P-Chlorocresol

Last updated
p-Chlorocresol
P-Chlorocresol.png
Names
Preferred IUPAC name
4-Chloro-3-methylphenol
Other names
p-chloro-m-cresol; PCMC; Preventol; CMK
Identifiers
3D model (JSmol)
ChEBI
ChEMBL
ChemSpider
ECHA InfoCard 100.000.392 OOjs UI icon edit-ltr-progressive.svg
EC Number
  • 200-431-6
KEGG
PubChem CID
RTECS number
  • GO7100000
UNII
UN number 2669
  • InChI=1S/C7H7ClO/c1-5-4-6(9)2-3-7(5)8/h2-4,9H,1H3 Yes check.svgY
    Key: CFKMVGJGLGKFKI-UHFFFAOYSA-N Yes check.svgY
  • InChI=1/C7H7ClO/c1-5-4-6(9)2-3-7(5)8/h2-4,9H,1H3
    Key: CFKMVGJGLGKFKI-UHFFFAOYAE
  • Oc1ccc(Cl)c(C)c1
Properties
C7H7ClO
Molar mass 142.58 g·mol−1
AppearanceWhite solid
Odor Phenolic
Density 1.37 g/cm3 (20 °C)
Melting point 55.55 °C (131.99 °F; 328.70 K)
Boiling point 235 °C (455 °F; 508 K)
3.8 g/L at 20 °C (in water)
Hazards
GHS labelling:
GHS-pictogram-acid.svg GHS-pictogram-exclam.svg GHS-pictogram-pollu.svg
Danger
H302, H314, H317, H335, H400, H412
P260, P261, P264, P270, P271, P272, P273, P280, P301+P312, P301+P330+P331, P302+P352, P303+P361+P353, P304+P340, P305+P351+P338, P310, P312, P321, P330, P333+P313, P363, P391, P403+P233, P405, P501
Flash point 118 °C (244 °F; 391 K)
Related compounds
Related compounds
 Chloroxylenol (4-chloro-3,5-dimethylphenol)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
X mark.svgN  verify  (what is  Yes check.svgYX mark.svgN ?)

p-Chlorocresol, or 4-chloro-3-methylphenol (ClC6H3CH3OH), also known as p-chloro-m-cresol, is a potent disinfectant and antiseptic. [1] It appears as a pinkish white crystalline solid. [2] It is also used as a preservative [3] in cosmetics and medicinal products for both humans and animals. It is used as an active ingredient in some preparations of veterinary medicines for tropical, oral and parenteral use. Normally, the concentration of p-Chlorocresol in oral and parenteral veterinary products are 0.1-0.2%. Concentrations are higher (~0.5%) in tropical veterinary products. p-Chlorocresol contains microbial activity against both gram positive and gram negative bacteria and fungi.

Contents

The use of p-Chlorocresol is regulated by government agencies such as the US Food and Drug administration, [4] and limits are set on the amount of p-Chlorocresol that can be present in various products.

Synthesis

p-Chlorocresol is synthesized from the monochlorination [5] of 3-methylphenol at position 4.

Metabolism

The biodegradation of p-Chlorocresol [6] is done in the liver, and then excreted primarily via the kidneys or in smaller amounts through the lungs. In facultative Thauera sp. strain DO, p-Chlorocresol was degraded aerobically either by dehalogenation followed by catechol degradation pathway, or methyl oxidation to 4-chlorobenzoate. [7] The exact reaction mechanism in humans is unknown.

Reactions and mechanisms

Oxidation

The oxidation reaction of p-Chlorocresol by hydrogen peroxide (H2O2) [8] can occur through a two-step process. In the first step, H2O2 is activated by a catalyst, such as a metal ion or an enzyme, to form a reactive oxygen species, such as a hydroxyl radical (HO•). This reactive species can then attack the aromatic ring of the 4-chloro-3-methylphenol molecule, leading to the formation of a quinone intermediate.

The quinone intermediate is an important intermediate in many biological and chemical processes. [5] It can undergo further oxidation to form a variety of compounds, including hydroquinones, catechols, and benzoquinones. In the case of p-Chlorocresol, the quinone intermediate can be further oxidized to form 4-chlorocatechol, which is a catechol compound.

