Cresol

Identification

Name
Cresol
Accession Number
DB11143
Type
Small Molecule
Groups
Approved
Description

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.

Synonyms
Not Available
Active Moieties
NameKindUNIICASInChI Key
Formaldehydeunknown1HG84L352550-00-0WSFSSNUMVMOOMR-UHFFFAOYSA-N
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Root Canal TherapyCresol (35 %) + Formaldehyde (19 %)LiquidDentalAr Medicom Inc.1999-11-262006-08-03Canada
Unapproved/Other Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Buckleys Formo CresolCresol (350 mg/1g)LiquidDentalDentsply Llc, Professional Division, Trading As "Sultan Healthcare"1963-02-19Not applicableUs
Formo CresolCresol (485 mg/1g)LiquidDentalDs Healthcare1963-02-19Not applicableUs
Formo CresolCresol (485 mg/1g)LiquidDentalDs Healthcare1963-02-19Not applicableUs
Categories
UNII
GF3CGH8D7Z
CAS number
1319-77-3
Weight
Not Available
Chemical Formula
Not Available
InChI Key
Not Available
InChI
Not Available
IUPAC Name
Not Available
SMILES
Not Available

Pharmacology

Indication

The primary medical indications for cresols in general include being used as bactericides, pesticides, and disinfectants [10]. Certain isomers of cresol, like m-cresol, may be used as inactive ingredients for the purpose of serving as a preservative in some pharmaceuticals [10]. Conversely, many other active pharmaceuticals are also derivatives of various cresol isomer precursors or intermediates [12].

Pharmacodynamics

All cresol isomers are absorbed across the respiratory and gastrointestinal tract and through the intact skin [9]. Limited data indicate that cresols are widely distributed throughout the body after uptake [9]. Cresols are mainly conjugated with glucuronic acid and inorganic sulfate and excreted as conjugates with the urine [9].

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 [9]. In addition to urinary excretion, cresols are excreted in the bile, but the most part undergoes enterohepatic circulation [9]. 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 [9].

Mechanism of action

When cresol isomers are used directly as the active ingredient in bactericides or disinfectants, it appears as if much of the evidence for the mechanism of action for such phenolic germicides indicates that their effect is due to physical damage of bacterial cell membranes [6]. Although not completely explained, some possibilities of how this effect occurs either involves the phenol germicide binding or coming into contact with and (a) causing changes in the permeability of the osmotic barrier of bacterial cell membranes, which therefore allows the escape or leakage of normal cytoplasmic constituents, (b) causing the uncoupling of cytoplasmic constituents with their subsequent leakage from the cell, or (c) a combination of these actions [6].

Absorption

In general, it is believed that cresols can be absorbed through intact skin and across respiratory and gastrointestinal linings [11]. 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 [5]. 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 [5]. 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 [5].

Volume of distribution

One study determined the volume of distribution of p-cresol in healthy rats as being approximately 2.9 +/- 1.4 L/kg [4].

Nevertheless, one case study reports detecting cresols in the blood (120 mg/litre), liver, brain, and urine of a human infant who passed away four hours after 20 ml of a cresol derivative had spilled on the infant's head [11]. Otherwise, very little data about the distribution of cresols in the human body is available [11].

Protein binding

P-cresyl sulfate and p-cresol, both of which are primary cresol metabolites that have been documented, have been observed to demonstrate relatively low protein binding with human serum albumin at about 13-20% binding [3]. The affinity of p-cresyl sulfate and p-cresol toward human serum albumin is evidently moderate at 25 degrees Celsius and becomes relatively weak at physiological temperature, 37 degrees Celsius [3]. Such protein binding largely involves van Der Waals category of interactions, and the binding sites of the two moieties are either identical or extremely close in proximity [3].

Metabolism

Once absorbed, cresols are mainly metabolized by the liver [7] and result in metabolites that are conjugated with glucuronic acid and inorganic sulfate and excreted as conjugates in the urine [9]. Some primary metabolites that have been documented subsequently include p-cresyl sulfate and the glucuronide p-cresol metabolite [7].

Route of elimination

The major route of excretion is likely in the urine [7].

Half life

There does not appear to be detailed information on the half-life of cresol in the human body [10]; the pharmacokinetics of cresol in the human body is usually discussed in the context of accidental exposure and ingestion and not as a formal research study. Nevertheless, various environmental [7] and laboratory animal [1] half-life values for administered cresol have been reported.

Clearance

As colonic microbial metabolism contributes significantly to uremic retention solutes in patients with chronic kidney disease, one study estimated the clearance of p-Cresyl sulfate and the glucuronide p-cresol metabolite - both of which are metabolites of cresol and representative uremic retention solutes - in such patients.

The total renal clearance of p-Cresyl sulfate was median 6.6 ml/min while that of the glucuronide p-cresol metabolite was median 98.9 ml/min [2]. Furthermore, the free solute renal clearance of p-Cresyl sulfate and the glucuronide p-cresol metabolite were observed to be about median 190,0 ml/min and about median 136.5 ml/min, respectively [2]. These results were obtained for a specific subject population that was comprised of 488 patients with chronic kidney disease stages 1 through 5, demonstrating a mean eGFR (ml/min per 1.73 m2) of 35 [2].

Additionally, endogenous p-cresol is produced from tyrosine, an amino acid that is found in most proteins, by anaerobic bacteria in the intestine [11]. It has been observed that healthy humans generally excrete an average of approximately 50 mg (out of a range of 16 to 74 mg) of such endogenously generated p-cresol daily in the urine [11].

