INTOX Home Page


    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
                       9.1.1.1   Laboratory studies
                       9.1.1.2   Field studies
               9.1.2. Terrestrial
                       9.1.2.1   Laboratory studies
                       9.1.2.2   Field studies

         9.2. Plants
               9.2.1. Aquatic
                       9.2.1.1   Laboratory studies
                       9.2.1.2   Field studies
               9.2.2. Terrestrial
                       9.2.2.1   Laboratory studies
                       9.2.2.2   Field studies
         9.3. Invertebrates
               9.3.1. Aquatic
                       9.3.1.1   Laboratory studies
                       9.3.1.2   Field investigations
               9.3.2. Terrestrial
                       9.3.2.1   Laboratory studies
                       9.3.2.2   Field studies
         9.4. Vertebrates
               9.4.1. Aquatic
                       9.4.1.1   Laboratory studies
                       9.4.1.2   Field studies
               9.4.2. Terrestrial
                       9.4.2.1   Laboratory studies
                       9.4.2.2   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.  Other publications have been
    concerned with epidemiological guidelines, evaluation of short-term
    tests for carcinogens, biomarkers, effects on the elderly and so
    forth.

         Since its inauguration the EHC Programme has widened its scope,
    and the importance of environmental effects, in addition to health
    effects, has been increasingly emphasized in the total evaluation of
    chemicals.

         The original impetus for the Programme came from World Health
    Assembly resolutions and the recommendations of the 1972 UN Conference
    on the Human Environment.  Subsequently the work became an integral
    part of the International Programme on Chemical Safety (IPCS), a
    cooperative programme of UNEP, ILO and WHO.  In this manner, with the
    strong support of the new 14 partners, the importance of occupational
    health and environmental effects was fully recognized. The EHC
    monographs have become widely established, used and recognized
    throughout the world.

         The recommendations of the 1992 UN Conference on Environment and
    Development and the subsequent establishment of the Intergovernmental
    Forum on Chemical Safety with the priorities for action in the six
    programme areas of Chapter 19, Agenda 21, all lend further weight to
    the need for EHC assessments of the risks of chemicals.

    Scope

         The criteria monographs are intended to provide critical reviews
    on the effect on human health and the environment of chemicals and of
    combinations of chemicals and physical and biological agents.  As
    such, they include and review studies that are of direct relevance for
    the evaluation.  However, they do not describe every study carried
    out.  Worldwide data are used and are quoted from original studies,
    not from abstracts or reviews.  Both published and unpublished reports
    are considered and it is incumbent on the authors to assess all the
    articles cited in the references.  Preference is always given to
    published data.  Unpublished data are only used when relevant
    published data are absent or when they are pivotal to the risk
    assessment.  A detailed policy statement is available that describes
    the procedures used for unpublished proprietary data so that this
    information can be used in the evaluation without compromising its
    confidential nature (WHO (1990) Revised Guidelines for the Preparation
    of Environmental Health Criteria Monographs. PCS/90.69, Geneva, World
    Health Organization).

         In the evaluation of human health risks, sound human data,
    whenever available, are preferred to animal data.  Animal and
     in vitro studies provide support and are used mainly to supply
    evidence missing from human studies.  It is mandatory that research on
    human subjects is conducted in full accord with ethical principles,
    including the provisions of the Helsinki Declaration.

         The EHC monographs are intended to assist national and
    international authorities in making risk assessments and subsequent
    risk management decisions.  They represent a thorough evaluation of
    risks and are not, in any sense, recommendations for regulation or
    standard setting.  These latter are the exclusive purview of national
    and regional governments.

    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.

    Procedures

         The order of procedures that result in the publication of an EHC
    monograph is shown in the flow chart.  A designated staff member of
    IPCS, responsible for the scientific quality of the document, serves
    as Responsible Officer (RO).  The IPCS Editor is responsible for
    layout and language.  The first draft, prepared by consultants or,
    more usually, staff from an IPCS Participating Institution, is based
    initially on data provided from the International Register of
    Potentially Toxic Chemicals, and reference data bases such as Medline
    and Toxline.

