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

- A toxicological evaluation of S2218 was completed for the purpose of assessing its safety for use in food and beverage applications.
- S2218 exhibited minimal oxidative metabolism in vitro, and was poorly orally bioavailable and rapidly eliminated in the rat.
- S2218 was not mutagenic in a bacterial reverse mutation assay, and neither clastogenic nor aneugenic in a mammalian cell micronucleus assay.
- In a subchronic toxicity study in rats, S2218 sulfate salt had a NOAEL of 140 mg/kg bw/day when administered in the diet for 13 consecutive weeks.
- S2218 sulfate salt had a NOAEL of 1000 mg/kg bw/day (oral gavage) for both maternal toxicity and embryo/fetal development in pregnant rats.

A toxicological evaluation of N-(1-((4-amino-2,2-dioxido-1H-benzo[c][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 in vitro, and in rat pharmacokinetic studies, the compound was poorly orally bioavailable and rapidly eliminated. S2218 was not found to be mutagenic in an in vitro bacterial reverse mutation assay, and was found to be neither clastogenic nor aneugenic in an in vitro 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.

The results of the ADME, genotoxicity, rodent toxicology and developmental toxicology studies conducted on a new flavour compound S2218 are reported. S2218 is a positive allosteric modifier (PAM) of the human sweet taste receptor and is structurally related to two other PAMs (S6973 and S617) currently available for use in human food as GRAS flavour ingredients.111