Toxicological evaluation of a novel umami flavour compound: 2-(((3-(2,3-Dimethoxyphenyl)-1H -1,2,4-triazol-5-yl)thio)methyl)pyridine

A toxicological evaluation of a umami flavour compound, 2-(((3-(2, 3-dimethoxyphenyl)-1H -1, 2, 4-triazol-5-yl)thio)methyl)pyridine (S3643, CAS 902136-79-2), was completed for the purpose of assessing its safety for use in food and beverage applications. S3643 undergoes extensive oxidative metabolism in vitro with rat microsomes producing the S3643-sulfoxide and 4′-hydroxy-S3643 as the major metabolites. In incubations with human microsomes, the O -demethyl-S3643 and S3643-sulfoxide were produced as the major metabolites. In pharmacokinetic studies in rats, the S3643-sulfoxide represents the dominant biotransformation product. S3643 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in CHO-WBL cells. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S3643 was 100 mg/kg bw/day (highest dose tested) when administered in the diet for 90 consecutive days

Toxicological evaluation of a novel cooling compound: 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(2-thienylmethyl)acetamide

A toxicological evaluation of a novel cooling agent, 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(2-thienylmethyl) acetamide (S2227; CAS 1374760-95-8), was completed for the purpose of assessing its safety for use in food and beverage applications. S2227 undergoes rapid oxidative metabolism in vitro, and in rat and dog pharmacokinetic studies is rapidly converted to its component carboxylic acid and secondary amine. S2227 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in polychromatic erythrocytes in vivo. The secondary amine hydrolysis product, N-(2-thienylmethyl)-1H-pyrazol-3-amine (M179), was also evaluated for genotoxicity. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S2227 was 100 mg/kg/day (highest dose tested) when administered by oral gavage for 90 consecutive days. Furthermore, S2227 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

Toxicological evaluation of the flavour ingredient 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylic acid

A toxicological evaluation of 4-amino-5-(3-(isopropylamino)-2,2-dimethyl-3-oxopropoxy)-2-methylquinoline-3-carboxylic acid(S9632; CAS 1359963-68-0), a flavour with modifying properties,was completed for the purpose of assessing its safety for use in food and beverage applications. No Phase I biotransformations of S9632 were observed in rat or human microsomes in vitro, and in rat pharmacokinetic studies, the compound was poorly orally bioavailable and rapidly eliminated. S9632 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei or indicate interactions with the mitotic spindle in an in vivo mouse micronucleus assay at oral doses up to 2000 mg/kg. In subchronic oral toxicity studies in rats, the NOEL was 100 mg/kg/day (highest dose tested) for S9632 when administered as a food ad-mix for 90 consecutive days. Furthermore, S9632 demonstrated a lack of maternal toxicity, as well as adverse effects on fetal morphology at the highest dose tested, providing a NOEL of 1000 mg/kg/day for both maternal toxicity and embryo/fetal development when administered orally during gestation to pregnant rats

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 and 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)-1-(3-hydroxybenzyl)-5,5-dimethylimidazolidine-2,4-dione

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. Keywords: S6821, S7958, FEMA GRAS, Subchronic toxicological evaluation, Genetic toxicological evaluatio

Toxicological evaluation of a novel umami flavour compound: 2-(((3-(2,3-Dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine

A toxicological evaluation of a umami flavour compound, 2-(((3-(2,3-dimethoxyphenyl)-1H-1,2,4-triazol-5-yl)thio)methyl)pyridine (S3643; CAS 902136-79-2), was completed for the purpose of assessing its safety for use in food and beverage applications. S3643 undergoes extensive oxidative metabolism in vitro with rat microsomes producing the S3643-sulfoxide and 4′-hydroxy-S3643 as the major metabolites. In incubations with human microsomes, the O-demethyl-S3643 and S3643-sulfoxide were produced as the major metabolites. In pharmacokinetic studies in rats, the S3643-sulfoxide represents the dominant biotransformation product. S3643 was not found to be mutagenic or clastogenic in vitro, and did not induce micronuclei in CHO-WBL cells. In subchronic oral toxicity studies in rats, the no-observed-adverse-effect-level (NOAEL) for S3643 was 100 mg/kg bw/day (highest dose tested) when administered in the diet for 90 consecutive days. Keywords: Umami flavour, S3643, FEMA GRAS, Subchronic toxicological evaluation, Genetic toxicological evaluatio