ABSTRACT
In 2015, the Expert Panel of the Flavor and Extract Manufacturers Association (FEMA) initiated a program for the re-evaluation of the safety of over 250 natural flavor complexes (NFCs) used as flavor ingredients. This publication, the sixth in the series, will summarize the re-evaluation of eight NFCs whose constituent profiles are characterized by significant amounts of eucalyptol and/or other cyclic ethers. This re-evaluation was based on a procedure first published in 2005 and subsequently updated in 2018 that evaluates the safety of naturally occurring mixtures for their intended use as flavoring ingredients. The procedure relies on a complete chemical characterization of the NFC intended for commerce and the organization of its chemical constituents into well-defined congeneric groups. The safety of the NFC is evaluated using the well-established and conservative threshold of toxicological concern (TTC) concept in addition to data on absorption, metabolism and toxicology of the constituents of the congeneric groups and the NFC under evaluation. Eight NFCs derived from the Eucalyptus, Melaleuca, Origanum, Laurus, Rosmarinus and Salvia genera were affirmed as generally recognized as safe (GRAS) under their conditions of intended use as flavor ingredients based on an evaluation of each NFC and the constituents and congeneric groups therein.
Subject(s)
Ethers, Cyclic/toxicity , Flavoring Agents/toxicity , Plant Oils/toxicity , Animals , CHO Cells , Cell Line, Tumor , Consumer Product Safety , Cricetulus , Ethers, Cyclic/chemistry , Eucalyptol/toxicity , Female , Flavoring Agents/chemistry , Humans , Male , Mice , Mutagenicity Tests , No-Observed-Adverse-Effect Level , Plant Oils/chemistry , Plants/chemistry , Pregnancy , Rats, Wistar , Risk Assessment , Salmonella typhimurium/drug effectsABSTRACT
Chemical and biocatalytic synthesis of seven previously undescribed marchantin A ester derivatives has been presented. Chemical synthesis afforded three peresterified bisbibenzyl products (TE1-TE3), while enzymatic method, using lipase, produced regioselective monoester derivatives (ME1-ME4). The antiproliferative activities of all prepared derivatives of marchantin A were tested on MRC-5 healthy human lung fibroblast, A549 human lung cancer, and MDA-MB-231 human breast cancer cell lines. All tested esters were less cytotoxic in comparison to marchantin A, but they also exhibited lower cytotoxicity against healthy cells. Monoesters displayed higher cytotoxic activities than the corresponding peresterified products, presumably due to the presence of free catechol group. Monohexanoyl ester ME3 displayed the same IC50 like marchantin A against MDA-MB-231 cells, but the selectivity was higher. In this way, regioselective enzymatic monoesterification enhanced selectivity of marchantin A. ME3 was also the most active among all derivatives against lung cancer cells A549 with the slightly lower activity and selectivity in comparison to marchantin A.
Subject(s)
Antineoplastic Agents, Phytogenic/chemistry , Bibenzyls/chemistry , Ethers, Cyclic/chemistry , A549 Cells , Antineoplastic Agents, Phytogenic/toxicity , Bibenzyls/toxicity , Drug Screening Assays, Antitumor , Esterification , Ethers, Cyclic/toxicity , HumansABSTRACT
: The use of this material under current conditions is supported by existing information. This material was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, as well as environmental safety. Data show that this material is not genotoxic nor does it have skin sensitization potential. The local respiratory toxicity endpoint was completed using the TTC (Threshold of Toxicological Concern) for a Cramer Class I material (1.4 mg/day). The repeated dose toxicity endpoint was completed using ethylene dodecanedioate (CAS # 54982-83-1) as a suitable read across analog, which provided a MOE > 100. The developmental and reproductive toxicity endpoint was completed using oxacyclohexadec-12-en-2-one, (12E)- (CAS # 111879-80-2) as a suitable read across analog, which provided a MOE > 100. The phototoxicity/photoallergenicity endpoint was completed based on suitable UV spectra along with data on the target material. The environmental endpoint was completed as described in the RIFM Framework along with data on the suitable read across analog oxacyclohexadec-12-en-2-one, (12E)- (CAS # 111879-80-2).
Subject(s)
Ethers, Cyclic/toxicity , Perfume/toxicity , Toxicity Tests/methods , Animals , Consumer Product Safety , DNA Damage/drug effects , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical , Endpoint Determination , Ethers, Cyclic/chemistry , No-Observed-Adverse-Effect Level , Perfume/chemistry , Rats , Risk AssessmentABSTRACT
Experiments on open-chest anaesthetized cats were made to test derivatives of crown ethers, such as benzylase-15-crown-5 and dibenzylase-15-crown-5 for their effects on myocardial ischemia and the functional status of a myocardial ischemic focus in temporary coronary occlusion during coronary spasm induced by dihydroergotamine and during coronary microthrombosis caused by ADP. When intravenously administered in doses of 0.5-15 mg/kg, the tested agents were found to enhance myocardial tolerance to ischemia, depressed ST segment in ischemia induced by coronary occlusion and administration of ATP, and prevented ST-segment depression during coronary spasm.
