Karanewsky Donald S, Arthur Amy J, Liu Hanghui, Chi Bert, Markison Stacy
Senomyx, Inc., 4767 Nexus Centre Drive, San Diego, CA 92121, USA.
Toxicol Rep. 2015 Sep 11;2:1291-1309. doi: 10.1016/j.toxrep.2015.09.001. eCollection 2015.
A toxicological evaluation of a novel cooling agent, 2-(4-methylphenoxy)--(1-pyrazol-3-yl)--(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 , 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 , and did not induce micronuclei in polychromatic erythrocytes . The secondary amine hydrolysis product, -(2-thienylmethyl)-1-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.
为评估一种新型冷却剂2-(4-甲基苯氧基)-2-(1-吡唑-3-基)-2-(2-噻吩基甲基)乙酰胺（S2227；CAS 1374760-95-8）在食品和饮料应用中的安全性，完成了一项毒理学评估。S2227经历快速氧化代谢，在大鼠和犬的药代动力学研究中迅速转化为其组成的羧酸和仲胺。未发现S2227具有致突变性或染色体断裂性，也未在多染红细胞中诱导微核形成。还对仲胺水解产物2-(2-噻吩基甲基)-1-吡唑-3-胺（M179）进行了遗传毒性评估。在大鼠的亚慢性经口毒性研究中，当连续经口灌胃给药90天时，S2227的无观察到有害作用水平（NOAEL）为100 mg/kg/天（测试的最高剂量）。此外，S2227在测试的最高剂量下未表现出母体毒性以及对胎儿形态的不良影响，在妊娠期间对怀孕大鼠经口给药时，母体毒性和胚胎/胎儿发育方面的NOAEL均为1000 mg/kg/天。
