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Cresols
Cresols M Badanthadka, Torrent Research Centre, Gujarat, India HM Mehendale, University of Louisiana at Monroe, Monroe, LA, USA Ó 2014 Elsevier Inc. All rights reserved.
Name: Cresol (o-Cresol; m-Cresol; p-Cresol) Chemical Abstracts Service Registry Number: 1319-77-3 (o-Cresol: 95-48-7; m-Cresol: 108-39-4; p-Cresol-106-44-5) l Synonyms: o-Cresol or 2-Methylphenol: 1-Hydroxy2-methylbenzene 2-hydroxy toluene; m-Cresol or 3-Methylphenol: 1-Hydroxy-3-methylbenzene-3-hydroxy toluene; p-Cresol or 4-Methylphenoi: 1-Hydroxy4-methylbenzene-4-hydroxy toluene l Molecular Formula: C7H8O l Chemical Structure: l l
OH
X
CH3
Background Pure cresol is colorless, yellowish, brownish-yellow, or pinkish liquid, o-cresol, m-cresol, and p-cresol are the three structural isomers of cresol. Boiling point is 191.0 C for o-cresol, 202 C for m-cresol and 201.9 C for p-cresol. Melting point for o-cresol is 29.8 C, for m-cresol is 11.8 and 35.5 C for p-cresol. The names of the three compounds indicate that hydrogen on the benzene ring of the molecule has been replaced. They are obtained from coal tar or petroleum. Because the boiling points of these three compounds are nearly the same, a separation of a mixture of the three into its pure components is impractical. The mixture of cresols obtained from coal tar is called cresylic acid, an important technical product used as a disinfectant and in the manufacture of resins and tricresyl phosphate. Cresols are useful as raw materials for various chemical products, disinfectants, and synthetic resins. The isomer o-cresol is a starting material for the herbicides 4,6-dinitro-o-cresol and 2-methyl-4-chlorophenoxyacetic acid. The isomers m-cresol and p-cresol are used in phenol–formaldehyde resins and are converted to tricresyl phosphate (a plasticizer and gasoline additive) and to di-t-butyl cresols (antioxidants called butylated hydroxytoluene). Professions that involve dealing with the combustion of coal or wood may be exposed to higher levels of cresols than the general population. Environmental tobacco smoke is also a source of cresol exposure. Average cresol concentration may vary between the brand and type of cigarette in a 45-cubic meter chamber after six cigarettes had been smoked (ranged from 0.17 to 3.9 mg m3), although low levels of cresol can be detected in certain foods and tap water, and these do not constitute major sources of exposure for most population. Detectable levels of cresols have been reported in several
Encyclopedia of Toxicology, Volume 1
consumer products including tealeaves, tomatoes, and ketchup as well as butter, oil, and various cheeses. Exposure to children occurs by the same routes that affect adults. Children are likely to be exposed to cresols through inhalation of contaminated air from automobile exhaust, waste incineration, and secondhand smoke.
Uses Cresols (mixtures of the ortho-, meta-, and para-isomers) are synthesized by sulfonation or oxidation of toluene compounds or can be derived from coal tar and petroleum. Commercial grade crude cresol is generally a mixture of 20% o-cresol, 40% m-cresol, and 30% p-cresol. Phenol and xylenols are often found as minor contaminants. Manufacture of synthetic resins, tricresyl phosphate, salicylaldehyde, coumarin, and herbicides employ cresols. Degreasing compounds in textile scouring, paintbrush cleaners as well as fumigants in photographic developers, and explosives contains cresols. Cresols are also often used as antiseptics, disinfectants, and antiparasitic agents in veterinary medicine. Estimated breakdown of cresol and cresylic acid use is 20% phenolic resins, 20% wire enamel solvents, 10% agricultural chemicals, 5% phosphate esters, 5% disinfectants and cleaning compounds, 5% ore flotation, and 25% miscellaneous purposes. Overall, use of cresols as antimicrobial outweighs any other property.
Environmental Fate and Behavior Cresol’s production and use as a solvent, disinfectant, and chemical intermediate in the production of synthetic resins may result in its release to the environment through various waste streams. Cresols are also released to the environment through automobile exhaust and tobacco smoke. Cresols are a group of widely distributed natural compounds formed as metabolites of microbial activity and excreted in the urine of mammals. Cresols occur in various plant lipid and oil constituents. If released to air, an extrapolated vapor pressure range of 0.11–0.299 mm Hg at 25 C for the various isomers indicates cresols will exist solely as a vapor in the ambient atmosphere. Vapor-phase cresols will be degraded in the atmosphere by photochemical reaction and produce hydroxyl radicals. The half-life for this reaction in air is estimated to be 6–9 h. If released to soil, cresols are expected to have high mobility based upon Koc values of 22–49 measured in soil. Volatilization from moist soil surfaces is expected to occur slowly based upon Henry’s Law constants. Cresols are not expected to volatilize from dry soil surfaces based upon the extrapolated vapor pressure range. Cresols biodegrade quickly in soils with half-lives of few days. If released into water, cresols do not adsorb to suspended solids and sediment in the water. Cresols biodegrade quickly in water with half-lives of several
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days to few weeks. Volatilization from water surfaces is expected to occur slowly based upon the range of Henry’s Law constants for the various isomers. Estimated volatilization halflives for a model river and model lake range from 21 to 29 and 235–327 days, respectively. Cresols are not expected to undergo hydrolysis since they lack functional groups that hydrolyze under environmental conditions. Direct photolysis in sunlit surface occurs and products occur at a much slower rate than biodegradation. Log bioconcentration factor values of 1.3 and 1.03 measured in ide and zebrafish respectively suggests that the potential for bioconcentration in aquatic organisms is low.
