INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 168 CRESOLS This report contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the United Nations Environment Programme, the International Labour Organisation, or the World Health Organization. First draft prepared by Dr L. Papa, US Environmental Protection Agency, Cincinnati, USA Published under the joint sponsorship of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization World Health Organization Geneva, 1995 The International Programme on Chemical Safety (IPCS) is a joint venture of the United Nations Environment Programme, the International Labour Organisation, and the World Health Organization. The main objective of the IPCS is to carry out and disseminate evaluations of the effects of chemicals on human health and the quality of the environment. Supporting activities include the development of epidemiological, experimental laboratory, and risk-assessment methods that could produce internationally comparable results, and the development of manpower in the field of toxicology. Other activities carried out by the IPCS include the development of know-how for coping with chemical accidents, coordination of laboratory testing and epidemiological studies, and promotion of research on the mechanisms of the biological action of chemicals. WHO Library Cataloguing in Publication Data Cresols (Environmental health criteria ; 168) 1.Cresols - adverse effects 2. Environmental exposure I.Series ISBN 92 4 157168 1 (NLM Classification: QV 223) ISSN 0250-863X The World Health Organization welcomes requests for permission to reproduce or translate its publications, in part or in full. Applications and enquiries should be addressed to the Office of Publications, World Health Organization, Geneva, Switzerland, which will be glad to provide the latest information on any changes made to the text, plans for new editions, and reprints and translations already available. (c) World Health Organization 1995 Publications of the World Health Organization enjoy copyright protection in accordance with the provisions of Protocol 2 of the Universal Copyright Convention. All rights reserved. The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the Secretariat of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. The mention of specific companies or of certain manufacturers' products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. CONTENTS ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS 1. SUMMARY 1.1. Identity, properties and analytical methods 1.2. Uses, sources and levels of exposure 1.3. Kinetics and metabolism 1.4. Effects on laboratory mammals; in vitro systems 1.5. Effects on humans 1.6. Effects on other organisms 1.7. Conclusion and recommendations 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1. Identity 2.2. Physical and chemical properties 2.3. Conversion factorsl 2.4. Analytical methods 2.4.1. Sampling 2.4.2. Analytical methods 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1. Natural occurrence 3.2. Anthropogenic sources 3.2.1. Production levels and processes 3.2.2. Uses 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1. Transport and distribution between media 4.1.1. Air 4.1.2. Water 4.1.3. Soil 4.2. Transformation 4.2.1. Abiotic transformation 4.2.2. Biodegradation 4.3. Bioaccumulation and biomagnification 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1. Environmental levels 5.1.1. Air 5.1.2. Water 5.1.3. Soil 5.1.4. Food and beverages 5.2. General population exposure 5.3. Occupational exposure 6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1. Absorption 6.2. Distribution 6.3. Metabolic transformation 6.4. Elimination and excretion 6.5. Endogenous cresols 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1. Single exposure 7.1.1. Inhalation route 7.1.2. Oral route 7.1.3. Dermal route 7.2. Short-term exposure 7.2.1. Inhalation route 7.2.2. Oral route 7.3. Long-term exposure 7.3.1. Inhalation route 7.3.2. Oral route 7.4. Skin and eye irritation 7.5. Reproductive toxicity, embryotoxicity and teratogenicity 7.5.1. Reproduction 7.5.2. Embryotoxicity and teratogenicity 7.6. Mutagenicity and related end-points 7.7. Carcinogenicity 7.8. Other special studies 7.8.1. Neurological effects 7.8.2. Effects on the skin 7.9. Mechanism of toxicity - mode of action 8. EFFECTS ON HUMANS 8.1. General population exposure 8.1.1. Poisoning incidents 8.1.2. Controlled human studies 8.1.3. Cancer 8.2. Occupational exposure 8.2.1. Poisoning incidents 8.2.2. Epidemiological studies 8.3. Subpopulations at special risk 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1. Microorganisms 9.1.1. Aquatic 18.104.22.168 Laboratory studies 22.214.171.124 Field studies 9.1.2. Terrestrial 126.96.36.199 Laboratory studies 188.8.131.52 Field studies 9.2. Plants 9.2.1. Aquatic 184.108.40.206 Laboratory studies 220.127.116.11 Field studies 9.2.2. Terrestrial 18.104.22.168 Laboratory studies 22.214.171.124 Field studies 9.3. Invertebrates 9.3.1. Aquatic 126.96.36.199 Laboratory studies 188.8.131.52 Field investigations 9.3.2. Terrestrial 184.108.40.206 Laboratory studies 220.127.116.11 Field studies 9.4. Vertebrates 9.4.1. Aquatic 18.104.22.168 Laboratory studies 22.214.171.124 Field studies 9.4.2. Terrestrial 126.96.36.199 Laboratory studies 188.8.131.52 Field studies 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1. Evaluation of human health risks 10.2. Evaluation of environmental risks 10.3. Guidance value 11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH 11.1. Conclusions 11.2. Recommendations 12. FURTHER RESEARCH REFERENCES RESUME RESUMEN NOTE TO READERS OF THE CRITERIA MONOGRAPHS Every effort has been made to present information in the criteria monographs as accurately as possible without unduly delaying their publication. In the interest of all users of the Environmental Health Criteria monographs, readers are kindly requested to communicate any errors that may have occurred to the Director of the International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland, in order that they may be included in corrigenda. * * * A detailed data profile and a legal file can be obtained from the International Register of Potentially Toxic Chemicals, Case postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone No. 9799111). * * * This publication was made possible by grant number 5 U01 ES02617-15 from the National Institute of Environmental Health Sciences, National Institutes of Health, USA, and by financial support from the European Commission. Environmental Health Criteria PREAMBLE Objectives In 1973 the WHO Environmental Health Criteria Programme was initiated with the following objectives: (i) to assess information on the relationship between exposure to environmental pollutants and human health, and to provide guidelines for setting exposure limits; (ii) to identify new or potential pollutants; (iii) to identify gaps in knowledge concerning the health effects of pollutants; (iv) to promote the harmonization of toxicological and epidemiological methods in order to have internationally comparable results. The first Environmental Health Criteria (EHC) monograph, on mercury, was published in 1976 and since that time an everincreasing number of assessments of chemicals and of physical effects have been produced. In addition, many EHC monographs have been devoted to evaluating toxicological methodology, e.g., for genetic, neurotoxic, teratogenic and nephrotoxic effects. 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Content The layout of EHC monographs for chemicals is outlined below. * Summary - a review of the salient facts and the risk evaluation of the chemical * Identity - physical and chemical properties, analytical methods * Sources of exposure * Environmental transport, distribution and transformation * Environmental levels and human exposure * Kinetics and metabolism in laboratory animals and humans * Effects on laboratory mammals and in vitro test systems * Effects on humans * Effects on other organisms in the laboratory and field * Evaluation of human health risks and effects on the environment * Conclusions and recommendations for protection of human health and the environment * Further research * Previous evaluations by international bodies, e.g., IARC, JECFA, JMPR Selection of chemicals Since the inception of the EHC Programme, the IPCS has organized meetings of scientists to establish lists of priority chemicals for subsequent evaluation. Such meetings have been held in: Ispra, Italy, 1980; Oxford, United Kingdom, 1984; Berlin, Germany, 1987; and North Carolina, USA, 1995. The selection of chemicals has been based on the following criteria: the existence of scientific evidence that the substance presents a hazard to human health and/or the environment; the possible use, persistence, accumulation or degradation of the substance shows that there may be significant human or environmental exposure; the size and nature of populations at risk (both human and other species) and risks for environment; international concern, i.e. the substance is of major interest to several countries; adequate data on the hazards are available. If an EHC monograph is proposed for a chemical not on the priority list, the IPCS Secretariat consults with the Cooperating Organizations and all the Participating Institutions before embarking on the preparation of the monograph. 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It is accepted that the following criteria should initiate the updating of an EHC monograph: new data are available that would substantially change the evaluation; there is public concern for health or environmental effects of the agent because of greater exposure; an appreciable time period has elapsed since the last evaluation. All Participating Institutions are informed, through the EHC progress report, of the authors and institutions proposed for the drafting of the documents. A comprehensive file of all comments received on drafts of each EHC monograph is maintained and is available on request. The Chairpersons of Task Groups are briefed before each meeting on their role and responsibility in ensuring that these rules are followed. WHO TASK GROUP MEETING ON ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS Members Dr D. Anderson, British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom Dr M.R. Elwell, National Institute of Health, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina, USA Dr A. Meharg, Institute of Terrestrial Ecology, Monks Wood, Abbots Ripton, Huntingdon, United Kingdom Dr C.-N. Ong, Department of Community, Occupational and Family Medicine, National University of Singapore, Singapore (Vice-Chairman) Dr Y. Pang, Division of Standard Setting, Chinese Academy of Preventive Medicine, Beijing, China Dr L. Papa, System Toxicants Assessment Branch, Office of Research and Development, Environmental Criteria and Assessment Office, US Environmental Protection Agency, Cincinnati, Ohio, USA (Rapporteur) Dr A. Pinter, National Institute of Hygiene, Budapest, Hungary Dr S. Soliman, Pesticide Chemistry and Toxicology, College of Agriculture and Veterinary Medicine, Bureidah, Saudi Arabia Dr F.M. Sullivan, Division of Pharmacology and Toxicology, St Thomas's Hospital, London, United Kingdom (Chairman) Secretariat Dr B.H. Chen, International Programme on Chemical Safety, World Health Organization, Geneva, Switzerland (Secretary) Dr D. McGregor, Unit of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, Lyon, France ENVIRONMENTAL HEALTH CRITERIA FOR CRESOLS A WHO Task Group on Environmental Health Criteria for Cresols met at the British Industrial Biological Research Association (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom, from 27 June to 1 July 1994. Dr D. Anderson opened the meeting and welcomed the participants on behalf of the host institution. Dr B.H. Chen, IPCS, welcomed the participants on behalf of the Director, IPCS, and the three cooperating organizations (UNEP/ILO/WHO). The Task Group reviewed and revised the draft monograph and made an evaluation of the risks for human health and the environment from exposure to cresols. Drs N.N. Molodkina, L.P. Kuzmina and A.L. Germanova, Centre for International Projects, Moscow, Russian Federation, prepared a preliminary draft. The first draft of this monograph was prepared by Dr L. Papa, US Environmental Protection Agency, Cincinnati, USA. The second draft was also prepared by Dr L. Papa, incorporating comments received following the circulation of the first draft to the IPCS Contact Points for Environmental Health Criteria monographs. Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS Central Unit, were responsible for the overall scientific content and technical editing, respectively. The efforts of all who helped in the preparation and finalization of the monograph are gratefully acknowledged. * * * * Financial support for this Task Group was provided by the United Kingdom Department of Health as part of its contributions to the IPCS. 1. SUMMARY 1.1 Identity, properties and analytical methods Cresols are isomeric substituted phenols with a methyl substituent at either the ortho, meta or para position relative to the hydroxyl group. Commercial cresol, also known as cresylic acid, contains all three isomers with small amounts of phenol and xylenols. However, commercial products contain up to 30% xylenol and 60% C9-phenols and are known as "cresylic acids". Physically, cresols consist either of a white crystalline solid or a yellowish liquid and have a strong, phenol-like odour. They are highly flammable and are soluble in water, ethanol, ether, acetone and alkali hydroxides. Cresols undergo electrophilic substitution reactions at the vacant ortho or para position relative to the hydroxyl group. They also undergo condensation reactions with aldehydes, ketones or dienes. Several methods can be used for determining the presence of cresols in both environmental and biological media. The most commonly used methods are gas chromatography with flame ionization detection (GC-FID), gas chromatography with mass spectrophotometry (GC-MS) and high-performance liquid chromatography (HPLC). Sampling of cresols in air can be done by passing air through absorption cells using sodium hydroxide or solid adsorbents. 1.2 Uses, sources and levels of exposure Cresols have a wide variety of uses as solvents or disinfectants or as intermediates in the production of numerous other substances. These compounds are most commonly used in the production of fragrances, antioxidants, dyes, pesticides and resins. Ortho- and para-cresols are used in the production of lubricating oils, motor fuels and rubber polymers, while meta-cresol is used in the manufacture of explosives. Cresols and cresol derivatives occur naturally in oils of various plants, including Yucca gloriosa flowers, jasmine, Easter lily, conifers, oaks and sandalwood trees, and are also a product of combustion from natural fires and volcanic activity. Para-cresol is found in the urine of animals and humans. Commercially cresols are produced as by-products in the fractional distillation of crude oil and coal tars. Small amounts are produced in vehicle exhaust, municipal waste incinerators and from coal and wood combustion. Cigarette smoke also contains cresols. The worldwide production of cresols is unknown; annual production in the USA in 1990 was reported to be 38 300 tonnes. Environmental transport of cresols occurs through the vapour phase of the atmosphere and from the atmosphere to surface water and soil by rain-scavenging. Due to their volatilization, binding to sediment and biodegradation, only small amounts of cresols are found in water. In soils, cresols are slightly to highly mobile depending on the sorption coefficient (Koc) of the soil. Cresols have been detected in ground water, and so leaching must occur in soil. Exposure to cresols can occur through air, water or food. The median air concentration of o-cresols was 1.59 µg/m3 (0.359 ppb) for 32 source-dominated sites in the USA. Surface water concentrations in the USA range from below the detection limit to 77 µg/litre (STORET, 1993). Levels of 204 µg/litre were reported in Japan in a river polluted by industrial effluents. Concentrations as high as 2100 µg/litre for o-cresol and 1200 µg/litre for mixed m- and p-cresols have been detected in waste waters. Rainwater concentrations range from 240 to 2800 ng/litre for o-cresol and 380 to 2000 ng/litre for p- and m-cresol combined. Cresols have been detected in foods and beverages. Concentrations in spirit beverages were found to be within the range of 0.01-0.2 mg/litre. The amount in tobacco smoke is 75 µg in a nonfilter American cigarette (85 mm). The general population can be exposed to cresols from air inhalation, drinking-water, food and beverage ingestion and dermal contact. In general, the lack of adequate monitoring data makes the quantitative estimates of daily intakes of cresol from these sources impossible. Occupational exposure levels as high as 5.0 mg/m3 have been reported. 1.3 Kinetics and metabolism Cresols are absorbed across the respiratory and gastrointestinal tracts and through the skin. The rate and extent of absorption of cresols has not been studied specifically. However, studies have shown that gastrointestinal and dermal absorption are rapid and extensive. Cresols are distributed to all the major organs. The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. Minor metabolic pathways for cresols include hydroxylation of the benzene ring and side-chain oxidation. The main route for elimination of cresols from the body is renal excretion in the form of conjugates. 1.4 Effects on laboratory mammals; in vitro systems Acute poisoning with cresol vapours is unlikely due to the low vapour pressure of these compounds. Mean lethal concentrations of cresols in rats have been reported to be 29 mg/m3 for o- and p-cresols and 58 mg/m3 for m-cresol. Oral LD50 values in rats have been reported to be 121, 207 and 242 mg/kg body weight for o-, p- and m-cresols, respectively. Interspecies comparisons show that all three isomers are more toxic to mice than to rats and that toxicity increases with concentration. Systemic toxicity and death can result from dermal exposure. Dermal LD50 values in rabbits were 890, 2830, 300 and 2000 mg/kg body weight for o-, m-, p-and mixed cresols, respectively. In rats dermal LD50 values were 620, 1100, 750 and 825 mg/kg body weight for o-, m-, p- and dicresol, respectively. Cresols are highly irritating to the skin and eyes of rabbits, rats and mice. Short-term exposure to inhaled mixtures of o-cresol aerosol and vapour resulted in irritation of the respiratory tract, small haemorrhages in the lung, body weight reduction and degeneration of heart muscle, liver, kidney and nerve cells. Short-term (28-days) oral exposure to daily doses of approximately 800 mg/kg body weight or more resulted in reduced body weights, organ weight changes and histopathological changes in the respiratory and gastrointestinal tracts of rats. In mice, similarly exposed at 1500 mg/kg body weight, more severe effects were reported, and at the highest concentrations death resulted from exposure to o-, m- and p-cresols but not from exposures to mixtures of isomers. Longer-term exposure of rats to vapours of o-, m- or p-cresol for up to 4 months resulted in weight loss, reduced locomotor activity, inflammation of nasal membranes and skin, and changes in the liver. Oral exposures for up to 13 weeks of mice, rats and hamsters resulted in mortality, tremor, reduced body weights, haematological effects, increase in organ weight, and hyperplasia of nasal and forestomach epithelium. Oral and inhalation exposure to cresol isomers result in lengthened estrus cycle and histopathological changes in the uterus and ovaries of rats and mice. No adverse effects on spermatogenesis were observed in rats or mice. Mild fetotoxic effects have been reported in rats and rabbits exposed to o- and p-cresols, but only minor treatment-related developmental effects have been reported. Some evidence of genotoxicity has been reported to result in vitro from treatment with o- and p- cresols but not m-cresol. No positive results were obtained in in vivo studies. However, some evidence of promotive activities in skin has been reported. No studies of carcinogenicity have been reported for any cresol isomers. 1.5 Effects on humans Ingestion of cresols results in burning of the mouth and throat, abdominal pain and vomiting. The target tissues/organs of ingested cresols in humans are the blood and kidneys, and effects on the lungs, liver, heart and central nervous system have also been reported. In severe cases, coma and death may result. Dermal exposure has been reported to cause severe skin burns, scarring, systemic toxicity and death. Occupational exposure to cresols usually results from dermal contact. Acute exposures can result in severe burns, anuria, coma and death. Very few data are available regarding reproductive effects and there are no data on carcinogenicity in humans. 1.6 Effects on other organisms Observations on microorganisms, invertebrates and fish have shown that cresols may represent a risk to non-mammalian organisms at point sources with high cresol concentration but not in the general environment. 1.7 Conclusion and recommendations At concentrations normally found in the environment, cresols do not pose any significant risk for the general population. However, the potential for adverse health effects exists in the case of people with renal insufficiency or specific enzymic deficiency and under conditions of high exposure. Cresols may represent a risk to microorganisms, invertebrates and fish at point sources with high cresol concentrations but not in the general environment. No information is available regarding the effects of chronic exposure to cresols. Therefore, there is inadequate information to assess the carcinogenic hazard of cresols. Based on the results of subchronic studies, an NOAEL of 50 mg/kg body weight per day can be established for all three cresol isomers. An uncertainty factor of 300 was recommended, composed as follows: 10 to account for interspecies variation; 10 to account for the lack of chronic toxicity studies and possible genotoxic and promoting activity of cresols, and 3 to account for intraspecies variation based on the rapid and complete metabolism. Therefore, an acceptable daily intake (ADI) of 0.17 mg/kg body weight per day can be established for cresols. 