p-Cresol fed to rabbits is excreted in the urine as the glucuronide (60%) and sulfate (15%) conjugates, some 10% is oxidized to p-hydroxybenzoic acid and a trace is hydroxylated to 3,4-dihydroxytoluene.
4-Methylphenol has known human metabolites that include 4-Hydroxybenzyl alcohol, 4-methyl-hydroquinone, 4-Methyl-2,5-cyclohexadien-1-one, and (2S,3S,4S,5R)-3,4,5-Trihydroxy-6-(4-methylphenoxy)oxane-2-carboxylic acid.
IDENTIFICATION AND USE: p-Cresol is a crystalline solid below 95 °F. It has been used in explosive, petroleum, photographic, paint and agricultural industries, for making synthetic resins; in disinfectants and fumigants; as industrial solvent. p-Cresol is used in the formulation of antioxidants. p-Cresol has many applications in the fragrance and dye industries. Synthetic food flavors also contain p-cresol. It is used as local antiseptic, parasiticide, disinfectant in veterinary. HUMAN EXPOSURE AND TOXICITY: p-Cresol, an end product of aromatic amino acids, is produced from food proteins by intestinal bacteria, and is detectable in blood, urine and feces. p-Cresol may contribute to atherosclerosis and thrombosis in patients with uremia. Higher serum levels of p-cresol in chronic kidney disease populations have been associated with increased cardiovascular mortality. p-Cresol reduced the spontaneous contraction rates of cardiomyocytes, and caused irregular cardiomyocyte beating. In acute p-cresol-poisoning and long-term exposure to cresol as in severe uremic patients, p-cresol may potentially inhibit blood clot formation and lead to hemorrhagic disorders via inhibition of platelet aggregation. p-Cresol may play a role in the immune defect of uremic patients. Studies on the induction of unscheduled DNA synthesis showed p-cresol to be positive in human lung fibroblast cells in the presence of hepatic homogenates. ANIMAL STUDIES: p-Cresol can cause severe local irritation and corrosion following dermal and ocular exposure. Glaucoma has been induced experimentally in rabbits & monkeys by injection of 0.5-1.0% p-cresol emulsion in physiologic saline into the anterior chamber. Application of 0.5% p-cresol to the skin for 6 weeks resulted in permanent depigmentation of the skin and hair in black and agouti mice. All three cresols isomers are more toxic to mice than to rats when administered by gavage. o-Cresol is the most toxic, followed by p-cresol and then m-cresol. The effects are similar to, but less severe than, those following phenol exposure. Phenol, o- and p-cresol have about equal toxicity in cats while m-cresol is slightly less toxic. 180-280 mg/kg of p-cresol given iv to rabbits in a single dose, resulted in convulsions, coma, and death. In a 28-day study, rats and mice of both sexes were given p-cresol at concentrations of 300 to 30,000 ppm in the diet. All rats survived until study termination; some mice died at the 10,000 and 30,000 ppm dietary levels. Increased liver weights and kidney weights were noted in both species at doses as low as 3000 ppm. Bone marrow hyperplasia, and atrophy of the uterus, ovary, and mammary gland were seen in the 10,000- and 30,000-ppm dietary groups. In a 90-day study, rats were gavaged with 50, 175, or 600 mg p-Cresol/kg bw. The treatment with the highest dose caused combined mortality and significant reduction in bw and food consumption; CNS effects included lethargy, ataxia, coma, dyspnea, tremor, and convulsions within 15-30 min after dosing. A detailed oral neurotoxicity study of intermediate duration was performed on rats using all three cresol isomers. A host of clinical observations indicative of neurotoxicity (including hypoactivity, rapid labored respiration, excessive salivation, and tremors) was reported at doses of 50 mg/kg/day or higher for all three isomers. Convulsions were reported at 450 mg/kg/day or higher. Fetotoxicity was observed at parenterally-toxic doses in two-generation reproduction studies in rats. In a study conducted on cultured rat embryos in vitro, p-cresol caused dose-related effects on growth and structural abnormalities. p-Cresol caused an increased estrus cycle length in rats at 7500 and 30,000 mg/kg; there were no effects on the estrus cycle in mice. Female mice were dosed with a single application of dimethylbenzanthracene followed 1 wk later by 25uL of a 20% solution of p-cresol in benzene twice weekly for 12 wk. p-Cresol produced 7/20 tumors (papillomas) on surviving mice. p-Cresol given in the feed produced an increased incidence of mild and moderate hyperplasia of the forestomach of hamsters exposed for 20 weeks. P-Cresol was not genotoxic in vivo and in vitro. ECOTOXICITY STUDIES: A waterborne concn of 0.028 mM p-cresol resulted in statistically significant increases in serum sorbitol dehydrogenase activities shown by rainbow trout after 96 hr of exposure. During a 48-hr pulsed exposure to 8 mg p-cresol/L, the mortality of walleyed pike was very high. Smallmouth bass showed visible stress; largemouth bass showed no visible stress but had stopped feeding. The effects of p-cresol were examined on benthic macroinvertebrate flora and fauna in an EPA outdoor experimental stream facility located at Monticello, Minnesota. The primary effect of p-cresol was on the photosynthetic and respiration processes of aquatic plants.
