Technical Information

Chloroxylenol Toxicology

Much of the toxicology information on chloroxylenol, PCMX, is summarized in a few documents: namely, (1) the 1985 “Final Report on the Safety Assessment of Chloroxylenol” in Journal of the American College of Toxicology (2), (2) “A Review of Available Toxicity Data on the Topical Antimicrobial Chloroxylenol” by Guess and Bruch in 1986 (3), (3) EPA Reregistration Eligibility Decision (RED) Chloroxylenol from 1994 (4), (4) Federal Register Notice: Tentative Final Monograph for Over The Counter (OTC) Healthcare Antiseptic Drug Products from 1994 (5), and the review by Bruch in 1996 on “Chloroxylenol: an old-new antimicrobial” (6). Only a brief review is provided here. Much of the regulatory toxicology review of PCMX has been done through the EPA as part of its registration of pesticides and the FDA as part of its review of Over-The-Counter (OTC) Drugs. This review is done primarily in a chronological manner.

PCMX was marketed in various formulations for nearly 40 years before animal toxicity studies were performed (3). Zondek in 1942 (7) reported that in animals and humans PCMX was well absorbed by the mucous membranes, the vulva, and the palms of the hands and that large amounts were eliminated in the urine. In humans, no toxic effects were noted after topical or subcutaneous dosing at 1g/kg. Free PCMX in urine averaged 15% of the administered dose and the amounts of glucuronide and sulfate metabolic products in humans were 31% of the dose. No PCMX was detected in cerebrospinal fluid of either rabbits or humans studied. Zondek and Finkelstein in 1946 (8) reported on achieving a blood concentration of 4mg% that showed no toxic effect to humans by applying PCMX to the skin.

In 1952 Joseph (9) conducted the first LD₅₀ study with PCMX. From intraperitoneal injections in mice of PCMX in aqueous solutions the LD₅₀ was 2.88 g/25 g mouse. Using the Reed-Muench formula the LD₅₀ was determined to be 120g/kg and the minimum lethal dose (MLD) was 115.2g/kg. In 1962 Calman (10) reported a survey of drugs with positive sensitization reactions (positive patch test results) from 1953 to 1960 from the Institute of Dermatology in England . Of antibacterials (other than antibiotics), PCMX was the third highest on the list with 53 of 220 cases recorded. Dettol (contains 4.8% PCMX, 10% isopropyl alcohol, and 20% terpineol in a castor oil soap base) and other similar products marketed in England around that time had fairly high PCMX concentrations. The author notes that use patterns and concentrations do affect the incidence of positive reactions and that the numbers reported and their proportions may reflect differences in sensitizing potential.

Early toxicology studies were carried out in support of products containing PCMX. In 1963 Elsea and Doyle (11) from the Hill Top Research Laboratories for the Ottawa Chemical Co. reported results on inhalation studies in rats of PCMX dissolved in ethanol and then formulated into an aerosol spray. PCMX was noted to not be toxic at a dose of 205mg/L air during a one hour exposure. In a further report in 1966 from Hill Top Research for the Ottawa Chemical Co. (12), by stomach tube oral administration in rats with corn oil as the vehicle, the oral LD₅₀ of PCMX was determined 3.83g/kg. In this study a rare insight into the only real toxic effect described for PCMX that the effect of dosing included depression, depressed righting, and other reflex depressions indicating central nervous system toxicity as the cause of death. Gross autopsies on all dead rats showed congested lungs, gastrointestinal irritation, dark livers, congested adrenals, and hemorrhagic kidneys. Gross autopsies on surviving animals at termination of the 14 day experiments showed no significant pathologic changes. In a study on eye irritation for the Ottawa Chemical Co. (13) thirty percent (w/v) PCMX in propylene glycol was tested for eye irritation by instillation of a single 0.1ml dose in one eye of each albino rabbits with the untreated eye serving as a control. Ocular responses, graded according to the Draize procedures, showed at 24 hours marked corneal opacity, iritis, and conjunctivitis. Eye irritation was characterized by erythema, edema, and discharge. In the majority of rabbits these signs did not subside appreciably over the 72-hour observation period. When tested by the same procedures, a foot powder containing 0.25% PCMX was a mild ocular irritant (14). Leichliter in 1965 (15) reported on animals exposed to 1.8% PCMX (Ottasept Extra) in polypropylene glycol vs. a control of polypropylene glycol alone. Minimal gross skin irritation with mild erythema and desquamation was noted in each group of animals. Teske and Estep in 1968 for the Ferro Corporation (formerly the Ottawa Chemical Co. and then a PCMX manufacturer) reported on eye irritation studiers in albino rabbits (16). PCMX was applied and the eyes irrigated causing mild to moderate erythema, edema, and discharge for 3-5 days but with no iritis or corneal damage.

