title: Toxicological evaluation of two flavors with modifying properties: 3-((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2,2-dimethyl-N-propylpropanamide and (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one.
abstract: A toxicological evaluation of two structurally related flavors with modifying properties, 3-((4-amino-2,2-dioxido-1H- benzo[c][1,2,6]thiadiazin-5-yl)oxy)-2,2-dimethyl-N-propylpropanamide (S6973; CAS 1093200-92-0) and (S)-1-(3-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidin-1-yl)-3-methylbutan-1-one (S617; CAS 1469426-64-9), was completed for the purpose of assessing their safety for use in food and beverage applications. Both compounds exhibited minimal oxidative metabolism in vitro, and in rat pharmacokinetic studies, were poorly absorbed and rapidly eliminated. Neither compound exhibited genotoxic concerns. S6973 and S617 were not found to be mutagenic or clastogenic, and did not induce micronuclei in vitro or in vivo. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-levels (NOAELs) were 20 mg/kg/day and 100 mg/kg/day (highest doses tested) for S6973 and S617, respectively, when administered as a food ad-mix for 90 consecutive days. Furthermore, S617 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/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats.
authors.affiliation: Senomyx, Inc., 4767 Nexus Centre Drive, San Diego, CA 92121, USA. Electronic address: amy.arthur@senomyx.com.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Arthur
authors.affiliation: Senomyx, Inc., 4767 Nexus Centre Drive, San Diego, CA 92121, USA.
authors.forename: Donald S
authors.initials: DS
authors.lastname: Karanewsky
authors.affiliation: Intrinsik Health Sciences Inc., 6605 Hurontario Street, Suite 500, Mississauga, Ontario L5T 0A3, Canada.
authors.forename: Mike
authors.initials: M
authors.lastname: Luksic
authors.affiliation: Intrinsik Health Sciences Inc., 6605 Hurontario Street, Suite 500, Mississauga, Ontario L5T 0A3, Canada.
authors.forename: Geoff
authors.initials: G
authors.lastname: Goodfellow
authors.affiliation: Intrinsik Health Sciences Inc., 6605 Hurontario Street, Suite 500, Mississauga, Ontario L5T 0A3, Canada.
authors.forename: Jon
authors.initials: J
authors.lastname: Daniels
mesh_terms: D000818:Animals; D001581:Benzothiadiazines / Q000633:toxicity*; D002869:Chromosome Aberrations / Q000139:chemically induced; D003499:Cyclic S-Oxides / Q000633:toxicity*; D004249:DNA Damage / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005421:Flavoring Agents / Q000493:pharmacokinetics / Q000633:toxicity*; D008252:Macaca fascicularis; D008297:Male; D015162:Micronucleus Tests; D009152:Mutagenicity Tests; D009153:Mutagens / Q000633:toxicity; D019055:No-Observed-Adverse-Effect Level; D009929:Organ Size / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D018675:Toxicity Tests
chemical_list: D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D005421:Flavoring Agents; D009153:Mutagens
keywords: FEMA GRAS; Flavors with modifying properties; Genetic toxicological evaluation; S617; S6973; Subchronic toxicological evaluation