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS 2.1 Identity Cresols are isomeric substituted phenols with a methyl substituent at either the ortho, meta or para positions relative to the hydroxyl group. Commercial cresol, also known as cresylic acid, contains all three isomers with small amounts of phenol and xylenols (Deichmann & Keplinger, 1981). Mixtures of m- and p-cresol and of o-, m- and p-cresol are occasionally called dicresol and tricresol, respectively (Fiege & Bayer, 1987). Pure and commercial cresol or cresylic acid is different from the commercial products called "cresylic acids". The substance "cresylic acids" is a mixture of phenolic compounds with a typical composition as follows: 0-1% m- and p-cresol; 0-3% 2,4- and 2,6-xylenols; 10-20% 2,3- and 3,5-xylenols; 20-30% 3,4-xylenol; and 50-60% C9-phenols (Sax & Lewis, 1987). The chemical identity of cresols is shown in Table 1. Commercial cresols are manufactured in a wide range of grades and purities to suit the user's requirements. Typically, technical grade cresol available in the USA contains about 20% o-cresol, 40% m-cresol, 30% p-cresol, and 10% phenol and xylenols (Deichmann & Keplinger, 1981). The individual isomers are available at purity levels as low as 85% and as high as > 99% from chemical suppliers in the USA. 2.2 Physical and chemical properties The physical properties of the three individual isomers and the mixture are given in Table 2. Chemically, cresols behave similarly to phenol. These compounds undergo electrophilic substitution reactions at the vacant ortho or para position relative to the hydroxyl group. Chlorination, bromination, sulfonation and nitration are examples of such substitution reactions. Cresols can undergo condensation reactions with aldehydes, ketones and dienes (Fiege & Bayer, 1987). 2.3 Conversion factors Air at 25°C: 1 ppm = 4.42 mg/m3 1 mg/m3 = 0.23 ppm Table 1. Chemical identity of cresols o-Cresol p-Cresol m-Cresol Mixture Chemical structure: Empirical formula: C7H8O C7H8O C7H8O C7H8O Relative molecular mass: 108.14 108.14 108.14 108.14 Common synonyms: 2-methyl phenol 4-methyl phenol 3-methyl phenol methyl phenol 2-hydroxy toluene 4-hydroxy toluene 3-hydroxy toluene hydroxy toluene o-cresylic acid p-cresylic acid m-cresylic acid cresylic acid acide cresylique (French) cresoli (Italian) kresolen (Dutch) krezol (Polish) kresol (German) IUPAC name: 2-hydroxy toluene 4-hydroxy toluene 3-hydroxy toluene hydroxy toluene CAS registry number: 95-48-7 106-44-5 108-39-4 RTECS: G06300000 G06475000 G06125000 G05950000 EEC number: 604-004-00-9 604-004-00-9 604-004-00-9 604-004-00-9 Table 2. Physical and chemical properties of cresolsa o-Cresol m-Cresol p-Cresol Mixturef Physical state and colour: white crystalline solid colourless to yellowish crystalline solid or colourless to yellowish or yellowish liquid liquid yellowish liquid liquid Odour: phenol-like phenol-like phenol-like phenol-like Air odour thresholdb: 1.4 mg/m3 0.007 mg/m3 0.004 mg/m3 ND Melting point (°C): 30.94 12.22 34.74 11-35 Boiling point at 1 atm (°C): 191.0 202.32 201.94 191-203 Flash point, closed cup (°C): 81 86 86 82 Ignition point (°C): 598 558 558 ND Vapour pressure at 25°C (mmHg): 0.31 0.143 0.13 0.975 (at 38-53°C)g Relative density at 25°C (g/cm3): 1.135 1.030 1.154 1.03-1.038 Refractive index at 25°C: 1.544 1.540 1.539 ND Vapour density (air = 1 at 20°C): 3.7 3.72 3.72 NDe Solubility in water at 25°C (g/litre)c: 25.95 22.70 21.52 ND Solubility in other solvents: soluble in ethanol, soluble in ethanol, soluble in ethanol, soluble in ethanol, ethyl ether, acetone, ethyl ether, acetone, ethyl ether, acetone, glycol, aqueous benzene, aqueous benzene, aqueous benzene, aqueous alkali hydroxides alkali hydroxides alkali hydroxides alkali hydroxides Table 2 (contd). o-Cresol m-Cresol p-Cresol Mixturef Sorption coefficient, Koc (all isomers)d 22-3420 Log n-octanol/water partition coefficiente (log Ko/w): 1.95 1.96 1.94 ND pKa (25°C): 10.287 10.09 10.26 ND Bioconcentration factorsh 14.1 19.9 ND ND Odour threshold in water (mg/litre)i,j 1.4 0.8 0.2 ND Taste threshold concentration in water (mg/litre)j 0.003 0.002 0.002 ND Saturation concentration in air (g/m3)j at 20°C 1.2 0.24 0.24 ND at 30°C 2.8 0.68 0.74 ND a Adapted from: Weast et al. (1988); Sax & Lewis (1987); Windholz et al. (1983); Riddick et al. (1986), unless otherwise specified b Amoore & Hautala (1983) c Yalkowsky et al. (1987) d Boyd (1982); Southworth & Keller (1986); Koch & Nagel (1988) e Hansch & Leo (1985) f No data g Parrish (1983) h Freitag et al., (1982) i Dietz & Traud (1978) j Verschuesen (1983) 2.4 Analytical methods 2.4.1 Sampling As is the case with any other analyte, sample loss and contamination should be avoided during the collection, storage and analysis of samples for cresol determination. Glass bottles, vials or tubes have been used for the collection of environmental samples (US EPA, 1982). Polyethylene containers are suitable for the collection of biological samples (US NIOSH, 1989). Environmental aqueous samples can be stored for a limited time (28 days) by adding sulfuric acid to a pH < 2 (US EPA, 1982). Thymol has been used as a preservative for biological samples (US NIOSH, 1989). Environmental and biological samples that are to be shipped from the collection site to the laboratory are cooled in ice. Cresols in air can be sampled by passing air through an absorption cell containing 0.1 N sodium hydroxide solution (Manita, 1966). More recent methods use solid adsorbents such as XAD-2 or silica gel for trapping cresols from air (Neiminen & Heikkila, 1986; US NIOSH, 1989). In a novel system, a miniaturized enrichment unit has been used to concentrate cresols and other water-soluble analytes in air by a water mist (Vecera & Janak, 1987). Aqueous samples can be collected either by manual grab methods or by automated samplers. Composite samples can be obtained by combining random samples collected manually or by automated samplers (US EPA, 1982). Several mechanical devices are available for collecting random or composite semi-solid and solid samples either by grab or automated methods (US EPA, 1982, 1986). 2.4.2 Analytical methods Some of the methods used in measuring cresols in various environmental and biological media are given in Table 3 along with their corresponding references. The problem with the determination of cresols by gas chromatography arises as a result of non-reproducible elution from the gas chromatography column due to the polar and volatile nature of cresols. Special columns or derivatization of the cresols may alleviate the problem. Cresols are present in biological samples as conjugates, and a hydrolysis method is used to release free cresols. There is no consensus on the reliability of total hydrolysis of the cresol conjugates (Balikova & Kohlicek, 1989). Chudyk et al. (1985) tested a remote fluorescence technique using ultraviolet laser fibre optics to analyse groundwater contaminants, including o-cresol, in artificially prepared solutions. No data were given on the detection limits or on the use of this technique in the field. However, the authors speculated that the sensitivity is at or below parts per billion levels at an instrument/analyte distance of 25 m. Hoshika & Muto (1978) described a simple and rapid gas-liquid-solid chromatographic (GLSC) method for the determination of trace concentrations of 11 phenols including all isomers of cresol in air. This method has been adopted and recommended by many other investigators for measuring cresols in air samples. To overcome interference by certain acidic compounds such as lower fatty acids and mercaptans, the method uses two precolumns, a Tenax-GC and a Tenax-GC plus alkaline. The gas chromatograph used was equipped with a flame ionization detector (FID), a digital integrator and a glass analytical column. With the Tenax-GC plus alkaline precolumn the phenol peaks disappeared completely in the chromatograms, enabling phenols to be identified by comparison with the chromatograms from the ordinary Tanex-GC precolumn. The detection limit for cresols by this method was reported to be at the ppb level. Table 3. Sampling and analytical methods for determining cresols in environmental and biological samples Sample Analytical Sample detection Percentage matrix Preparation method methodb Isomer limit recovery Reference Air Air pump air through adsorbent tube; HPLC/UV o, m, p 0.3 ppt 90-110% Kuwata & Tanaka desorb with methanol (1988) Air aerodispersive enrichment into HPLC/ED o no data no data Vecera & Janak water (1987) Air pump air through silica gel tube; GC-FID o, m, p no data 98% at US NIOSH (1989) desorb with acetone 22 mg/m3 Air pump air through mixed cellulose HPLC-UV o, m, p 0.5 ppb 52.4% Risner (1993) ester membrane connected to silica Sep-Pak, desorp with 1% acetic acid in acetonitrile Auto exhaust vapour collected in fritted bubbler HPLC-UV o, m, p 0.1-0.5 no data Kuwata et al. and tobacco with aqueous NaOH buffered to pH 11.5; ng/sample (1981) smoke add p-nitrobenzene-diazonium tetra-fluoroborate; extract with CCl4 Air and water Air and water mix NaOH solution from bubbler in case spectrophotometry o, m, p 0.005-0.03 no data Druyan (1974) of air and distillate of water samples (TLC) µg/sample in 1 N NaOH solution with p-nitrophenyl-diazonium at pH 7-9; extract with ether; spot on TLC plate Table 3 (contd). Sample Analytical Sample detection Percentage matrix Preparation method methodb Isomer limit recovery Reference Water adjust pH to 11; extract with GC/MS o, p 10 µg/litre no data US EPA (1988) CH2Cl2; concentrate Water solvent extraction, liquid GC/MS not no data no data Hites (1979) chromatography prefractionation specified Water adjust pH to 8-9; extract with spectrophotometry o, m 4 µg/litre 99-100.1% Hassan et al. chloroform-ether; back extract (VIS) at 5-120 (1987) in 0.1 N aqueous NaOH; add NaNO2 µg/litre and H2SO4; remove excess NO; add resorcinol Water direct flow and spectrophotometry o, m 10-30 µg/litre 90-115% Khalaf et al. stopped-flow injection, then (VIS) (1993) derivatization with p-aminophenol Rainwater direct injection onto ion exchange HPLC/CD o, m, p no data no data Hoffman & column Tanner (1986) Rainwater acidify; extract with CH2Cl2; GC/MS o, m, p no data > 50% Kawamura & concentrate, methylate Kaplan (1986) Soil Soil, extract sample with CH2Cl2 using GC/MS o, p 330 ppb no data US EPA (1988) sediment ultrasonic probe Table 3 (contd). Sample Analytical Sample detection Percentage matrix Preparation method methodb Isomer limit recovery Reference Sediment extract rapidly stirred sediment GC/MS not no data no data Goodley & Gordon slurry with CH2Cl2 or ether, specified (1976) concentrate Biological samples Expired draw air through XAD-2 adsorbent HPLC/ED o, m, p 8 µg/m3 no data Neiminen & air tube; acetonitrile desorbtion Heikkila (1986) Expired collect breath in Teflon bag; GC/MS not no data no data Krotoszynski & air concentrate on Tenax GC absorbent; specified O'Neill (1982) thermal desorption Beef steam distil; extract distillate HRGC/MS o, m, p 0.2 mg/kg 83-98% at Matsumoto et al. with ether 20-100 µg (1989) per sample Urine hydrolyse with sulfuric acid; GC/FID o, m, p no data 78-97% Needham et al. extract with ethyl acetate (1984) Urine hydrolyse with HCl and extract with HPLC/UV o, m, p 1 mg/litre 97-102% Yoshikawa et al. isopropyl ether; remove solvent; (1986) dissolve residue in water; add ß-cyclodextrin Urine acidify; steam distil; extract with GC/MS o no data no data Angerer & Wulf methylene chloride (1985) Urine hydrolyse with sulfuric acid; extract HPLC/UV o no data no data DeRosa et al. with CH2Cl2; concentrate (1987) Table 3 (contd). Sample Analytical Sample detection Percentage matrix Preparation method methodb Isomer limit recovery Reference Urine hydrolyse with HCl or HClO4; extract GC-FID p 0.5 mg/litre 95% at US NIOSH (1989) with ether 50 µg/ml Urine and hydrolyse with H3PO4; extract with GC-FID o, m, p 1 mg/litre 69.4-73.3% Balikova & serum n-hexane, acetylate extract at 50 Kohlicek (1989) mg/litre Faeces and homogenize faeces and hydrolyse HPLC-fluorescence p < 1 µg/kg for 99.4-101.9% Murray & Adams urine urine buffered to pH 5.5, steam detector faeces; (1988) distil < 1 µg/litre for urine a 0.01 nmol = 1.08 ng b CD = conductivity detector; ED = electrochemical detector; FID = flame ionization detector; GC = gas chromatography; HPLC = high-performance liquid chromatography; HRGC = high-resolution gas chromatography; m = meta-cresol; MS = mass spectrometry; o = ortho-cresol; p = para-cresol; UV = ultraviolet detector 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE 3.1 Natural occurrence Cresols and cresol derivatives occur naturally in various plants. They are present in oils from jasmine, cassia, Easter lily, ylang ylang, and Yucca gloriosa flowers and in peppermint, eucalyptus and camphor. Oils from conifers, oaks and sandalwood trees also contain cresol (Fiege & Bayer, 1987). Mammalian urine and faeces naturally contain p-cresol (section 6.5). Poultry manure reportedly contains p-cresol at an average concentration of 11.7 mg/kg (Yasuhara, 1987). Cresols are frequently produced as metabolic intermediates in the degradation of bound phenols by soil microorganisms. They are also products of combustion and can be released to the atmosphere from natural fires associated with lightning, spontaneous combustion and volcanic activity (McKnight et al., 1982). 3.2 Anthropogenic sources Cresols are contained in crude oil and coal tar. Therefore, the dominant anthropogenic sources of cresols are accidental and process discharge during the manufacture, use, transport and storage of cresols or associated products of the coal tar and petroleum industries. Cresols are also produced during coal gasification (Giabbai et al., 1985; Neufeld et al., 1985), coal liquefaction (Fedorak & Hrudey, 1986) and shale oil production (Snider & Manning, 1982; Dobson et al., 1985). Low levels of cresols are present in the exhaust of vehicles powered with petroleum-based fuels (Hampton et al., 1982; Johnson et al., 1989), stack emissions from municipal waste incinerators (Junk & Ford, 1980; James et al., 1984), and emissions from the incineration of vegetable materials (Liberti et al., 1983). Cresols are also found in fly ash from coal and wood combustion (Junk & Ford, 1980; Hawthorne et al., 1988, 1989). Cigarette smoke contains cresols (Wynder & Hoffmann, 1967). In addition, the atmospheric reaction of toluene with photochemically generated hydroxyl radicals (HO*) produces cresols (Leone et al., 1985). 3.2.1 Production levels and processes The oldest cresol production method used in the USA is fractional distillation of coal tar. Most cresols in the USA are obtained via catalytic and thermal cracking of naphtha fractions during petroleum distillation. Since 1965, quantities of coal tar and petroleum isolates have been insufficient to meet the rising demand for cresols in the USA. Consequently, several processes for the manufacture of the various isomers have been developed. One method of producing o-cresol is by the methylation of phenol in the presence of catalysts. Another method uses toluene sulfonation followed by alkaline hydrolysis to produce p-cresol. Until 1972, cresols were also produced by the cymene-cresol process, where cymene ( p-isopropyltoluene) is oxidized to cymene hydroperoxide, which decomposes to cresols and acetone. This method is capable of producing p- or m-cresol from the corresponding cymene isomer. Alkaline chlorotoluene hydrolysis is used to produce a cresol mixture with a high m-cresol content (Fiege & Bayer, 1987). The total production of cresols in the USA, excluding production from coke oven and gas-retort ovens, was 34 400 tonnes in 1989 and 38 300 tonnes in 1990 (USITC, 1990, 1991). According to the Toxic Release Inventory (TRI) database, maintained by the US EPA, manufacturing and processing industries in the USA in 1987 released or transferred 52 tonnes of cresols to air, water and land, 172.5 tonnes to wastewater treatment plants, and 20.45 tonnes to off-site locations for disposal (US EPA, 1989). The TRI data may have under-estimated the actual release since only certain types of facilities were required to report. 3.2.2 Uses A considerable amount of o-cresol is consumed directly as either a solvent or disinfectant. o-Cresol is also used as a chemical intermediate for a variety of products, including deodorizing and odour-enhancing compounds, pharmaceuticals, fragrances, antioxidants, dye and dye intermediates, pesticides and resins. Recently, an increasing proportion of o-cresol has been devoted to the formulation of epoxy- o-cresol novolak resins (sealing materials for integrated circuits silicon chips). o-Cresol is also used as an additive to phenol-formaldehyde resins (Windholz et al., 1983; Fiege & Bayer, 1987; Sax & Lewis, 1987). p-Cresol is mainly used in the formulation of antioxidants such as 2,6-di- tert-butyl- p-cresol for lubricating oil and motor fuels, rubber, polymers, elastomers and food products. It is also used as an intermediate in the fragrance and dye industries (Windholz et al., 1983; Fiege & Bayer, 1987; Sax & Lewis, 1987). m-Cresol, either pure or mixed with p-cresol, is important in the production of contact herbicides and insecticides. Furthermore, many flavour and fragrance compounds and several important antioxidants are produced from m-cresol. It is also used in the manufacture of explosives (Fiege & Bayer, 1987). Mixtures of m- and p-cresol are used as disinfectants and preservatives. Crude cresols are used as wood preservatives. Tricresyl phosphate and diphenyl cresyl phosphate produced from m- and p-cresol mixtures are used as flame-retardant plasticizers for polyvinyl chloride and other plastics, fire-resistant hydraulic fluids, additives for lubricants and air filter oils. Cresol mixtures condensed with formaldehyde are important for modifying phenolic resins. Cresols are also used in paints and textiles. Mixtures of cresols are used as solvents for synthetic resin coatings such as wire enamels, metal degreasers, cutting oils and agents to remove carbon deposits from combustion engines. They are also used in ore flotation, fibre treatment and photography (Deichmann & Keplinger, 1981; Windholz, 1983; Fiege & Bayer, 1987). 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION 4.1 Transport and distribution between media 4.1.1 Air The levels of cresols in the atmosphere will be regulated by the physical properties of the compounds, their chemical reactivity and by prevailing weather conditions (wind speed, precipitation, temperature inversions, etc.). The vapour pressures of cresols range from 0.13 to 0.31 mmHg (Table 2); compounds with values greater than 0.0001 mmHg should exist predominantly in the vapour phase (Eisenreich et al., 1981) as opposed to the particulate-bound phase (Cautreels & van Cauwenberghe, 1978). Photochemical attack (section 4.2) and rain scavenging (Leuenberger et al., 1985; Czuczwa et al., 1987) rapidly remove cresols from the vapour phase, counteracting the tendency of compounds that exist in the vapour phase to be transported over long distances. 4.1.2 Water The processes that control the transport of cresols from water and their distribution in water are volatility, values for the sorption coefficient (Koc) to suspended solids and sediment, and bioaccumulation in aquatic organisms. The bioaccumulation of cresols in aquatic organisms is discussed in section 4.3. The volatility of a compound can be qualitatively predicted from its Henry's Law constant (H). The rate of volatilization from water is high for compounds with H values ranging from 10-2 to 10-3 atm-m3/mol, and it is very low for compounds with H values of 10-7 atm-m3/mol or less (Lyman et al., 1990). Therefore, transport of cresols with H values of 1.26 × 10-6 to 7.92 × 10-7 atm-m3/mol from water to the atmosphere will not be significant. Furthermore, the ability of these phenolic compounds to dissociate and to form hydrogen bonds, leading to binding with both suspended solids or sediments, will decrease the rate of volatilization even further. Since the cresols are soluble in water (see Table 2), the small amounts of cresols typically found in the aquatic environment will be present mostly in the aqueous phase. However, transport of cresols from water to bottom sediment is possible as a result of sorption and subsequent precipitation. For hydrophobic compounds, the importance of the sorption process can usually be predicted from the Koc values. Details of Koc levels are given in section 4.1.3. 4.1.3 Soil Koc values in soil of between 22 and 3420 have been reported (Boyd, 1982; Southworth & Keller, 1986; Koch & Nagel, 1988). The sorption of cresols to several soils correlates well with both pH and clay mineral content in soil (Artiola-Fortuny & Fuller, 1982), and several investigators reported that hydrogen bonding plays an important role in the sorption of cresols to soil (Boyd, 1982; Southworth & Keller, 1986). The transport of cresols from soil to the atmosphere will occur as a result of volatilization. The volatilization of cresols from soil will be directly proportional to H values and inversely proportional to Koc. Since the H values for cresols are low and the Koc in soils capable of hydrogen bonding can be as high as 3420, volatilization will not be significant in such soils. However, some volatilization may occur due to the relatively high vapour pressure of cresols (Table 2) and to the diffusion gradient between the soil and the atmosphere. Loss of cresols by volatilization has been shown to occur from highly contaminated soils (Evangelista et al., 1990). Another process that may transport cresols from soil to ground water is leaching. The leaching of cresols from soil will depend on the Koc. This is variable so that with values near 3000, cresols will be slightly mobile, whereas cresols in soil with Koc values in the lowest range will be highly mobile (Swann et al., 1983). The horizontal transport of cresols from one land area to another or to surface water as a result of run-off will also occur to a certain extent, dependent among other factors on the soil Koc value. 