Functional Category
Antimicrobial preservative; disinfectant
Applications in Pharmaceutical Formulation
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. C 168 Chlorocresol 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.
Description
Colorless or almost colorless, dimorphous crystals or crystalline powder with a characteristic phenolic odor.
Stability and Storage Conditions
Chlorocresol is stable at room temperature but is volatile in steam. Aqueous solutions may be sterilized by autoclaving. On exposure to 1.5 0.0 1000 −1.5 × [2nd deriv. log(1/R)] 1100 1300 1500 1136 1669 1771 1193 1712 2137 2267 2312 2432 2252 2416 1700 1900 2100 2300 2500 Wavelength/nm −0.1 0.5log(1/R) Figure 1: Near-infrared spectrum of chlorocresol measured by reflectance. C Chlorocresol 169 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.
Incompatibilities
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)
Safety
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