Exposure and Exposure Monitoring Estimates indicate that nearly 1.2 million people are exposed to cresols each year via manufacturing, processing, and/or use activities. Cresols are released in to the atmosphere by auto and diesel exhaust, during coal tar and petroleum refining, wood pulping, and during its use in manufacturing, metal refining, etc. Wastewater from these industries as well as municipal wastewater treatment plants contain cresols. Occupational exposure is through inhalation and dermal contact either at workplace where the cresol isomers are produced or used. The general population may be exposed to cresols via inhalation of ambient air, use of tobacco products, and ingestion of food or contaminated drinking water, and dermal contact with this compound from consumer products containing cresol.
changes in the lung and necrotic, and degenerative changes in the liver and kidneys. In another study, investigators reported that rats survived an 8 h exposure to substantially saturated cresol vapors at room temperature; the liquid penetrated the skin to a dangerous extent and caused severe skin and corneal injury. Short-term oral exposure resulted in decreased body weight, organ weight, corrosion in the gastrointestinal tract and mouth of rats with similar effects as phenol. Kidney tubule damage, nodular pneumonia, and congestion of the liver with pallor and necrosis of the hepatic cells were also reported. More severe effects were reported in mice. At the highest concentrations, death resulted from exposure to o-, m-, and p-cresols but not from exposure to cresol itself. Subchronic exposure in mice appeared to tolerate single, brief exposures of saturated vapors of cresol, but repeated exposures to saturated concentrations for 1 h day1 for 10 days caused irritation of the nose and eyes and death of some mice. Acute exposure for concentrated cresols instilled into the eyes of rabbits caused permanent opacification and vascularization. A drop of 33% solution of cresol applied to rabbit eyes and removed with saline irrigation within 60 s caused only moderate injury, which was reversible. All three cresol isomers, either alone or in combination, are severely irritating to rabbit skin, producing visible and irreversible tissue destruction. Acute exposure can cause muscular weakness, GI disturbances, severe depression, collapse, and death.
Human
Toxicokinetics
Mechanisms of Toxicity
Cresols are highly irritating upon dermal contact, eye contact, and contact with any mucous membranes. Ingestion of cresols results in burning of the mouth and throat, abdominal pain, and vomiting. The target tissues/organs affected are the blood, kidneys, lungs, liver, heart, and CNS. In acute exposures, severe burns, anuria, coma, and death may result. Dermal exposure has been reported to cause severe skin burns, scarring, systemic toxicity, and death. Very few data are available regarding reproductive effects and there are no data on carcinogenicity in humans. At concentrations normally found in the environment, cresols do not pose any significant risk for the general population. However, under conditions of high exposure, people with renal insufficiency or enzyme deficiency will develop potential adverse health effects.
It acts by disruption of the cell membrane by denaturation of proteins and enzymes of the cell.
Chronic Toxicity
Cresols are absorbed across the respiratory and gastrointestinal tracts, and through the skin. Gastrointestinal and dermal absorption are rapid and extensive. Cresols are distributed to all the major organs. The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. Minor metabolic pathways include hydroxylation of the benzene ring and side-chain oxidation. The major route for elimination is renal excretion in the form of conjugate metabolites.
Animal
Acute or Short-Term Toxicity Animal Cresols are highly irritating to the skin and eyes of rabbits, rats, and mice. The mean lethal concentration of the cresol vapor or aerosol mixture is 178 mg m3. Clinical signs of toxicityincluded irritation of mucous membranes and neuromuscular excitation that progressed from twitching of individual muscles to clonic convulsions. Hematuria was reported at very high concentrations. Microscopic examination revealed edematous
Exposure to vapors of o-, m-, and p-cresol resulted in weight loss, reduced locomotor activity, inflammation of nasal membranes and skin, and changes in the liver. Oral exposures to mice, rats, and hamsters for 13 weeks resulted in mortality, tremor, reduced body weights, hematological effects, increase in organ weight, hyperplasia of nasal, and stomach epithelium. Oral and inhalation exposure to cresol isomers results in lengthened estrus cycle, histopathological changes in the uterus and ovaries of rats as well as mice further support this finding. No adverse effects on spermatogenesis are observed. Mild
Cresols
fetotoxic effects have been reported upon exposure of pregnant mice. Some evidence of genotoxicity has been reported from in vitro experiment using sister-chromatid exchange (SCE) assay. However, cresol is not genotoxic after in vivo exposure.
Human Prolonged or repeated absorption of low concentrations of cresol through the skin, mucous membranes, or respiratory tract may cause chronic systemic poisoning. Symptoms and signs of chronic poisoning include vomiting, difficulty in swallowing, salivation, diarrhea, loss of appetite, headache, fainting, dizziness, mental disturbances, and skin rash. Death may result if there has been severe damage to the liver and kidneys.
Immunotoxicity Studies demonstrating the immunotoxicity of cresols by any exposure route in any species or gender are either scanty or not available.
Reproductive Toxicity Ortho cresol causes mild effects on the body weight and pup weight in the second-generation mating trial. The relative reproductive toxicity of ortho cresol is absent at lower doses. Mixture of m- and p-cresol was a reproductive toxicant in Swiss CD-1 mice, as evidenced by fewer F1 pups per litter, and reduced pup weight in both generations. There were also reductions in the weights of reproductive organs at necropsy at the high or middle and high dose levels. However, changes in pup growth and weights of somatic organs occurred at all dose levels. Thus, m- and p-cresols are not selective toxicants in Swiss CD-1 mice.