4.2 Transformation 4.2.1 Abiotic transformation Two abiotic transformation processes, namely reaction with hydroxyl HO* and nitrate NO3* radicals, are most important for determining the fate of cresols in air. The rate constants for the reaction with HO* are 4.2 × 10-11, 6.4 × 10-11 and 4.7 × 10-11 cm3/molecule-sec for o-, m- and p-cresol, respectively (Atkinson et al., 1992). It may be estimated from the range of HO* concentrations in the lower troposphere (from below the limits of detection at 1 × 106 radicals/cm3 to a maximum of 5 × 106 radicals/cm3) (Atkinson, 1985), that the half-lives for the cresols during the daytime may range from 3 to 5 h. The major products of the reactions of HO* with cresols in the presence of nitrogen oxides are pyruvic acid, acetaldehyde, formaldehyde, peroxyacetylnitrate and nitrocresols (Atkinson et al., 1980; Grosjean, 1984, 1985). NO3* is formed in the atmosphere as a result of the reaction of nitrogen oxide with ozone and is photodecomposed quickly by sunlight (Carter et al., 1981). Therefore, the reaction of atmospheric pollutants with NO3* can be significant only during the night. The determined rate constants for the reaction of NO3* with vapour-phase cresols are 1.37 × 10-11, 9.74 × 10-12 and 1.07 × 10-11 cm3/molecule-sec for o-, m- and p-cresol, respectively (Carter et al., 1981; Atkinson et al., 1992). Assuming that the average concentration of NO3* in a typical night-time urban atmosphere is 2.4 × 108 molecules/cm3, cresols are estimated to be removed from the atmosphere with half-lives of 5-10 min (Atkinson, 1985). Abiotic reactions, such as photolysis, hydrolysis and oxidation by photolytically produced HO* and singlet oxygen, play a minor role in determining the fate of cresols in water (Smith et al., 1978; Faust & Hoigné, 1987). However, the photolysis of o- and p-cresol is accelerated in the presence of fulvic and humic materials present in water. The estimated half-life for the disappearance of p-cresol in pure water containing humic acid (9.5 mg/litre) and exposed to April sunlight at 37.5°N latitude was 3 days (Smith et al., 1978). In a polluted eutrophic Swiss lake with a dissolved organic matter concentration of 3.1 mg/litre, the estimated natural half-lives for p- and o-cresol in the top metre as a result of exposure to June sunlight were 4.4 and 11 days, respectively (Faust & Hoigné, 1987). The investigators concluded that photochemically produced organic peroxide radicals generated from dissolved organic matter controlled the sensitized photooxidation of cresols in the Swiss lake. In addition, laboratory experiments have shown that iron (FeOOH) and manganese (III/IV) oxides (MnOOH and MnO2), commonly found in surface water particulate and soil, can oxidize cresols in solution particularly at low pH (< 4) (Stone, 1987). However, oxidation of cresols occurs more readily in fog and rain water due to the higher concentration of manganese and iron oxide and low pH of these waters (Stone, 1987). Direct attack of cresols by ozone may also occur in water and follows first-order reaction kinetics: 3 moles of ozone are required to cause ring-opening of 1 mole of cresol (Zheng et al., 1993a,b). The overall rate constant for the reaction increases with increasing pH and temperature. Ozonation may be a possible remediation treatment for cresol-contaminated waters. Photochemical reactions will only occur in the upper few millimetres of the soil surface, and it is unlikely that photochemical attack will be an important pathway for cresol removal from soil. As in the case of water, the abiotic hydrolysis of cresols in moist soil may not be significant since there is no evidence that any soil component is capable of accelerating this reaction. The oxidation of cresols by iron(III) and manganese (III/IV) is likely in soils that have low pH; however, laboratory or field data assessing the importance of this reaction in determining the fate of cresols in soil are not available. 4.2.2 Biodegradation Biotic processes, namely biodegradation, may be more important than other processes in determining the fate of cresols in water (Smith et al., 1978). Cresols degraded rapidly in aerobic biodegradation screening and sewage treatment plant simulation studies (McKinney et al., 1956; Ludzack & Ettinger, 1960; Malaney, 1960; Chambers et al., 1963; Tabak et al., 1964; Alexander & Lustigman, 1966; Malaney & McKinney, 1966; Young et al., 1968; Pauli & Franke, 1971; Baird et al., 1974; Pitter, 1976; Singer et al., 1979; Lund & Rodriguez, 1984; Babeu & Vaishnav, 1987; Brown & Grady, 1990; Klecka et al., 1990). According to one screening study, the rate of aerobic biodegradation of the three isomeric cresols increased in the following order: p- > m- > o-. While no lag time for biodegradation was observed for m- and p-cresol, o-cresol showed a lag time of 6 days (Liu & Pacepavicius, 1990). Aerobic biodegradation in salt water (estuarine and sea water) is slower than in fresh water, but the decrease in the rate is not enough to preclude biodegradation as an important removal pathway in salt water (Palumbo et al., 1988). Mixed and pure culture studies indicate that aerobic biodegradation of cresols proceeds by initial formation of hydroxylation products followed by ring-opening reactions (Bayly & Wigmore, 1973; Masunaga et al., 1983, 1986). Biodegradation reaction rates are widely variable and depend on a number of interrelated factors or conditions of the source waters. Results of several investigations have shown that factors such as substrate and nutrient concentration, spatial and temporal sampling, bacterial growth, biofilm formation, pH and temperature all influence reaction rates. In general, higher nutrient concentrations and temperatures (summer versus winter) increase the biodegradation of cresols. However, degradation will decrease with increased humic acid content (Visser et al., 1977; Smith et al., 1978; Paris et al., 1983, Spain & van Veld 1983; Rogers et al., 1984; Lewis et al. 1984,1986; Shimp & Pfaender, 1985a,b; Kollig et al., 1987; Gantzer et al., 1988; Hwang et al. 1989). The anaerobic biodegradation potential of cresols in aquatic media has been observed in the presence of an electron acceptor, as occurs in nitrate reduction, methanogenesis and sulfate reduction conditions (Shelton & Tiedje, 1981; Horowitz et al., 1982; Boyd et al., 1983; Fedorak & Hrudey, 1984; Bak & Widdel, 1986; Roberts et al., 1987; Battersby & Wilson, 1988, 1989; Wang et al., 1988, 1989). Cresols biodegrade more slowly under anaerobic conditions than under aerobic conditions. While several investigators observed a lag period before the onset of anaerobic biodegradation (Suflita et al., 1988; Battersby & Wilson, 1989; Liu & Pacepavicius, 1990), Young & Rivera (1985) observed no significant increase in the rate of p-cresol metabolism as a result of acclimation. The anaerobic biodegradation rate for cresols was p- > m- > o- (Suflita et al., 1988; Wang et al., 1988; Battersby & Wilson, 1989). Other investigators have reported that o-cresol is more biodegradable under anaerobic conditions than p-cresol. The m-cresol isomer was found to be the least biodegradable (Liu & Pacepavicius, 1990). The anaerobic biodegradation of o- and p-cresol appears to proceed metabolically by oxidation of the methyl group to produce first the corresponding hydroxybenzaldehyde and then hydroxy-benzoic acid. The hydroxybenzoic acid is then decarboxylated or dehydroxylated to produce phenol or benzaldehyde, respectively (Smolenski & Suflita, 1987; Kühn et al., 1988; Suflita et al., 1988, 1989). The metabolic pathway for anaerobic biodegradation of m-cresol may be different from the pathway for o- and p-cresols (Suflita et al., 1989). Pseudomonads and other bacteria contain a flavocytochrome enzyme, p-cresol methylhydroxylase (PCMH), which is capable of oxidizing p-cresol without the participation of exogenous oxygen (Hopper, 1976, 1978; Hopper & Taylor, 1977; Keat & Hopper, 1978). This enzyme catalyses the dehydrogenation and hydration of p-cresol and its homologues to the corresponding alcohols and their further dehydrogenation to the corresponding aldehydes or ketones. Thus, p-cresol is oxidized under this condition to p-hydroxybenzyl alcohol and then to p-hydroxybenzaldehyde. Isolation and then resolution of the flavocytochrome PCMH into subunits and reconstitution of the enzyme were studied by Keat & Hopper (1978), McIntire et al. (1981, 1984, 1985, 1986), McIntire & Singer (1982), Shamala et al. (1985, 1986) and Koerber et al. (1985). The biodegradation of cresols in soil under aerobic conditions is rapid. However, complete metabolism (to CO2 and H2O) of the intermediate metabolites is slower (Medvedev & Davidov, 1981a,b; Dobbins & Pfaender, 1988; Namkoong et al., 1988). Biodegradation is likely to control the fate of cresols in soils. In surface soils from an uncultivated grassland site, the estimated half-life for the pseudo-first-order disappearance of the parent compound was 1.6 days for o-cresol and 0.6 days for m-cresol. It could not be calculated for p-cresols as the concentration had fallen below the detection limits at the first sampling, which was 24 h after initiation of the experiment (Namkoong et al., 1988). The half-lives for complete metabolism in different soils ranged from 39 days to about 1 year (Dobbins & Pfaender, 1988; Swindoll et al., 1988). 4.3 Bioaccumulation and biomagnification The measured bioconcentration factors for o-cresol and m-cresol in aquatic organisms were 14.1 and 19.9, respectively (Freitag et al., 1982; Sabljic, 1987). There is no evidence in the literature to indicate that biotransfer of cresols via the food chain causes biomagnification of these compounds. 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE 5.1 Environmental levels 5.1.1 Air Ambient air monitoring data for cresols are sparse. These compounds are short-lived in the air (see section 4.2.1) unless large amounts are released over a short period of time. According to the National Ambient Volatile Organic Compounds (VOCs) Data Base, a compilation of published and unpublished air monitoring data in the USA from 1970 to 1987, the median air concentration of o-cresol at source-dominated sites was 1.59 µg/m3 (0.359 ppb) (range from below detection limit to 10.58 µg/m3, 2.394 ppb) for 32 samples (Shah & Heyerdahl, 1989). According to the same data base, o-cresol was not detected in air samples from one urban, one rural and one remote area, and m-cresol was also not detected in air samples from one urban, one suburban, and one remote area in the USA. This data base does not contain any monitoring data for p-cresol. The concentration of o-cresol in one sample of the ambient air near a phenolic resin factory in Japan was 179 µg/m3 (40 ppb) (Hoshika & Muto, 1978). In air samples from rooms with a fireplace, cresol concentrations around 5 mg/m3 have been detected (Risner, 1993). 5.1.2 Water In general, cresols will degrade in surface waters very rapidly. The STORET data base, a computerized data base maintained by US EPA, contains water quality data. According to STORET (1993), the mean, minimum and maximum concentrations of ocresol in surface water were 10.89, below the detection limit and 68 µg/litre, respectively, out of 315 samples reported; for p- or m-cresol they were 12.5, 3.4 and 25 µg/litre out of 52 samples; and for p-cresol they were 12.45, below the detection limit and 77 µg/litre out of 285 samples. In addition, the three isomers of cresol were qualitatively detected in Spirit Lake, a freshwater lake in the state of Washington, USA. o-Cresol was also detected in two other freshwater bodies in the same state. The presence of cresols was attributed to the Mount St. Helens eruption (McKnight et al., 1982). Whether or not the cresols originated from woodfires or the actual eruption was not clarified in this study. p-Cresol was detected at a concentration of 200 µg/litre in water samples from the lower Tennessee River near Calvert City, Kentucky, USA (Goodley & Gordon, 1976). m-Cresol was qualitatively detected in St. Joseph River of the Lake Michigan Basin (Great Lakes Water Quality Board, 1983). Cresols (isomers unseparated) were not detected in Delaware River water samples taken between Marcus Hook, Pennsylvania, and Trenton, New Jersey, USA, during summer months, but were detected at 2 µg/litre in winter (Sheldon & Hites, 1978). Concentrations of p-cresol as high as 204 µg/litre have been detected in a river in Japan polluted by effluents from a leather factory (Yasuhara et al., 1981). Although o-cresol has been qualitatively detected in drinking-water in the USA (Clark et al., 1986), quantitative data regarding cresol levels in drinking-water are not available. Cresols have been qualitatively detected in effluent from sewage treatment plants in the USA (Ellis et al., 1982). Concentrations of 70-150 µg/litre (isomer unidentified) have been measured in the wastewater from a chemical manufacturing plant (Jungclaus et al., 1978), and concentrations as high as 2100 µg/litre for o-cresol and 1200 µg/litre for mixed m- and p-cresol have been measured in wastewater from a shale oil plant (Hawthorne & Sievers, 1984). Cresols were detected at 20 µg/litre in the treated secondary effluent from Philadelphia Northeast Sewage Treatment Plant, but were not detected in Delaware River water near the discharge point of the effluents or further downstream (Hites, 1979; Sheldon & Hites, 1979). Furthermore, cresols have been detected in treated coke oven aqueous condensates, wastewater from petroleum refineries and wood-preserving plants, and aqueous effluents from synfuel processing (US EPA, 1982). Cresols may persist in groundwater due to a lack of microorganisms. Very little information regarding the concentration of individual isomers has been reported in the literature. Cresol concentrations measured in groundwater from hazardous waste and landfill sites are shown in Table 4. Although the concentration of p-cresol was below the detection limit (30 µg/litre), o- and m-cresol concentrations of around 1400 µg/litre have been detected in creosote-contaminated groundwater in Denmark (Flyvbjerg et al., 1993). According to STORET (1993), the mean, minimum and maximum levels in groundwater from undefined sources for o-cresol were 234.3, 0.9 and 100 000 µg per litre out of 1848 samples collected; for m-cresol were 1421.3, below the detection limit and 100 000 µg/litre out of 712 samples; and for p-cresol were 15.79, 0.09 and 4800 µg/litre out of 1147 samples, respectively. Rainwater from Portland, Oregon, collected during seven falls of rain in 1984, contained o-cresol concentrations of 0.24-2.8 µg per litre (mean of 1.02 µg/litre) and combined p- and m-cresol concentrations of 0.38-2.0 µg/litre (mean of >1.1 µg/litre) (Leuenberger et al., 1985). The concentration of o-cresol in rainwater at a rural site in Switzerland (Greppen) ranged from undetectable to 1.3 µg/litre. The combined concentration range of m- and p-cresols in the same rainwater was 0.65-9.3 µg/litre (Czuczwa et al., 1987). Table 4. Cresol concentrations in the ground water of hazardous waste sites and landfills in the USA No. of samples/ Concentration Type/location Sampling date no. detecteda Isomer (mg/litre) Reference Hazardous waste, no data 1/1 o 2.3 Weber & Matsumoto (1987) Buffalo, New York 1/1 p 15.0 Former pine-tar manufacturing, no data 11/10 o 0.002-5.2 McCreary et al. (1983) Gainesville, Florida 11/10 m and p 0.0004-11.1 Former wood preserving, 1984 19/6 o 0.04-7.1 Goerlitz et al. (1985) Pensacola, Florida 19/3 p 0.02-6.2 19/4 m 0.05-13.7 Former coal gasification, no data 3/3 o 0.063-6.6 Stuermer et al. (1982) Hoe Creek, Wyoming 3/3 m and p 0.096-16.0 Municipal landfill, 1982-1983 1/1 p 1.5 Sawhney & Kozloski (1984) Southington, Connecticut 1982-1983 1/1 m 0.6 Underground solvent 1983 10/1 unseparated 0.04 Oliveira & Sitar (1985) storage tanks, Santa Clara, California Hazardous waste, 1979-1984 4/1 unseparated 0.11 Ram et al. (1985) Coventry, Rhode Island a Number of samples compared with number in which cresols were detected 5.1.3 Soil Cresols have been detected in about 1% of soil samples from 1300 Superfund (hazardous waste sites listed by US EPA in the National Priority List) sites. The geometric mean concentrations of o- and p-cresols in these samples were 409 and 677 µg/kg, respectively (HAZDAT, 1992). 5.1.4 Food and beverages Cresols have been detected in certain foods and beverages, such as tomatoes, tomato ketchup, cooked asparagus, various cheeses, butter, oil, red wine, spirits, raw and roasted coffee, black tea, smoked foods and tobacco (Fiege & Bayer, 1987). Cresols were identified as volatile components of fried chicken (Ho et al., 1983). Quantitative data regarding cresols in food and beverages are limited. Cresols have been detected in various beverages including Scotch whisky (0.01-0.20 mg/litre), whiskies made outside of Scotland (0.01-0.07 mg/litre), brandies including cognac and armagnac (trace to 0.02 mg/litre), and white and dark rums (trace to 0.20 mg/litre) (Lehtonen, 1983). The total amount of cresols in the smoke from a nonfilter American cigarette (85 mm) is about 75 µg (Wynder & Hoffmann, 1967). 5.2 General population exposure The general population can be exposed to cresols from air inhalation, drinking-water and food ingestion, and dermal contact with water or consumer products that contain cresols. Due to the lack of adequate monitoring data regarding cresol levels in ambient air and drinking-water, it is not possible to estimate quantitatively the daily intake of cresols from these sources. Similarly, to estimate the daily intake of cresol from food for a member of the general population requires data concerning the level of these compounds in total diet samples (various categories and quantities of food consumed daily by a typical individual), and these data are not available. Dermal contact to cresols may also result from use of certain consumer products, since cresols may be used as disinfectants in some soap and as wood preservatives. It is likely that people who live near certain kinds of emission sources (e.g., heavy vehicular traffic, certain incinerators, and landfill sites, such as abandoned coal tar or creosote producer/user sites) will be exposed to higher levels of cresols than the general population. Since both mainstream and sidestream smoke of cigarettes contain cresols (Wynder & Hoffmann, 1967), smokers and those who inhale sidestream smoke may be exposed to a higher level of cresols. 5.3 Occupational exposure Occupational exposure to cresols is likely among workers involved in the production of cresols or processes that produce cresols (coal gasification, shale oil retorting) and those who use cresols or products containing cresols (such as creosote). Little information regarding occupational exposure to cresols is available. The concentration of cresols in the workroom air of a pilot coal gasification plant in the USA was < 0.44 mg/m3 (< 0.1 ppm) (Dreibelbis et al., 1985). The extent of worker exposure to cresols and other pollutants was measured in a facility in Finland that used creosote for impregnation of wood. The highest observed mean concentration of cresols in the air was 0.6 mg/m3 during periods in which the cylinder used for impregnation was opened, followed by a concentration of 0.2 mg/m3 during periods in which the cylinder was closed (Heikkila et al., 1987). All 14 countries listed in ILO Occupational Exposure Limits for Airborne Toxic Substances (1991) have set an environmental concentration of 22.1 mg/m3 (5 ppm) for time-weighted average (TWA) exposure for all isomers of cresol. 6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS 6.1 Absorption Cresols are absorbed across the respiratory and gastrointestinal linings and through the intact skin. Absorption of cresols through the lungs has not been studied quantitatively. However, the occurrence of mortality and other systemic effects in animals exposed to cresol aerosols and vapours in air shows that absorption through the lungs does occur (Uzhdavini et al., 1972; Pereima, 1975). The rate and extent of gastrointestinal absorption of cresols have not been studied specifically. However, they are suggested by data showing that rabbits exposed orally to cresols excreted 65-84% (depending on the isomer) of the administered dose in the urine within 24 h (Bray et al., 1950), indicating that at least that amount was absorbed within that time period. The occurrence of coma, death and systemic effects in humans after dermal exposure to cresols (see section 8) indicates that these compounds can be absorbed through the skin. In the case of an infant who had coal tar fluid (90% cresols in water) spilled on his head, unconsciousness occurred within 5 min and death within 4 h, showing that absorption was rapid (Green, 1975). An in vitro study of the permeability of human skin to cresols showed that these substances have permeability coefficients greater than that of phenol, which is known to be readily absorbed across the human skin (Roberts et al., 1977). Permeability coefficients (Kp) were estimated from the steady-state slopes of the relation between the cumulative amount of cresol isomer per unit area of membrane with time. The following Kp values were determined: m-cresol = 2.54 × 10-4 cm/minute; o-cresol = 2.6 × 10-4 cm/minute; and p-cresol = 2.92 × 10-4 cm/minute (Roberts et al., 1977). In a similar study, Hinz et al. (1991) showed rapid percutaneous transport of p-cresol across mouse skin in vitro. Approximately 70% of the dose was transported within 6 h. 6.2 Distribution Very few data are available regarding the distribution of cresols into various tissues. Oral exposure studies in dogs indicate that cresols in the body concentrate in the blood, liver and brain initially, but soon become more widespread, appearing in the lungs, kidneys and other organs (Gadaskina & Filov, 1971). Cresols were detected in the blood (120 mg/litre), liver, brain and urine of a human infant who died 4 h after 20 ml of a cresol derivative was spilled on his head (Green, 1975). 6.3 Metabolic transformation The primary metabolic pathway for cresols is conjugation with glucuronic acid and inorganic sulfate. At physiological pH, the conjugated metabolites are ionized, thus reducing renal reabsorption and aiding urinary excretion. After oral administration of cresols to rabbits, 60-72% of the dose was recovered as ether glucuronide, and an additional 10-15% was recovered as ethereal sulfate in the urine (Bray et al., 1950). Similarly, in an earlier study in rabbits, 14.5-23.5% of orally administered cresols was found to be conjugated with sulfate in the urine (Williams, 1938). By analogy with other phenols, it may be expected that the relative amounts of glucuronide and sulfate conjugates will differ between species and will also vary with dose. Minor metabolic pathways for cresols include hydroxylation of the benzene ring (primarily for o- and m-cresols) and side-chain oxidation (only for p-cresol). In orally dosed rabbits, 3% of the administered dose was recovered in the urine as conjugated 2,5-dihydroxytoluene for both o- and m-cresols (Bray et al., 1950). For p-cresol, only a trace amount of 3,4-dihydroxytoluene was found, but 10% of the dose was recovered as p-hydroxybenzoic acid. After cresols were administered to rabbits, only 1-2% of the dose was found as unconjugated free cresol in the urine (Bray et al., 1950). Thompson et al. (1994) studied the metabolism of [14C]- p-cresol in rat liver slices and a microsomal fraction. They found that [14C]- p-cresol is metabolized to a reactive intermediate which co-valently binds to proteins in the liver slices and that the binding is inhibited by n-acetylcysteine. In microsomal incubations and a NADPH-generating system, covalent binding of [14C]- p-cresol metabolites was also observed. This binding was inhibited by glutathione (GSH) resulting in the formation of a glutathione conjugate. In the absence of GSH, p-hydroxybenzyl alcohol was the major microsomal metabolite formed from p-cresol. Yashiki et al. (1989) reported the recovery of conjugated cresols in the biological fluids of a 46-year-old man following the ingestion of 100 ml saponated cresol soap solution (42%). Conjugated and free m- and p-cresols were measured in both the serum and urine 2 h after ingestion. Of the total recovered in the serum, 79% p-cresol and 75% m-cresols were in the conjugated form while over 99% of m- and p-cresols recovered in the urine was conjugated. 