Cresol

Absorption

In general, it is believed that cresols can be absorbed through intact skin and across respiratory and gastrointestinal linings . Although the rates and extents to which cresols are absorbed across the lungs and gastrointestinal tract do not yet appear to have been studied in detail, an in-vitro study regarding the permeability of human skin to cresols demonstrated that cresols possess permeability coefficients larger than that of phenol, which is already known to be readily absorbed across the human skin . In particular, the permeability coefficients (Kp) were approximated from the steady-state slopes of the relation between the cumulative amount of cresol isomer per unit area of membrane with time . The particular Kp values calculated for m-, o-, and p-cresol were 2.54 x 10^-4, 2.6 x 10^-4, and 2.92 x 10^-4 cm/minute, respectively .

Toxicity

In general, the human ingestion of cresols results in burning of the mouth and throat, abdominal pain, and vomiting . The blood circulation, kidneys, lungs, liver, heart, and even the central nervous system have been reported as target sites for ingested cresols . Dermal exposure to cresols have been observed to cause severe skin burns, scarring, systemic toxicity, and even death . Acute exposures can result in severe burns, anuria, coma, and even possibly death . Cresol, in its general form is very unlikely to be indicated or used as any kind of health product for humans or animals to ingest or apply .
The Immediately Dangerous to Life or Health (IDLH) value as documented by the Centers for Disease Control and Prevention (CDC) National Institute for Occupational Safety and Health (NIOSH) for cresol (comprised of the ortho-, meta-, and para- isomers) is 250 ppm, based upon acute inhalation toxicity data in animals .
Moreover, one study suggests the lethal concentration of cresol in blood to be approximately 12 mg% (120 ug/mL) and the smallest amount of cresol that produced death was 4 mL of a 25% to 50% cresol solution in an 11 month old child .
Certain studies report the human lethal dose (LD) to be about 50-500 mg/kg bw .

Description

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 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.

Chemical properties

Cresol,a clear amber to red liquid, also known as cresylic acid, methylphenol, and tricresol,is a mixture of three isomers of cresol derived from coaltar and is used in making plastics, ore flotation, refining petroleum, and as a strong antiseptic. Orthocresol is a color less solid with a melting point of 30 °C(86 OF) that is soluble in alcohol,but only slightly soluble in water. It is used in making disinfectants and as a plasticizer. Metacresol is a colorless liquid used in the manufacture of photographic developers,printing inks, and paint removers.It is also used as a leather preservative.The least soluble isomer, paracresol, is a colorless solid and is used in the production of dyes and pharmaceuticals.

Chemical properties

Cresol is a mixture of the three isomeric cresols, o-, m-, and p-cresol. Cresols are slightly soluble in water. m-Isomer: Colorless or yellow liquid with characteristic odor.

Chemical properties

Cresol consists of a mixture of cresol isomers, predominantly mcresol,and other phenols obtained from coaltar or petroleum.It is a colorless,yellowish to pale brownish-yellow,or pink-colored liquid, with a characteristic odor similar to phenol but more tarlike. An aqueous solution has a pungent taste.

The Uses of Cresol

Cresol is used in disinfectants and fumigants,in the manufacture of synthetic resins, inphotographic developers and explosives.

The Uses of Cresol

Disinfectant, phenolic resins, tricresyl phosphate, ore flotation, textile scouring agent, organic intermediate, manufacture of salicylaldehyde, coumarin, and herbicides, surfactant, synthetic food flavors (para isomer only).

The Uses of Cresol

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.

Background

Cresol is a hydroxytoluene that can be extracted naturally from coal tar or made synthetically. Pure cresol is a mixture of ortho-, meta-, and para- isomers. Cresols are precursors or synthetic intermediates to various other compounds and materials, including plastics, pesticides, pharmaceuticals, disinfectants, and dyes. Ingestion of cresol induces toxicity in humans and can lead to burning of the mouth and throat, abdominal pain, and/or vomiting. At concentrations normally found in the environment however, cresols do not pose any significant risk for the general population.

What are the applications of Application

Cresol mixture of isomers is a group of organic compounds which are methylphenols

Indications

The primary medical indications for cresols in general include being used as bactericides, pesticides, and disinfectants . Certain isomers of cresol, like m-cresol, may be used as inactive ingredients for the purpose of serving as a preservative in some pharmaceuticals .

Definition

A mixture of isomers obtained from coal tar or petroleum.

Production Methods

Cresol may be obtained from coal tar or prepared synthetically by either sulfonation or oxidation of toluene.

General Description

Colorless to yellow liquids with a tarry odor. Flash point 178°F. Insoluble in water. Density 8.7 lb / gal. Poisonous by ingestion and skin absorption and corrosive to skin.

Air & Water Reactions

Insoluble in water.

Reactivity Profile

Mixing CRESOL in equal molar portions with any of the following substances in a closed container caused the temperature and pressure to increase: chlorosulfonic acid, nitric acid, oleum, [NFPA 1991].

Hazard

Irritant, corrosive to skin and mucous membranes, absorbed via skin. Questionable carcinogen.

Health Hazard

LIQUID: Will burn skin and eyes. Harmful if swallowed.

