Toxicological evaluation of a novel cooling compound: 2-(4-methylphenoxy)-N-(1H-pyrazol-3-yl)-N-(2-thienylmethyl)acetamide. (2015)

• Record Type: Journal Article
• Authors: Karanewsky, Donald S.; Arthur, Amy J.; Liu, Hanghui; Chi, Bert; Markison, Stacy
• Is Part Of: Toxicology reports. Volume 2(2015)
• Page Start: 1291
• Page End: 1309
• Publication Date: 2015
• Subjects: AUC area under the curve -- CL plasma clearance -- Cmax peak plasma concentration -- CYP450 cytochrome P450 -- FDA Food and Drug Administration -- FEMA Flavour and Extract Manufacturers Association of the United States -- GMP Good Manufacturing Practices -- HPBL human peripheral blood lymphocytes -- JV jugular vein -- LC/MS liquid chromatography with mass spectrometry -- MC methylcellulose -- mnPCE micronucleated bone marrow polychromatic erythrocytes -- NOAEL no-observed-adverse-effect-level -- NOEL no-observed-effect-level -- OECD Organization for Economic Cooperation and Development -- PCE polychromatic erythrocytes -- PK pharmacokinetics -- PV portal vein -- RCG Relative Cell Growth -- RMI Relative Mitotic Index -- t1/2 half-life -- Tmax time to reach Cmax -- TE total erythrocytes -- TK toxicokinetics -- TRPM8 transient receptor potential melastatin 8 -- Vss volume of distribution at steady-state; Cooling agent -- S2227 -- FEMA GRAS -- Subchronic toxicological evaluation -- Genetic toxicological evaluation; Toxicology -- Periodicals; Clinical toxicology -- Periodicals; Drug-Related Side Effects and Adverse Reactions; Hazardous Substances; Poisoning; Toxicology; Electronic journals; Periodicals; Periodicals; 571.9505
• DOI: 10.1016/j.toxrep.2015.09.001
• Languages: English
• ISSNs: 2214-7500

Abstract

Abstract: A toxicological evaluation of a novel cooling agent, 2-(4-methylphenoxy)- N -(1 H -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)-1 H -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.