6.4 Elimination and excretion Significant amounts of cresols are excreted in the bile, but most of the cresols excreted in this manner are reabsorbed from the intestine following hydrolysis by gut bacteria (Deichmann & Keplinger, 1981). The main route for removing cresols from the body is renal elimination. 6.5 Endogenous cresols Healthy humans excrete an average of about 50 mg (range 16-74 mg) of p-cresol in the urine daily (Bone et al., 1976; Renwick et al., 1988). Endogenous p-cresol is produced from tyrosine, an amino acid present in most proteins, by anaerobic bacteria in the intestine (Bone et al., 1976). Free p-cresol formed in this way is absorbed from the intestine and eliminated in the urine as conjugates. 7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS 7.1 Single exposure 7.1.1 Inhalation route Acute poisoning with cresol vapour is unlikely due to the low vapour pressure of these compounds. However, inhalation of an aerosol and vapour mixture may cause death. Uzhdavini et al. (1972) conducted studies into the acute toxicity of o-cresol in mice. The mean lethal concentration of the vapour/aerosol mixture was 178 mg/m3 (duration of exposure not specified). Clinical signs of toxicity included irritation of mucous membranes and neuromuscular excitation that progressed from twitching of individual muscles to clonic convulsions. Haematuria was reported at very high concentrations. Microscopic examination revealed oedematous changes in the lung and necrotic and degenerative changes in the liver (fatty degeneration, centrilobular necrosis) and kidneys (oedema, swelling of the glomeruli, degeneration of the tubular epithelium, and perivascular haemorrhage). Mean lethal concentrations of cresols in rats were reported to be 29 mg/m3 for o- and p-cresols and 58 mg/m3 for m-cresol (Pereima, 1975). 7.1.2 Oral route Oral LD50 values for cresols are shown in Table 5. A comparison of the LD50 values for all three cresol isomers from these studies (e.g., Deichmann & Witherup, 1944; Bio-Fax, 1969) shows that o-cresol is the most toxic isomer, followed by p-cresol and then m-cresol. Interspecies comparisons reveal that all three isomers are more toxic to mice than to rats, by this route of administration, the LD50 values being 3-4 times higher in rats than in comparably treated mice (Uzhdavini et al., 1972; Pereima, 1975). The data also show that for all three isomers toxicity increases with concentration; undiluted cresols were more toxic than cresols delivered as 10% solutions in oil. In addition, there is some evidence that the delivery vehicle affects toxicity; the LD50 value for m-cresol was lower in rats given a 10% solution in water than in rats given a 10% solution in oil. Clinical signs of toxicity that preceded death in acute oral lethality studies of all three cresol isomers were hypoactivity and lethargy, excess salivation, dyspnoea, haemorrhagic rhinitis ( p-cresol only), incoordination, prostration, muscle twitches and tremors, convulsions and coma (Deichmann & Witherup, 1944; Mellon Institute, 1949; Bio-Fax, 1969; Hornshaw et al., 1986). Necropsy of rats that died revealed gastrointestinal inflammation and haemorrhage, as well as hyperaemia of the lungs, liver and kidney (Mellon Institute, 1949; Bio-Fax, 1969). Necropsy of survivors after 14 days of observation revealed only gastro-intestinal tract inflammation in rats treated with p-cresol and no gross lesions in rats treated with o- or m-cresol (Bio-Fax, 1969). Table 5. Oral LD50 values for cresols LD50 Cresol Species Vehicle (mg/kg) Reference o-Cresol Rat 10% in oil 1470 Uzhdavini et al. (1976) 10% in oil 1350 Deichmann & Witherup (1944) 50% in oil 360 FDRL (1975) Undiluted 121 Bio-Fax (1969) Mouse 10% in oil 344 Uzhdavini et al. (1976) Rabbit 10% in oil 940 Uzhdavini et al. (1976) m-Cresol Rat 10% in oil 2010 Pereima (1975) 10% in oil 2020 Deichmann & Witherup (1944) 10% in water 520 Mellon Institute (1949) Undiluted 242 Bio-Fax (1969) Mouse 10% in oil 600 Pereima (1975) 10% in oil 828 Uzhdavini et al. (1976) p-Cresol Rat 10% in oil 1430 Pereima (1975) 10% in oil 1460 Uzhdavini et al. (1976) 10% in oil 1800 Deichmann & Witherup (1944) Undiluted 207 Bio-Fax (1969) Mouse 10% in oil 440 Pereima (1975) 10% in oil 344 Uzhdavini et al. (1976) Dicresol Rat 10% in oil 1625 Uzhdavini et al. (1976) Mouse 10% in oil 651 Uzhdavini et al. (1976) 7.1.3 Dermal route Cresols may cause death when applied to the skin. Dermal LD50 values in rabbits were 890, 2830, 300 and 2000 mg/kg for o-, m-, p- and mixed cresols, respectively, following 24-h dermal exposure (Vernot et al., 1977). In rats, the dermal LD50 values were 620, 1100, 750 and 825 mg/kg for o-cresol, m-cresol, p-cresol and dicresol (a mixture of m- and p-cresols), respectively (Uzhdavini et al., 1974, 1976). 7.2 Short-term exposure 7.2.1 Inhalation route Uzhdavini et al. (1972) exposed mice to a mixture of o-cresol aerosol and vapour 2 h/day, 6 days/week for 1 month; exposure concentrations varied from 26 to 76 mg/m3, with an average of 50 mg/m3. No mortality was recorded. Clinical signs of toxicity during the daily exposure periods were limited to signs of respiratory irritation at the start of the exposure, followed by a period of hypoactivity lasting until the end of the exposure. The tails of some animals mummified and fell off after 18-20 days. Body weight gain was slightly reduced compared to controls. Microscopic examination revealed signs of irritation in the respiratory tract; these included oedema, cellular proliferation, and small haemorrhages in the lung. Other lesions included degeneration of heart muscle, liver, kidney and nerve cells and glial elements of the central nervous system. 7.2.2 Oral route Female B6C3Fl mice (8-10 weeks of age) were exposed to o-cresol at concentrations of 0, 6.5, 32.5, 65 or 130 mg/kg per day ad libitum in the drinking water) for 14 days (CIIT, 1983). Immunotoxicity or altered host resistance was measured as changes in haematological values, lymphoid organ weights, altered lymphoid cell morphology and cell or humoral-mediated immune function. No evidence of immunotoxicity was seen in any of the parameters tested. No changes in immune functions were reported at any dose level. Therefore the threshold for immune response in these studies is above 130 mg/kg per day (see Table 6). US NTP (1992) conducted 28-day studies in which Fischer 344/N rats and B6C3F1 mice were exposed to o-, m-, p- or m-/ p-cresol (60:40 mixture of the m- and p-) in the feed. For each substance, groups of five animals of each sex and each species were fed ad libitum diets containing 0, 300, 1000, 3000, 10 000 or 30 000 mg/kg. Estimated daily doses (mg/kg body weight per day) in males and females of each species exposed to each test substance are shown in Table 7. None of the cresols caused mortality in rats. All cresols reduced feed consumption during the first week of the study and body weight gain throughout the study in rats exposed at the highest level. However, feed consumption of all dosed groups was comparable to that of controls after the first week. Clinical signs of toxicity were not observed in rats treated with o- or m-cresol, but rats exposed to 30 000 mg p-cresol/kg had hunched posture, rough hair coat and thin appearance. Thin appearance was also noted in rats exposed to the highest dose of m-/ p-cresol. Organ weight changes in rats included increases in absolute and relative liver weight and kidney weight compared to brain weight. Increases in several other organ weights, relative to body weight were reported, but as there was a very marked decrease in body weight at the highest dose levels, only the increased liver and kidney weights, relative to brain weight, were regarded as being of biological significance. No gross or microscopic lesions were found in rats exposed to o-cresol. m-Cresol caused minimal-t o-mild atrophy of the uterus in females exposed to 30 000 mg/kg. p-Cresol also caused uterine atrophy in females exposed to 30 000 mg/kg, as well as bone marrow hypo-cellularity and nasal lesions (atrophy of olfactory epithelium and hyperplasia and squamous metaplasia of respiratory epithelium) in rats exposed to > 3000 mg/kg. m-/ p-Cresol caused hyperplasia of the respiratory epithelium in the nasal cavity at > 1000 mg/kg, increased colloid within thyroid follicles at > 3000 mg/kg, mild hyperplasia and hyperkeratosis of the oesophageal epithelium and forestomach at > 3000 and > 10 000 mg/kg, respectively, and mild bone marrow hypocellularity at > 10 000 mg/kg. A no-observed-adverse-effect level (NOAEL) of 3000 mg/kg was established for o, m and m/p cresols and a NOAEL of 1000 mg/kg for p-cresol based on organ weight and body weight changes at higher doses. In the mice exposed in this study death was caused by o-, m-and p-cresol at 30 000 mg/kg and only by m- or p-cresol at 10 000 mg/kg. The m-/ p-mixture was not lethal to mice at any concentration. For all cresols, high-dose mice that survived exposure lost weight during the study, and body weight gain was generally decreased in the 10 000 mg/kg groups as well. Clinical signs of toxicity seen at > 10 000 mg/kg in mice exposed to m-and p-cresols and 30 000 mg/kg in mice exposed to o- and m-/ p-cresols included hunched posture, thin appearance, rough hair coat, lethargy, hypothermia, rapid breathing and tremors. Organ weight changes in mice were increased in absolute and relative liver Table 6. Short-term toxicity of cresolsa Species/ Number/ Compound Route Dose Length of Effects References strain sex exposure Mice/ NR/F (8-10 o-cresol oral 0, 6.5, 32.5, 14 days No effects noted in haematology or CIIT (1983) B6C3Fl weeks old) (drinking) 65 or 130 immune functions water mg/kg/day Mice/ 5/sex f/m o-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg death, (2 males & 1 US NTP B6C3Fl 1000, 3000, female) tremors, rough hair coat, (1992) 10 000 or ovarian atrophy; > 10 000 mg/kg 30 000 body weight decreased, uterine mg/kg diet atrophy; > 3000 mg/kg increased relative liver weight Mice/ 5/sex f/m m-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg increased brain weight, US NTP B6C3Fl 1000, 3000, ovarian, uterine and mammary gland (1992) 10 000 or atrophy; 10 000 mg/kg (1 female) 30 000 and 30 000 mg/kg (2 male, 2 female) mg/kg diet death, decreased body weight, clinical signs of toxicity; > 3000 mg/kg increased kidney weight; > 300 mg/kg increased liver weight Mice/ 5/sex f/m p-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg death all animals; US NTP B6C3Fl 1000, 3000, 10 000 mg/kg (1 male) death, clinical (1992) 10 000 or signs of toxicity, reduced body 30 000 weight; > 3000 mg/kg increased liver mg/kg diet weight; > 300 mg/kg nasal respiratory lesions Table 6 (cont'd). Species/ Number/ Compound Route Dose Length of Effects References strain sex exposure Mice/ 5/sex f/m m-/p-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg clinical toxicity, and US NTP B6C3Fl (60:40 ratio) 1000, 3000, respiratory metaplasia and atrophy of (1992) 10 000 or nasal epithelium; > 3000 mg/kg 30 000 hyperplasia lungs, oesophagus and mg/kg diet forestomach, uterine and ovarium atrophy Mink 5/sex f/m o-cresol oral (diet) 0, 240, 432, 28 days 2520 mg/kg reduced body weight Hornshaw 178, 1400 gain, increased relative heart weight, et al., or 2520 decreased haemoglobin; > 1400 (1986) mg/kg diet mg/kg decreased RBC count; > 432 mg/kg increase relative liver weight Ferrets 5/sex f/m o-cresol oral (diet) 0, 432, 778, 28 days 4536 mg/kg decreased RBC count; > Hornshaw 1400, 2520, 1400 mg/kg increased relative liver et al., 4536 and kidney weight (1986) mg/kg diet Rats/ 5/sex f/m o-cresol oral (diet) 0, 300, 28 days > 3000 mg/kg increased relative liver US NTP Fischer-344 1000, 3000, and kidney weight; 30 000 mg/kg (1992) 10 000, decreased body weight 30 000 mg/kg diet Rats/ 5/sex f/m m-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg decreased body US NTP Fischer-344 1000, 3000, weight; increased relative kidney (1992) 10 000, weight; mild atrophy of uterus; > 30 000 10 000 mg/kg increased relative liver mg/kg diet weight Table 6 (cont'd). Species/ Number/ Compound Route Dose Length of Effects References strain sex exposure Rats/ 5/sex f/m p-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg reduced body weight, US NTP Fischer-344 1000, 3000, rough coat, thin appearance, uterine (1992) 10 000 or atrophy, bone marrow and nasal 30 000 lesions; > 10 000 mg/kg increased mg/kg diet relative kidney weight; > 3000 mg/kg increased relative liver weight Rats/ 5/sex f/m m-/p-cresol oral (diet) 0, 300, 28 days 30 000 mg/kg reduced body weight, US NTP Fischer-344 (60:40 1000, 3000, thin appearance, > 10 000 mg/kg (1992) mixture) 10 000 or increased kidney weight, > 1000 30 000 mg/kg histopathogenic changes, and mg/kg diet increased relative liver weight Mice/NR NR/NR o-cresol inhalation 50 mg/m3 2 h/day inactivity, reduced body weight gain, Uzhdavini 6 days/ CNS effects; histopathological et al. week for changes of lungs, kidney, liver, heart (1972) 1 month and CNS a NR = not reported Table 7. Comparative mean compound consumption by rats and mice in US NTP (1992) 28-day studiesa Dose o-Cresol m-Cresol p-Cresol m-/p-Cresolb Species (mg/kg diet) M F M F M F M F Rats 0 0 0 0 0 0 0 0 0 300 27 27 25 25 25 25 26 27 1000 87 89 85 83 87 83 90 95 3000 266 271 252 252 256 242 261 268 10 000 861 881 870 862 835 769 877 886 30 000 2610 2510 2470 2310 2180 2060 2600 2570 Mice 0 0 0 0 0 0 0 0 0 300 66 82 53 66 50 60 50 65 1000 193 280 193 210 163 207 161 200 3000 558 763 521 651 469 564 471 604 10 000 1650 1670 1730 2080 1410 1590 1490 1880 30 000 4480 5000 4710 4940 no datac no data 4530 4730 a Compound consumption given in mg/kg body weight per day; M = male, F = female b 60% m-cresol/40% p-cresol c No data calculated due to 100% mortality weight. Increases in several organ weights, relative to body weight, were observed, but as there was a very marked decrease in body weight at the highest dose level, only the increased liver weight, relative to brain weight, was regarded as being of biological significance. o-Cresol caused uterine atrophy in mice exposed to > 10 000 mg/kg and ovarian atrophy in those exposed to 30 000 mg/kg diet. m-Cresol caused uterine and ovarian lesions and mammary gland atrophy in mice exposed to 30 000 mg/kg diet. These changes could have been secondary to the marked loss of body weight. p-Cresol caused nasal lesions in mice at all concentrations tested; these lesions consisted mostly of mild hyperplasia and squamous metaplasia of the respiratory epithelium. Effects on the olfactory epithelium (atrophy, necrosis) were generally observed only in mice in the 30 000 mg/kg diet group. Other lesions in the 30 000 mg/kg diet mice, which all died early in the study, were renal tubular and hepatic necrosis together with lymphoid depletion and necrosis in several organs. m-/ p-Cresol caused hyperplasia of the respiratory epithelium at > 3000 mg/kg diet. Atrophy and metaplasia of the olfactory epithelium were observed in mice exposed to 30 000 mg/kg diet. Other lesions observed at this level were mild bronchiolar hyperplasia, bone marrow hypocellularity, minimal hyperplasia of the oesophagus and forestomach, and uterine and ovarian atrophy. A NOAEL of 1000 mg/kg diet could be identified for m-/pcresol and o- or p-cresol, respectively, based on organ weight and body weight and histopathological changes at higher doses. For m-cresol, the lowest dose tested (300 mg/kg diet) resulted in a small increase in relative liver weight in females only, and so could be regarded as a NOAEL. Hornshaw et al. (1986) conducted 28-day feeding studies using mink and ferrets. Groups of five mink of each sex were fed diets containing 0, 240, 432, 778, 1400 or 2520 mg/kg diet of o-cresol. Doses were calculated to be 0, 35, 80, 125, 200 and 320 mg/kg body weight per day in males and 0, 55, 120, 190, 300 and 480 mg/kg body weight per day in females. No deaths occurred during the study, and no clinical signs of toxicity were observed. Consumption of feed by mink exposed to 2520 mg/kg diet was reduced during the first week of the study, and body weight gain was depressed in this group over the course of the study. Haematological analyses revealed decreases in red blood cell count at > 1400 mg/kg diet and in haemoglobin at 2520 mg/kg diet. No lesions were detected by gross necropsy, but liver:body weight ratio was increased at > 432 mg/kg diet and heart:body weight ratio was increased at 2520 mg/kg diet. An NOAEL of 240 mg/kg diet was identified in this study for male and female mink exposed to o-cresol. A similar study in ferrets was also conducted using groups of five animals of each sex exposed to dietary concentrations of 0, 432, 778, 1400, 2520 and 4536 mg/kg diet of o-cresol. Doses were calculated to be 0, 45, 85, 140, 290 and 400 mg/kg body weight per day in males and 0, 80, 150, 240, 530 and 720 mg/kg body weight per day in females. No mortality was recorded and no clinical signs of toxicity were observed. Feed consumption was slightly reduced at 4536 mg/kg diet, but no effect on body weight gain was noted. Red blood cell count was decreased at 4536 mg/kg diet. Increases in liver:brain weight ratio and kidney: brain weight ratio were reported at > 1400 mg/kg diet and 4536 mg/kg diet, respectively. No lesions were found by gross necropsy. A NOAEL of 778 mg/kg diet was identified for male and female ferrets based on increased relative liver weight at doses > 1400 mg/kg diet. 7.3 Long-term exposure 7.3.1 Inhalation route Rats were exposed to an average concentration of 9 mg/m3 of o-cresol vapour 4-6 h/day, 5 days/week for 4 months (Uzhdavini et al., 1972). The number of animals and strain was not reported in the study. Effects of o-cresol exposure in rats included accelerated loss of conditioned defensive reflex, leukocytosis, decreased erythroid/myeloid ratio in the bone marrow, increased duration of hexanol narcosis (indicating possible impaired liver function) and morphological changes in respiratory tissues (inflammation and irritation of the upper respiratory tract, oedema, and perivascular sclerosis in the lungs) (see Table 8). In three other studies rats were administered individual cresol isomers or a mixture of isomers by the inhalation route for 3 to 4 months at doses ranging from 0.05 to 10 mg/m3 (Uzhdavini & Gilev, 1976; Pereima, 1975; Uzhdavini et al., 1976). In each study a decrease in body weight gain was reported for rats exposed to cresols. Organ weight changes and histological alterations in the liver and kidney were also reported in all three studies. Because of the limited reporting of data regarding the exposure methods, number of animals and results, these studies could not be adequately evaluated. 