Identity and chemistry
P-cresol is an isomer of o-cresol and m-cresol. Cresols are a group of aromatic organic compounds, widely occurring phenols that may be natural or manufactured. In p-cresol the methyl group sits at the para position of the phenol ring. Its pKa is 10.26. Like other phenols, cresols are slowly oxidized by air, and the resulting impurities often give samples a yellow to brownish red tint. The preferred IUPAC name is 4-methylphenol, and the molar mass is 108.14 g/mol. It boils at about 202 °C. With a molecular weight of 108.1 Da it is highly permeable and can cross both the intestinal barrier and the blood-brain barrier. The solid may be colourless, white or pink, and it darkens on exposure to light and air. It is miscible with ethanol.
Occurrence in nature
P-cresol is produced by bacterial fermentation of protein in the human large intestine. It is excreted in feces and urine, and is a component of human sweat that attracts female mosquitoes. In humans, intestinal anaerobic bacteria, particularly Clostridium difficile, decompose tyrosine to p-cresol. Some microorganisms also convert p-HPA taken up from outside into p-cresol; under antibiotic exposure Clostridium difficile raises the enzymes that decarboxylate p-HPA, which increases its p-cresol production, inhibits competing gut commensals and supports its colonization of the colon. The p-HPA itself slows the growth of gut bacteria, and Gram-negative species are more sensitive to it than Gram-positive ones. In the other route, Radical S-adenosylmethionine converts tyrosine into dehydroglycine, and ThiH cleaves the Cα-Cβ bond of dehydroglycine to give p-cresol. This pathway is the first step in the biosynthesis of thiamine, and p-cresol is formed as a by-product. Phenylalanine can be hydroxylated to tyrosine and so lead to p-cresol synthesis. The colon microbiota converts tyrosine and phenylalanine into protein-bound solutes such as p-cresol, which are excreted in urine through the glomerulus. When kidney function is impaired, p-cresol accumulates, especially in patients with chronic kidney disease. P-cresol is a constituent of tobacco smoke.
P-cresol is a major component in pig odor. Examination of temporal gland secretion showed the presence of phenol and p-cresol during musth in male elephants. It is one of the very few compounds to attract the orchid bee Euglossa cyanura and has been used to capture and study the species. It is a component of horse urine during estrus and can elicit the Flehmen response. It is also an estrus-specific volatile compound in livestock species. It can be detected in the urine, vaginal mucus and feces of buffaloes during their estrus period.
P-cresol is present in the floral scent of sapromyophilous Stemona species and in the scent of Narcissus viridiflorus. It gives rise to the distinct 'horse urine-like' odor of Gastrodia elata. It is found in numerous essential oils, typically in trace quantities where its intense odour imparts an animalic character. Environmental sources of p-cresol include rainwater, petroleum, solvents, perfumes and cosmetics.
Low levels of cresols have been found in some foods, such as tomatoes, tomato ketchup, asparagus, cheeses, butter, bacon and smoked foods. Some drinks also contain them: coffee, black tea, wine, Scotch whisky, brandy and rum. Cresols are released to the environment when wood, coal and fossil fuels burn, and they are normal constituents of human urine. In air they are usually broken down within one to two days, and in water microorganisms degrade them within days.
Industrial uses and hazards
P-cresol is an intermediate in the production of other chemicals. It is consumed mainly in the production of antioxidants, such as butylated hydroxytoluene (BHT). Industrially, BHT has been made by reacting p-cresol with isobutylene in the presence of sulfuric acid as catalyst. The monoalkylated derivatives of p-cresol couple to give a large family of diphenol antioxidants, which are valued because they are relatively low in toxicity and nonstaining. Cresols in general are precursors or synthetic intermediates to plastics, pesticides, pharmaceuticals and dyes. Cresols have also been used to manufacture carbon nanotubes at scale that are separated and not twisted, without additional chemicals that change the surface properties of the tubes. Cresol disinfectants act by destroying bacterial cell membranes. When inhaled, ingested or applied to the skin, cresols can be very harmful. Effects observed in people include irritation and burning of the skin, eyes, mouth and throat, abdominal pain and vomiting, heart damage, anemia, liver and kidney damage, facial paralysis, coma and death. The permissible exposure limit set by the Occupational Safety and Health Administration is 5 ppm (22 mg/m³) as an eight-hour time-weighted average, and the National Institute for Occupational Safety and Health recommends 2.3 ppm (10 mg/m³).
Regulation in fragrance
The IFRA Standard on p-Cresol applies to CAS 106-44-5 and also to mixed cresols (CAS 1319-77-3). Its implementation dates concern the supply of fragrance mixtures (formulas) only, not the finished consumer products on the market. The Standard sets maximum concentrations in the finished product for each of 12 product categories: 0.0050% in most of them, 0.0017% in categories 5D, 8, 11A and 11B, and no restriction in category 12. The Joint FAO/WHO Expert Committee on Food Additives last evaluated p-cresol as a flavouring agent in 2000 and found no safety concern at current levels of intake.
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