Burry in 1969 (17) reported on a retrospective study of 363 cases of dermatological patients with eczema and there was only one case of sensitization to PCMX suggesting that there is a low incidence. Schoor in 1971 (18) commented on the sensitization potential of PCMX and stressed the potential for cross-reactions within the phenol group of antibacterials.

In the early 1970s the FDA convened panels to review ingredients in various drug classes (3). The Panels were charged to review data submitted voluntarily and largely from manufacturers files. This was supplemented with the available literature and expert advice and opinion. Based on the available information the Panels were to decide on the safety and effectiveness of the active ingredients. The Panels were asked to place the ingredients into one of three categories that over the years came to be defined as: (1) Category I- generally recognized as safe and effective and not misbranded, (2) Category II- not generally recognized as safe and effective or misbranded, and (3) Category III- available data are insufficient to classify as safe and effective, and further testing is required. The Antimicrobial I Panel determined that chloroxylenol (PCMX) be classified as Category III. Subsequent to this declaration various groups have continued the evaluation of PCMX and products containing it and have referred such data to the Panel. Some of these studies are summarized here.

Many of the toxicity studies on PCMX had been conducted utilizing Dettol, a product marketed primarily in England . This formulation contained 4.8% PCMX, 10% alcohol, and 20% terpineol in a castor oil based soap. In general, studies on such formulations complicate the interpretation of the toxicity profile of PCMX because it is possible that the inherent toxicity of the vehicle components can be contributory. However, even with the additional potential from added ingredients factored in, a very low order of toxicity emerges from a profile projected from the various toxicological studies. Standard Dettol in various dilutions was evaluated in a primary skin irritation test in rabbits by Harland et al. in 1970 (19). Undiluted and 40% Dettol caused severe necrosis, 10% and 20% dilutions caused severe irritation, and the 2.5% dilution which was normally used on skin showed no edema and only slight irritation and was considered a mild irritant. For the same test on guinea pigs no irritation was found with Dettol dilutions of 2.5% or 25%. Primary skin irritation tests on rabbits with Pakistan Dettol DA102 with and without CX42 were reported by Harland et al. in 1971(20). These studies showed that a 5% dilution was less irritating than the 10% dilution and that the addition of CX42 caused less irritation showing that the specific formulation does make a difference in the agent’s irritant properties.

Dawes and Precce in 1972 (21) reported results of a standard Draize eye irritation test in rabbit eyes of Dettol. Using 0.1 ml of undiluted Dettol, lesions of the cornea and iris persisted for 7 days thereby classifying Dettol as a severe eye irritant. Washing the eyes immediately after instillation greatly reduced the irritative effect. In studying the skin irritating effect a 1% PCMX aqueous solution was evaluated on albino rabbits (22). One tenth of a milliliter of the material was applied to a filter disc and held in contact with the intact, shaved skin of each rabbit under occlusion. After removing the disc in 24 hours the test sites were graded for irritation and edema. No skin reactions were observed. A foot powder containing 0.25% PCMX diluted 1:1 in aqueous solution was applied repeatedly for 4 days. This diluted product (0.125% PCMX) was considered a slight skin irritant (23). Cowen (24) studied undiluted Dettol on the skin of eight human subjects. Dettol caused transient erythema when the skin is covered but the reaction was gone after 24 hours. In studies of PCMX in various vehicles at various concentrations these parameters are seen to influence the results. Marzulli and Maiback in 1973 (25) carried out Draize repeat insult patch testing in 384 males with a racial distribution with 0.5 g PCMX in petrolatum. They found no evidence of sensitization.