         The draft document, when received by the RO, may require an
    initial review by a small panel of experts to determine its scientific
    quality and objectivity.  Once the RO finds the document acceptable as
    a first draft, it is distributed, in its unedited form, to well over

    150 EHC contact points throughout the world who are asked to comment
    on its completeness and accuracy and, where necessary, provide
    additional material.  The contact points, usually designated by
    governments, may be Participating Institutions, IPCS Focal Points, or
    individual scientists known for their particular expertise.  Generally
    some four months are allowed before the comments are considered by the
    RO and author(s).  A second draft incorporating comments received and
    approved by the Director, IPCS, is then distributed to Task Group
    members, who carry out the peer review, at least six weeks before
    their meeting.

         The Task Group members serve as individual scientists, not as
    representatives of any organization, government or industry.  Their
    function is to evaluate the accuracy, significance and relevance of
    the information in the document and to assess the health and
    environmental risks from exposure to the chemical.  A summary and
    recommendations for further research and improved safety  aspects  are 
    also  required. The composition of the Task Group is dictated by the
    range of expertise required for the subject of the meeting and by the
    need for a balanced geographical distribution.

    FIGURE 1

         The three cooperating organizations of the IPCS recognize the
    important role played by nongovernmental organizations.
    Representatives from relevant national and international associations
    may be invited to join the Task Group as observers.  While observers
    may provide a valuable contribution to the process, they can only
    speak at the invitation of the Chairperson. Observers do not
    participate in the final evaluation of the chemical; this is the sole
    responsibility of the Task Group members.  When the Task Group
    considers it to be appropriate, it may meet in camera.

         All individuals who as authors, consultants or advisers
    participate in the preparation of the EHC monograph must, in addition
    to serving in their personal capacity as scientists, inform the RO if
    at any time a conflict of interest, whether actual or potential, could
    be perceived in their work.  They are required to sign a conflict of
    interest statement. Such a procedure ensures the transparency and
    probity of the process.

         When the Task Group has completed its review and the RO is
    satisfied as to the scientific correctness and completeness of the
    document, it then goes for language editing, reference checking, and
    preparation of camera-ready copy.  After approval by the Director,
    IPCS, the monograph is submitted to the WHO Office of Publications for
    printing.  At this time a copy of the final draft is sent to the
    Chairperson and Rapporteur of the Task Group to check for any errors.

         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:
                               FIGURE 2

    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

    9.1.1.1  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).

    9.1.1.2  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
    9.3.1.2), 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

    9.1.2.1  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 9.1.1.1.

    9.1.2.2  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

    9.2.1.1  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.

    9.2.1.2  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

    9.2.2.1  Laboratory studies

         Laboratory investigations regarding the effects of cresols on
    terrestrial plants were not located in the available literature.

    9.2.2.2  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

    9.3.1.1  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
    

    9.3.1.2  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
    9.1.1.2), 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

    9.3.2.1  Laboratory studies

         Laboratory investigations into the impact of cresols on
    terrestrial invertebrates were not located in the available
    literature.

    9.3.2.2  Field studies

         Field investigations  concerning cresols were also not located in
    the available literature.

    9.4  Vertebrates

    9.4.1  Aquatic

    9.4.1.1  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.

    9.4.1.2  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

    9.4.2.1  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).

    9.4.2.2  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.  There
    is no information regarding the chronic toxicity of cresols and no
    adequate data regarding the carcinogenic potential of these compounds.

    11.2  Recommendations

    a)   Cresols and mixtures containing cresols, including household   
         products, should be clearly labelled, warning of the acute   
         toxicity and corrosivity.

    b)   Cresols can readily penetrate the skin.  Following direct   
         contact, contaminated areas should be washed immediately with
         water and all contaminated clothing removed.  Workers using
         cresols or solutions containing cresols should wear protective
         clothing.

    c)   Occupational exposure should be minimized.