p-Cresol is a cholinesterase or acetylcholinesterase (AChE) inhibitor. A cholinesterase inhibitor (or 'anticholinesterase') suppresses the action of acetylcholinesterase. Because of its essential function, chemicals that interfere with the action of acetylcholinesterase are potent neurotoxins, causing excessive salivation and eye-watering in low doses, followed by muscle spasms and ultimately death. Nerve gases and many substances used in insecticides have been shown to act by binding a serine in the active site of acetylcholine esterase, inhibiting the enzyme completely. Acetylcholine esterase breaks down the neurotransmitter acetylcholine, which is released at nerve and muscle junctions, in order to allow the muscle or organ to relax. The result of acetylcholine esterase inhibition is that acetylcholine builds up and continues to act so that any nerve impulses are continually transmitted and muscle contractions do not stop. Among the most common acetylcholinesterase inhibitors are phosphorus-based compounds, which are designed to bind to the active site of the enzyme. The structural requirements are a phosphorus atom bearing two lipophilic groups, a leaving group (such as a halide or thiocyanate), and a terminal oxygen.
CLASSIFICATION: C; possible human carcinogen. BASIS FOR CLASSIFICATION: Based on an increased incidence of skin papillomas in mice in an initiation-promotion study. The three cresol isomers produced positive results in genetic toxicity studies both alone and in combination. HUMAN CARCINOGENICITY DATA: Inadequate. ANIMAL CARCINOGENICITY DATA: Limited.
Humans normally excrete approximately 50 mg of p-cresol in the urine daily. p-Cresol is produced endogenously from tyrosine by anaerobic bacteria in the gastrointestinal tract.
Healthy humans excrete an average of about 50 mg (range 16-74 mg) of p-cresol in the urine daily. Endogenous p-cresol is produced from tyrosine, an amino acid present in most proteins, by anaerobic bacteria in the intestine. Free p-cresol formed in this way is absorbed from the intestine and eliminated in the urine as conjugates.
Practical Process for the Air Oxidation of Cresols: Part A. Mechanistic Investigations
摘要:
The catalytic air oxidation of p-cresol and 2,6-di-tert-butyl-4-methylphenol to the corresponding benzaldehydes was investigated to determine the mechanism at work in these oxidation reactions. A number of intermediates and byproducts, mainly in the form of dimers, were observed during the course of the reactions, and their structures were elucidated by spectroscopic and chromatographic methods. The existence of these compounds in the reaction mixtures, and their proposed methods of formation, provided further insight into the mechanism involved in these oxidations.
A Facile Synthesis of Hydroxamic Acids of<i>N<sup>α</sup></i>-Protected Amino Acids Employing BDMS, a Study of Their Molecular Docking and Their Antibacterial Activities
作者:K. Uma、H. S. Lalithamba、V. Chandramohan、K. Lingaraju
DOI:10.1080/00304948.2019.1579039
日期:2019.3.4
Hydroxamic acids have received much attention as biologically active compounds. Synthetic hydroxamic acids enhance the growth of plant sources and improve the soil quality, act as antibiotics, cell...
This invention relates to derivatives of acrylic acid useful as fungicides, to processes for preparing them, to fungicidal compositions containing them, and to methods of combating fungi, especially fungal infections in plants, using them.
Nitrosonium ion catalysis: aerobic, metal-free cross-dehydrogenative carbon–heteroatom bond formation
作者:Luis Bering、Laura D’Ottavio、Giedre Sirvinskaite、Andrey P. Antonchick
DOI:10.1039/c8cc08328b
日期:——
coupling of heteroarenes with thiophenols and phenothiazines has been developed under mild and environmentally benign reaction conditions. For the first time, NOx+ was applied for catalytic C–S and C–N bond formation. A comprehensive scope for the C–H/S–H and C–H/N–H cross-dehydrogenative coupling was demonstrated with >60 examples. The sustainable cross-coupling conditions utilize ambient oxygen as the
杂芳烃与硫酚和吩噻嗪的催化交叉脱氢偶联已在温和且环境友好的反应条件下得到发展。首次将NO x +用于催化C–S和C–N键的形成。用60多个例子证明了C–H / S–H和C–H / N–H交叉脱氢偶联的综合范围。可持续的交叉偶联条件利用环境氧作为末端氧化剂,而水是唯一的副产物。
[EN] PYRAZOLE DERIVATIVES USEFUL AS INHIBITORS OF FAAH<br/>[FR] DÉRIVÉS DE PYRAZOLE UTILES COMME INHIBITEURS DE FAAH
申请人:MERCK & CO INC
公开号:WO2009151991A1
公开(公告)日:2009-12-17
The present invention is directed to certain imidazole derivatives which are useful as inhibitors of Fatty Acid Amide Hydrolase (FAAH). The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including osteoarthritis, rheumatoid arthritis, diabetic neuropathy, postherpetic neuralgia, skeletomuscular pain, and fibromyalgia, as well as acute pain, migraine, sleep disorder, Alzheimer disease, and Parkinson's disease
Compositions for Treatment of Cystic Fibrosis and Other Chronic Diseases
申请人:Vertex Pharmaceuticals Incorporated
公开号:US20150231142A1
公开(公告)日:2015-08-20
The present invention relates to pharmaceutical compositions comprising an inhibitor of epithelial sodium channel activity in combination with at least one ABC Transporter modulator compound of Formula A, Formula B, Formula C, or Formula D. The invention also relates to pharmaceutical formulations thereof, and to methods of using such compositions in the treatment of CFTR mediated diseases, particularly cystic fibrosis using the pharmaceutical combination compositions.