Toxicity

In general, the human ingestion of cresols results in burning of the mouth and throat, abdominal pain, and vomiting [7]. The blood circulation, kidneys, lungs, liver, heart, and even the central nervous system have been reported as target sites for ingested cresols [7]. Dermal exposure to cresols have been observed to cause severe skin burns, scarring, systemic toxicity, and even death [7]. Acute exposures can result in severe burns, anuria, coma, and even possibly death [7]. 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 [7].

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 [8].

Moreover, one study suggests the lethal concentration of cresol in blood to be approximately 12 mg% (120 ug/mL) [7] 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 [7].

Certain studies report the human lethal dose (LD) to be about 50-500 mg/kg bw [9].

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteraction
AcetaminophenAcetaminophen may decrease the excretion rate of Cresol which could result in a higher serum level.
Acetylsalicylic acidAcetylsalicylic acid may decrease the excretion rate of Cresol which could result in a higher serum level.
AcyclovirAcyclovir may decrease the excretion rate of Cresol which could result in a higher serum level.
Adefovir DipivoxilAdefovir Dipivoxil may decrease the excretion rate of Cresol which could result in a higher serum level.
AlmotriptanAlmotriptan may decrease the excretion rate of Cresol which could result in a higher serum level.
AlprazolamAlprazolam may decrease the excretion rate of Cresol which could result in a higher serum level.
AmantadineAmantadine may decrease the excretion rate of Cresol which could result in a higher serum level.
AmilorideAmiloride may increase the excretion rate of Cresol which could result in a lower serum level and potentially a reduction in efficacy.
AmitriptylineCresol may decrease the excretion rate of Amitriptyline which could result in a higher serum level.
AmlodipineAmlodipine may decrease the excretion rate of Cresol which could result in a higher serum level.
Food Interactions
Not Available

References

General References
  1. Lesaffer G, De Smet R, D'Heuvaert T, Belpaire FM, Lameire N, Vanholder R: Comparative kinetics of the uremic toxin p-cresol versus creatinine in rats with and without renal failure. Kidney Int. 2003 Oct;64(4):1365-73. doi: 10.1046/j.1523-1755.2003.00228.x. [PubMed:12969155]
  2. Poesen R, Evenepoel P, de Loor H, Kuypers D, Augustijns P, Meijers B: Metabolism, Protein Binding, and Renal Clearance of Microbiota-Derived p-Cresol in Patients with CKD. Clin J Am Soc Nephrol. 2016 Jul 7;11(7):1136-44. doi: 10.2215/CJN.00160116. Epub 2016 Apr 15. [PubMed:27084876]
  3. Berge-Lefranc D, Chaspoul F, Calaf R, Charpiot P, Brunet P, Gallice P: Binding of p-cresylsulfate and p-cresol to human serum albumin studied by microcalorimetry. J Phys Chem B. 2010 Feb 4;114(4):1661-5. doi: 10.1021/jp9059517. [PubMed:20067224]
  4. Lesaffer G, De Smet R, D'heuvaert T, Belpairea FM, Lameire N, Vanholder R: Kinetics of the protein-bound, lipophilic, uremic toxin p-cresol in healthy rats. Life Sci. 2001 Sep 28;69(19):2237-48. [PubMed:11669466]
  5. Roberts MS, Anderson RA, Swarbrick J: Permeability of human epidermis to phenolic compounds. J Pharm Pharmacol. 1977 Nov;29(11):677-83. [PubMed:22602]
  6. JUDIS J: Studies on the mechanism of action of phenolic disinfectants. I. Release of radioactivity from carbon-14-labeled Escherichia coli. J Pharm Sci. 1962 Mar;51:261-5. [PubMed:14452711]
  7. TOXNET: Cresol [Link]
  8. CDC NIOSH: Cresol (o, m, p isomers) [Link]
  9. OCED SIDS UNEP Publications: M/P-Cresol Catgory [Link]
  10. Interim Specific Ground Water Criterion: o, m, p-Cresol [Link]
  11. International Programme On Chemical Safety (IPCS) INCHEM Environmental Health Criteria 168: Cresols [Link]
  12. Wikipedia: Cresol [Link]
  13. IPCS INCHEM: o-cresol [Link]
  14. IPCS INCHEM: m-cresol [Link]
  15. IPCS INCHEM: p-cresol [Link]
External Links
PubChem Substance
347911133
Wikipedia
Cresol
MSDS
Download (123 KB)

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
FormRouteStrength
LiquidDental350 mg/1g
LiquidDental485 mg/1g
LiquidDental
Prices
Not Available
Patents
Not Available

Properties

State
Liquid
Experimental Properties
PropertyValueSource
melting point (°C)o-cresol: 29.8/ m-cresol: 11.8/ p-cresol: 35.5Not Available
boiling point (°C)o-cresol: 191.0/ m-cresol: 202.0/ p-cresol: 201.9Not Available
water solubilityo-cresol: 2.5g/100ml / m-cresol: 2.4g/100ml / p-cresol: 1.9g/100mlNot Available
pKao-cresol: 10.287/ m-cresol: 10.09/ p-cresol: 10.26Not Available
Predicted Properties
Not Available
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Drug created on December 03, 2015 09:51 / Updated on October 01, 2018 14:56