Name: Chlorocresol
CAS No: 4-Chloro-3-methylphenol [59-50-7]
BP: Chlorocresol PhEur: Chlorocresol USP-NF: Chlorocresol
Aptal; Baktol; chlorocresolum; 4-chloro-m-cresol; p-chloro-mcresol; 1-chloro-4-hydroxy-2-methylbenzene; 2-chloro-5-hydroxytoluene; 6-chloro-3-hydroxytoluene; 4-chloro-3-methylphenol; 3- methyl-4-chlorophenol; Nipacide PC; parachlorometacresol; PCMC.
4-Chloro-3-methylphenol [59-50-7]
C7H7ClO 142.58
Chlorocresol is used as an antimicrobial preservative in cosmetics and pharmaceutical formulations. It is generally used in concentrations up to 0.2% in a variety of preparations except those intended for oral administration or that contact mucous membrane.Chlorocresol is effective against bacteria, spores, molds, and yeasts; it is most active in acidic media. Preservative efficacy may be reduced in the presence of some other excipients, particularly nonionic surfactants; see Sections 10 and 12. In higher concentrations, chlorocresol is an effective disinfectant. See Table I.
Colorless or almost colorless, dimorphous crystals or crystalline powder with a characteristic phenolic odor
See Table II
Acidity/alkalinity pH = 5.6 for a saturated aqueous solution Antimicrobial activity Chlorocresol has bactericidal activity against both Gram-positive and Gram-negative organisms (including Pseudomonas aeruginosa), spores, molds, and yeasts. It is most active in acidic solutions, with antimicrobial effectiveness decreasing with increasing pH; it is inactive above pH 9. Antimicrobial activity may also be reduced by loss of chlorocresol from a formulation due to incompatibilities with packaging materials or other excipients, such as nonionic surfactants; see Section 12. Synergistic antimicrobial effects between chlorocresol and other antimicrobial preservatives, such as 2-phenylethanol, have been reported.(1,2) Reported minimum inhibitory concentrations (MICs) for chlorocresol are shown in Table III.(3) Like most antimicrobials, chlorocresol has a non-linear dose response.(4,5) Bacteria Concentrations of approximately 0.08%, with a contact time of 10 minutes, are bactericidal. A typical MIC is 0.02%. Fungi Chlorocresol is active against molds and yeasts. Fungicidal concentrations (after 24 hours of contact) are in the range 0.01–0.04%. Spores At temperatures of 808C or above and in concentrations greater than 0.012%, chlorocresol is active against spores. It is much less active at room temperature. Heating at 98–1008C for 30 minutes in the presence of 0.2% chlorocresol has previously been used as a compendial method for the sterilization of solutions of substances that would not withstand autoclaving. Boiling point 2358C Dissociation constant pKa = 9.55 Flash point 117.88C Melting point Dimorphous crystals with a melting point of 55.58C and 658C. NIR spectra see Figure 1. Partition coefficients Cyclohexane/water = 0.15; Hexane : water = 0.34; Liquid paraffin : water = 1.53; Octanol : water = 3.10; Peanut oil : water = 117. Refractive index 1.5403 Solubility see Table IV. Specific gravity 1.37 at 208C Vapor pressure 0.008 kPa at 208C; 0.67 kPa at 1008C.
Chlorocresol is stable at room temperature but is volatile in steam. Aqueous solutions may be sterilized by autoclaving. On exposure to air and light, aqueous solutions may become yellow colored. Solutions in oil or glycerin may be sterilized by heating at 1608C for 1 hour. The bulk material should be stored in a well-closed container, protected from light, in a cool, dry place.
Chlorocresol can decompose on contact with strong alkalis, evolving heat and fumes that ignite explosively. It is also incompatible with oxidizing agents, copper, and with solutions of calcium chloride, codeine phosphate, diamorphine hydrochloride, papaveretum, and quinine hydrochloride.(7) Chlorocresol is corrosive to metals and forms complex compounds with transition metal ions; discoloration occurs with iron salts. Chlorocresol also exhibits strong sorption or binding tendencies to organic materials such as rubber, certain plastics, and nonionic surfactants.(8–11) Chlorocresol may be lost from solutions to rubber closures, and in contact with polyethylene may initially be rapidly removed by sorption and then by permeation, the uptake being temperature dependent. Presoaking of components may reduce losses due to sorption, but not those by permeation.(12,13) Chlorocresol may also be taken up by polymethylmethacrylate and by cellulose acetate. Losses to polypropylene or rigid polyvinyl chloride are usually small.(14) At a concentration of 0.1%, chlorocresol may be completely inactivated in the presence of nonionic surfactants, such as polysorbate 80.(9) However, other studies have suggested an enhancement of antimicrobial properties in the presence of surfactants.(15,16) Bactericidal activity is also reduced, due to binding, by cetomacrogol, methylcellulose, pectin, or cellulose derivatives.(9,11) In emulsified or solubilized systems, chlorocresol readily partitions into the oil phase, particularly into vegetable oils, and higher concentrations will be required for efficient preservation.(10,17)
Chlorocresol is prepared by the chlorination of m-cresol.