Esterification

The esterification reaction of p-Chlorocresol with acetic anhydride to obtain 4-chloro-3-methylphenyl acetate. [9]

Step 1: Protonation of the phenol group Acetic anhydride is a source of acetyl cation (CH3CO+). In the presence of a Lewis acid catalyst like sulfuric acid, the acetyl cation can react with the lone pair of electrons on the oxygen atom of the phenol group of p-Chlorocresol to protonate it, forming a resonance-stabilized carbocation intermediate.

Step 2: Nucleophilic attack of the carbocation intermediate by acetic anhydride The carbocation intermediate is attacked by the nucleophilic oxygen atom of an acetic anhydride molecule, which results in the formation of a new bond between the carbocation and the acetyl group. This leads to the formation of an intermediate with an acylated phenol ring.

Step 3: Deprotonation of the intermediate The intermediate formed in Step 2 is then deprotonated by water or the acid catalyst, which regenerates the catalyst and releases the 4-chloro-3-methylphenyl acetate product.

Dehalogenation

Dehalogenation of p-chlorocresol to remove the chlorine atom. Biological dehalogenation can be used to remove halogens from organic molecules. [7] This process involves the use of microorganisms such as bacteria or fungi that have the ability to break down and remove halogens from compounds. However, the use of biological methods for dehalogenation is still relatively new and requires further research and development.

Indications

p-Chlorocresol is a potent disinfectant and antiseptic agent [10] due to its antimicrobial and antifungal properties and is therefore used for wound and skin disinfection. [11] It also has preservative properties and is commonly found in topical creams and cosmetics. These properties also allow it to be used in paints and inks.

Molecular mechanism of action

A phenolic preservative agent, the bacteriostatic mechanism of p-Chlorocresol arises from its ability to induce cytoplasmic [12] leakage in bacteria, disrupting membrane permeability to potassium and phosphate ions. Cytoplasmic leakage also results in dissipation of the proton motive force, causing uncoupling of respiration from ATP synthesis. [13]

Efficacy

p-Chlorocresol has been shown to be effective as a bactericide in handwash at 0.2% 2/2 a.s in 60 seconds with 6 ml applied. [14] It is also effective against prions such as scrapie in hamsters. [15]

As an ingredient in cosmetic creams and lotions, p-chlorocresol has a 75% dermal absorption value. Up to 100% [6] dermal absorption may be possible when it is dermally applied to broken skin (eg. for eczema).

Adverse effects

Allergic contact dermatitis resulting from hypersensitivity to p-Chlorocresol has been reported, [16] and it is classified as hazardous with the risk phrase “May cause sensitisation by skin contact’ in the HSIS (Safe Work Australia). [17] However, Draize tests conducted on human subjects showed no positive reactions among healthy male subjects at 5%, 10% and 20% chlorocresol via dermal route. [18]

There has been a documented case of recurrent unilateral facial palsy of a woman after exposure to p-chlorocresol. [19] The brief neurological disturbance was relieved by exposure to fresh air and was determined to be a result of pharmacological hyperreactivity.

Toxicity

Human exposure to p-Chlorocresol is mostly through body lotions as it is not found naturally in the environment. Above the critical effect level (21 mg/ kg/ bw/ day), p-chlorocresol exposure may result in a decrease in absolute adrenal gland weights. [6] In 2021, it was classified as a compound that may constitute a danger to human life or health by the Government of Canada as the margins of exposure of the critical effect level and the estimated levels of exposure were considered inadequate.

Similar to phenol, neurolytic effects have also been reported for chlorocresol. [20] However, this reaction is rare and may be due to interindividual hypersensitivity.

p-Chlorocresol does not significantly bioaccumulate in organisms due to low Kow and bioconcentration factors. It is not found to be genotoxic or carcinogenic [21] and has been safely used in human medicine for many years. [22]

Effects on animals Effects on animals p-Chlorocresol has low to moderate acute oral toxicity in rats and mice, with a median lethal dose (LD50) of 1830mg/kg in male Wistar rats. [23] It has also been shown to be corrosive to the skin of New Zealand White rabbits when applied dermally, and an irritant to rabbit eyes. [24] Similar reactions have been recorded in Pirbright White guinea pigs. [25] However, p-Chlorocresol has also been used as a disinfectant to reduce the infectivity levels of hamsters infected with scrapies, [15] showing its effectiveness as an antiseptic even in animals.

A Committee for Veterinary Medicinal Products found p-Chlorocresol to be rapidly metabolized and excreted with no potential to accumulate in tissues and of low toxicity. In rats, up to 95% of the p-Chlorocresol was excreted via the urine and 0.4% in the faeces within 24 hours. [23]

See also

Related Research Articles

<span class="mw-page-title-main">Phenol</span> Organic compound (C6H5OH)

Phenol, or Benzenol, is an aromatic organic compound with the molecular formula C6H5OH. It is a white crystalline solid that is volatile. The molecule consists of a phenyl group bonded to a hydroxy group. Mildly acidic, it requires careful handling because it can cause chemical burns.

<span class="mw-page-title-main">Creosote</span> Tar distillation byproduct used as wood preservative

Creosote is a category of carbonaceous chemicals formed by the distillation of various tars and pyrolysis of plant-derived material, such as wood, or fossil fuel. They are typically used as preservatives or antiseptics.

<span class="mw-page-title-main">Butylated hydroxytoluene</span> Chemical compound

Butylated hydroxytoluene (BHT), also known as dibutylhydroxytoluene, is a lipophilic organic compound, chemically a derivative of phenol, that is useful for its antioxidant properties. BHT is widely used to prevent free radical-mediated oxidation in fluids and other materials, and the regulations overseen by the U.S. F.D.A.—which considers BHT to be "generally recognized as safe"—allow small amounts to be added to foods. Despite this, and the earlier determination by the National Cancer Institute that BHT was noncarcinogenic in an animal model, societal concerns over its broad use have been expressed. BHT has also been postulated as an antiviral drug, but as of December 2022, use of BHT as a drug is not supported by the scientific literature and it has not been approved by any drug regulatory agency for use as an antiviral.

Cresols are a group of aromatic organic compounds. They are widely-occurring phenols which may be either natural or manufactured. They are also categorized as methyl phenols. Cresols commonly occur as either solids or liquids because their melting points are generally close to room temperature. Like other types of phenols, they are slowly oxidized by exposure to air, and the resulting impurities often give the samples a yellow to brownish red tint. Cresols have an odor characteristic to that of other simple phenols, reminiscent to some of a "coal tar" smell. The name "cresol" is an adduct of phenol and their traditional source, creosote.

<span class="mw-page-title-main">Beckmann rearrangement</span> Chemical rearrangement

The Beckmann rearrangement, named after the German chemist Ernst Otto Beckmann (1853–1923), is a rearrangement of an oxime functional group to substituted amides. The rearrangement has also been successfully performed on haloimines and nitrones. Cyclic oximes and haloimines yield lactams.

<span class="mw-page-title-main">Fischer–Speier esterification</span>

Fischer esterification or Fischer–Speier esterification is a special type of esterification by refluxing a carboxylic acid and an alcohol in the presence of an acid catalyst. The reaction was first described by Emil Fischer and Arthur Speier in 1895. Most carboxylic acids are suitable for the reaction, but the alcohol should generally be primary or secondary. Tertiary alcohols are prone to elimination. Contrary to common misconception found in organic chemistry textbooks, phenols can also be esterified to give good to near quantitative yield of products. Commonly used catalysts for a Fischer esterification include sulfuric acid, p-toluenesulfonic acid, and Lewis acids such as scandium(III) triflate. For more valuable or sensitive substrates other, milder procedures such as Steglich esterification are used. The reaction is often carried out without a solvent or in a non-polar solvent to facilitate the Dean-Stark method. Typical reaction times vary from 1–10 hours at temperatures of 60-110 °C.

<span class="mw-page-title-main">Pentachlorophenol</span> Chemical compound

Pentachlorophenol (PCP) is an organochlorine compound used as a pesticide and a disinfectant. First produced in the 1930s, it is marketed under many trade names. It can be found as pure PCP, or as the sodium salt of PCP, the latter of which dissolves easily in water. It can be biodegraded by some bacteria, including Sphingobium chlorophenolicum.

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<i>p</i>-Cresol Chemical compound

para-Cresol, also 4-methylphenol, is an organic compound with the formula CH3C6H4(OH). It is a colourless solid that is widely used intermediate in the production of other chemicals. It is a derivative of phenol and is an isomer of o-cresol and m-cresol.

<i>m</i>-Cresol Chemical compound

meta-Cresol, also 3-methylphenol, is an organic compound with the formula CH3C6H4(OH). It is a colourless, viscous liquid that is used as an intermediate in the production of other chemicals. It is a derivative of phenol and is an isomer of p-cresol and o-cresol.

Peracetic acid (also known as peroxyacetic acid, or PAA) is an organic compound with the formula CH3CO3H. This peroxy acid is a colorless liquid with a characteristic acrid odor reminiscent of acetic acid. It can be highly corrosive.

Chloroxylenol, also known as para-chloro-meta-xylenol (PCMX), is a chlorine substituted phenol with an white to off-white appearance and a phenolic odor. The discovery of chloroxylenol was the result of efforts to produce improved antiseptics that began at the end of the 1800s. First synthesized in Germany in 1923, it was borne out of the study of coal tar components that began a decade earlier.

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<span class="mw-page-title-main">Acetic acid</span> Colorless and faint organic acid found in vinegar

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2-Chloro-<i>m</i>-cresol Chemical compound

2-Chloro-m-cresol is a chlorinated cresol. The compound is difficult to synthesise as chlorination of m-cresol yields the para-product (4-chloro-3-methylphenol). Historically synthesis has been achieved via a para-selective nitration, followed by conversion to a diazonium compound and a Sandmeyer reaction to insert the chlorine into the 2-position.

ortho-Cresol (IUPAC name: 2-methylphenol, also known as 2-hydroxytoluene or ortho-Toluenol) is an organic compound with the formula CH3C6H4(OH). It is a colourless solid that is widely used intermediate in the production of other chemicals. It is a derivative of phenol and is an isomer of p-cresol and m-cresol.

Creolin is a generic name for disinfectants whose composition varies according to origin. One of its uses is as a disinfectant. It is extracted from the dry distillation of wood. The residue remaining in the autoclave vessel is a dark, syrupy mass called creosote, which is composed mainly of phenolic acid and cresylic acid. The original composition of creolin was this creosote tar oil, caustic soda, soaps, and very little water. It is of low technology and a very powerful disinfectant.