7.3.2 Oral route In 13-week feed studies, groups of 20 male and 20 female Fischer 344/N rats were fed diets containing 0 to 30 000 mg/kg diet of o-cresol or a 60:40 mixture of m-/ p-cresol (US NTP, 1992). Estimated daily doses (mg/kg body weight per day) are shown in Table 9. No treatment-related deaths were caused by either isomer (Table 8). For both isomers, food consumption during the first week was decreased at 30 000 mg/kg diet, and body weight gain was reduced at > 15 000 mg/kg diet. Clinical signs of toxicity were not observed in rats fed o-cresol, but rough hair coat and thin appearance were noted in rats fed m-/ p-cresol at 30 000 mg/kg diet. Organ weight changes in both males and females administered cresols included increases in absolute and relative liver weight (> 7500 mg/kg diet for both cresols) and kidney weight (> 7500 mg/kg diet for m-/ p-cresol). Increases for several other organ weights (relative to body weight) were reported but as there was a marked decrease in body weight at the highest dose levels, only the increases in liver and kidney weight relative to brain weight were regarded as biologically significant. Haematology analyses were not significantly affected by treatment with cresols. Results of urinalysis did not indicate any significant renal damage. The most noteworthy finding of clinical chemistry analyses of plasma was a dose-related increase in total bile acids in males and females exposed to both isomers (significant at dose > 1880 mg/kg diet for m-/ p-cresol and > 15 000 mg/kg diet for o-cresol), indicating decreased hepatocellular function. Transitory increases in alanine aminotransferase and/or sorbitol dehydrogenase near the start of the study in rats exposed to both isomers suggest that hepatocellular injury may have occurred and regressed. Histopathological changes included a dose-related increase in the incidence and severity of hyperplasia in the nasal respiratory epithelium of rats exposed to m-/ p-cresol in the feed (> 1880 mg/kg diet), increased colloid within thyroid follicles (> 3750 mg/kg diet), uterine atrophy (> 15 000 mg/kg diet), and bone marrow hypocellularity (> 15 000 mg/kg diet). The only lesion in rats treated with o-cresol was bone marrow hypocellu-larity at > 7500 mg/kg diet. Both isomers appeared to lengthen the estrus cycle in treated female rats. An NOAEL in rats of 3750 mg/kg diet was identified for o-cresol. However, for m-/ p-cresol the lowest dose tested resulted in changes in clinical chemistry and hyperplasia, and so a threshold dose for m/ p-cresol could not be determined. Table 8. Long-term toxicity of cresols Species/ Number/ Compound Route Dose Length of Effects References strain sex exposure Rat/NR NR/NR o-cresol inhalation 9 ± 0.9 4 months: 2 decreased reflexes, leukocytosis, Uzhdavini mg/m3 months at 6 h/ bone marrow loss, histopathological et al., day, 5 days/week; changes and increased narcosis (1972) 2 months at 4 h/ day, 5 days/week Rat/ 20 of each o-cresol oral (diet) 0, 1880, 13 weeks 30 000 mg/kg diet: reduced body US NTP Fischer- sex F/M 3750, 7500, weight increase; > 15 000 mg/kg diet: (1992) 344N 15 000, increased kidney weight, bile acids; 30 000 > 7500 mg/kg diet: increased liver mg/kg diet weight, length of estrus cycle and altered bone marrow Rat/ 20 of each m-/p-cresol oral (diet) 0, 1880, 13 weeks 30 000 mg/kg diet: reduced body US NTP Fischer- sex F/M (60:40 3750, 7500, weight and clinical toxicity; (1992) 344N mixture) 15 000, > 15 000 mg/kg diet: bone marrow 30 000 changes, uterine atrophy; > 7500 mg/kg mg/kg diet diet: lengthened estrous cycle, liver and kidney weight increased; > 3750 mg/kg diet: thyroid changes; > 1880 mg/kg diet: increased bile salts, histological changes in nasal epithelium Table 8 (contd). Species/ Number/ Compound Route Dose Length of Effects References strain sex exposure Mice/ 10 of each o-cresol oral (diet) 0, 1250, 13 weeks > 20 000 mg/kg diet: lengthened US NTP B6C3F1 sex F/M 2500, 5000 estrus cycle, hyperplasia forestomach; (1992) 10 000, 10 000 mg/kg diet: clinical toxicity; 20 000 > 5000 mg/kg diet: reduced body weight; mg/kg diet > 2500 mg/kg diet: increased relative and absolute liver and kidney weight Mice/ 10 of each m-/p- oral (diet) 0, 625, 13 weeks 10 000 mg/kg diet: reduced body US NTP B6C3F1 sex F/M cresols 1250, 2500, weight, clinical toxicity; (1992) (60/40 5000, 10 000 > 7500 mg/kg diet: hyperplasia in mixtures) mg/kg diet respiratory tract; > 2500 mg/kg diet: increased relative and absolute liver and kidney weight Rat/ 30 of each o-cresol oral (diet) 0, 50, 175 13 weeks 600 mg/kg: death, coma, tremors, MBA Sprague- sex F/M and 600 reduced body weight; (1988a) Dawley mg/kg body 175 mg/kg: tremors (females) weight per day Rat/ 30 of each m-cresol oral (diet) 0, 50, 150 13 weeks 450 mg/kg: tremors and lethargy; MBA Sprague- sex F/M and 450 > 150 mg/kg: reduced body weight (1988b) Dawley mg/kg body weight per day Table 8 (contd). Species/ Number/ Compound Route Dose Length of Effects References strain sex exposure Rat/ 30 of each p-cresol oral (diet) 0, 50, 175, 13 weeks 600 mg/kg: death, coma, tremors MBA Sprague- sex F/M 600 mg/kg and reduced body weight; altered (1988c) Dawley body weight clinical chemistry > 175 mg/kg: per day decreases in erythrocyte count, haemoglobin and haemocrit, increased kidney weight (males) > 50 mg/kg: mild nephropathy (males only) Table 9. Cresols consumption in the US NTP (1992) 13-week feed studiesa Cresol Concentration Males (mg/kg Females (mg/kg diet) body weight) (mg/kg body weight) Rats o-Cresol 0 0 0 1880 126 129 3750 247 256 7500 510 513 15 000 1017 1021 30 000 2028 2024 m-/p-Cresol 0 0 0 1880 123 131 3750 241 254 7500 486 509 15 000 991 1024 30 000 2014 2050 Mice o-Cresol 0 0 0 1250 199 237 2500 400 469 5000 790 935 10 000 1460 1663 20 000 2723 3205 m/p-Cresol 0 0 0 625 96 116 1250 194 239 2500 402 472 5000 776 923 10 000 1513 1693 a Doses given in mg/kg body weight/day; food consumption was measured twice weekly and averaged over the 13-week period to give a daily average dose based on body weight. US NTP (1992) also conducted 13-week studies in groups of 10 B6C3F1 mice of each sex fed diets containing 0 to 20 000 mg/kg diet of o-cresol or 0 to 10 000 mg/kg diet of 60:40 m-/ p-cresol. Estimated daily doses (mg/kg body weight per day) are shown in Table 9. No deaths were recorded in treated mice. Feed consumption was reduced during the first week of the study for mice exposed to 20 000 mg/kg diet of o-cresol or 10 000 mg/kg diet of m-/ p-cresol. Reduced body weight occurred at 5000 mg/kg diet for o-cresol and 10 000 mg/kg diet for m-/ p-cresol. Hunched posture and rough hair coat were observed in mice exposed to > 10 000 mg/kg diet of either isomer. At doses of 2500 and 5000 mg/kg diet both relative and absolute liver weights were significantly increased (p < 0.01) for both o- and m-/ p-cresols, respectively. Increases in other organ weights (relative to body weight) were reported but as there was a marked decrease in body weight at the highest dose levels, they were not regarded as being biologically significant. No significant effects were detected in haematology, urinalysis or clinical chemistry analyses. Histo-pathological examination revealed mild hyperplasia of the respiratory epithelium of the nose in mice fed m-/ p-cresol at > 2500 mg/kg diet and minimal forestomach epithelial hyperplasia in mice fed o-cresol at 20 000 mg/kg diet. Exposure to o-cresol resulted in a lengthened estrus cycle in treated mice in the 20 000 mg/kg diet group. Based on these results, an NOAEL of 1250 mg/kg diet and 625 mg/kg diet can be identified for mice exposed to o-cresol and m-/ p-cresols, respectively. Several 13-week studies of gavage exposure were conducted. Groups of 30 male and 30 female Sprague-Dawley rats were treated with 0, 50, 175 and 600 mg/kg body weight ( o- and p-cresols) or 0, 50, 150 and 450 mg/kg body weight ( m-cresol) daily for 13 weeks by gavage in corn oil in a volume of 5 ml/kg (MBA, 1988a,b,c). Both o- and p-cresols caused mortality at the high dose of 600 mg/kg; m-cresol was not lethal at the high dose of 450 mg/kg. All three isomers caused lethargy and tremors in high-dose rats. In many of the rats exposed to o- and p-cresols these signs were followed by convulsions and coma. Although clinical signs of toxicity were mostly limited to the high-dose groups, two female rats exposed to 175 mg/kg of o-cresol also developed tremors, and one became comatose. In the case of rats that survived, clinical signs disappeared one hour after dosing. Body weight gain was reduced in high-dose rats exposed to all three isomers and also in rats exposed to 150 mg/kg of m-cresol. No other treatment-related effects were observed for o- and m-cresols. However, a number of effects were detected in rats treated with p-cresol. Mild reductions in red blood cell count, haemoglobin, and haematocrit were noted in females treated with > 175 mg/kg. Serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels were increased in 4/10 females exposed to 600 mg/kg. Other changes in clinical chemistry parameters were increased serum cholesterol in females at 600 mg/kg and increased serum protein (mostly globulins) in males at > 175 mg/kg. Increases in some organ weights (relative to body weight) were reported, but as there was a marked decrease in body weight at the highest dose levels, they were not regarded as biologically significant. Epithelial metaplasia of the trachea occurred in high-dose males and females. In male rats there was a slight but statistically significant (p < 0.5) increase in the incidence of nephropathy in the 50 mg/kg (11/20) and 600 mg/kg (12/20) dose groups compared to the controls (4/20). However there was no significant increase in the incidence of nephropathy at the 150 mg/kg dose level (7/20) and the average severity of nephropathy was not increased in any dose group. In the control groups of male rats from the o-cresol and m-cresol studies, which were conducted concurrently at the same laboratory, the incidences of nephropathy were 10/20 and 7/20, respectively. Because of the variable incidence of this spontaneously occurring lesion even among control groups, the absence of a dose-related increased incidence or severity and the absence of an effect on the kidney of female rats, it was considered that nephropathy was a questionable treatment-related effect in male rats. For this reason 50 mg/kg was regarded as a NOAEL for p-cresol, based on the presence of haematological effects at 175 mg/kg. A NOAEL of 50 mg/kg body weight per day was identified for o- and m-cresols. The NOAEL for o-cresol was based on reduced body weight and tremors in female at doses of > 175 mg/kg; for m-cresol the NOAEL of 50 mg/kg body weight per day was based on reduced body weight in females and males at doses > 150 mg/kg. Hamsters exposed to 1.5% p-cresol in the feed for 20 weeks developed an increased incidence of mild-t o-moderate forestomach hyperplasia compared to controls (Hirose et al., 1986). Results of longer-term studies are summarized in Table 8. 7.4 Skin and eye irritation Dermal application of cresols (0.5 ml of o-, m- or p-cresol or a technical mixture of all three isomers) for 4 h caused visible and irreversible tissue destruction in rabbits (Vernot et al., 1977). Severe skin and eye irritation was reported in other laboratory tests (Mellon Institute, 1949; Bio-Fax, 1969; Younger Labs, 1974; FDRL, 1975; Scientific Associates, 1976; Dow Chemical, 1978). Eye irritation was also observed in rats and mice briefly exposed to high concentrations of cresols ( o-cresol and technical cresol mixtures) in the air (Campbell 1941; FDRL, 1975; Dow Chemical, 1978). 7.5 Reproductive toxicity, embryotoxicity and teratogenicity 7.5.1 Reproduction BRRC (1989a,b,c) conducted 2-generation reproduction studies on rats using o-, m- and p-cresols. For each isomer, groups of 25 male and 25 female Sprague-Dawley CD rats were given 0, 30, 175 or 450 mg cresol/kg body weight daily by gavage in corn oil for 10 weeks prior to breeding. Dosing of females was continued through a 3-week mating period, gestation and lactation. After weaning, male and female pups were given the same doses as their parents for 11 weeks. As was the case for the F0 females, dosing of F1 females was continued through a 3-week mating period, gestation and lactation. All F2 pups were sacrificed at weaning. All three cresol isomers caused toxic effects in the parental animals. In the F0 rats, toxic effects were mostly limited to the 450 mg/kg groups and included death, reduced body weight gain and clinical signs such as hypoactivity, ataxia, twitches, tremors, prostration, rapid and laboured respiration, urine stains and perioral wetness. In the F1 rats, some clinical signs of toxicity occurred in the 175 mg/kg groups as well. However, effects on reproductive function or the morphology of reproductive tissues were not detected in these studies, even at doses producing overt parental toxicity. Decreased numbers of spermatozoa and atrophy of seminal vesicles in some F0 males treated with 450 mg m-cresol/kg was attributed to postmortem changes or nonspecific stress; decreased spermatozoa in some F1 males treated with 450 mg p-cresol/kg was also considered not to be treatment-related. Similarly, Hornshaw et al. (1986) did not observe reproductive effects in mink in a 1-generation study in which male and female mink were fed a diet containing 0, 100, 400 or 1600 mg o-cresol/kg diet for 2 months before mating and through weaning. Estimated daily doses were 0, 5, 25 and 105 mg/kg body weight for males and 0, 10, 40 and 190 mg/kg body weight for females. Parental toxicity occurred in the mink fed 1600 mg/kg diet (reduced body weight gain in males, increased relative liver weight and increased erythrocyte count). The US NTP (1992) study, discussed in detail in section 7.3.2, included determination of sperm motility and concentration in male F344/N rats and B6C3Fl mice after treatment with o-cresol and m-/ p-cresol for 13 weeks. The length and stages of the estrus cycles were also determined in female rats and mice. For both o-and m-/ p-cresol, the rats were treated with 1880, 7500 or 30 000 mg/kg in the diets. For o-cresol, the mice were treated with 1250, 5000 or 20 000 mg/kg in the diet, and for m-/ p-cresol mice were treated with 625, 2500 or 10 000 mg/kg in the diet. No adverse effects on sperm motility or concentration were observed at any dose level in rats or mice with either o- or m-/ p-cresol. o-Cresol caused an increased length in the estrus cycle in mice (increased time in estrus) at 30 000 mg/kg only. A similar, but nonsignificant trend was observed in rats. The decrease in body weight by itself was thought not to be the cause for this effect. m-/ p-Cresol caused an increased estrus cycle length in rats at 7500 and 30 000 mg/kg (all stages affected) which was not related to body weight changes; there were no effects on the estrus cycle in mice. Increased testis weight was observed in ferrets dosed with o-cresol 2520 and 4536 mg/kg in the diet (Hornshaw et al., 1986). No adverse effects on the testis were observed in rats treated daily with 600 mg o- or p-cresol per kg body weight or 450 mg mcresol per kg body weight by gavage for 13 weeks (MBA, 1988a,b,c). Pashkova (1972, 1973) studied the reproductive effects of tricresol (a mixture of o-, m- and p-cresols) in white rats. The rats were exposed to tricresol concentrations of 0, 0.6 or 4.0 mg/m3 in air for 4 months (daily exposure not specified). Tricresol at a concentration of 4 mg/m3 had a detrimental effect on the function and structure of the ovaries. The functional change observed was a prolongation of both the estrus cycle and the estrus stage of the cycle, accompanied by a shortening of the diestrus stage of the cycle. Morphological analysis of the ovaries revealed a decreased number of primary follicles and increased atresia. Similar, but less pronounced morphological changes were produced by 0.6 mg/m3. Izard et al. (1992) (abstract only) evaluated the reproductive toxicity of o-cresol and a mixture of m- and p-cresol (59% +41%) in CD-1 Swiss mice using the continuous breeding protocol. Mice received cresols in feed at 0.25, 1.0 and 1.5% (2500, 10 000 and 15 000 mg/kg diet) of m- plus p-cresol or 0.05, 0.2 and 0.5% (500, 2000 and 5000 mg/kg diet) of o-cresol for 14 weeks. The authors found that the m- plus p-cresol mixture at 1.5% in the feed (equivalent to 2100 mg/kg body weight per day) significantly reduced litter size (80% of control) and adjusted pup weight and increased cumulative days to litter in the 2nd to 5th litters by 3 to 4 days. Cross-over breeding of control and 1.5% m- plus p-cresol mixture Fo animals resulted in decreased adjusted live pup weight of litters with a treated parent of either sex. At necropsy, high-dose Fo males had decreased body weight (90%) and relative seminal vesicle weight. Relative kidney and liver weight increased at 1.0 and 1.5% in males. In females, relative liver weight increased at all doses; this was accompanied by decreased (94%) body weight at 1.5%. The cresol mixture at levels of 1.0 and 1.5% adversely affected pre- and post-weaning growth and survival. In the F1 generation, the m- plus p-cresol mixture had no effect on reproductive competence, but F1 postnatal growth and survival and F2 live pup weight were decreased at 1.5% of the mixture. At necropsy, F1 males had reduced body weight and relative seminal vesicle and prostate weights at the 1.0 and 1.5% tested levels of the cresol mixture. Females had reduced body weight at 1.0 and 1.5% levels of the mixture, and relative liver and kidney weights were increased at all doses and for both sexes. o-Cresol at doses up to 0.5% (equivalent to 550 mg/kg body weight per day) did not affect reproductive or general toxicity parameters in either generation. They concluded that the m- plus p-cresol mixture at > 1.0% caused minimal adult reproductive toxicity but significant postnatal toxicity was observed. o-Cresol was negative at the doses tested. 7.5.2 Embryotoxicity and teratogenicity Developmental toxicity studies were conducted for o-, m- and p-cresols in rats and rabbits (BRRC, 1988a,b). For each isomer, groups of 25 inseminated female rats were given doses of 0, 30, 175 or 450 mg cresol/kg in corn oil by gavage on days 6-15 of gestation. Maternal toxicity was evident at 450 mg/kg for all three isomers; effects included death, reduced food consumption, decreased body weight gain, and clinical signs such as audible respiration, hypoactivity, ataxia and tremors. m-Cresol caused no effects on the developing embryos at any dose, but o- and p-cresols both caused mild fetotoxic effects at 450 mg/kg (increased incidences of dilated lateral ventricles in the brain and minor skeletal variations, respectively), which could have been secondary to maternal toxicity. In the rabbit studies, groups of 14 inseminated females were given cresol (0, 5, 50 or 100 mg/kg body weight daily) in corn oil by gavage on days 6-18 of gestation. Maternal effects, including audible respiration, ocular discharge, hypoactivity and death ( p-cresol only), were seen after exposure to > 50 mg/kg. o-Cresol caused fetotoxicity (increased incidences of subepidermal haematoma on the head and poorly ossified sternebrae) in rabbits treated with 100 mg/kg. Neither m- nor p-cresol caused any developmental effects in rabbits at any dose. Developmental end-points were also monitored in the 2-generation reproduction studies on rats discussed in section 7.5.1 (BRRC, 1989a,b,c). All three cresol isomers caused effects on pup body weight at some time during development in these studies. Most of the deficiencies in pup body weight or growth occurred in rats exposed to 450 mg/kg body weight per day, a dose that also caused overt toxicity in parental rats. There were occasional body weight changes in lower-dose groups (especially those treated with m-cresol), but it is not clear that these changes were treatment-related. In addition to its effect on pup body weight, m-cresol reduced F2 pup survival from birth through lactation in the 450 mg/kg group. In a developmental toxicity screening study, p-cresol was found to cause maternal toxicity (reduced body weight gain) at a dose of 410 mg/kg body weight, but failed to elicit effects on post-implantation loss or litter weight at any dose tested (Kavlock, 1990). In a study conducted on cultured rat embryos in vitro, p-cresol caused dose-related effects on growth (reduced crown-rump length, somite number and DNA content) and structural abnormalities (increased hind limb bud absence and total tail defects). The significance of these results is not clear (Oglesby et al., 1992). 7.6 Mutagenicity and related end-points Data regarding the genotoxicity of cresols are presented in Tables 10-14. Most of these data are for individual isomers, but some information is also available for mixed isomers ( m/p and o/m/p mixtures). In vitro DNA repair assays (unscheduled DNA synthesis) were negative in rat hepatocytes treated with o- or m-cresol, but a weakly positive result was obtained with human lymphocytes treated with p-cresol. There is no evidence that cresols are mutagenic to Salmonella typhimurium. None of the individual isomers induced mutations at the tk locus of L5178Y mouse lymphoma cells, whereas the o/m/p mixture of isomers was active in the presence of S9 mix. In Drosophila melanogaster, sex-linked recessive lethal mutations were not induced by either o- or p-cresol. Chromosomal aberrations were induced in Chinese hamster (CHO) cells in both the presence and absence of S9 mix, following treatment with o- and p-cresols, but not with m-cresol. In mice in vivo, there was no induction of chromosomal aberrations in bone marrow cells by m-cresol or of micronuclei in peripheral blood erythrocytes by o-cresol or the m/p isomer mixture. Sister-chromatid exchanges (SCE) were induced in CHO cells by o-cresol and by the o/m/p isomer mixture, but were not induced by o-, m- or p-cresol in cultured human fibroblasts, after testing only in the absence of S9 mix. In mice, in vivo tests for SCE induction were inconclusive with o-cresol and negative with m- and p-cresol. No dominant lethal effects were observed following treatment of male mice with either o- or p-cresol. Table 10. Genotoxicity of o-cresol Resultsa With Without Assay Indicator organism activation activation Reference In vitro Reverse mutation Salmonella typhimurium - - Douglas et al. (1980); Florin et (on plates) al. (1980); Litton Bionetics (1981); Pool & Lin (1982); Haworth et al. (1983) Forward mutation L5178Y mouse lymphoma cells - - Litton Bionetics (1981) Unscheduled DNA synthesis primary rat hepatocytes ND - Litton Bionetics (1981) Chromosomal aberrations Chinese hamster ovary cells + + Hazleton Labs (1988a) Sister-chromatid exchange Chinese hamster ovary cells + + Litton Bionetics (1981) Sister-chromatid exchange cultured human fibroblasts ND - Cheng & Kligerman (1984) Cell transformation mouse BALBc/3T3 cells - - Hazleton Labs (1988b); Litton Bionetics (1981) Viral DNA amplification SV-40 transformed Chinese ND - Pool et al. (1989) hamster cell line Table 10 (contd). Resultsa With Without Assay Indicator organism activation activation Reference In vivo Sex-linked recessive lethal Drosophila melanogaster - Hazleton Labs (1989d) Sister-chromatid exchange mouse ? Cheng & Kligerman (1984) (bone marrow, alveolar macrophages, and regenerating liver cells) Micronucleus, peripheral mouse - US NTP (1992) blood erythrocytes Dominant lethal mouse - Hazleton Labs (1989a) a - = negative result; + = positive result; ND = no data; ? = inconclusive Table 11. Genotoxicity of m-cresol Resultsa With Without Assay Indicator organism activation activation Reference In vitro Reverse mutation Salmonella typhimurium - - Douglas et al. (1980); Florin et (on plates) al. (1980); Haworth et al. (1983); Pool & Lin (1982) Forward mutation L5178Y mouse lymphoma cells - - Hazleton Labs (1988c) Unscheduled DNA synthesis freshly cultured rat hepatocytes ND - Hazleton Labs (1988e) Chromosomal aberrations Chinese hamster ovary cells - - Hazleton Labs (1988a) Sister-chromatid exchange cultured human fibroblasts ND - Cheng & Kligerman (1984) Cell transformation mouse BALBc/3T3 cells - - Hazleton Labs (1988d,f) SV40 induction Syrian hamster kidney cells ND (+) Moore & Coohill (1983) Viral DNA amplification SV-40 transformed Chinese ND - Pool et al. (1989) hamster cell line Table 11 (contd). Resultsa With Without Assay Indicator organism activation activation Reference In vivo Chromosomal aberrations mouse - Hazleton Labs (1989c) (bone marrow) Sister-chromatid exchange mouse - Cheng & Kligerman (1984) (bone marrow, alveolar macrophages, and regenerating liver cells) a - = negative result; (+) = weakly positive; ND = no data Table 12. Genotoxicity of p-cresol Resultsa With Without Assay Indicator organism activation activation Reference In vitro Reverse mutation Salmonella typhimurium - - Douglas et al. (1980); Florin et (on plates) al. (1980); Pool & Lin (1982); Haworth et al. (1983) Forward mutation L5178Y mouse lymphoma cells - - Hazleton Labs (1988c) Semiconservative/repair DNA human peripheral lymphocytes ND (+) Daugherty & Franks (1986) synthesis Chromosomal aberrations Chinese hamster ovary cells + + Hazleton Labs (1988a) Sister-chromatid exchange cultured human fibroblasts ND - Cheng & Kligerman (1984) Cell transformation mouse BALBc/3T3 cells ND + Hazleton Labs (1988d) Viral DNA amplification SV-40 transformed Chinese ND - Pool et al. (1989) hamster cell