In two human bathing studies reported by Jordan et al (26, 27) very little PCMX was shown to be adsorbed from intact skin. In the first study 25 ml of Dettol were added to 125L of water (total PCMX of about 120 mg) and volunteers bathed for 10 minutes. The peak urine concentration of metabolite occurred between 1 and 4 hours and the calculated total amount absorbed after analysis of urine, bath mats, towels, or other materials was about 0.5%. In the second study a single volunteer had 1 ml (46 mg PCMX) of Dettol applied to a 20 m² area of the back and occluded with foil for 30 minutes. Analyses showed that 15.7% of the dose was on or in the skin. Analysis of the urine for up to 48 h showed a recovery of 4.4% PCMX as its conjugate indicating that about 10% of the applied dose had actually been absorbed.

In oral gavage in rats for 4 weeks with varying concentrations from 25-100% of Dettol reported by Hunter et al. in 1973 (28) undiluted Dettol produced emesis so that only a 2 mg/kg per day was tolerated. At a PCMX dose of 240mg/kg salivation and increased resistance to handling occurred. At 120mg/kg some of the same signs were produced and at 6mg/kg the only sign was a slight reduction in food intake in the female rats only. Chesterman et al. in 1973 (29) reported that Dettol caused emetic action and vomiting but it was well tolerated at 2ml/kg/day doses in beagle dogs in 4 week studies. The authors of this study concluded that 5ml/kg/day of a 50% solution of Dettol would be a suitable dose level in a long term study. In a 13 week follow up study by Chesterman et al. (30) the test material was given at doses of PCMX of 1.2, 60, and 120mg/kg/day. The authors reported no deaths, only occasional vomiting (probably vehicle-induced) at the higher doses, no adverse effects on body weight, no effect on food consumption, no eye changes, no histopathologic changes, and no hematologic or biochemical changes related to dosage.

Havler reported in 1974 (31) on the metabolism patterns of PCMX after oral and percutaneous adsorption of carbon-14 labeled chloroxylenol in Dettol. Excretion studies in both rats and dogs after oral dosing showed that PCMX was well absorbed and almost totally excreted in the urine within 24 hours. In a percutaneous study about one-half of the PCMX was absorbed from an occluded patch in 6 hours and excretion in the urine was complete in 24 hours. Plasma levels of radiolabeled material reached a peak concentration of 7.8±0.9μg/ml in 2 hours following percutaneous administration. The same dose given orally peaked at 38.8μg/ml plasma within 30 minutes of dosing. In a dog given only one quarter the dose in rats, peak plasma levels of 39.4-48.0μg/ml were reached in 45-60 minutes. The half life in plasma was 60 minutes in rats and 50 minutes in dogs. All tissues examined showed essentially no radioactivity at the end of 24 hours and most had disappeared by the sixth hour. Urine collected during the first 24 hours showed that metabolism occurred by similar paths in both the rat and dog and PCMX was excreted in a conjugated form as a mixture of glucuronide and sulfate conjugates in a ratio of 6:1 with very low levels of free PCMX. No signs of toxicity were reported.

Davies in 1974 (32) documented the use of Dettol on rabbit vaginal mucosa. At a PCMX dose of 4.8mg/kg/day there were no significant histological changes while at 9.6mg/kg/day some epithelial ulceration in some sections of the vaginal tract were reported. In all other aspects of the study (including food consumption, blood chemistries, hematology, and ophthalmoscopic findings, organ weights, and macroscopic and microscopic pathology) the rabbits treated with these two solutions of Dettol remained similar to controls. Dettol, when tested in a primary irritation test in rabbits, was noted to be a moderate irritant by Moore and Upman (33). When Dettol was tested at its recommended dilution (2.5% PCMX) no edema was found but some erythema was evident scoring it as a mild irritant. When tested on quinea pigs the 2.5% concentration caused no edema or erythema. As Dettol contains 10% alcohol and about 20% terpineol both ingredients probably increase its irritation potential. Ward et al in 1976 (34) determined the Dettol oral LD₅₀ levels in rats to be 17.4ml/kg (range 15.7-19.7). This translates to an oral LD₅₀ of PCMX of 83.52mg/kg. In male rats the oral LD₅₀ was 15.91ml/kg or an LD₅₀ of PCMX of 76.37mg/kg. Bradberry and Hayden reported in 1976 (35) on the effect of Dettol on wound healing evaluated in rats following a midline incision. Five percent Dettol had no effect on the rate of wound healing. Undiluted Dettol did show a delay in healing but at the tenth day the difference was not significant.

