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)

Autor: Bert Chi, Andrew Patron, Michael Saganich, Sara Werner, Catherine Tachdjian, Guy Servant, Amy J. Arthur, Joseph R. Fotsing, Lily Ida, Hanghui Liu, Donald S. Karanewsky
Rok vydání: 2017
Předmět:
0301 basic medicine
CL
plasma clearance
Health
Toxicology and Mutagenesis
S2218
Pharmacology
Toxicology
LC/MS
liquid chromatography with mass spectrometry
AUC
area under the curve
t1/2
half-life
Ingredient
MC
methylcellulose
Genetic toxicological evaluation
GLP
Good Laboratory Practices
TK
toxicokinetics
Flavours with modifying properties
Chemistry
FL-no
FLAVIS number
04 agricultural and veterinary sciences
040401 food science
Micronucleus test
amu
atomic mass units
CYP
cytochrome P450
Gestation
CBPI
cytokinesis-blocked proliferation index
Tmax
time to reach Cmax
FEMA GRAS
03 medical and health sciences
Clastogen
0404 agricultural biotechnology
stomatognathic system
Pharmacokinetics
lcsh:RA1190-1270
Full Length Article
Vss
volume of distribution at steady-state
FMP
flavour with modifying properties
Developmental toxicity evaluation
OECD
Organization for Economic Cooperation and Development
lcsh:Toxicology. Poisons
Fetus
GMP
Good Manufacturing Practices
Subchronic toxicological evaluation
NOAEL
no-observed-adverse-effect-level
FEMA
Flavour and Extract Manufacturers Association of the United States
FDA
Food and Drug Administration
In vitro
EIC
extracted ion chromatogram
Bioavailability
030104 developmental biology
HPBL
human peripheral blood lymphocytes
PK
pharmacokinetics
Cmax
peak plasma concentration
Zdroj: Toxicology Reports, Vol 4, Iss, Pp 507-520 (2017)
Toxicology Reports
ISSN: 2214-7500
Popis: Graphical abstract 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.
Highlights • 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.
Databáze: OpenAIRE
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