Health Hazard

The toxic actions of cresol are similar tothose of phenol. The para-isomer is somewhat more toxic than the other two isomers.The toxic symptoms are weakness, confu-sion, depression of the central nervous system, dyspnea, and respiratory failure. It isan irritant to the eyes and skin. Skin con-tact can cause burn and dermatitis. Chroniceffects are gastrointestinal disorders, nervousdisorders, tremor, confusion, skin eruptions,oliguria, jaundice, and liver damage. SkinLD50 values in rats for o-, m-, and p-phenolsare 620, 1100, and 750 mg/kg, respectively.
Dietz and Mulligan (1988a,b) have investigated the subchronic toxicity of meta- andpara-cresols in Sprague-Dawley rats after13 weeks of oral gavage. There was noadverse effects from a dose of 50 mg/kg/day.High dose levels of 150 mg/kg/day producedcentral nervous system depression and reduction of body weight gain. p-Cresol was foundto be hepatotoxic and nephrotoxic, inducinga mild anemic effect. The acute toxicity ofmethyl phenols did not show any relationshipto the number or position of methyl groupson the phenol nucleus. In an acute toxicitystudy on Daphnia magna, Devillers (1988)found cresols to be more toxic than phenol,xylenols, and trimethylphenols.

Fire Hazard

Combustible. POISONOUS GASES MAY BE PRODUCED IN FIRE. Flammable toxic vapors given off in a fire. Sealed closed containers can build up pressure if exposed to heat.

Chemical Reactivity

Reactivity with Water No reaction; Reactivity with Common Materials: No reaction; Stability During Transport: Stable; Neutralizing Agents for Acids and Caustics: Not pertinent; Polymerization: Not pertinent; Inhibitor of Polymerization: Not pertinent.

Pharmaceutical Applications

Cresol is used at 0.15-0.3% concentration as an antimicrobial preservative in intramuscular, intradermal, and subcutaneous injectable pharmaceutical formulations. It is also used as a preservative in some topical formulations and as a disinfectant. Cresol is not suitable as a preservative for preparations that are to be freeze-dried.

Pharmacokinetics

All cresol isomers are absorbed across the respiratory and gastrointestinal tract and through the intact skin . Limited data indicate that cresols are widely distributed throughout the body after uptake . Cresols are mainly conjugated with glucuronic acid and inorganic sulfate and excreted as conjugates with the urine .
At physiological pH, the conjugated metabolites are ionized to a greater extent than the parent compound, which reduces renal reabsorption and increases elimination with the urine . In addition to urinary excretion, cresols are excreted in the bile, but the most part undergoes enterohepatic circulation . There are know species differences in the specific conjugation reactions of cresol isomers and the relative amounts of glucuronide and sulfate conjugates therefore differ between species and also vary with dose .

Safety

Reports of adverse reactions to cresol are generally associated with the use of either the bulk material or cresol-based disinfectants, which may contain up to 50% cresol, rather than for its use as a preservative. However, a recent case of cutaneous hypersensitivity reaction to the m-cresol component of an insulin formulation detected via intradermal and patch testing has been reported.
Cresol is similar to phenol although it is less caustic and toxic. However, cresol is sufficiently caustic to be unsuitable for skin and wound disinfection. In studies in rabbits, cresol was found to be metabolized and excreted primarily as the glucuronide.
A patient has survived ingestion of 12g of cresol though with severe adverse effects.
LD50 (mouse, oral): 0.76g/kg
LD50 (rabbit, skin): 2g/kg
LD50 (rat, oral): 1.45g/kg

Potential Exposure

Cresol is used as a disinfectant and fumigant; as an ore flotation agent, and as an intermediate in the manufacture of chemicals, dyes, plastics, and antioxidants. A mixture of isomers is generally used; the concentrations of the components are determined by the source of the cresol.

First aid

If this chemical gets into the eyes, remove anycontact lenses at once and irrigate immediately for at least15 min, occasionally lifting upper and lower lids. Seek medical attention immediately. If this chemical contacts theskin, remove contaminated clothing and wash immediatelywith soap and water. Seek medical attention immediately. Ifthis chemical has been inhaled, remove from exposure,begin rescue breathing (using universal precautions, including resuscitation mask) if breathing has stopped and CPR ifheart action has stopped. Transfer promptly to a medicalfacility. When this chemical has been swallowed, get medical attention. Give large quantities of water and inducevomiting. Do not make an unconscious person vomit.Medical observation is recommended for 24-48 h afterbreathing overexposure, as pulmonary edema may bedelayed. As first aid for pulmonary edema, a doctor orauthorized paramedic may consider administering a corticosteroid spray.

Environmental Fate

It acts by disruption of the cell membrane by denaturation of proteins and enzymes of the cell.

Metabolism

Once absorbed, cresols are mainly metabolized by the liver and result in metabolites that are conjugated with glucuronic acid and inorganic sulfate and excreted as conjugates in the urine . Some primary metabolites that have been documented subsequently include p-cresyl sulfate and the glucuronide p-cresol metabolite .

storage

Cresol and aqueous cresol solutions darken in color with age and on exposure to air and light. Cresol should be stored in a well-closed container, protected from light, in a cool, dry place.

Shipping

UN2076 Cresols, liquid, Hazard class: 6.1; Labels: 6.1-Poisonous materials, 8-Corrosive material. UN3455 Cresols, solid, Hazard class: 6.1; Labels: 6.1- Poisonous materials, 8-Corrosive material.

Toxicity evaluation

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 severaldays 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.

Incompatibilities

Vapors may form explosive mixture with air. Incompatible with strong acids; oxidizers, alkalies, aliphatic amines; amides, chlorosulfonic acid; oleum. Decomposes on heating, producing strong acids and bases, causing fire and explosion hazard. Liquid attacks some plastics and rubber. Attacks many metals.

Incompatibilities

Cresol has been reported to be incompatible with chlorpromazine. Antimicrobial activity is reduced in the presence of nonionic surfactants.

Waste Disposal

Wastewaters may be subjected to biological treatment. Concentrations may be further reduced by ozone treatment. High concentration wastes may be destroyed in special waste incinerators.

Regulatory Status

Included in the FDA Inactive Ingredients Database (IM, IV, intradermal, and SC injections). Included in parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients.