Wikipedia

p-Chlorocresol

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.

p-Chlorocresol
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 Edit this at Wikidata
EC Number
  • 200-431-6
KEGG
RTECS number
  • GO7100000
UNII
UN number 2669
  • InChI=1S/C7H7ClO/c1-5-4-6(9)2-3-7(5)8/h2-4,9H,1H3 checkY
    Key: CFKMVGJGLGKFKI-UHFFFAOYSA-N checkY
  • 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
Appearance White 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:
GHS05: CorrosiveGHS07: Exclamation markGHS09: Environmental hazard
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).
☒N verify (what is checkY☒N ?)

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.

Chlorocresol was first introduced as a bactericide in 1897 by Kalle & Co. [de][5] after scientists gradually discovered that more substituted and more lipophylic phenols are less toxic, less irritant and more powerful.[6]

Synthesis

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p-Chlorocresol is synthesized from the monochlorination[7] of 3-methylphenol at position 4.

Metabolism

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The biodegradation of p-Chlorocresol[8] 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.[9] The exact reaction mechanism in humans is unknown.

Reactions and mechanisms

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Oxidation

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The oxidation reaction of p-Chlorocresol by hydrogen peroxide (H2O2)[10] 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.[7] 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

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The esterification reaction of p-Chlorocresol with acetic anhydride to obtain 4-chloro-3-methylphenyl acetate.[11]

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

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Dehalogenation of p-chlorocresol to remove the chlorine atom. Biological dehalogenation can be used to remove halogens from organic molecules.[9] 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

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p-Chlorocresol is a potent disinfectant and antiseptic agent[12] due to its antimicrobial and antifungal properties and is therefore used for wound and skin disinfection.[13] 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

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A phenolic preservative agent, the bacteriostatic mechanism of p-Chlorocresol arises from its ability to induce cytoplasmic[14] 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.[15]

Efficacy

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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.[16] It is also effective against prions such as scrapie in hamsters.[17]

As an ingredient in cosmetic creams and lotions, p-chlorocresol has a 75% dermal absorption value. Up to 100%[8] dermal absorption may be possible when it is dermally applied to broken skin (eg. for eczema).

Adverse effects

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Allergic contact dermatitis resulting from hypersensitivity to p-Chlorocresol has been reported,[18] and it is classified as hazardous with the risk phrase “May cause sensitisation by skin contact’ in the HSIS (Safe Work Australia).[19] However, Draize tests conducted on human subjects showed no positive reactions among healthy male subjects at 5%, 10% and 20% chlorocresol via dermal route.[20]

There has been a documented case of recurrent unilateral facial palsy of a woman after exposure to p-chlorocresol.[21] The brief neurological disturbance was relieved by exposure to fresh air and was determined to be a result of pharmacological hyperreactivity.

Toxicity

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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.[8] 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.[22] 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[23] and has been safely used in human medicine for many years.[24]

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 1830 mg/kg in male Wistar rats.[25] 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.[26] Similar reactions have been recorded in Pirbright White guinea pigs.[27] However, p-Chlorocresol has also been used as a disinfectant to reduce the infectivity levels of hamsters infected with scrapies,[17] 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.[25]

See also

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References

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  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. ^ Sneader, Walter (2005-06-23). Drug Discovery: A History. John Wiley & Sons. p. 362. ISBN 978-0-471-89979-2.
  6. ^ de Solis, Nilka M. G. (1993). Effect of plasmids that confer preservative-resistance on the performance of bacteria in preservative efficacy tests (Doctoral thesis). University College London. p. 31.
  7. ^ a b Fiege, H., Voges, H. W., Hamamoto, T., Umemura, S., Iwata, T., Miki, H., ... & Paulus, W. (2000). Phenol derivatives. Ullmann's encyclopedia of industrial chemistry.
  8. ^ a b c "Screening assessment phenol, 4-chloro-3-methyl- (Chlorocresol)". www.canada.ca. 2021-05-21. Retrieved 2023-08-25.
  9. ^ a b 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.
  10. ^ 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.
  11. ^ 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.
  12. ^ National Center for Advancing Translational Sciences(2007). Inxight Drugs Chlorocresol. Retrieved march 1,2023 from: https://drugs.ncats.io/drug/36W53O7109#publications
  13. ^ "PCMC (Parachlorometacresol) |". atamankimya.com. Retrieved 2023-08-25.
  14. ^ 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
  15. ^ Denyer, S.P. (October 1995). "Mechanisms of action of antibacterial biocides". International Biodeterioration & Biodegradation. 36 (3–4): 227–245. Bibcode:1995IBiBi..36..227D. doi:10.1016/0964-8305(96)00015-7.
  16. ^ 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
  17. ^ a b 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.
  18. ^ 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.
  19. ^ "Safe Work Australia". hcis.safeworkaustralia.gov.au. Retrieved 2023-08-25.
  20. ^ 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
  21. ^ 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.
  22. ^ D’Souza, Ryan S. “Neurolytic Blocks.” StatPearls - NCBI Bookshelf, 2022, www.ncbi.nlm.nih.gov/books/NBK537360/#_NBK537360_pubdet_.
  23. ^ http://archive.epa.gov/pesticides/reregistration/web/pdf/3046red.pd [bare URL]
  24. ^ 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
  25. ^ a b 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
  26. ^ "RTECS Number GO7100000". ccinfoweb2.ccohs.ca. Retrieved 2023-08-25.
  27. ^ Hazardous Substances Data Bank (HSDB). National Library of Medicine. Accessed December 2015 at http://toxnet.nlm.nih.gov
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