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positive, and o-cresol was negative. Positive mutagenic responses were found at noncytotoxic doses.
Carcinogenicity Based on increased incidence of skin papillomas in mice cresols are considered as possible human carcinogen. All the three cresol isomers produced positive results in genetic toxicity studies either alone or in combination.
Clinical Management Oral exposure: Liquid intake should be avoided because dilution may enhance absorption. Immediate administration of activated charcoal is recommended to limit systemic toxicity. Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures. Gastric lavage is effective only within 1 h after ingestion. Patients should be treated symptomatically. Convulsions are controlled with diazepam. Inhalation exposure: Victims should be removed to fresh air. Respiratory distress should be monitored and consult healthcare personnel. Eye and dermal exposure: Decontamination with water is necessary. Copious dilution with room temperature water is appropriate after dermal and eye exposure. Consult a physician if required.
Ecotoxicology A bioaccumulation factor for m-cresol is 20 in fish indicates no major bioaccumulation potential in higher trophic levels. A bioaccumulation factor of 4900 in algae indicates, however, a risk for bioaccumulation in lower organisms. Aquatic toxicity of m-cresol
Genotoxicity 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, the mixture of the three isomers to be weakly positive in primary rat hepatocytes, and o-cresol to be negative in rat hepatocytes. No isomer, when tested individually, induced SCEs in vivo, but the mixture of the three isomers induced SCEs in Chinese hamster ovary cells in vitro. Only o-cresol induced SCEs in human lung fibroblasts. In a reverse mutation assay, a mixture of three cresol isomers at 0.005–50 ml per plate with or without S-9 from Aroclor-induced rats (activating system) was negative in Salmonella typhimurium strains at all doses. In a forward mutation assay, a mixture of three cresol isomers at 0.488–750 nl ml1, with or without S-9 from Aroclor induced rats (activating system) produced dose related increase in mutation. In mouse lymphoma cell culture; without activation, results suggest weak mutagenic activity. In an alternative in vitro test, in cell transformation assay using BALB/3T3 cells, a mixture of three cresol isomers was
LC50 (mg l 1)
Species
Duration
Leuciscus idus (fish)
48
6
Brachydanio rerio (freshwater fish)
96
15.9
Salmo gairdneri (estuary, freshwater fish)
96
8.6
Daphnia magna (crustacea)
48
18.8
Daphnia magna (crustacea)
24
8.9
(Effect endpoint: immobilization).
Atmospheric Fate Cresols are not expected to persist in the atmosphere because: (1) cresols have low estimated half-lives (less than 1 day); (2) they are sensitive to photolysis; and (3) the water solubility of cresols may cause transport of cresols from the atmosphere to the soil or aqueous environment. The photodegradation halflife of cresol isomers during the daytime is 8–10 h while at night it is approximately 2–4 min. Daytime half-lives would be reduced under smog conditions. Cresols are highly soluble
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compounds and gas scavenging will be an efficient removal process as is reflected by high concentrations in rain.
Terrestrial Fate While there is substantial release of cresols to the soil, this route of environmental exposure is not expected to be a problem. Cresols are readily biodegraded by soil microflora and moves to lower layer of soil. Therefore, cresols will not persist in soils and will probably be leached, due to their water solubility, into the aquatic environment where they will be degraded by microorganisms. The degradation rates of cresols in soil may decrease at lower temperatures (2 to 5 C).
Aquatic Fate Cresols do not contain any functional groups that are hydrolyzable. Therefore, hydrolysis of these compounds in aquatic media is unlikely. However, it will degrade primarily due to biodegradation in eutrophic waters, although photolysis may make a contribution in oligotrophic lakes based on modeling studies. Biodegradation generally occurs within 8 h after several days of acclimation, except in oligotrophic lakes, estuarine, and marine waters where degradation takes several days. Degradation is much slower under anaerobic conditions especially for the ortho isomer. m-Cresol biodegrades in water and its halflives are in the range of 2–29 days (aerobic water) and 15–49 days (anaerobic water). Two factors that may influence the biodegradation rate of cresols in natural aquatic media are the temperature and the quality of the water. In general, freshwater media have the maximum biotransformation rate for cresols. Rates for marine waters are much lower than freshwater. A decrease in temperature from 24 to 11 C increased the biotransformation half-life by a factor of >20; however, the rate of biodegradation of cresols in marine water was so low that the lowering of water temperature would not change the biodegradation rate appreciably. LC50 values for aquatic organisms Gammarus fasciatus/(scud/immature stage)
7.0 mg l1 48 h1a
Asellus militaris/(aquatic sowbug/immature stage)
21.6 mg l1 48 h1a
Ophryotrocha diadema (polychaete worm)
33–100 mg l1 48 h1
Gammarus fasciatus/(scud/adult male)
24.9 mg l1 48 h1
– Do –, (adult female)
34.3 mg l1 48 h1
– Do –, oviparous female
33.9 mg l1 48 h1a
Asellus militaris/(aquatic sowbug/adult male)
65.4 mg l1 48 h1
– Do –, (adult female)
68.0 mg l1 48 h1
– Do –, oviparous females
61.9 mg l1 48 h1a
Pimephales promelas (fathead minnow, 29 days old, size 20.8 mm)
12.8 mg l1 96 h1
Gambusia affinis (mosquitofish, adult females)
22 mg l1 96 h1a
*Selenastrum capricornutum (green alga, 14 day old culture; growth inhibition)
137 mg l1 14 days1a
*EC50 value, a, static.