line Table 12 (contd). Resultsa With Without Assay Indicator organism activation activation Reference In vivo Sex-linked recessive lethal Drosophila melanogaster - Hazleton Labs (1989e) Sister-chromatid exchange mouse - Cheng & Kligerman (1984) (bone marrow, alveolar macrophages, and regenerating liver cells) Dominant lethal mouse - Hazleton Labs (1989b) a - = negative result; + = positive result; (+) = weakly positive; ND = no data Table 13. In vitro genotoxicity of a 1:1:1 mixture of o-, m- and p-cresol Resultsa With Without Assay Indicator organism activation activation Reference Reverse mutation Salmonella typhimurium - - Litton Bionetics (1980) (on plates) Forward mutation L5187Y mouse lymphoma cells + ? Litton Bionetics (1980) Sister-chromatid exchange Chinese hamster ovary cells + + Litton Bionetics (1980) Cell transformation mouse BALBc/3T3 cells + ND Litton Bionetics (1980) a - = negative result; + = positive result; ? = inconclusive; ND = no data Table 14. Genotoxicity of 60:40 m/p-cresol Results With Without Assay Indicator organism activation activation Reference Reverse mutation (on plates) Salmonella typhimurium - - US NTP (1992) Micronuclei, peripheral blood mouse - US NTP (1992) erythrocytes BALBc/3T3 cells were transformed by p-cresol and the o/m/p mixture, but not by o- or m-cresol. A weakly positive result was obtained, however, in a viral enhancement assay with m-cresol. Viral DNA amplification did not occur in SV-40-transformed Chinese hamster embryo cells treated with o-, m- or p-cresol. Antimutagenic effects of o- and p-cresol, but not of m-cresol, have been demonstrated in methylnitrosoguanidine-induced mutagenesis in Escherichia coli when given after the MNNG treatment (Kushi & Yoshida, 1987). In summary, these data indicate that m-cresol has little or no genotoxic potential, and whereas both o- and p-cresol can induce chromosomal aberrations in vitro and o-cresol can increase SCE in vitro, they do not do so in vivo. 7.7 Carcinogenicity There are no adequate bioassays or chronic studies available to assess the carcinogenic potential of cresols. Two studies (Boutwell & Bosch, 1959; Yanysheva et al., 1993) have indicated that cresols have potential tumour-promoting activity. However, no conclusions can yet be made regarding the carcinogenic potential of these compounds. Boutwell & Bosch (1959) investigated the tumour-promoting ability of cresols using a mouse skin-painting model. Groups of 27-29 mice were given a single dermal application of 9,10-dimethyl- 1,2-benzanthracene, a cancer initiator, followed by application of 20% solutions of o-, m- or p-cresol in benzene, twice a week for 12 weeks. Significant non-tumour-related mortality was produced by all three cresol isomers. Among the survivors at 12 weeks, both the average number of skin papillomas per mouse and the percentage of exposed mice with at least one papilloma were increased by treatment with cresols. o-Cresol was the most potent isomer and p-cresol the least. No carcinomas were observed following treatment with cresols. It should be noted that the vehicle used for cresols in this study was benzene, a known carcinogen. The presence of benzene did not appear to affect the results, however, since no papillomas were observed in benzene-treated controls. This study suggests that cresols may act as promoters. Yanysheva et al. (1993) reported that o-cresol administered orally (1 mg) twice weekly for up to 30 weeks to mice simultaneously with benzo[ a]pyrene (1 mg) increased the incidence and malignancy of tumours produced by benzo[ a]pyrene and shortened the latency period for tumour development. These effects were not seen when higher (10 mg) or lower (0.02 mg) doses of o-cresol and benzo[ a]pyrone were administered. Administration of o-cresol before or after benzo[ a]pyrene had the opposite effect, decreasing the carcinogenicity of that chemical. 7.8 Other special studies 7.8.1 Neurological effects A neurotoxicity study was performed on CD rats using all three cresol isomers (TRL, 1986). Groups of 10 rats of each sex were treated with o-cresol (0, 50, 175, 450 or 600 mg/kg body weight), m-cresol (0, 50, 150 or 450 mg/kg), or p-cresol (0, 50, 175 or 600 mg/kg) in corn oil by gavage daily for 13 weeks. Both o- and p-cresol caused death in the groups exposed to 600 mg/kg. Convulsions were seen only in the groups treated with > 450 mg/kg. Hypoactivity, rapid laboured respiration and excessive salivation were observed sporadically at doses of > 50 mg/kg for all three isomers. In spite of the observed clinical signs, few significant changes were found in performance on neurobehavioural test batteries, no brain weight changes were noted, and no gross or histopathological lesions in the brain or other nervous tissues were found for any isomer. Savolainen (1979) studied the effect on biochemical parameters in the brain of Wistar rats (40 males) after exposure to o-cresol in the drinking-water for 20 weeks. The administered concentration was 300 mg/litre, which provided daily doses of about 36 mg/kg body weight. Increased activity of 2',3'-cyclic nucleotide 3'-phosphohydrolase in glial cells, and reductions in azoreductase and glutathione in brain homogenate were found. No other treatment-related effects were detected. o-Cresol produced excitation of both the somatosensory evoked potential and electroencephalogram in male Fischer-344 rats given a 1% solution intravenously at the rate of 0.9 mg/min for 15 min (total dose of 13.5 mg) (Mattsson et al., 1989). The rats were conscious and responsive to stimuli. Muscle tremors developed if exposure was sufficiently long. 7.8.2 Effects on the skin Application of 0.5% p-cresol to the skin for 6 weeks resulted in permanent depigmentation of the skin and hair in black and agouti mice (Shelley, 1974). Depigmentation was accompanied by a caustic effect in one black strain of mice, but not in another. In identical trials, neither o- nor m-cresol caused depigmentation in mice. 7.9 Mechanisms of toxicity - mode of action The main effects of cresols at the area of first contact are irritancy or corrosivity, depending upon the concentration. These primary effects are followed after absorption by haematoxicity, hepatotoxicity and neurotoxicity. The mechanisms by which these effects occur have not been specifically studied with respect to cresols. It is frequently assumed that the basis for cresol toxicity is similar to that for phenol. However, phenol has certain unique properties, e.g., cardiac toxicity, which has not been reported for cresols except in one human case of acute poisoning involving a very high exposure (Arthur et al., 1977). Cresols are relatively soluble in water and have been shown in vitro to have high permeability coefficients for human skin (Thompson et al., 1994). Consequently, they can be rapidly absorbed and distributed throughout the body. Cresol metabolism is mainly conjugation followed by urinary excretion as glucuronides and sulfates (Bray et al., 1950). In addition, in vitro studies have shown that microsome-dependent covalent binding to proteins occurs, but the importance of this process is unknown (Thompson et al., 1994). In an in vitro study, cresol caused inhibition of K-dependent phosphatase activity of Na/K ATPase in erythrocyte membrane (Wardle, 1978). Dermally applied p-cresol inhibits ATPase activity, as measured in both erythrocytes and brain. This could contribute to toxicity by disturbing electrolyte balance across cell membranes, which could result in haemolysis. Another factor leading to erythrocyte damage could be the binding of cresols to iron complexes (analogous to the process described in clay soils, see section 4.2.1). If, indeed, this should occur, then it may contribute to methaemoglobin formation, haemolysis and, in the liver, a compensatory response leading to enlargement. Neurotoxic mechanisms have received little study. At a concentration of approximately 0.25 mM, p-cresol inactivates dopamine ß-hydroxylase (DeWolf et al., 1988), and could thereby affect neurotransmission by interfering with noradrenaline biosynthesis. 8. EFFECTS ON HUMANS 8.1 General population exposure 8.1.1 Poisoning incidents The most commonly reported cases of cresol poisoning involve accidental or intentional ingestion of cresol-containing substances. Cresols are strong irritants, and their ingestion results in burning of the mouth and throat, abdominal pain and vomiting (Isaacs, 1922; Jouglard et al., 1971; Wiseman et al., 1980). The primary targets of ingested cresols in humans appear to be the central nervous system, blood and kidneys. Some effects on the lungs, heart and liver have also been reported (Isaacs, 1922; Labram & Gervais, 1968; Chan et al., 1971; Jouglard et al., 1971; Cote et al., 1984; Minami et al., 1990). Chan et al. (1971) described two cases of oral cresol poisoning. In one case, a woman swallowed about 250 ml disinfectant containing 50% mixed cresols. The patient was in a deep coma when admitted to the hospital 2 h after ingestion, but regained consciousness 10 h later. Haematological changes were remarkable. Within 7 h of admission, erythrocyte glutathione levels were markedly reduced, and methaemoglobinaemia was detected. Within 3 days, severe haemoglobinaemia and haemoglobinuria were evident, along with extensive Heinz body formation, indicating that massive intravascular haemolysis had occurred. The patient died the next day, apparently from thrombus formation and kidney failure secondary to acute intravascular haemolysis. Autopsy revealed moderate fatty degeneration in the liver and, in the kidney, fibrin clumps in the glomeruli and moderate tubular degeneration consistent with intravascular thrombosis. The authors also described the case of a second woman who recovered after drinking about 100 ml of the same cresol-containing disinfectant. The patient was semiconscious when admitted to the hospital 1.5 h after ingestion. Methaemoglobin was detected in the blood at admission, but not 6 h later. Heinz bodies were observed 6 h after admission, but disappeared within 2 days. Haemolytic anaemia and associated changes have been described in other case reports. Heinz body formation, haemoglobinaemia and haemoglobinuria were evidence of haemolytic anaemia in a man who drank 100 ml of "penetrating oil", a petroleum distillate containing 12% mixed cresols (Cote et al., 1984). Severe haemolytic anaemia developed during the second week following cresol ingestion in a man who swallowed approximately 250 ml of a concentrated cresol mixture (Jouglard et al., 1971). Dark urine and methaemoglobinaemia were observed upon hospital admission in a man who had swallowed a commercial disinfectant containing cresols 2 h earlier (Minami et al., 1990). The concentration of methaemoglobin in the blood was monitored regularly and was seen to increase markedly 15 h after admission to the hospital. The patient was then given a blood transfusion, after which methaemoglobin levels decreased to normal and the patient recovered. Labram & Gervais (1968) reported the case of a woman who swallowed between 500 and 750 ml of a concentrated cresol mixture. Upon admission to the hospital 45 min later, the patient was in a deep coma and exhibited tachycardia with polymorphic ventricular extrasystoles. A transient episode of ventricular fibrillation was followed by cardiac arrest 24 h after admission to the hospital. At autopsy, the most notable finding was massive eosinophilic necrosis in the proximal tubule of the kidney. The investigators considered it likely that this lesion occurred prior to death and represented a target organ effect of cresol. Diffuse necrosis of the bronchial epithelium was also thought to have occurred prior to death. Pulmonary oedema and haemorrhage were also observed, but may have been secondary to death. Diffuse lesions in other organs were also considered to be secondary to death. Isaacs (1922) reported symptoms of cresol poisoning in 52 patients who ingested 4-120 ml of disinfectant containing 25-50% cresols. Mouth and throat burns, abdominal pain and vomiting were common symptoms of cresol poisoning. Coma was also a frequent occurrence; in some cases, unconsciousness occurred very soon after exposure and lasted 14 h or more. Renal irritation and reduced phenolsulfonephthalein output indicated the occurrence of kidney effects in some patients. Darkly coloured urine was produced in most cases and may have been due to haemoglobinuria. Blood abnormalities were not detected, but details regarding blood analyses were not reported; it is possible that some haematological changes (e.g., methaemoglobinaemia, Heinz body formation) may have been overlooked. Only two of the 52 patients died; both deaths occurred within 30 min of cresol ingestion. Arthurs et al. (1977) reported a case of a 32-year-old man who was admitted after he had taken more than 45 ml of cresols. This patient was conscious upon admission. However, he became increasingly dyspnoeic and developed tachycardia and systolic hypotension within the next 12 h. The total serum phenol levels were elevated 24 h after admission. The patient died 4 days later of myocardial failure and pulmonary oedema. Not all poisoning incidents with cresols involve oral exposure. Accidental dermal exposure has also been reported, usually causing corrosive damage to the skin (Herwick & Treweek, 1933; Green, 1975; Wiseman et al., 1980; Pegg & Campbell, 1985). In one patient, disfiguring scars remained visible a year after exposure (Herwick & Treweek, 1933). Systemic effects of dermal exposure were reported by Green (1975), who described the case of a 1-year-old baby who had 20 ml of a cresol derivative (90% mixed cresols in water) spilled on his head. The spill area, shown by burning on the face and scalp, covered about 7% of his body surface. The baby fell into a coma after 5 min and died within 4 h. Autopsy revealed haemorrhagic oedema in the lungs, extensive centrilobular to mid-zonal necrosis in the liver, congestion, swelling and tubular necrosis in the kidneys, and congestion and swelling in the brain. In some cases, cresols have been injected intentionally into the vagina and uterus for the illegal purpose of inducing abortion. Signs and symptoms in women exposed to cresols in this manner include vaginal bleeding, abdominal cramps, severe burning pain, coma, massive haemolysis, severe kidney nephrosis and failure, severe pulmonary oedema with oil emboli, and death (Vance, 1945; Presley & Brown, 1956; Finzer, 1961). 8.1.2 Controlled human studies Uzhdavini et al. (1972) found that 6 mg/m3 was the threshold concentration for the production of mucosal irritation by o-cresol (vapour/aerosol mixture) in humans. At this concentration, 8 out of 10 subjects complained of symptoms such as dryness, nasal constriction and throat irritation. However, the duration of exposure or the composition of the compound (i.e. purity) were not specified in the report. No reaction to cresol was noted in humans when the compound was applied to the skin of the elbow as a 1% solution in alcohol (Reimann, 1933). 8.1.3 Cancer Epidemiological data regarding cancer and cresol exposure in humans are not available in the literature. Two studies have examined the production of endogenous p-cresol in cancer patients. Bone et al. (1976) compared urinary p-cresol levels in six patients with large bowel cancer with levels in 10 healthy patients and found no difference in average daily urinary excretion of p-cresol. Similarly, Renwick et al. (1988) found no difference in average daily urinary excretion of p-cresol among 32 patients with transitional cell carcinoma of the bladder and matched controls. 8.2 Occupational exposure 8.2.1 Poisoning incidents Acute cresol poisoning during occupational exposure is usually a result of dermal contact. In one case, a man fell into a vat containing a cresylic acid derivative (Cason, 1959). The man suffered burns on 15% of his body surface and developed anuria 36 h after exposure. Blood urea levels increased steadily over the following days. He fell into a coma 9 days after admission to the hospital and died on the following day due to congestive heart failure. Anuria was also observed in a man who worked with an antiseptic solution containing concentrated mixed cresols for 2 days before becoming ill (Larcan et al., 1974). Other significant observations in this patient were haematological changes similar to those observed after oral exposure, including methaemoglobinaemia, Heinz body formation and massive haemolysis. The man died 3 days after admission to the hospital. Klinger & Norton (1945) reported the case of a man who had his hands immersed in a 6% cresylic acid solution for 5-6 h. The man survived, but experienced persistent eye-watering, followed by pain on the side of his face and, ultimately, marked facial paralysis. Thirteen cases of accidental burns were reported in workers exposed to cresol (2), dichlorophenol (1) and phenol (10) (Ma et al., 1982). Burns were diagnosed as first and second degree, small in area and covered 0.5-10% of the body surface. The patients generally demonstrated (in the following order) white, red, brown and black skin colour, and then crusting, necrosis and sloughing. Patients were treated immediately by washing affected areas. Twelve of 13 patients fully recovered within 15 days with no scarring of skin. Wu & Kwan (1984) reported a case of acute renal failure in a healthy 50-year-old male technician accidentally exposed to a mixture of cresols. The burned area was immediately irrigated with water. The patient experienced dizziness, pain and numbness of burnt skin and abdominal pain followed by oliguria and vomiting 8 h later. He developed severe abdominal pain and vomiting and lesser oliguria 1 day after the exposure. The patient was admitted to hospital 3 days after exposure. A follow-up examination revealed decreased pulse rate, urinary volume (70-190 ml/24 h), blood urea nitrogen (440-1240 mg/litre), combining power of CO2 (40-42 vol %). Burnt skin was light brown in colour and there was slight swelling and tactile pain. The patient was treated for acute renal failure, and complete recovery occurred within 27 days following exposure. Ma & Wang (1989) reported a case of acute cresol burn and poisoning in a 18-year-old woman accidentally exposed to cresol. Exposure of face, hand, feet, thighs and perineum occurred. Face, hand and feet were immediately irrigated with water, but contaminated trousers were not taken off and thighs and perineum were not washed. Burns were first and second degree in severity and covered 20% of the body. After 10 min she exhibited erythema, discoloration of the skin, and became delirious followed by coma. Pulmonary oedema and haemoglobinuria were reported after treatment with a diuretic and intravenous infusion. Additional therapy included peritoneal dialysis, strict control of intravenous fluids, intravenous rogitine, oral nitroglycerin and nifedipine etc. Peritoneal dialysis was continued for 20 days. The patient was discharged 38 days later. No scarring of the skin occurred. 8.2.2 Epidemiological studies Molodkina et al. (1985) studied 174 female workers aged between 20 and 50 in an enamel wire production plant using mainly tricresol. Seventy percent of the study population had been exposed to this compound for at least 10 years. Tricresol concentrations averaged 1.4 mg/m3 per shift, with maximum recorded levels of 3.6-5.0 mg/m3. Reported effects included circulatory disturbances and minor haematological changes (decreases in red blood cell count, white blood cell count and platelets). There were also reported to be decreases in the activity of glucose-6-phosphate dehydrogenase and the concentration of sulfhydryl groups within erythrocytes. Erythrocytes were reported to have a shorter lifespan. Syrovadko & Malysheva (1977) studied reproductive endpoints in female workers exposed to tricresol and chlorobenzene during the manufacture of enamel-insulated wire. Several reproductive disorders were reported, including hormonal shifts, menstrual problems and elevated incidences of perinatal mortality and abnormal development of offspring. A group of 58 women (without pre-existing genital disease), exposed to tricresol and phosphoryl chloride in the production of tricresylphosphate, comprised the study population investigated by Pashkova (1973). There was an elevated incidence of menstrual disturbances in the study population, with changes in the cycle accompanied by difficult and painful menstruation. Changes in the cycle were found to be the result of increased estrogen and decreased progesterone activity, indicating ovarian dysfunction. In neither of the above two studies was there any documentation of the degree of exposure to cresols or any quantification of the physiological changes mentioned. Therefore, the significance of these studies cannot be assessed. 8.3 Subpopulations at special risk Several populations have been identified that may be at special risk from cresol exposure. For instance, in persons with renal insufficiency, the renal clearance of phenol and p-cresol is impaired, leading to accumulation of cresol in the blood (Niwa, 1993). Individuals with glucose-6-phosphate dehydrogenase (G6DP) deficiency may also have heightened sensitivity to the haematological effects of cresols. In experiments in which blood was exposed to a disinfectant containing 50% cresols in vitro, increased methaemoglobin formation and decreased glutathione levels were more pronounced in blood from subjects with glucose-6-phosphate dehydrogenase deficiency than blood from normal subjects (Chan et al., 1971). 9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD 9.1 Microorganisms 9.1.1 Aquatic 184.108.40.206 Laboratory studies Growth studies have shown that cresols are moderately toxic to aquatic bacteria, cyanobacteria (blue-green algae) and protozoa. Growth inhibition thresholds for the bacterium Pseudomonas putida, were 33 and 53 mg/litre for o- and m-cresol, respectively (Bringmann & Kühn, 1976; Bringmann & Kühn, 1980), 6.8 and 13 mg/litre for the cyanobacterium Microcystis aeruginosa, 17 and 31 mg/litre for the bacteriovorous flagellate protozoan Entosiphon sulcatum (Bringmann & Kühn, 1978a,b, 1980) and 132 and 114 mg/litre for the saprozoic flagellate protozoan Chilomonas paramecium (Bringmann & Kühn, 1980). The ciliate protozoan Tetrahymena pyriformis showed low sensitivity to o-cresol and p-cresol, 48-h EC50 values for growth inhibition being 203 and 168 mg/litre, respectively (Schultz & Riggin, 1985; Schultz, 1987). The yeasts Pichia sp. and Rhodotorula rubra had 50% growth reduction following 12 h of incubation with 400 and 200 mg p-cresol/litre, respectively (Kwasniewski & Kaiser, 1983). Bacterial luminescence assays, which provide an indirect measure of population inhibition, have been conducted in Photobacterium phosphoreum. For p-cresol, 5-min EC50 (50% reduction of light) values ranged from 1.5 to 1.72 mg/litre (Bulich & Isenberg, 1980, 1981; Bulich et al., 1981; Ribo & Kaiser, 1983). The potential impact of m-cresol on wastewater treatment systems appears to be minimal; the measured I50 (50% inhibition of activated sludge respiration rates) is 458.1 mg/litre (Dow Chemical, 1984). 