 mg/kg bw/day (highest dose tested) for S2218 sulfate salt (S8069) when administered as a food ad-mix for 13 consecutive weeks. Furthermore, S2218 sulfate salt demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOAEL of 1000 mg/kg bw/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.