Other Hazards Fire-Fighting Measures For small fires, use media such as alcohol foam, dry chemical, or carbon dioxide. For large fires apply water as far as possible. Use very large quantities (flooding) of water applied as a mist or spray; solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Carbon oxides will generate from the substance or mixture. Wear self-contained breathing apparatus for fire fighting if necessary.
Accidental Release Measures Wear respiratory protection. Avoid breathing vapors, mist, or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapors accumulating to form explosive concentrations and can accumulate in low areas. Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Spillage should be collected with a sponge or good absorbing material. Electrically operated vacuum cleaner should not be used. Keep disposals in suitable closed container to discard according to local regulations.
Precautions for Safe Handling and Storage Skin and eye contacts should be avoided. Inhalation of vapor or mist should be avoided. Keep away from sources of ignition, no smoking near the product. Take measures to prevent the build-up of electrostatic charge. Store in cool place. Keep container tightly closed in a dry and wellventilated place.
Exposure Standards and Guidelines Occupational Safety and Health Administration permissible exposure limit is 5 ppm (22 mg m3) for 8 h time-weighted average (TWA). The threshold limit value for cresol and its isomers is 5 ppm for 8 h TWA. National Institute of Occupational Safety and health recommended exposure limit is 2.3 ppm (10 mg m3) for 10 h TWA for all isomers.
See also: Coal Tar; Pesticides.
Further Reading Andersen, A., 2006. Final report on the safety assessment of sodium p-chlorom-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol. Int. J. Toxicol. 25 (Suppl. 1), 29–127. Aranha, M.M., Matos, A.R., Teresa Mendes, A., et al., 2007. Dinitro-o-cresol induces apoptosis-like cell death but not alternative oxidase expression in soybean cells. J. Plant Physiol. 164 (6), 675–684. Chan, C.P., Yuan-Soon, H., Wang, Y.J., et al., 2005. Inhibition of cyclooxygenase activity, platelet aggregation and thromboxane B2 production by two environmental toxicants: m- and o-cresol. Toxicology 208 (1), 95–104.
Cresols Cuoghi, A., Caiazzo, M., Bellei, E., et al., 2012. Quantification of p-cresol sulphate in human plasma by selected reaction monitoring. Anal. Bioanal. Chem. 404 (6–7), 2097–2104. Lesaffer, G., De Smet, R., D’Heuvaert, T., et al., 2003. Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure. Kidney Int. 64, 1365–1373. Morinaga, Y., Fuke, C., Arao, T., Miyazaki, T., 2004. Quantitative analysis of cresol and its metabolites in biological materials and distribution in rats after oral administration. Leg. Med. (Tokyo) 6, 32–40. Neirynck, N., Vanholder, R., Schepers, E., et al., 2013. An update on uremic toxins. Int. J. Urol. Nephrol. 45 (1), 139–150. Onesios, K.M., Bouwer, E.J., 2012. Biological removal of pharmaceuticals and personal care products during laboratory soil aquifer treatment simulation with different primary substrate concentrations. Water Res. 46 (7), 2365–2375. Peng, Y.S., Ding, H.C., Lin, Y.T., et al., 2012. Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. Toxicology 302 (1), 11–17. Suarez-Ojeda, M.E., Guisasola, A., Baeza, J.A., et al., 2007. Integrated catalytic wet air oxidation and aerobic biological treatment in a municipal WWTP of a highstrength o-cresol wastewater. Chemosphere 66 (11), 2096–2105. Sun, C.Y., Chang, S.C., Wu, M.S., 2012. Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-tomesenchymal transition. PLoS One 7 (3), e34026. http://dx.doi.org/10.1371/ journal.pone.0034026. Epub March 30, 2012. Sun, C.Y., Hsu, H.H., Wu, M.S., 2013. p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol. Dial. Transplant 28 (1), 70–78.
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Watanabe, H., Miyamoto, Y., Honda, D., et al., 2013. p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int. 83 (4), 582–592. Wu, M.L., Tsai, W.J., Yang, C.C., Deng, J.F., 1998. Concentrated cresol intoxication. Vet. Hum. Toxicol. 40 (6), 341–343. Zhu, J.Z., Zhang, J., Yang, K., et al., 2012. p-cresol, but not p-cresylsulphate, disrupts endothelial progenitor cell function in vitro. Nephrol. Dial. Transplant. 27 (12), 4323–4330.
Relevant Websites http://www.atsdr.cdc.gov/toxprofiles/tp34-c2.pdf – ATSDR-CDC. http://www.seagrant.umn.edu/water/report/chemicalsofconcern/cresols/cresols.pdf – ATSDR database. http://www.cdc.gov/niosh/idlh/cresol.html – CDC. http://www.cdc.gov/niosh/docs/81-123/pdfs/0154.pdf – Occupational Safety and Health Guideline for Cresol, All Isomers, CDC, Atlanta, GA. http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id¼PC32877 – PAN Pesticide database. http://webwiser.nlm.nih.gov/ – Substance List, Search for Cresol. http://toxnet.nlm.nih.gov/ – TOXNET, Specialized Information Service, National Library of Medicine, Search for Cresols.