Chlorocresol is used primarily as a preservative in topical pharmaceutical formulations but has also been used in nebulized solutions(18) and ophthalmic and parenteral preparations. It should not, however, be used in formulations for intrathecal, intracisternal, or peridural injection. Chlorocresol is metabolized by conjugation with glucuronic acid and sulfate and is excreted in the urine, mainly as the conjugate, with little chlorocresol being excreted unchanged. Although less toxic than phenol, chlorocresol may be irritant to the skin, eyes, and mucous membranes, and has been reported to cause some adverse reactions when used as an excipient.(19,20) Sensitization reactions may follow the prolonged application of strong solutions to the skin, although patch tests have shown that chlorocresol is not a primary irritant at concentrations up to 0.2%. Chlorocresol is recognized as a rare cause of allergic contact dermatitis.(21) Cross sensitization with the related preservative chloroxylenol has also been reported.(22,23) At concentrations of 0.005% w/v, chlorocresol has been shown to produce a reversible reduction in the ciliary movement of human nasal epithelial cells in vitro, and at concentrations of 0.1% chlorocresol produces irreversible ciliostasis; therefore it should be used with caution in nasal preparations.(24) However, a clinical study in asthma patients challenged with chlorocresol or saline concluded that preservative might be used safely in nebulizer solution.(18) Chlorocresol is approved as safe for use in cosmetics in Europe at a maximum concentration of 0.2%, although not in products intended to come in contact with mucous membranes.(25) Chlorocresol at a concentration as low as 0.05% produces ocular irritation in rabbits.(20) Despite such reports, chlorocresol has been tested in ophthalmic preparations.(26,27) When used systemically, notably in a heparin injection preserved with chlorocresol 0.15%, delayed irritant and hypersensitivity reactions attributed to chlorocresol have been reported.(28,29) See also Section 18. LD50 (mouse, IV): 0.07 g/kg(30) LD50 (mouse, oral): 0.6 g/kg LD50 (mouse, SC): 0.36 g/kg LD50 (rabbit, dermal): >5 g/kg LD50 (rat, dermal): >2 g/kg LD50 (rat, oral): 1.83 g/kg LD50 (rat, SC): 0.4 g/kg
Observe normal precautions appropriate to the circumstances and quantity of material handled. Chlorocresol can be irritant to the skin, eyes, and mucous membranes. Eye protection, gloves, and protective clothing are recommended. Chlorocresol presents a slight fire hazard when exposed to heat or flame. It burns to produce highly toxic fumes containing phosgene and hydrogen chloride.
Included in the FDA Inactive Ingredients Database (topical creams and emulsions). Included in nonparenteral and parenteral medicines licensed in the UK. Included in the Canadian List of Acceptable Non-medicinal Ingredients. In Europe, chlorocresol is approved for use in cosmetics at a maximum concentration of 0.2%; however, it is prohibited for use in products intended to come into contact with mucous membranes. In Japan, use of chlorocresol in cosmetics is restricted to a level of 0.5 g/100 g.
Cresol; chloroxylenol.
A specification for chlorocresol is contained in the Japanese Pharmaceutical Excipients (JPE).(31) The Japanese Pharmaceutical Excipient Directory (JPED) states a maximum concentration of 1 mg/g of chlorocresol in external pharmaceutical preparations.(32) Chlorocresol has a characteristic odor which is difficult to mask in formulations, even at concentrations of 0.05–0.1%. Although used in Europe, chlorocresol is not used in the USA in parenteral formulations. Chlorocresol has also been used as an experimental in vitro diagnostic agent for the diagnosis of hyperthermia.(33,34) The EINECS number for chlorocresol is 200-431-6.