    12.  FURTHER RESEARCH

    There is a need for the following types of studies:

    a)   chronic toxicity and carcinogenicity studies in animals

    b)   studies on the toxic mechanisms of cresols

    c)   studies on workers occupationally exposed to cresols.

    REFERENCES

    Alexander M & Lustigman BK (1966) Effect of chemical structure on
    microbial degradation of substituted benzenes. J Agric Food Chem,
    14: 410-413.

    Altmann HJ, Grunow W, Mohr U, Richter-Reichhelm HB, & Wester PW (1986)
    Effects of BHA and related phenols on the forestomach of rats. Food
    Chem Toxicol, 24(10/11): 1183-1188.

    Amoore JE & Hautala E (1983) Odor as an aid to chemical safety: Odor
    thresholds compared with threshold limit values and volatilities for
    214 industrial chemicals in air and water dilution. J Appl Toxicol,
    3: 272-290.

    Angerer J & Wulf H (1985) Occupational chronic exposure to organic
    solvents.  XI. Alkylbenzene exposure of varnish workers: Effects on
    hematopoietic system. Int Arch Occup Environ Health, 56: 307-321.

    Arthurs GJ, Wise CC & Coles GA (1977) Poisoning by cresols.
    Anesthesia, 32:642-643.

    Artiola-Fortuny J & Fuller WH (1982) Adsorption of some
    monohydroxybenzene derivatives by soils. Soil Sci, 133: 18-26.

    Atkinson R (1985) Kinetics and mechanisms of the gas phase reactions
    of the hydroxyl radical with organic compounds under atmospheric
    condition. Chem Rev, 85: 69-201.

    Atkinson R, Carter WPL, Darnall KR, Winer AM, & Pitts JN Jr (1980) A
    smog chamber and modeling study of the gas phase NOx air
    photo-oxidation of toluene and the cresols. Int J Chem Kinet,
    12: 779-836.

    Atkinson R, Carter WPL, Plum CN, Winer AM, & Pitts JN Jr (1984)
    Kinetics of the gas-phase reactions of NO3 radicals with a series of
    aromatics at 296±2 K. Int J Chem Kinet, 16: 887-898.

    Atkinson R, Aschmann SM, & Avery J (1992)  Reaction of OH and NO3
    radicals with phenol, cresols and 2-nitrophenol at 296±K.  Environ Sci
    Technol, 26: 1397-1403.

    Babeu L & Vaishnav DD (1987) Prediction of biodegradability for
    selected organic chemicals. J Ind Microbiol, 2: 107-115.

    Baird RB, Kuo CL, Shapiro JS, & Yanko WA (1974) The fate of phenolics
    in wastewater - determination by direct-injection GLC and Warburg
    respirometry. Arch Environ Contam Toxicol, 2: 165-178.

    Bak F & Widdel F (1986) Anaerobic degradation of phenol and phenol
    derivatives by Desulfobacterium phenolicum new species. Arch
    Microbiol, 146(2): 177-180.

    Balikova M & Kohlicek J (1989) Gas chromatography of simple phenolics
    in biological fluids. J Chromatogr, 497: 159-167.

    Bartholomew GW & Pfaender FK (1983) Influence of spatial and temporal
    variations on organic pollutant biodegradation rates in an estuarine
    environment. Appl Environ Microbiol, 45(1): 103-109.

    Battersby NS (1990) A review of biodegradation kinetics in the aquatic
    environment. Chemosphere, 21(10-11): 1243-1284.

    Battersby NS & Wilson V (1988) Evaluation of a serum bottle technique
    for assessing the anaerobic biodegradability of organic chemicals
    under methanogenic conditions. Chemosphere, 17: 2441-2460.

    Battersby NS & Wilson V (1989) Survey of the anaerobic biodegradation
    potential of organic chemicals in digesting sludge. Appl Environ
    Microbiol, 55: 433-439.

    Bayly RC & Wigmore GJ (1973) Metabolism of phenol and cresols by
    mutants of  Pseudomonas putida. J Bacteriol, 113: 1112-1120.

    Bidleman TF (1988) Atmospheric processes. Environ Sci Technol,
    22: 361-367.

