Toxicological evaluation of two novel bitter modifying flavour compounds: 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1

Autor: Donald S, Karanewsky, Amy J, Arthur, Hanghui, Liu, Bert, Chi, Lily, Ida, Stacy, Markison
Rok vydání: 2015
Předmět:
TE
total erythrocytes
CL
plasma clearance
FEMA GRAS
LC/MS
liquid chromatography with mass spectrometry
Article
AUC
area under the curve
MSDI
maximized survey-derived intake
t1/2
half-life
MC
methylcellulose
Genetic toxicological evaluation
Vss
volume of distribution at steady-state
PCE
polychromatic erythrocytes
OECD
Organization for Economic Cooperation and Development
GLP
Good Laboratory Practices
SPET
single portion exposure technique
TK
toxicokinetics
MRM
multiple-reaction monitoring
NOEL
no-observed-effect-level
GMP
good manufacturing practices
Subchronic toxicological evaluation
NOAEL
no-observed-adverse-effect-level
MTD
maximum tolerated dose
FEMA
Flavour and Extract Manufacturers Association of the United States
GPCR
G protein-coupled receptors
FDA
Food and Drug Administration
JECFA
Joint FAO/WHO Expert Committee on Food Additives
mnPCE
micronucleated bone marrow polychromatic erythrocytes
S6821
HPBL
human peripheral blood lymphocytes
S7958
CYP
cytochrome P450
PK
pharmacokinetics
Cmax
peak plasma concentration
Tmax
time to reach Cmax
Zdroj: Toxicology Reports
ISSN: 2214-7500
Popis: A toxicological evaluation of two novel bitter modifying flavour compounds, 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)imidazolidine-2,4-dione (S6821, CAS 1119831-25-2) and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione (S7958, CAS 1217341-48-4), were completed for the purpose of assessing their safety for use in food and beverage applications. S6821 undergoes oxidative metabolism in vitro, and in rat pharmacokinetic studies both S6821 and S7958 are rapidly converted to the corresponding O-sulfate and O-glucuronide conjugates. S6821 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in bone marrow polychromatic erythrocytes in vivo. S7958, a close structural analog of S6821, was also found to be non-mutagenic in vitro. In short term and subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for both S7958 and S6821 was 100 mg/kg bw/day (highest dose tested) when administered as a food ad-mix for either 28 or 90 consecutive days, respectively. Furthermore, S6821 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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