In a subchronic 90-day oral gavage study in rats by Harr reported for Pennwalt Company in 1978 (36) comparison was made between PCMX in propylene glycol (3.75% PCMX in 50% propylene glycol) with hexachlorophene at doses of 1 ml/kg or PCMX doses of 8, 24, and 75 mg/kg. At 90 days the results of weight, pathology, clinical signs, and hematology assessments indicated that there were no treatment effects at the 8 mg/kg dose level while the effects from both the 24 and 75 mg/kg doses were very mild with slight hemoconcentration, leukocytosis, and monocytosis. There was no dose effect relationship. At the highest dose the animal responses were considered nonspecific with some animals showing nasal and ocular exudates. There was no specific target organ identified.

In a summary of accidental poisonings from a hospital in England from 1969-1976, Rickitt and Colman reported 1,819 involved PCMX pine products of which 687 were specific to Dettol (37). There were four deaths: one male (age unknown) and three women aged 69, 78, and 92 years. The amount consumed was unknown in one case, about 250 ml for the male and from 150 ml to one bottle for the others. In other cases quantities of up to 350 ml of Dettol containing 16.8 g PCMX were consumed and only signs of sore throat, diarrhea, or gastric pain were reported. Reckitt and Coleman also reported nine adverse reactions from 1973 to 1976 (38) mostly involving dermatitis and from 1962 through 1973 three deaths from Dettol ingestion were recorded, all suicides. In a case report by Meek in 1977 (39) a 66 year old women ingested about 300 ml of Dettol and died about 38 hours afterwards. In the studies by Roberts et al. (40) the permeability coefficient of PCMX to human skin was determined to be 9.84x10⁴ cm/minute. No threshold concentration for damage was observed for any aqueous concentration up to saturation and it produced little or no damage to the skin. Joubert et al. in 1978 (41) reported a case of intentional ingestion of 350 ml of Dettol containing 16.8g of PCMX. Large amounts of conjugated PCMX and minute amounts of free PCMX were found in the urine whereas phenolic compounds presumed to be metabolites and conjugation products were present in the blood. The authors noted that the body has very efficient mechanisms for rapidly metabolizing and eliminating PCMX.

Nelson in 1981 (42) evaluated Ultradex (Dexide, Inc.), a formulated scrub product with 3% PCMX, in an eye irritation test with washing 4 sec. and 30 sec. After instillation only conjunctival redness was observed at 24 hours. This product was not an eye irritant. In 1982 an OTC Panel on antimicrobial drug products concluded that PCMX was safe for topical antifungal use at 0.5 to 3.75% concentrations (43). In a computer model for predicting the general percutaneous absorption kinetics for chemicals based on recognized penetrant molecular weight and lipophilicity, Stavchansky in 1985 (44) showed that there was little chance for accumulation of PCMX in the body even after exaggerated exposures and elevated dose levels because of its rapid metabolism and elimination. The computer model predicted a half life on the order of 2.5 hours which was close to animal data showing an excretion half life on the order of 1 hour.

PCMX at a concentration of 0.2 to 1.0 μg/plate was nonmutagenic in the Salmonella mutagenesis assay, both in the presence and absence of metabolic activation (45). There was no evidence that the liver preparation used metabolized PCMX to mutagenic derivatives. The investigators emphasized that extreme caution should be exercised in any extrapolation of in vitro assay results to projections of in vivo activity. They noted that false positive and false negative results are known to occur with compounds of known toxicity.