Name: Cresol (o-Cresol; m-Cresol; p-Cresol) Chemical Abstracts Service Registry Number: 1319-77-3 (o-Cresol: 95-48-7; m-Cresol: 108-39-4; p-Cresol-106-44-5) l Synonyms: o-Cresol or 2-Methylphenol: 1-Hydroxy2-methylbenzene 2-hydroxy toluene; m-Cresol or 3-Methylphenol: 1-Hydroxy-3-methylbenzene-3-hydroxy toluene; p-Cresol or 4-Methylphenoi: 1-Hydroxy4-methylbenzene-4-hydroxy toluene l Molecular Formula: C7H8O l Chemical Structure: l l
OH
X
CH3
Background Pure cresol is colorless, yellowish, brownish-yellow, or pinkish liquid, o-cresol, m-cresol, and p-cresol are the three structural isomers of cresol. Boiling point is 191.0 C for o-cresol, 202 C for m-cresol and 201.9 C for p-cresol. Melting point for o-cresol is 29.8 C, for m-cresol is 11.8 and 35.5 C for p-cresol. The names of the three compounds indicate that hydrogen on the benzene ring of the molecule has been replaced. They are obtained from coal tar or petroleum. Because the boiling points of these three compounds are nearly the same, a separation of a mixture of the three into its pure components is impractical. The mixture of cresols obtained from coal tar is called cresylic acid, an important technical product used as a disinfectant and in the manufacture of resins and tricresyl phosphate. Cresols are useful as raw materials for various chemical products, disinfectants, and synthetic resins. The isomer o-cresol is a starting material for the herbicides 4,6-dinitro-o-cresol and 2-methyl-4-chlorophenoxyacetic acid. The isomers m-cresol and p-cresol are used in phenol–formaldehyde resins and are converted to tricresyl phosphate (a plasticizer and gasoline additive) and to di-t-butyl cresols (antioxidants called butylated hydroxytoluene). Professions that involve dealing with the combustion of coal or wood may be exposed to higher levels of cresols than the general population. Environmental tobacco smoke is also a source of cresol exposure. Average cresol concentration may vary between the brand and type of cigarette in a 45-cubic meter chamber after six cigarettes had been smoked (ranged from 0.17 to 3.9 mg m3), although low levels of cresol can be detected in certain foods and tap water, and these do not constitute major sources of exposure for most population. Detectable levels of cresols have been reported in several
Encyclopedia of Toxicology, Volume 1
consumer products including tealeaves, tomatoes, and ketchup as well as butter, oil, and various cheeses. Exposure to children occurs by the same routes that affect adults. Children are likely to be exposed to cresols through inhalation of contaminated air from automobile exhaust, waste incineration, and secondhand smoke.
Uses Cresols (mixtures of the ortho-, meta-, and para-isomers) are synthesized by sulfonation or oxidation of toluene compounds or can be derived from coal tar and petroleum. Commercial grade crude cresol is generally a mixture of 20% o-cresol, 40% m-cresol, and 30% p-cresol. Phenol and xylenols are often found as minor contaminants. Manufacture of synthetic resins, tricresyl phosphate, salicylaldehyde, coumarin, and herbicides employ cresols. Degreasing compounds in textile scouring, paintbrush cleaners as well as fumigants in photographic developers, and explosives contains cresols. Cresols are also often used as antiseptics, disinfectants, and antiparasitic agents in veterinary medicine. Estimated breakdown of cresol and cresylic acid use is 20% phenolic resins, 20% wire enamel solvents, 10% agricultural chemicals, 5% phosphate esters, 5% disinfectants and cleaning compounds, 5% ore flotation, and 25% miscellaneous purposes. Overall, use of cresols as antimicrobial outweighs any other property.
Environmental Fate and Behavior Cresol’s production and use as a solvent, disinfectant, and chemical intermediate in the production of synthetic resins may result in its release to the environment through various waste streams. Cresols are also released to the environment through automobile exhaust and tobacco smoke. Cresols are a group of widely distributed natural compounds formed as metabolites of microbial activity and excreted in the urine of mammals. Cresols occur in various plant lipid and oil constituents. If released to air, an extrapolated vapor pressure range of 0.11–0.299 mm Hg at 25 C for the various isomers indicates cresols will exist solely as a vapor in the ambient atmosphere. Vapor-phase cresols will be degraded in the atmosphere by photochemical reaction and produce hydroxyl radicals. The half-life for this reaction in air is estimated to be 6–9 h. If released to soil, cresols are expected to have high mobility based upon Koc values of 22–49 measured in soil. Volatilization from moist soil surfaces is expected to occur slowly based upon Henry’s Law constants. Cresols are not expected to volatilize from dry soil surfaces based upon the extrapolated vapor pressure range. Cresols biodegrade quickly in soils with half-lives of few days. If released into water, cresols do not adsorb to suspended solids and sediment in the water. Cresols biodegrade quickly in water with half-lives of several
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days to few weeks. Volatilization from water surfaces is expected to occur slowly based upon the range of Henry’s Law constants for the various isomers. Estimated volatilization halflives for a model river and model lake range from 21 to 29 and 235–327 days, respectively. Cresols are not expected to undergo hydrolysis since they lack functional groups that hydrolyze under environmental conditions. Direct photolysis in sunlit surface occurs and products occur at a much slower rate than biodegradation. Log bioconcentration factor values of 1.3 and 1.03 measured in ide and zebrafish respectively suggests that the potential for bioconcentration in aquatic organisms is low.