220.127.116.11 Field studies Field studies on the degradation of fresh poplar leaves in experimental streams dosed with 8 mg p-cresol/litre had decreased rates of decomposition compared to control streams (Stout & Cooper, 1983). Although, treatment of the stream with p-cresol changed the dynamics of invertebrate communities on the leaves (see section 18.104.22.168), the authors suggested that the principal factor in decreasing decomposition was inhibition of aerobic microbial degraders, due to the drop in dissolved oxygen concentrations below 1 mg/litre, which followed p-cresol addition. 9.1.2 Terrestrial 22.214.171.124 Laboratory studies Although there have been many investigations regarding the degradation of cresols by soil isolates in laboratory culture systems (section 4.2.2), laboratory studies regarding the toxicity of cresols to soil microorganisms are rare. One study using Pseudomonas putida, a species common to both aquatic and terrestrial environments, is discussed in section 126.96.36.199. 188.8.131.52 Field studies Reports are available on cresol decomposition in soils (section 4.2.2), but field studies on the impact of cresols on the soil microbial community have not been reported in the available literature. 9.2 Plants 9.2.1 Aquatic 184.108.40.206 Laboratory studies Laboratory investigations into the toxicity of cresols to plants are summarized and referenced in Table 15. Studies have been conducted in five species of algae and one vascular plant. Growth inhibition threshold levels in algae ranged from 7.8 to 65 mg/litre, indicating that cresols are moderately toxic to the species tested. Similar levels of toxicity for algae have been observed for the three isomers. EC50 values (mortality, reproduction and dry weight) from static and flow-through tests on duckweed are similar and demonstrate a low level of sensitivity of this species to o-cresol. 220.127.116.11 Field studies The effects of p-cresol on respiration and photosynthesis in the filamentous green alga Spyrogyra sp. were studied in a set of open channel experimental streams (Stout & Kilham, 1983). Continuous dosing of one channel for 48 h with 8 mg p-cresol/litre led to a decrease in the oxygen concentration of the stream (to below 1 mg/litre). The large decrease in dissolved oxygen in the channel resulting from p-cresol addition could only be partially accounted for by inhibition of algal function and was mainly attributed to microbial heterotrophs utilizing p-cresol as a substrate. This was substantiated when laboratory results showed that exposure of Spyrogyra sp. for 1 h to p-cresol (0, 0.9, 4.6, 14, 34 or 71 mg per litre) resulted in dissolved oxygen concentrations of 7.0, 6.2, 6.8, 5.4, 5.2 and 5.6 mg/litre, respectively, while oxygen levels in the dosed stream (field study) often fell well below these levels. The algae turned brown at the three highest exposure levels. Table 15. Toxicity of cresols to aquatic plants under static conditionsa Test species Test chemical Age/size Temperature pH Test duration Effectb Concentration Reference (°C) (days) (mg/litre) Green alga o-cresol 10-day-old 27 7 7 NOEL 11 Bringmann & Kühn (Scenedesmus culture (1978a,b, 1980) quadricauda) m-cresol 8 15 Green alga p-cresol log phase NR 8 2 NOEL 7.8 Kuhn & Pattard (S. subspicatus) (1990) Green alga o-cresol log phase 25 7 2 NOEL 36 Slooff et al. (S. pannonicus) (1983) Green alga o-cresol log phase 26 7 4 NOEL 65 Slooff et al. (Selenastrum (1983) capricornutum) Green alga (S. o-, m-, 14-day-old NR NR 14 EC50 for growth 137 Gaur (1988) capricornutum) p-cresol culture inhibition Green alga o-cresol log phase 25 7 2 growth 34 Slooff et al. (Chlorella inhibition (1983) pyrenoidosa) Table 15 (contd). Test species Test chemical Age/size Temperature pH Test duration Effectb Concentration Reference (°C) (days) (mg/litre) o-cresol steady state 25 8.8 3 EC50 for 100 Huang & Gloyna m-cresol chlorophyl (1968) p-cresol inhibition (72 h) Duckweed o-cresol 4.8-5.2 EC50 for Davis (1981) (Lemna gibba) mortality 540 reproduction 245 dry weight 16.98 a Water was unchanged for the duration of the test; NR = not recorded b EC50 = Concentration effecting 50% of the population; NOEL = no-observed-effect level 9.2.2 Terrestrial 18.104.22.168 Laboratory studies Laboratory investigations regarding the effects of cresols on terrestrial plants were not located in the available literature. 22.214.171.124 Field studies No data relating to the impact of cresols on terrestrial plants under field conditions could be located in the available literature. 9.3 Invertebrates 9.3.1 Aquatic 126.96.36.199 Laboratory studies Laboratory investigations on the acute toxicity of cresols to invertebrate species are presented in Table 16. Fifteen freshwater and four marine species from a wide range of taxonomic groups have been studied. LC50 values range from 1.4 to 165 mg/litre, representing moderate to low levels of toxicity. Kühn et al. (1989a) reported acute and 21-day NOEL values for reproductive effects in Daphnia magna of 2.5 and 1.0 mg/litre, respectively, following exposure to p-cresol. Devillers (1988) studied the relative acute toxicity to Daphnia magna of phenols and three cresol isomers. The results showed that, following 24 h of exposure at pH 7.8-8.2 and under static condition, the immobilization concentrations (IC50) for the 3 isomers were 18, 19 and 12 mg/litre. There were no significant differences in the magnitude of toxicity of the three cresol isomers, p-cresol being only slightly more toxic than o- or m-cresol. In a laboratory study by Emery (1970), cresol (isomers not specified) solutions were used to determine the relative toxic responses of three immature phases and three mature states of Gammarus faoccatus and Asellus militasis. Exposures of 48 h revealed that adults were more tolerant than immature animals. Asellids were about twice as tolerant as gammarids and mature gammarids were 4 times more tolerant than immature animals. The most susceptible phase of these crustaceans' life cycle was the first instar. Table 16. Acute toxicity of cresols to aquatic invertebrates Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Waterflea o-cresol stat NR NR NR NR 48 LC50 9.5 Slooff et al. (Daphnia magna) (1983) NOEC 2.9 Bringmann & Kühn (1977) o-cresol stat 24 h 20-22 7.6-7.7 70 24 LC50 19 o-cresol NR NR NR NR NR 48 LC50 5 Parkhurst et al. (1979) m-cresol stat 24 h 20-22 7.6-7.7 70 24 LC50 8.9 Bringmann & Kühn (1977) m-cresol NR NR NR NR NR 48 LC50 18.8 Parkhurst et al. (1979) p-cresol NR NR NR NR NR 48 LC50 1.4 Parkhurst et al. (1979) p-cresol stat 6-24 20 8.0 NR 24 EC50 14 Kühn et al. (1989b) Waterflea o-cresol stat NR NR 7 NR 48 LC50 9.6 Slooff et al. (D. pulex) NOEC 5.2 (1983) Table 16 (contd). Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Waterflea o-cresol flow NR 14 7.6-8.3 569-865 48 LC50 > 94 Degraeve et al. (D. pulicaria) (1980) m-cresol flow NR 14 7.6-8.3 569-865 48 LC50 > 99.5 Degraeve et al. (1980) p-cresol flow NR 14 7.6-8.3 569-865 48 LC50 22.7 Degraeve et al. (1980) Aquatic sowbug o-cresol stat NR 20 7 NR 48 LC50 23 Slooff (1983) (Asellus aquaticus) Scud o-cresol stat NR 20 7 NR 48 LC50 21 Slooff (1983) Gammarus pulex) Marine scud o-cresol stat adult 23 NR NR 96 LC50 10.2 Lee & Nicol (Elasmopus (1978) pectinicrus) Marine sand o-cresol SR 3.8 cm 10 NR NR 59 LC50 14.2 McLeese et al. shrimp (Crangon (1979) septemspinosa) Mayfly o-cresol stat NR 20 7 NR 48 LC50 50 Slooff (1983) (Cloeon dipterum) Table 16 (contd). Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Waterbug o-cresol stat NR 20 7 NR 48 LC50 80 Slooff (1983) (Corixa punctatum) Mosquito o-cresol stat 3rd 26 7 NR NR LC50 80 Slooff (1983) (Aedes aegypti) instar Midge o-cresol stat NR 20 7 NR 48 LC50 34 Slooff (1983) (Chironomus thumni) Dragonfly o-cresol stat NR 20 7 NR 48 LC50 46 Slooff (1983) (Ischnura elegans) Stonefly o-cresol stat NR 20 7 NR 48 LC50 10 Slooff (1983) (Nemoura cinerea) Hydra o-cresol stat budless 17 7 NR 48 LC50 75 Slooff (1983); (Hydra Slooff et al. oligactis) (1983) Pond Snail o-cresol NR 3-4 20 7 NR 48 LC50 160 Slooff (1983); (Lymnaea weeks Slooff et al. stagnalis) (1983) Table 16 (contd). Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Flatworm o-cresol stat NR 20 7 NR 48 LC50 24 Slooff (1983) (Dugesia lugubris) Oligochaete o-cresol stat 20 7 NR NR 48 LC50 165 Slooff (1983) family (Tubificidae) Marine o-cresol stat 20 7 NR NR 48 LC50 135 Slooff (1983) polychaete (Ophryotrocha diadema) o-, m-, stat NR NR NR NR 48 LC50 33-100 Parker (1984) p-cresol Marine green o-cresol stat eggs 5 NR NR 96 EC50 30 Falk-Petersen sea urchin development et al. (1985) (Strongylocentrotus droebachien) m-cresol stat eggs 5 NR NR 96 EC50 30 Falk-Petersen development et al. (1985) p-cresol stat eggs 5 NR NR 96 EC50 5 Falk-Petersen development et al. (1985) a stat = static conditions (water unchanged for the duration of the test); flow = intermittent flow-through conditions; NR = not reported b LC50 = concentration resulting in lethality of 50% of the test animals; NOEC = no-observed-effect concentration; EC50 = concentration resulting in effects among 50% of the test animals 188.8.131.52 Field investigations The effect of p-cresol on invertebrate colonization of leafpacks was studied in open channel experimental streams (Stout & Cooper, 1983). Two types of dosing regimes were used in an attempt to distinguish between the direct toxicity of p-cresol and the indirect effect of decreased dissolved oxygen concentration caused by the stream microorganisms utilizing p-cresol as a substrate (section 184.108.40.206), previously shown to occur in p-cresol-treated streams. Channels were either continuously dosed for 96 h with 8 mg p-cresol/litre or intermittently dosed at the same level, with temporary cessations of dosing when dissolved oxygen concentrations decreased considerably compared to the control. Leafpacks containing fresh Populus deltoides (poplar) leaves were added to the streams and monitored for invertebrate colonization. Changes in colonization patterns in the treated streams significantly altered the biomass of invertebrates over time, and responses were less severe in the intermittent-dose channels than in the continuous-dose ones. Leeches and isopods, normally found among root mats, entered the water column and became highly abundant leafpack colonists in the continuous-dose channels compared to intermittent-treated and control streams. Snails and flatworms, which are normal colonists on leafpacks, increased dramatically in numbers, while freshwater scuds, also normal leafpack colonists, decreased markedly and dead scuds were found floating in the stream following dosing. Prior tests with scud showed a 44% mortality rate in aerated water dosed with 5 mg/litre for 96-h, while the 96-h LC50 in unaerated water was 2 mg/litre. These data suggest the aquatic invertebrate community may be damaged more from decreased available oxygen, an indirect effect of p-cresol in the water, than by a direct toxic action of the substance. 9.3.2 Terrestrial 220.127.116.11 Laboratory studies Laboratory investigations into the impact of cresols on terrestrial invertebrates were not located in the available literature. 18.104.22.168 Field studies Field investigations concerning cresols were also not located in the available literature. 9.4 Vertebrates 9.4.1 Aquatic 22.214.171.124 Laboratory studies The acute toxicity of cresols to vertebrates has been studied in nine species of fish (eight freshwater and one marine species) and two species of freshwater amphibians (Table 17). LC50 values range from 7.9 to 40 mg/litre, indicating that the test materials are similar in their level of toxicity and that they are moderately toxic to aquatic vertebrates. Studies conducted in fathead minnows exposed to o-cresol show that the toxicity of the compound is not affected by water hardness. 126.96.36.199 Field studies The effect of p-cresol on five fish species (smallmouth bass, largemouth bass, fathead minnows, walleyed pike and bluegill sunfish) was determined in an outdoor experimental stream (Cooper & Stout, 1982). Exposure over a 24-h period to a concentration of 8 mg/litre caused no mortality, but examination of fish guts showed that they had ceased feeding. There was no serious reduction in dissolved oxygen during the experiment. Total body burden measurements showed that the fish had a bioaccumulation factor of 2.1 for p-cresol at the end of the exposure period. Body burdens showed a rapid decrease on removal of the contaminant. During a 48-h pulsed exposure to 8 mg p-cresol/litre, the mortality of walleyed pike was very high. Smallmouth bass showed visible stress; largemouth bass showed no visible stress but had stopped feeding. There were large decreases in dissolved oxygen during the experiment. Bioaccumulation was determined in specific body parts for bluegill sunfish. p-Cresol levels in eyes, mussels and gills were low (2.8, 4.7 and 7.3 mg/kg, respectively) but were high in liver and intestines (76 and 97 mg/kg, respectively). Again, p-cresol was rapidly eliminated from the fish. In the case of a 96-h exposure to 8 mg p-cresol/litre, the mortality was very high in all species. Large, sustained drops in dissolved oxygen also occurred. Table 17. Acute toxicity of cresols to aquatic vertebrates Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Rainbow trout o-cresol NR 5-8 15 7-8 NR 48 LC50 13 Slooff et al. (Oncorhynchus weeks NOEC 3.8 (1983) mykiss) o-cresol flow 7.9 cm 14 7.6-8.3 569-865 96 LC50 8.4 DeGraeve et al. (1980) m-cresol flow 7.9 cm 14 7.6-8.3 569-865 96 LC50 8.9 DeGraeve et al. (1980) p-cresol flow 7.3 cm 14 7.6-8.3 569-865 96 LC50 7.9 DeGraeve et al. (1980) Fathead minnow o-cresol NR 3-4 20 NR NR 48 LC50 34 Slooff et al. (Pimephales weeks NOEC 30 (1983) promelas) o-cresol stat 17.9 mm; 25 7.7 47 96 LC50 14 Geiger et al. 29 days (1990) o-cresol stat 3.8-6.4 25 7.5 20 96 LC50 12.55 Pickering & cm Henderson (1966) Table 17 (contd). Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) o-cresol stat 3.8-6.4 25 8.2 360 96 LC50 13.42 Pickering & cm Henderson (1966) o-cresol flow 5.0 cm 14 7.6-8.3 569-865 96 LC50 18.2 DeGraeve et al. (1980) m-cresol flow 4.9 cm 14 7.6-8.3 569-865 96 LC50 55.9 DeGraeve et al. (1980) p-cresol flow 5.2 cm 14 7.6-8.3 569-865 96 LC50 28.6 DeGraeve et al. (1980) p-cresol stat 4-8 18-22 < 5.9 soft 96 LC50 19 Mattson et al. weeks (artificial) (1976) 1.1-3.1 cm Fathead minnow p-cresol flow 28 days 24 7.8 48 96 LC50 16.5 Geiger et al. (P. promelas) 20.9 mm (1986) o-, m-, flow 29 days 25 7.6 46 96 LC50 12.8 Geiger et al. p-cresol 20.8 mm (1990) Bluegill o-cresol stat 3.8-6.4 25 7.5 20 96 LC50 20.8 Pickering & sunfish cm Henderson (1966) (Lepomis macrochirus) Table 17 (contd). Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Goldfish o-cresol stat 3.8-6.4 25 7.5 20 96 LC50 23.25 Pickering & (Carassius cm Henderson (1966) auratus) o-, m-, stat 60-90 mm 18-23 7.8 hard 5 days mortality 1.0 Ellis (1937) p-cresol < 5 days NOEC 0.1 Mosquitofish o-, m-, stat adult 17-20 7.3-7.7 NR 96 LC50 22 Wallen et al. (Gambusia p-cresol females (1957) affinis) Guppy o-cresol NR NR NR NR NR 48 LC50 38 Slooff et al. (Poecilia NOEC 27 (1983) reticulata) o-cresol stat 1.9-2.5 25 7.5 20 96 LC50 18.85 Pickering & cm Henderson (1966) Golden orfe o-cresol NR NR NR NR NR 48 LC50 18 Slooff et al. (Leuciscus (1983) idus) Japanese o-cresol NR 4-5 24 NR NR 48 LC50 41 Slooff et al. killifish weeks NOEC 32 (1983) (Oryzias latipes) Table 17 (contd). Test species Test Test Age/ Temperature pH Hardness Test Parameterb Concentration Reference chemical typea size (°C) (mg CaCO3/ duration (mg/litre) litre) (h) Atlantic cod o-cresol stat eggs 5 NR NR 96 EC50 12 Falk-Petersen (Gadus morhus) (development) et al. (1985) m-cresol stat eggs 5 NR NR 96 EC50 > 30 Falk-Petersen (development) et al. (1985) Atlantic cod p-cresol stat eggs 5 NR NR 96 EC50 5 Falk-Petersen (G. morhus) (development) et al. (1985) Clawed toad o-cresol stat 3-4 20 NR NR 48 LC50 38 Slooff et al. (Xenopus weeks NOEC 24 (1983); laevis) Slooff & Baerselman (1980) Salamander o-cresol stat 3-4 20 NR NR 48 LC50 40 Slooff et al. (Ambystoma weeks NOEC 32 (1983); mexicanum) Slooff & Baerselman (1980) a Stat = static conditions (water unchanged for the duration of the test); flow = intermittent flow through conditions; NR = not reported b LC50 = concentration resulting in lethality of 50% of the test animals; NOEC = no-observed-effect concentration; EC50 = concentration resulting in effects among 50% of the test animals Laboratory dose-response data for the species, investigated under aerated conditions, showed that all species could withstand high levels of p-cresol (up to 40 mg/litre) over a 96-h exposure period. Thus the very high mortality observed in the experimental streams at a p-cresol concentration of 8 mg/litre was due to the decreases in dissolved oxygen and/or the synergistic effect of p-cresol and dissolved oxygen on fish function. 9.4.2 Terrestrial 188.8.131.52 Laboratory studies The acute oral toxicity for cresols was determined in wild-trapped redwinged blackbirds (Agelaius phoeniceus) preconditioned to captivity for 2-6 weeks and then dosed by gavage with cresols formulated with propylene glycol over an 18-h period. The LD50 values were calculated to be > 113 and > 96 mg/kg for m- and p-cresol, respectively (Schafer et al., 1983). 184.108.40.206 Field studies No data concerning field observations of the effects of cresols on terrestrial vertebrates were present in the available literature. 10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT 10.1 Evaluation of human health risks Cresols consist either of a white crystalline solid or a yellowish liquid. They have a phenolic-like odour and are freely soluble in water. Cresols are found naturally in various plants and oils and can be produced as combustion by-products from environmental fires. They are also produced synthetically. Cresols have a wide variety of uses as solvents and disinfectants or chemical intermediates for pharmaceuticals, fragrances, antioxidants, dyes, pesticides and resins. Cresols have been detected in ambient air, surface- and groundwater, and wastewater. They have also been detected in food and beverages. Cresols are rapidly absorbed by inhalation, ingestion and dermal contact. They are readily distributed throughout the body. The primary route of elimination is through the urine following conjugation with glucuronides and sulfates. The acute toxicity of cresols is mainly a consequence of their strong irritant and corrosive activity. Toxic effects and clinical signs following ingestion are burning of the mouth and throat, abdominal pain and vomiting. More severe reactions may result in coma and death. Target tissues and organs of ingested cresols in humans are the blood, kidneys, lungs, heart, central nervous system and liver. Inhalation of cresol vapour produces irritation of the nasal membranes, throat and lungs. Acute poisoning during occupational exposure is usually a result of dermal contact, which may result in severe burns and scarring of the skin, haematological changes, kidney failure, coma and death. There are very little data regarding potential reproductive effects and no data on carcinogenicity in humans. There is limited evidence to suggest that special populations may be at greater risk from cresol exposure, e.g., individuals with glucose-6-phosphate dehydrogenase deficiency or renal insufficiency and the very young. 10.2 Evaluation of environmental risks Cresols are present in the air, water and soil. They undergo a number of chemical and biological reactions such as photolysis, hydrolysis, oxidation and biodegradation. It appears, therefore, that cresols will be relatively labile in the environment and will not bioaccumulate to any significant extent. There are limited data available on the levels of cresols in the ambient environment. A median air concentration of 1.59 µg/m3 (0.359 ppb) has been reported in the USA for source-dominated sites. Cresols have also been detected in contaminated groundwater and surface water and at hazardous waste sites. Observations on microorganisms, invertebrates and fish are available and show that cresols may represent a risk to non-mammalian organisms at point sources with high cresol concentrations but not in the general environment. 10.3 Guidance value No information is available regarding the effects of chronic exposure to cresols. Therefore, there is inadequate information to assess carcinogenic hazard of cresols. Based on the results of subchronic studies, a NOAEL of 50 mg/kg body weight per day can be established for all three cresol isomers. An uncertainty factor of 300 was recommended, composed as follows: 10 to account for interspecies variation; 10 to account for the lack of chronic toxicity studies and possible genotoxic and promoting activity of cresols, and 3 to account for intraspecies variation based on the rapid and complete metabolism. Therefore, applying the uncertainty factor of 300, an acceptable daily intake (ADI) of 0.17 mg/kg body weight per day can be established for cresols. 11. CONCLUSIONS AND RECOMMENDATIONS FOR PROTECTION OF HUMAN HEALTH 11.1 Conclusions There is clear evidence in humans that, during dermal or oral exposure, high concentrations of cresols are corrosive, absorbed rapidly and produce severe toxicity that may result in death. Inhalation may result in irritation of the respiratory tract. 