In a study to assess the teratogenetic effects of PCMX Jain and Gangwar (46) reported on chicken eggs dipped into 1% Dettol. The embryos were removed and inspected for developmental malformation and no teratogenic effects were observed. The CIR Panel did not believe this study was adequate for assessing the teratogenicity of PCXM.

As of 1981 cosmetic firms participating in the FDA voluntary cosmetic reregistration program reported that PCMX was used as an ingredient in 93 cosmetic products at concentrations of up to 5%. On the basis of the data the CIR Expert Panel concluded that PCMX is safe as a cosmetic ingredient (2).

From the review of data through 1986 as reported by Guess and Bruch (3), PCMX was found to be essentially nontoxic to both animals and humans because of its rapid complete metabolism and elimination. Up to 15% of an applied dose is absorbed through the skin with the percentage dependent on concentration, length of exposure, degree of occlusion and other factors. The data supports that absorbed PCMX is metabolized and excreted so rapidly that blood levels of PCMX cannot be detected unless extremely high doses of PCMX are used. PCMX is an eye irritant but its severity is dependent on the concentration and vehicle used. PCMX is a skin irritant when used in concentrations over 3.75% but the degree of irritation is significantly influenced by the product formulation.

In September, 1994 the US EPA completed its reregistration eligibility review (RED) for chloroxylenol (4). From a toxicology assessment it was noted that the toxicological data base is adequate and supports reregistration. It was reported that chloroxylenol has moderate to low oral, dermal, and inhalation acute toxicity. The actual toxicology is a function of the formulation. In acute oral toxicity studies of chloroxylenol in rats, the LD₅₀ was reportedly 3.83 g/kg in one study (MRID 40223120; guideline 81-1) (4) and greater than 5 g/kg in another (MRID 00147438; guideline 81-1) (4). An acute dermal toxicity study in rats showed an LD₅₀ of greater than 2.0 g/kg (MRID 00137439; guideline 81-2) (47) and an acute inhalation toxicity of an LC₅₀ greater than 6.29 mg/L (MRID 00137440; guideline 81-3) (48). In acute eye irritation studies chloroxylenol is highly toxic (MRID 00069585; guideline 81-4; MRID 00092252; guideline 81-4; and MRID 00137441; guideline 81-4) (49-51). It does not appear to be a dermal irritant or sensitizer (MRID 00137442; guideline 81-5; MRID 41886601; guideline 81-6; and MRID 40223125) (51, 53, 4). In subchronic dermal studies in rabbits the systemic NOEL (No Observed Effect Level) was 180 mg/kg/day and the NOEL for skin irritation was 18 mg/kg/day. The LOEL (Lowest Observed Effect Level) for skin effects was 180 mg/kg/day. In a developmental toxicity study in rats the maternal NOEL was 100 mg/kg/day and the LOEL 500 mg/kg/day. The NOEL for developmental toxicity was 1000 mg/kg/day, the highest dose (MRID 42002702; guideline 83-3) (54). An Ames mutagenicity study in Salmonella typhmurium concluded chloroxylenol was negative for inducing reversion in the standard strains (MRID 41310301) (55), it did not induce a genotoxic effect up to cytotoxic levels (MRID 40704101) (4), and no evidence of mutagenicity or genetic toxicity was found in an in vivo mouse micronucleus assay (MRID 41085301) (56). Tests of a 25 percent solution of chloroxylenol in rats demonstrated the chemical was practically all eliminated in the first 24 hours, mostly in the urine, with small amounts in the feces, after oral or dermal exposure. Except for eye irritation, no toxicological endpoints of concern for acute, short term or chronic exposure to chloroxylenol through occupational or residential exposure have been identified.