Subject(s)
Crown Ethers , Ethers, Cyclic/therapeutic use , Myocardial Ischemia/drug therapy , Animals , Cats , Disease Models, Animal , Drug Evaluation, Preclinical , Drug Tolerance , Electrocardiography/drug effects , Ethers, Cyclic/toxicity , Female , Lethal Dose 50 , Male , Mice , Myocardial Ischemia/physiopathologySubject(s)
Acrylamides , Carcinogens , Alkaloids/toxicity , Animals , Carcinogenicity Tests , Carcinogens/analysis , Cells, Cultured , Cnidarian Venoms/toxicity , Enzyme Induction , Ethers, Cyclic/toxicity , Mice , Okadaic Acid , Ornithine Decarboxylase/biosynthesis , Plant Extracts/toxicity , Plants, Medicinal , Protein Kinase C/antagonists & inhibitors , Skin/drug effects , Staurosporine , Tetradecanoylphorbol Acetate/toxicity , Thapsigargin , Vasoconstrictor Agents/toxicityABSTRACT
Methyl palmoxirate, an inhibitor of long-chain fatty acid oxidation, was administered by gavage (0, 1, 5, or 20 mg/kg/day) to female rats over the last third of gestation and throughout lactation. Weight gain (mid- and high-dosage group) and survivability (high-dosage group) were significantly (p less than or equal to 0.05) reduced in offspring of methyl palmoxirate-treated dams as compared to control offspring. Mid- and high-dosage male offspring found dead after Day 4 of lactation exhibited grossly distended bladders and renal pelves. A dosage-related increased incidence of dilated renal pelves was observed in both sexes at necropsy of 21-day-old mid- and high-dosage group pups. Microscopic examination of the urinary tracts of a number of affected pups revealed renal parenchymal atrophy and urethral obstruction. Drug disposition studies indicated lactating pups were exposed to significant amounts of methyl palmoxirate via mammary secretions. Cross-fostering experimentation suggested that some of the adverse effects observed in offspring were due to lactational, rather than in utero, exposure.
Subject(s)
Epoxy Compounds/toxicity , Ethers, Cyclic/toxicity , Fatty Acids/metabolism , Hydronephrosis/chemically induced , Propionates/toxicity , Animals , Blood Urea Nitrogen , Dose-Response Relationship, Drug , Female , Kidney/drug effects , Kidney/pathology , Lactation , Milk/metabolism , Oxidation-Reduction , Pregnancy , Proteins/metabolism , Rats , Rats, Inbred Strains , Urethra/drug effectsABSTRACT
The authors studied antiarrhythmic properties of macrocyclic polyesters. Some of the esters exhibited antiarrhythmic activity coupled with low toxicity. It was found that antiarrhythmic action of these substances is not mediated via acetylcholine and/or catecholamine system responsible for nervous regulation of the cardiac activity. The compounds under study were found to have marked antifibrillar properties. Experiments on an isolated rat heart demonstrated calcium specificity of the antifibrillar action of cyclolactones. It is assumed that macrocyclic polyesters represent a new class of antiarrhythmic agents having a direct cardiotropic action.
Subject(s)
Anti-Arrhythmia Agents/therapeutic use , Ethers, Cyclic/therapeutic use , Aconitine , Animals , Anti-Arrhythmia Agents/toxicity , Arrhythmias, Cardiac/chemically induced , Arrhythmias, Cardiac/drug therapy , Calcium Chloride , Drug Evaluation, Preclinical , Ethers, Cyclic/toxicity , Mice , Rats , Strophanthins , Ventricular Fibrillation/chemically induced , Ventricular Fibrillation/drug therapySubject(s)
Heterocyclic Compounds/pharmacology , Adjuvants, Immunologic , Animals , Anti-Arrhythmia Agents , Anti-Infective Agents , Antibody Formation/drug effects , Antineoplastic Agents , Bridged Bicyclo Compounds/pharmacology , Cell Membrane/drug effects , Chemical Phenomena , Chemistry, Physical , Ethers, Cyclic/pharmacology , Ethers, Cyclic/toxicity , Heterocyclic Compounds/toxicity , Immunity, Cellular/drug effects , Ion Channels/drug effects , Macromolecular Substances , Membrane Potentials/drug effects , Mice , Myocardial Contraction/drug effects , Rats , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitorsABSTRACT
Thirty dogs in four different treatment schedules and 14 monkeys in a single multiple-treatment schedule were used to evaluate the toxicity of dianhydrogalactitol. Highest nontoxic, low toxic, high toxic, and lethal doses were established in single injection doses and five daily injections in dogs, and in five daily injections in monkeys. Dose ranges of 20-320 mg/m2 (single injection) and 5-80 mg/m2 (five daily injections) in dogs, and 3-96 mg/m2 (five daily injections) in monkeys were established. The monkeys were more sensitive than dogs to the low toxic dose and more tolerant to the high toxic dose in the repeated daily injections. The dose-response curves for the dogs and monkeys had similar slopes and inflection points. Because of the steep slope between the lethal dose and the highest nontoxic dose in both species, caution should be used in the initial clinical trials.