Exposure and Exposure Monitoring Estimates indicate that nearly 1.2 million people are exposed to cresols each year via manufacturing, processing, and/or use activities. Cresols are released in to the atmosphere by auto and diesel exhaust, during coal tar and petroleum refining, wood pulping, and during its use in manufacturing, metal refining, etc. Wastewater from these industries as well as municipal wastewater treatment plants contain cresols. Occupational exposure is through inhalation and dermal contact either at workplace where the cresol isomers are produced or used. The general population may be exposed to cresols via inhalation of ambient air, use of tobacco products, and ingestion of food or contaminated drinking water, and dermal contact with this compound from consumer products containing cresol.
changes in the lung and necrotic, and degenerative changes in the liver and kidneys. In another study, investigators reported that rats survived an 8 h exposure to substantially saturated cresol vapors at room temperature; the liquid penetrated the skin to a dangerous extent and caused severe skin and corneal injury. Short-term oral exposure resulted in decreased body weight, organ weight, corrosion in the gastrointestinal tract and mouth of rats with similar effects as phenol. Kidney tubule damage, nodular pneumonia, and congestion of the liver with pallor and necrosis of the hepatic cells were also reported. More severe effects were reported in mice. At the highest concentrations, death resulted from exposure to o-, m-, and p-cresols but not from exposure to cresol itself. Subchronic exposure in mice appeared to tolerate single, brief exposures of saturated vapors of cresol, but repeated exposures to saturated concentrations for 1 h day1 for 10 days caused irritation of the nose and eyes and death of some mice. Acute exposure for concentrated cresols instilled into the eyes of rabbits caused permanent opacification and vascularization. A drop of 33% solution of cresol applied to rabbit eyes and removed with saline irrigation within 60 s caused only moderate injury, which was reversible. All three cresol isomers, either alone or in combination, are severely irritating to rabbit skin, producing visible and irreversible tissue destruction. Acute exposure can cause muscular weakness, GI disturbances, severe depression, collapse, and death.
Human
Toxicokinetics
Mechanisms of Toxicity
Cresols are highly irritating upon dermal contact, eye contact, and contact with any mucous membranes. Ingestion of cresols results in burning of the mouth and throat, abdominal pain, and vomiting. The target tissues/organs affected are the blood, kidneys, lungs, liver, heart, and CNS. In acute exposures, severe burns, anuria, coma, and death may result. Dermal exposure has been reported to cause severe skin burns, scarring, systemic toxicity, and death. Very few data are available regarding reproductive effects and there are no data on carcinogenicity in humans. At concentrations normally found in the environment, cresols do not pose any significant risk for the general population. However, under conditions of high exposure, people with renal insufficiency or enzyme deficiency will develop potential adverse health effects.
It acts by disruption of the cell membrane by denaturation of proteins and enzymes of the cell.
Chronic Toxicity
Cresols are absorbed across the respiratory and gastrointestinal tracts, and through the skin. Gastrointestinal and dermal absorption are rapid and extensive. Cresols are distributed to all the major organs. The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. Minor metabolic pathways include hydroxylation of the benzene ring and side-chain oxidation. The major route for elimination is renal excretion in the form of conjugate metabolites.
Animal
Acute or Short-Term Toxicity Animal Cresols are highly irritating to the skin and eyes of rabbits, rats, and mice. The mean lethal concentration of the cresol vapor or aerosol mixture is 178 mg m3. Clinical signs of toxicityincluded irritation of mucous membranes and neuromuscular excitation that progressed from twitching of individual muscles to clonic convulsions. Hematuria was reported at very high concentrations. Microscopic examination revealed edematous
Exposure to vapors of o-, m-, and p-cresol resulted in weight loss, reduced locomotor activity, inflammation of nasal membranes and skin, and changes in the liver. Oral exposures to mice, rats, and hamsters for 13 weeks resulted in mortality, tremor, reduced body weights, hematological effects, increase in organ weight, hyperplasia of nasal, and stomach epithelium. Oral and inhalation exposure to cresol isomers results in lengthened estrus cycle, histopathological changes in the uterus and ovaries of rats as well as mice further support this finding. No adverse effects on spermatogenesis are observed. Mild
Cresols
fetotoxic effects have been reported upon exposure of pregnant mice. Some evidence of genotoxicity has been reported from in vitro experiment using sister-chromatid exchange (SCE) assay. However, cresol is not genotoxic after in vivo exposure.
Human Prolonged or repeated absorption of low concentrations of cresol through the skin, mucous membranes, or respiratory tract may cause chronic systemic poisoning. Symptoms and signs of chronic poisoning include vomiting, difficulty in swallowing, salivation, diarrhea, loss of appetite, headache, fainting, dizziness, mental disturbances, and skin rash. Death may result if there has been severe damage to the liver and kidneys.
Immunotoxicity Studies demonstrating the immunotoxicity of cresols by any exposure route in any species or gender are either scanty or not available.
Reproductive Toxicity Ortho cresol causes mild effects on the body weight and pup weight in the second-generation mating trial. The relative reproductive toxicity of ortho cresol is absent at lower doses. Mixture of m- and p-cresol was a reproductive toxicant in Swiss CD-1 mice, as evidenced by fewer F1 pups per litter, and reduced pup weight in both generations. There were also reductions in the weights of reproductive organs at necropsy at the high or middle and high dose levels. However, changes in pup growth and weights of somatic organs occurred at all dose levels. Thus, m- and p-cresols are not selective toxicants in Swiss CD-1 mice.
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positive, and o-cresol was negative. Positive mutagenic responses were found at noncytotoxic doses.
Carcinogenicity Based on increased incidence of skin papillomas in mice cresols are considered as possible human carcinogen. All the three cresol isomers produced positive results in genetic toxicity studies either alone or in combination.