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J Water Pollut Control Fed, 40: R354-R367. Younger Labs (1974) Skin irritation in albino rabbits after application of o-, m-, and p-cresol. St. Louis, Missouri, Younger Laboratories (Unpublished data submitted to the US Environmental Protection Agency, Office of Toxic Substances) (Fiche No. OTS0517499). Zheng Y, Hill DO, & Kuo CH (1993a) Destruction of cresols by chemical oxidation. J Hazard Mater, 34:245-260. Zheng Y, Hill DO, & Kuo CH (1993b) Rates of ozonation of cresol isomers in aqueous solutions. Ozone Sci Eng, 15: 267-278. RESUME 1. Identité, propriétés et méthodes d'analyse Les crésols sont des phénols isomères substitués par un groupement méthyle en position ortho, méta ou para par rapport au groupement hydroxyle. Le crésol du commerce, également connu sous le nom d'acide crésylique, contient les trois isomères à côté d'un peu de phénol et de xylènes. Toutefois certains produits du commerce contiennent jusqu'à 30% de xylénol et 60% de phénols en C9 et sont également désignés sous le nom "d'acides crésyliques". Physiquement, les crésols se présentent sous la forme d'un solide cristallin blanc ou d'un liquide jaunâtre à forte odeur phénolique. Ils sont très inflammables et sont solubles dans l'eau, l'éthanol, l'éther, l'acétone et les hydroxydes alcalins. Les crésols subissent des réactions de substitution électrophiles en position ortho ou para du groupement hydroxyle. Ils donnent également lieu à des réactions de condensation avec les aldéhydes, les cétones ou les diènes. On peut utiliser plusieurs méthodes pour rechercher la présence de crésols dans l'environnement ou les milieux biologiques. Les plus couramment utilisées sont la chromatographie en phase gazeuse avec détection par ionisation de flamme, la chromatographie en phase gazeuse couplée à la spectrophotométrie de masse et enfin la chromatographie liquide à haute performance. Pour l'échantillonnage dans l'air, on peut faire passer celui-ci dans un absorbeur contenant de l'hydroxyde de sodium ou des adsorbants solides. 2. Usages, sources et niveaux d'exposition Les crésols sont très largement utilisés comme solvants ou désinfectants ou encore comme intermédiaires dans la production d'un grand nombre d'autres substances. Ces composés sont le plus souvent utilisés pour la production d'arômes, d'antioxydants, de colorants, de pesticides et de résines. L' ortho- et le para-crésol sont utilisés pour la production d'huiles lubrifiantes, de combustibles pour véhicules à moteur et d'élastomères, le meta-crésol étant utilisé à la fabrication d'explosifs. Les crésols et leurs dérivés existent à l'état naturel dans les huiles essentielles de diverses plantes telles que les fleurs de Yucca gloriosa, dans le jasmin, le lys, les conifères, les chênes et le santal, et ils constituent également un produit de la combustion naturelle de certaines substances et de l'activité volcanique. On trouve du para-crésol dans l'urine des animaux et de l'homme. Les crésols du commerce sont des sous-produits de la distillation fractionnée du pétrole brut et du goudron de houille. Ils se retrouvent en petites quantités dans les échappements des véhicules à moteur, lors de l'incinération des déchets municipaux et de la combustion de la houille et du bois. La fumée de cigarettes contient également des crésols. On ignore quelle est la production mondiale totale de crésols; pour les Etats-Unis d'Amérique, on indiquait en 1990 une production annuelle totale de 38 300 tonnes. Le transport des crésols dans le milieu s'effectue dans la phase gazeuse de l'atmosphère, et de l'atmosphère aux eaux de surface et au sol par entraînement avec les précipitations. En raison de leur volatilité, de leur fixation aux sédiments et de leur biodégradation, les crésols ne se retrouvent dans l'eau qu'en petites quantités. Dans le sol, ils peuvent être légèrement ou fortement mobiles en fonction du coefficient d'adsorption du sol (Koc). On a décelé la présence de crésols dans les eaux souterraines, de sorte qu'un lessivage doit se produire. Il peut y avoir exposition aux crésols par l'intermédiaire de l'air, de l'eau ou de la nourriture. La concentration médiane dans l'air des o-crésols a été trouvée égale à 1,59 µg/m3 (0,359 ppm) sur 32 sites des Etats-Unis d'Amérique dominés par des sources de pollution. Dans ce même pays, les concentrations dans les eaux de surface vont de valeurs inférieures à la limite de détection jusqu'à 77 µg/litre (STORET, 1993). Au Japon, on a trouvé une concentration de 204 µg/litre dans une rivière polluée par des effluents industriels. Des teneurs pouvant atteindre 2100 µg/litre dans le cas de l' o-crésol et 1200 µg/litre dans le cas d'un mélange de m- et de p-crésols ont été mesurées dans des eaux usées. Dans l'eau de pluie, les concentrations vont de 240 à 2800 ng/litre dans le cas de l' o-crésol et de 380 à 2000 ng/litre pour le mélange de p- et de m-crésols. On a décelé la présence de crésols dans des denrées alimentaires et des boissons. Dans les spiritueux, des concentrations se situant entre les limites 0,01-0,02 mg/litre ont été mesurées. Dans la fumée émise par une cigarette américaine sans bout-filtre (85 mm), la teneur est de 75 µg. La population générale peut être exposée aux crésols par suite de l'inhalation d'air, de l'ingestion d'eau, de nourriture et de boissons diverses ainsi que par contact cutané. En général il est impossible d'évaluer quantitativement la dose de crésols absorbée à partir de ces sources par suite de l'absence de données de surveillance suffisantes. En ce qui concerne l'exposition professionnelle, on a fait état de concentrations atteignant 5,0 mg/m3. 3. Cinétique et métabolisme Les crésols sont résorbés au niveau des voies respiratoires et digestives ainsi que de l'épiderme. La vitesse et l'ampleur de cette absorption n'ont pas fait l'objet d'études particulières. Cependant certains travaux montrent qu'au niveau des voies digestives et de l'épiderme, l'absorption est rapide et importante. Les crésols se répartissent dans l'ensemble des principaux viscères. La principale voie métabolique des crésols consiste dans une conjugaison avec l'acide glucuronique et les sulfates inorganiques. Il existe des voies métaboliques secondaires comportant une hydroxylation du cycle benzénique ainsi qu'une oxydation de la chaîne latérale. Les crésols sont principalement éliminés par les reins sous forme de conjugués. 4. Effets sur les mammifères de laboratoire et les systèmes in vitro Une intoxication aiguë par les vapeurs de crésols est peu probable en raison de la faible tension de vapeur de ces composés. Chez le rat, on a observé des concentrations létales moyennes de 29 mg/m3 pour l' o- et le p-crésol et de 58 mg/m3 pour le m-crésol. Chez le même animal, les valeurs de la DL50 par voie orale sont respectivement de 121, 207 et 242 mg/kg de poids corporel pour l' o-, le p- et le m-crésol respectivement. Les comparaisons interspécifiques montrent que les trois isomères sont tous plus toxiques pour la souris que pour le rat et que leur toxicité croît avec la concentration. L'exposition cutanée peut entraîner une intoxication générale mortelle. Chez le lapin on a relevé pour la DL50 des valeurs respectivement égales à 890, 2830, 300 et 2000 mg/kg de poids corporel pour l' o-, le m- et le p-crésol et leurs mélanges. Chez le rat, la DL50 cutanée se situait respectivement à 620, 1100, 750 et 825 mg/kg de poids corporel pour l' o-, le m- et le p-crésol ainsi que pour le dicrésol. Chez le lapin, le rat et la souris, les crésols sont extrêmement irritants pour la peau et les yeux. Chez des animaux à qui l'on avait fait respirer pendant une courte durée des mélanges d'aérosols et de vapeurs d' o-crésol, on a observé une irritation des voies respiratoires, de petites hémorragies au niveau des poumons, une réduction du poids corporel ainsi qu'une dégénérescence cellulaire du myocarde, du foie, du rein et des nerfs. En faisant absorber à des rats pendant une courte durée (28 jours) des doses quotidiennes d'environ 800 mg ou plus de crésols par kg de poids corporel, on a constaté une réduction du poids corporel, une modification du poids des organes ainsi que des anomalies histopathologiques au niveau des voies respiratoires et digestives. Chez des souris exposées de la même manière à des doses de 1500 mg/kg de poids corporel, les effets ont été plus sévères et les animaux sont morts aux concentrations les plus élevées d' o-, de m- et de p-crésol, à l'exclusion des mélanges de ces isomères. L'exposition prolongée de rats à des vapeurs d' o-, de m- ou de p-crésol (pendant une durée allant jusqu'à 4 mois) a eu pour effets une perte de poids, une réduction de l'activité locomotrice, une inflammation des muqueuses nasales et de la peau ainsi que des anomalies au niveau du foie. Exposés par voie orale à des crésols pendant 13 semaines, des souris, des rats et des hamsters ont présentés les effets suivants: mortalité, tremblements, réduction du poids corporel, effets hématologiques, accroissement du poids des organes, hyperplasie de l'épithélium nasal et de celui de la portion cardiaque de l'estomac. L'exposition de rats et de souris à des crésols isomères par voie orale ou par voie respiratoire provoque un allongement du cycle oestral ainsi que des modifications histopathologiques au niveau de l'utérus et des ovaires. On n'a en revanche pas observé d'effets indésirables sur la spermatogénèse. De légers effets cytotoxiques ont été signalés chez des rats et des lapins exposés à de l' o- et du p-crésol, mais on n'a observé sur le développement que des effets mineurs qui puissent être attribuables à ce traitement. Le traitement in vitro par de l' o- et du p-crésol, à l'exclusion du m-crésol, entraînerait une certaine génotoxicité. En revanche les études in vivo n'ont pas fait ressortir de résultats positifs. Pourtant, il existe des signes d'activité promotrice au niveau cutané. Aucune étude de cancérogénicité n'a été publiée sur l'un quelconque des isomères du crésol. 5. Effets sur l'homme L'ingestion de crésols provoque des brûlures de la bouche et de la gorge, des douleurs abdominales et des vomissements. Après ingestion, les tissus et les organes-cibles sont, chez l'homme, le sang et les reins et l'on a également fait état d'effets sur les poumons, le foie, le coeur et le système nerveux central. Dans les cas graves, on peut observer un coma mortel. Après exposition cutanée, on a signalé de graves brûlures laissant subsister des cicatrices, une intoxication générale et la mort. En général, l'exposition professionnelle aux crésols résulte d'un contact cutané. Une exposition aiguë peut provoquer de graves brûlures, une anurie et un coma mortel. On ne dispose que de très peu de données sur les effets au niveau de l'appareil reproducteur et on n'a aucun renseignement sur la cancérogénicité de ces produits pour l'homme. 6. Effets sur les autres êtres vivants Les observations effectuées sur des microorganismes, des invertébrés et des poissons montrent que les crésols peuvent constituer un risque pour les organismes non-mammaliens là où des sources ponctuelles de pollution déterminent de fortes concentrations, mais ce n'est pas le cas dans l'environnement en général. 7. Conclusions et recommandations Aux concentrations généralement présentes dans l'environnement, les crésols ne constituent pas un risque important pour la population générale. Toutefois il y a possibilité d'effets indésirables pour les insuffisants rénaux ainsi que pour les personnes présentant certains déficits enzymatiques; ce risque existe également en cas de forte exposition. Les crésols peuvent constituer un risque pour les microorganismes, les invertébrés et les poissons là où des sources ponctuelles de pollution déterminent de fortes concentrations, mais ce n'est pas le cas dans l'environnement en général. On ne dispose d'aucune donnée concernant les effets de l'exposition chronique aux crésols. Dans ces conditions, il n'est pas possible d'évaluer le risque cancérogène imputable à ces produits. Si on s'appuie sur les résultats d'études sub-chroniques, on peut estimer à 50 mg/kg de poids corporel par jour la dose sans effets indésirables observables. Il a été recommandé d'appliquer un facteur d'incertitude de 300 qui est établi comme suit: 10 pour tenir compte des variations interspécifiques; 10 pour tenir compte de l'absence de données de toxicité chronique ainsi que de l'activité génotoxique et promotrice possible des crésols et enfin 3 pour tenir compte des variations intraspécifiques tenant à un métabolisme plus ou moins rapide et complet. Dans ces conditions, on peut fixer à 0,17 mg/kg de poids corporel par jour la dose journalière acceptable (DJA) de crésols. RESUMEN 1. Identidad, propiedades y métodos analíticos Los cresoles son fenoles sustituidos isoméricos con un sustituyente metilo en una de las posiciones orto, para o meta respecto al grupo hidróxilo. El cresol comercial, conocido también como ácido cresílico, contiene los tres isómeros con pequeñas cantidades de fenol y xilenoles. Sin embargo, los productos comerciales, conocidos como "ácidos cresílicos", contienen hasta un 30% de xilenol y un 60% de C9-fenoles. Físicamente, los cresoles consisten en un sólido cristalino blanco o un líquido amarillento y tienen un fuerte olor a fenol. Son altamente inflamables y se disuelven en agua, etanol, éter, acetona e hidróxidos alcalinos. Los cresoles sufren reacciones de sustitución electrofílica en la posición orto o para libre en relación con el grupo hidróxilo. Asimismo, experimentan reacciones de condensación con aldehídos, cetonas o dienos. La presencia de cresoles tanto en medios naturales como biológicos puede ser determinada usando varios métodos. Los más corrientes son la cromatografía de gases con detector de ionización de llama (GC-FID), la cromatografía de gases con espectrofotometría de masas (GC-MS) y la cromatografía líquida de alta resolución (HPLC). El muestreo de los cresoles en la atmósfera puede realizarse pasando aire a través de células de absorción, utilizando hidróxido de sodio o adsorbentes sólidos. 2. Usos, fuentes y niveles de exposición Los cresoles ofrecen gran variedad de usos como solventes o desinfectantes, o como intermedios en la producción de muchas otras sustancias. Estos compuestos son utilizados principalmente en la producción de perfumes, antioxidantes, tintes, plaguicidas y resinas. Los cresoles orto- y para- se utilizan en la producción de aceites lubricantes, combustibles para motores y polímeros de caucho, mientras que el meta-cresol interviene en la fabricación de explosivos. Los cresoles y sus derivados se encuentran naturalmente en los aceites de diversas plantas (tales como flores de Yucca gloriosa, jazmín, Lilium longiflorum var. eximium, coníferas, roble y sándalo) y como producto de combustión de los incendios naturales y la actividad volcánica. El para-cresol está presente en la orina de animales y del hombre. Comercialmente, los cresoles son generados como subproductos de la destilación fraccional de petróleo crudo y alquitranes de hulla. Asimismo, se producen pequeñas cantidades en caños de escape de vehículos, incineradores municipales de desechos y mediante la combustión del carbón y de la madera. El humo de cigarrillo también contiene cresoles. No se conoce la producción mundial de cresoles; el total registrado en los Estados Unidos en 1990 ascendió a 38 300 toneladas. El transporte de cresoles en el medio ambiente se realiza en la fase vapor de la atmósfera, y de la atmósfera a las aguas superficiales y al suelo por el lavado de las lluvias. Debido a su volatilización, su adherencia a sedimentos y su biodegradación, los cresoles se encuentran sólo en pequeñas cantidades en el agua. Su movilidad en suelos va de leve a alta, según el coeficiente (Koc) de sorción del suelo. Se han detectado cresoles en aguas subterráneas, lo cual sugiere que algún grado de lixiviación debe ocurrir en el suelo. La exposición a los cresoles puede ocurrir a través del aire, del agua o de los alimentos. En 32 sitios identificados de los Estados Unidos se halló una concentración atmosférica mediana de o-cresoles de 1,59 µg/m3 (0,359 partes por mil millones). En los Estados Unidos, las concentraciones en aguas superficiales van de niveles inferiores al umbral de detección a 77 µg/litro (STORET, 1993). En el Japón, se hallaron niveles de 204 µg/litro en un río contaminado por efluentes industriales. En aguas residuales, ha sido posible detectar concentraciones de hasta 2100 µg/litro para el o-cresol y de 1200 µg/litro para m- y p-cresoles combinados. En el agua de lluvia, las concentraciones van de 240 a 2800 ng/litro para el o-cresol y de 380 a 2000 ng/litro para p- y m-cresoles combinados. También se han detectado cresoles en alimentos y bebidas. En bebidas alcohólicas se determinaron concentraciones del orden de 0,01-0,2 mg/litro. En el humo de tabaco, esta cantidad es de 75 µg para un cigarrillo americano sin filtro (85 mm). La exposición de la población general a los cresoles puede darse por inhalación, por el agua potable, por la ingestión de alimentos y bebidas, y por contacto cutáneo. En general, la falta de datos adecuados de seguimiento impide realizar estimaciones cuantitativas de la ingesta diaria de cresol por estas vías. Se han señalado niveles de exposición ocupacional de hasta 5,0 mg/m3. 3. Cinética y metabolismo Los cresoles se absorben a través de los tractos respiratorio y gastrointestinal y por contacto con la piel. Si bien el índice y la magnitud de la absorción no han sido estudiados específicamente, diversos estudios han probado que la absorción gastrointestinal y dérmica es rápida y extensa. Los cresoles se distribuyen a todos los principales órganos. Su principal vía metabólica es la conjugación con ácido glucurónico y sulfato inorgánico; las vías metabólicas secundarias incluyen la hidroxilación del anillo de benceno y la oxidación de cadena lateral. La principal vía de eliminación es la excreción renal en forma de conjugados. 4. Efectos en mamíferos de laboratorio; sistemas in vitro La intoxicación aguda con cresoles es poco probable, debido a la baja presión de vapor de estos compuestos. Se han señalado concentraciones letales medias en ratas de 29 mg/m3 para o- y p-cresoles y de 58 mg/m3 para m-cresoles. En ratas, los valores orales DL50 notificados han sido de 121, 207 y 242 mg/kg de peso corporal para o-, p- y m-cresoles, respectivamente. Las comparaciones entre especies revelan que los tres isómeros son más tóxicos en ratones que en ratas y que la toxicidad aumenta con la concentración. La exposición cutánea puede provocar toxicidad sistémica y muerte. Los valores dérmicos DL50 en conejos fueron de 890, 2830, 300 y 2000 mg/kg de peso corporal para cresoles o-, m-, p- y combinados, respectivamente. En ratas, se registraron valores dérmicos DL50 de 620, 1100, 750 y 825 mg/kg de peso corporal para o-, m-, p- cresoles y dicresol, respectivamente. Los cresoles ocasionan graves irritaciones dérmicas y oculares en conejos, ratas y ratones. La exposición por breves periodos a mezclas inhaladas de aerosoles y vapores de o-cresol provocó irritación del tracto respiratorio, pequeñas hemorragias pulmonares, pérdida de peso corporal y degeneración de músculo cardiaco, hígado, riñón y células nerviosas. La exposición oral por breves periodos (28 días) a dosis diarias de unos 800 mg/kg de peso corporal o más produjo pérdida de peso corporal, alteración del peso de los órganos y cambios histopatológicos en los tractos respiratorio y gastrointestinal de las ratas. Más graves fueron los efectos constatados en ratones expuestos a una administración similar de dosis de 1500 mg/kg de peso corporal; a concentraciones más elevadas, la muerte fue causada por la exposición a o-, m- y p-cresoles, mas no por exposiciones a mezclas de isómeros. Una exposición más prolongada de ratas, de hasta 4 meses, a vapores de o-, m- y p-cresol provocó pérdida de peso, reducción de la actividad locomotriz, cambios hepáticos e inflamación de membranas nasales y piel. La exposición oral de ratones, ratas y hámsters por periodos de hasta 13 semanas ocasionó muerte, temblores, pérdida de peso corporal, alteraciones hematológicas, aumento del peso de los órganos e hiperplasia del epitelio nasal y del cardias. La exposición oral y por inhalación a isómeros del cresol da lugar a ciclos estruales prolongados y modificaciones histopatológicas del útero y los ovarios de ratas y ratones. No se observaron efectos sobre la espermatogénesis en ratas y ratones. En ratas y conejos expuestos a o- y p-cresoles se registraron efectos embriotóxicos moderados; no obstante, sólo se han señalado anomalías menores del desarrollo relacionadas con el tratamiento. Ciertos indicios de genotoxicidad han sido constatados in vitro como consecuencia del tratamiento con o- y p-cresoles, pero no con m-cresol. No se obtuvieron resultados positivos en estudios in vivo; sin embargo, se observaron indicios de actividad promotora en la piel. No se han notificado estudios de carcinogenicidad para ninguno de los isómeros del cresol. 5. Efectos en la especie humana La ingestión de cresoles provoca quemaduras de boca y esófago, dolores abdominales y vómitos. Los tejidos y órganos afectados por la ingestión de cresoles son la sangre y los riñones, aunque también se han señalado efectos en los pulmones, el hígado, el corazón y el sistema nervioso central. En casos graves, puede producirse coma y muerte. La exposición cutánea ha ocasionado graves quemaduras de piel, cicatrices, toxicidad sistémica y muerte. En el medio laboral, la exposición a los cresoles suele producirse por contacto cutáneo. La exposición aguda puede dar por resultado graves quemaduras, anuria, coma y muerte. Existen muy pocos datos sobre sus efectos en la reproducción, y ninguno sobre la carcinogenicidad en el ser humano. 6. Efectos en otros organismos Las observaciones en microorganismos, invertebrados y peces han revelado que los cresoles pueden suponer un riesgo para organismos diferentes de los mamíferos en puntos específicos con altas concentraciones de cresol, pero no en el medio ambiente en general. 7. Conclusión y recomendaciones En las concentraciones normalmente halladas en el medio ambiente, los cresoles no presentan un riesgo significativo para la población general. Con todo, pueden darse efectos adversos en personas que padecen de insuficiencia renal o de una deficiencia enzimática específica, así como en condiciones de alta exposición. Los cresoles pueden suponer un riesgo para microorganismos, invertebrados y peces en puntos específicos con una alta concentración de cresoles, pero no en el medio ambiente en general. Al no disponerse de datos sobre las consecuencias de una exposición crónica, no existe una información adecuada que permita evaluar el riesgo carcinogénico de los cresoles. Partiendo de los resultados de estudios subcrónicos, puede establecerse un nivel sin efectos adversos observados (NOAEL) de 50 mg/kg de peso corporal al día para los tres isómeros del cresol. Se ha recomendado un factor de incertidumbre 300, que se descompone así: 10 por la variación entre especies; 10 por la falta de estudios de toxicidad crónica y por la posible actividad genotóxica y promotora de los cresoles; y 3 por la variación dentro de la misma especie basada en el metabolismo completo y rápido. Por consiguiente, puede establecerse para los cresoles una ingesta diaria admisible de 0,17 mg/kg de peso corporal.
See Also: Cresol, mixed isomers (CHEMINFO)