While there is little or no evidence of toxic effects from dosing with chloroxylenol (6), the FDA has continued to request long-term studies more in conformity to new drug standards, rather than those of the OTC review for the repeated used handwashing products. Based on their review of the available data in 1994 the OTC Panel in its Monograph has continued to classify PCXM as Category III (57). The Antimicrobial II Panel concluded that PCMX is generally recognized as safe for topical use in athlete’s foot and jock-itch preparations. The Agency also concluded in the amended tentative final monograph for OTC first aid antiseptic drug products that PCMX (0.24% to 3.75%) was safe but not effective for short term use as an OTC topical first aid antiseptic and that the data is insufficient to support a Category I classification of the safety and effectiveness for other long term uses, e.g. antiseptic hand wash or health care personnel hand wash and surgical hand scrub. The Agency concluded that PCMX remains classified in Category III as an active ingredient for these uses. However, the ingredient would be considered safe for short term use as a patient preoperative skin preparation but remains in Category III due to a lack of effectiveness data in this use. The Agency recognizes that the safety data are sufficient to establish safety for short term use such as for a patient preoperative skin preparation drug product but concerns still exist about the long term chronic toxicity. In light of past reviews the Agency agrees with the Panel’s conclusions concerning the safety of using the ingredient in OTC topical antifungal drug products for the treatment of athlete’s foot, jock itch, and ringworm (maximum treatment duration 4 weeks). At the time of review the Agency noted that many of the subchronic studies of PCMX are of limited usefulness because they were conducted using a formulated product that contained isopropyl alcohol, terpineols, and castor oil soap in addition to PCMX. The Agency also concluded that the information was not adequate to characterize the level of adsorption, the distribution, the metabolism, and the excretion of PCMX following topical administration. Regarding the effectiveness of PCMX, the Agency noted that while claims for broad spectrum activity have been made the Commissioner finds that inadequate effectiveness data were submitted and many studies were old and not performed with modern antiseptic testing procedures. They go on to say that while the data regarding the antiseptic activity of PCMX itself are not adequate, the data are considered sufficient to support in vitro effectiveness for the finished products. The finished products contain several additional ingredients which contribute to germicidal activity. The agency supports that PCMX at the concentrations of 0.24% to 3.75% be classified as Category I for safety and Category III for effectiveness for short term uses, i.e. antiseptic hand wash or health care personnel hand wash and surgical hand scrub.

EnviroSystems has commissioned toxicology studies on its formulation of disinfectant cleaner with a 0.2% concentration of PCMX and a PCMX concentration of 50% higher (0.3% PCMX). In primary eye irritation studies in rabbits the product was minimally irritating and met the requirements for EPA Toxicity Category IV for ocular irritation (55). In primary skin irritation studies in rabbits the product was classified as non-irritating and met the requirements for EPA Toxicity Category IV for skin irritation (58). In 2001 the EPA assigned an EnviroSystems’ disinfectant cleaner product with PCMX at a 0.2% concentration as Toxicity Category IV (no harmful dermal, ocular, inhalation, or ingestion affects).

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52. Cummins H, Gardner J. 1983; 4-chloro-3,5-xylenol (PCMX): Acute dermal irritation/corrosivity test in rabbits: LSR Report No. 83/BPT026/246. (Unpublished study received December 27, 1983 under 49403-1; prepared by Life Science Research , Eng.; submitted by Nipa Laboratories, Inc. Wilmington, DE; CDL:252039-E).

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54. Siglin J. 1991; 4-chloro-3,5-xylenol (PCMX): Teratology study in rats. Unpublished study prepared by Springborn Laboratories, Inc. 266p.

55. May K. 1989; Nipacide MX (parpchlorometaxylenol): Assessment of mutagenic potential in histidine auxotrophs of Salmonella typhmurium. Lab Project No.: 89/0690: Nipa/1989/8. Unpublished study prepared by EG & G, Bionomics. 12p.

56. Ivett J. 1989; Mutagenicity test on chloroxylenol in the in vivo mouse micronucleus assay. Final report: Project ID: HLA Study No.:10555-0-455. Unpublished study prepared by Hazleton Laboratories America, Inc. 21p.

57. Federal Register, Proposed Rules. June 17, 1994 ; pp. 31413-39.

58. EnviroSystems, Inc. Unpublished study.