Clinical Management Oral exposure: Liquid intake should be avoided because dilution may enhance absorption. Immediate administration of activated charcoal is recommended to limit systemic toxicity. Ipecac-induced emesis is not recommended because of the potential for CNS depression and seizures. Gastric lavage is effective only within 1 h after ingestion. Patients should be treated symptomatically. Convulsions are controlled with diazepam. Inhalation exposure: Victims should be removed to fresh air. Respiratory distress should be monitored and consult healthcare personnel. Eye and dermal exposure: Decontamination with water is necessary. Copious dilution with room temperature water is appropriate after dermal and eye exposure. Consult a physician if required.
Ecotoxicology A bioaccumulation factor for m-cresol is 20 in fish indicates no major bioaccumulation potential in higher trophic levels. A bioaccumulation factor of 4900 in algae indicates, however, a risk for bioaccumulation in lower organisms. Aquatic toxicity of m-cresol
Genotoxicity 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, the mixture of the three isomers to be weakly positive in primary rat hepatocytes, and o-cresol to be negative in rat hepatocytes. No isomer, when tested individually, induced SCEs in vivo, but the mixture of the three isomers induced SCEs in Chinese hamster ovary cells in vitro. Only o-cresol induced SCEs in human lung fibroblasts. In a reverse mutation assay, a mixture of three cresol isomers at 0.005–50 ml per plate with or without S-9 from Aroclor-induced rats (activating system) was negative in Salmonella typhimurium strains at all doses. In a forward mutation assay, a mixture of three cresol isomers at 0.488–750 nl ml1, with or without S-9 from Aroclor induced rats (activating system) produced dose related increase in mutation. In mouse lymphoma cell culture; without activation, results suggest weak mutagenic activity. In an alternative in vitro test, in cell transformation assay using BALB/3T3 cells, a mixture of three cresol isomers was
LC50 (mg l 1)
Species
Duration
Leuciscus idus (fish)
48
6
Brachydanio rerio (freshwater fish)
96
15.9
Salmo gairdneri (estuary, freshwater fish)
96
8.6
Daphnia magna (crustacea)
48
18.8
Daphnia magna (crustacea)
24
8.9
(Effect endpoint: immobilization).
Atmospheric Fate Cresols are not expected to persist in the atmosphere because: (1) cresols have low estimated half-lives (less than 1 day); (2) they are sensitive to photolysis; and (3) the water solubility of cresols may cause transport of cresols from the atmosphere to the soil or aqueous environment. The photodegradation halflife of cresol isomers during the daytime is 8–10 h while at night it is approximately 2–4 min. Daytime half-lives would be reduced under smog conditions. Cresols are highly soluble
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Cresols
compounds and gas scavenging will be an efficient removal process as is reflected by high concentrations in rain.
Terrestrial Fate While there is substantial release of cresols to the soil, this route of environmental exposure is not expected to be a problem. Cresols are readily biodegraded by soil microflora and moves to lower layer of soil. Therefore, cresols will not persist in soils and will probably be leached, due to their water solubility, into the aquatic environment where they will be degraded by microorganisms. The degradation rates of cresols in soil may decrease at lower temperatures (2 to 5 C).
Aquatic Fate Cresols do not contain any functional groups that are hydrolyzable. Therefore, hydrolysis of these compounds in aquatic media is unlikely. However, it will degrade primarily due to biodegradation in eutrophic waters, although photolysis may make a contribution in oligotrophic lakes based on modeling studies. Biodegradation generally occurs within 8 h after several days of acclimation, except in oligotrophic lakes, estuarine, and marine waters where degradation takes several days. Degradation is much slower under anaerobic conditions especially for the ortho isomer. m-Cresol biodegrades in water and its halflives are in the range of 2–29 days (aerobic water) and 15–49 days (anaerobic water). Two factors that may influence the biodegradation rate of cresols in natural aquatic media are the temperature and the quality of the water. In general, freshwater media have the maximum biotransformation rate for cresols. Rates for marine waters are much lower than freshwater. A decrease in temperature from 24 to 11 C increased the biotransformation half-life by a factor of >20; however, the rate of biodegradation of cresols in marine water was so low that the lowering of water temperature would not change the biodegradation rate appreciably. LC50 values for aquatic organisms Gammarus fasciatus/(scud/immature stage)
7.0 mg l1 48 h1a
Asellus militaris/(aquatic sowbug/immature stage)
21.6 mg l1 48 h1a
Ophryotrocha diadema (polychaete worm)
33–100 mg l1 48 h1
Gammarus fasciatus/(scud/adult male)
24.9 mg l1 48 h1
– Do –, (adult female)
34.3 mg l1 48 h1
– Do –, oviparous female
33.9 mg l1 48 h1a
Asellus militaris/(aquatic sowbug/adult male)
65.4 mg l1 48 h1
– Do –, (adult female)
68.0 mg l1 48 h1
– Do –, oviparous females
61.9 mg l1 48 h1a
Pimephales promelas (fathead minnow, 29 days old, size 20.8 mm)
12.8 mg l1 96 h1
Gambusia affinis (mosquitofish, adult females)
22 mg l1 96 h1a
*Selenastrum capricornutum (green alga, 14 day old culture; growth inhibition)
137 mg l1 14 days1a
*EC50 value, a, static.
Other Hazards Fire-Fighting Measures For small fires, use media such as alcohol foam, dry chemical, or carbon dioxide. For large fires apply water as far as possible. Use very large quantities (flooding) of water applied as a mist or spray; solid streams of water may be ineffective. Cool all affected containers with flooding quantities of water. Carbon oxides will generate from the substance or mixture. Wear self-contained breathing apparatus for fire fighting if necessary.