References

  1. ↑ Susan C Smolinske (1992), Handbook of Food, Drug, and Cosmetic Excipients, p. 87
  2. ↑ "4-Chloro-3-methylphenol". pubchem.ncbi.nlm.nih.gov. Retrieved 2023-08-25.
  3. ↑ C. Glen Mayhall (2004), Hospital Epidemiology and Infection Control, p. 1741
  4. ↑ "CFR - Code of Federal Regulations Title 21". www.accessdata.fda.gov. Retrieved 2023-08-25.
  5. 1 2 Fiege, H., Voges, H. W., Hamamoto, T., Umemura, S., Iwata, T., Miki, H., ... & Paulus, W. (2000). Phenol derivatives. Ullmann's encyclopedia of industrial chemistry.
  6. 1 2 3 "Screening assessment phenol, 4-chloro-3-methyl- (Chlorocresol)". www.canada.ca. 2021-05-21. Retrieved 2023-08-25.
  7. 1 2 Ha, Duc Danh; Nguyen, Oanh Thi (February 2020). "Degradation of p-chlorocresol by facultative Thauera sp. strain DO". 3 Biotech. 10 (2). doi:10.1007/s13205-019-2025-9. PMC   6954914 . PMID   31988840.
  8. ↑ Kronholm, Juhani; Huhtala, Sami; Haario, Heikki; Riekkola, Marja-Liisa (September 2002). "Oxidation of 4-chloro-3-methylphenol in pressurized hot water in liquid and vapor phases". Advances in Environmental Research. 6 (3): 199–206. doi:10.1016/S1093-0191(01)00051-X.
  9. ↑ Dofe, Vidya S.; Sarkate, Aniket P.; Kathwate, Santosh H.; Gill, Charansingh H. (2017-08-01). "Synthesis, antimicrobial activity and anti-biofilm activity of novel tetrazole derivatives". Heterocyclic Communications. 23 (4): 325–330. doi: 10.1515/hc-2017-0016 . ISSN   2191-0197.
  10. ↑ National Center for Advancing Translational Sciences(2007). Inxight Drugs Chlorocresol. Retrieved march 1,2023 from: https://drugs.ncats.io/drug/36W53O7109#publications
  11. ↑ "PCMC (Parachlorometacresol) |". atamankimya.com. Retrieved 2023-08-25.
  12. ↑ S P Denver, Valerie D Harding, W B Hugo, The Mechanism of Bacteriostatic Action of Chlorocresol (CC) on Staphylococcus Aureus.Journal of Pharmacy and Pharmacology vol. 27,12(1985): 93. doi:10.1111/j.2042-7158.1985.tb14165.x
  13. ↑ Denyer, S.P. (October 1995). "Mechanisms of action of antibacterial biocides". International Biodeterioration & Biodegradation. 36 (3–4): 227–245. doi:10.1016/0964-8305(96)00015-7.
  14. ↑ European Chemicals Agency (2016),Proposal for Harmonised Classification and Labelling for p-chloro-m-cresol (CMK). Retrieved from: https://echa.europa.eu/documents/10162/ac5f5b9f-59fc-630c-3137-59c7304c06d0
  15. 1 2 Riemer, Constanze; Bamme, Theresa; Mok, Simon Wing Fai; Baier, Michael (July 2006). "3-Methyl-4-Chlorophenol for Prion Decontamination of Medical Devices". Infection Control & Hospital Epidemiology. 27 (7): 778–780. doi:10.1086/504450. PMID   16807860. S2CID   35661326.
  16. ↑ Gómez de la Fuente, E.; Andreu-Barasoain, M.; Nuño-González, A.; López-Estebaranz, J.L. (January 2013). "Allergic Contact Dermatitis Due To Chlorocresol In Topical Corticosteroids". Actas Dermo-Sifiliográficas (English Edition). 104 (1): 90–92. doi: 10.1016/j.adengl.2012.11.016 .
  17. ↑ "Safe Work Australia". hcis.safeworkaustralia.gov.au. Retrieved 2023-08-25.
  18. ↑ Cosmetic Ingredient Review (CIR, 2006). Final Report on the Safety Assessment of Sodium p-Chloro-m-Cresol, p-Chloro-mCresol, Chlorothymol, Mixed Cresols, m-Cresol, o-Cresol, p-Cresol, Isopropyl Cresols, Thymol, o-Cymen-5-ol, and Carvacrol. International Journal of Toxicology 25(Supp 1):29-127. Accessed December 2015 at http://gov.personalcarecouncil.org/ctfastatic/online/lists/cir-pdfs/pr277.pdf
  19. ↑ Dossing, M; Wulff, C H; Olsen, P Z (1 December 1986). "Repeated facial palsies after chlorocresol inhalation". Journal of Neurology, Neurosurgery & Psychiatry. 49 (12): 1452–1454. doi:10.1136/jnnp.49.12.1452. PMC   1029136 . PMID   3806124. S2CID   8183536.
  20. ↑ D’Souza, Ryan S. “Neurolytic Blocks.” StatPearls - NCBI Bookshelf, 2022, www.ncbi.nlm.nih.gov/books/NBK537360/#_NBK537360_pubdet_.
  21. ↑ http://archive.epa.gov/pesticides/reregistration/web/pdf/3046red.pd
  22. ↑ The European Agency for the Evaluation of Medicinal Products Veterinary Medicines Evaluation Unit. “Chlorocresol(4-chloro-3-methylphenol).” Retrieved from:https://www.ema.europa.eu/en/documents/mrl-report/chlorocresol-4-chloro-3-methylphenol-summary-report-committee-veterinary-medicinal-products_en.pdf
  23. 1 2 IMAP. “Chlorocresol and its sodium salt: Human health tier II assessment.” retrieved from: https://www.industrialchemicals.gov.au/sites/default/files/Chlorocresol%20and%20its%20sodium%20salt_Human%20health%20tier%20II%20assessment.pdf
  24. ↑ "RTECS Number GO7100000". ccinfoweb2.ccohs.ca. Retrieved 2023-08-25.
  25. ↑ Hazardous Substances Data Bank (HSDB). National Library of Medicine. Accessed December 2015 at http://toxnet.nlm.nih.gov
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