Accidental Release Measures Wear respiratory protection. Avoid breathing vapors, mist, or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapors accumulating to form explosive concentrations and can accumulate in low areas. Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided. Spillage should be collected with a sponge or good absorbing material. Electrically operated vacuum cleaner should not be used. Keep disposals in suitable closed container to discard according to local regulations.
Precautions for Safe Handling and Storage Skin and eye contacts should be avoided. Inhalation of vapor or mist should be avoided. Keep away from sources of ignition, no smoking near the product. Take measures to prevent the build-up of electrostatic charge. Store in cool place. Keep container tightly closed in a dry and wellventilated place.
Exposure Standards and Guidelines Occupational Safety and Health Administration permissible exposure limit is 5 ppm (22 mg m3) for 8 h time-weighted average (TWA). The threshold limit value for cresol and its isomers is 5 ppm for 8 h TWA. National Institute of Occupational Safety and health recommended exposure limit is 2.3 ppm (10 mg m3) for 10 h TWA for all isomers.
See also: Coal Tar; Pesticides.
Further Reading Andersen, A., 2006. Final report on the safety assessment of sodium p-chlorom-cresol, p-chloro-m-cresol, chlorothymol, mixed cresols, m-cresol, o-cresol, p-cresol, isopropyl cresols, thymol, o-cymen-5-ol, and carvacrol. Int. J. Toxicol. 25 (Suppl. 1), 29–127. Aranha, M.M., Matos, A.R., Teresa Mendes, A., et al., 2007. Dinitro-o-cresol induces apoptosis-like cell death but not alternative oxidase expression in soybean cells. J. Plant Physiol. 164 (6), 675–684. Chan, C.P., Yuan-Soon, H., Wang, Y.J., et al., 2005. Inhibition of cyclooxygenase activity, platelet aggregation and thromboxane B2 production by two environmental toxicants: m- and o-cresol. Toxicology 208 (1), 95–104.
Cresols Cuoghi, A., Caiazzo, M., Bellei, E., et al., 2012. Quantification of p-cresol sulphate in human plasma by selected reaction monitoring. Anal. Bioanal. Chem. 404 (6–7), 2097–2104. Lesaffer, G., De Smet, R., D’Heuvaert, T., et al., 2003. Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure. Kidney Int. 64, 1365–1373. Morinaga, Y., Fuke, C., Arao, T., Miyazaki, T., 2004. Quantitative analysis of cresol and its metabolites in biological materials and distribution in rats after oral administration. Leg. Med. (Tokyo) 6, 32–40. Neirynck, N., Vanholder, R., Schepers, E., et al., 2013. An update on uremic toxins. Int. J. Urol. Nephrol. 45 (1), 139–150. Onesios, K.M., Bouwer, E.J., 2012. Biological removal of pharmaceuticals and personal care products during laboratory soil aquifer treatment simulation with different primary substrate concentrations. Water Res. 46 (7), 2365–2375. Peng, Y.S., Ding, H.C., Lin, Y.T., et al., 2012. Uremic toxin p-cresol induces disassembly of gap junctions of cardiomyocytes. Toxicology 302 (1), 11–17. Suarez-Ojeda, M.E., Guisasola, A., Baeza, J.A., et al., 2007. Integrated catalytic wet air oxidation and aerobic biological treatment in a municipal WWTP of a highstrength o-cresol wastewater. Chemosphere 66 (11), 2096–2105. Sun, C.Y., Chang, S.C., Wu, M.S., 2012. Uremic toxins induce kidney fibrosis by activating intrarenal renin-angiotensin-aldosterone system associated epithelial-tomesenchymal transition. PLoS One 7 (3), e34026. http://dx.doi.org/10.1371/ journal.pone.0034026. Epub March 30, 2012. Sun, C.Y., Hsu, H.H., Wu, M.S., 2013. p-Cresol sulfate and indoxyl sulfate induce similar cellular inflammatory gene expressions in cultured proximal renal tubular cells. Nephrol. Dial. Transplant 28 (1), 70–78.
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Watanabe, H., Miyamoto, Y., Honda, D., et al., 2013. p-Cresyl sulfate causes renal tubular cell damage by inducing oxidative stress by activation of NADPH oxidase. Kidney Int. 83 (4), 582–592. Wu, M.L., Tsai, W.J., Yang, C.C., Deng, J.F., 1998. Concentrated cresol intoxication. Vet. Hum. Toxicol. 40 (6), 341–343. Zhu, J.Z., Zhang, J., Yang, K., et al., 2012. p-cresol, but not p-cresylsulphate, disrupts endothelial progenitor cell function in vitro. Nephrol. Dial. Transplant. 27 (12), 4323–4330.
Relevant Websites http://www.atsdr.cdc.gov/toxprofiles/tp34-c2.pdf – ATSDR-CDC. http://www.seagrant.umn.edu/water/report/chemicalsofconcern/cresols/cresols.pdf – ATSDR database. http://www.cdc.gov/niosh/idlh/cresol.html – CDC. http://www.cdc.gov/niosh/docs/81-123/pdfs/0154.pdf – Occupational Safety and Health Guideline for Cresol, All Isomers, CDC, Atlanta, GA. http://www.pesticideinfo.org/Detail_Chemical.jsp?Rec_Id¼PC32877 – PAN Pesticide database. http://webwiser.nlm.nih.gov/ – Substance List, Search for Cresol. http://toxnet.nlm.nih.gov/ – TOXNET, Specialized Information Service, National Library of Medicine, Search for Cresols.