    Bio-Fax (1969) Toxicity data sheets for  o-,  p-, and  m-cresol.
    Northbrook, Illinois, Industrial Bio-Fax Laboratories, Inc.
    (Unpublished data submitted to the US Environmental Protection Agency,
    Office of Toxic Substances) (Fiche No. OTS205862).

    Bone E, Tamm A, & Hill M (1976) The production of urinary phenols by
    gut bacteria and their possible role in the causation of large bowel
    cancer.  Am J Clin Nutr, 29: 1448-1454.

    Boutwell RK & Bosch DK (1959) The tumor-promoting action of phenol and
    related compounds for mouse skin. Cancer Res, 19: 413-424.

    Boyd SA (1982) Adsorption of substituted phenols by soil. Soil Sci,
    134: 337-343.

    Boyd SA, Shelton DR, Berry D, & Tiedje JM (1983) Anaerobic
    biodegradation of phenolic compounds in digested sludge. Appl Environ
    Microbiol, 46: 50-54.

    Bray HG, Thrope WV, & White K (1950) Metabolism of derivatives of
    toluene.  Biochem J, 46: 275-278.

    Bringmann G & Kühn R (1976) Comparative results of the damaging
    effects of water pollutants against bacteria  (Pseudomonas putida)
    and blue algae  (Microcystis aeruginosa). Gas Wasserfach
    Wasser-Abwasser, 117(9): 410-413.

    Bringmann G & Kühn (1977) [Results of the damaging effect of water
    pollutants on  Daphnia magna.] Z Wasser Abwasser Forsch,
    10(5): 161-166 (in German).

    Bringmann G & Kühn R (1978a) [Limiting values for the noxious effects
    of water pollutant material to blue algae  (Microcystis aeruginosa) and
    green algae  (Scenedesmus).] Vom Wasser, 50: 45-60 (in German).

    Bringmann G & Kühn R (1978b) Testing of substances for their toxicity
    threshold: Model organisms  Microcystis (Diplocystis) seruginosa and
     Scenedesmus quadricauda. Mitt Int Ver Theor Angew Limnol, 21: 275-284.

    Bringmann G & Kühn R (1980) Comparison of the toxicity thresholds of
    water pollutants to bacteria, algae, and protozoa in the cell
    multiplication inhibition test. Water Res, 14(3): 231-241.

    Brown SC and Grady CPL Jr (1990) Biodegradation kinetics of
    substituted phenolics: Demonstration of a protocol based on
    electrolytic respirometry.  Water Res, 24(7): 853-862.

    BRRC (1988a) Developmental toxicity evaluation of  o-,  m-, or
     p-cresol administered by gavage to Sprague Dawley (CD) rats. Export,
    Pennsylvania, Bushy Run Research Center (Unpublished data submitted to
    the US Environmental Protection Agency, Office of Toxic Substances)
    (Fiche No. OTS0517695).

    BRRC (1988b) Developmental toxicity evaluation of  o-,  m-, or
     p-cresol administered by gavage to New Zealand white rabbits.
    Export, Pennsylvania, Bushy Run Research Center (Unpublished data
    submitted to the US Environmental Protection Agency, Office of Toxic
    Substances) (Fiche No. OTS0517695).

    BRRC (1989a) Two-generation reproduction study of  o-cresol (CAS No.
    95-48-7) administered by gavage to Sprague-Dawley (CD) rats. Export,
    Pennsylvania, Bushy Run Research Center (Project report 51-614)
    (Unpublished data submitted to the Chemical Manufacturers Association
    Cresols Panel, Washington).

    BRRC (1989b) Two-generation reproduction study of  p-cresol (CAS No.
    106-44-5) administered by gavage to Sprague-Dawley (CD) rats. Export,
    Pennsylvania, Bushy Run Research Center (Project report 52-512)
    (Unpublished data submitted to the Chemical Manufacturers Association
    Cresols Panel, Washington).

    BRRC (1989c) Two-generation reproduction study of  m-cresol (CAS No.
    108-39-4) administered by gavage to Sprague-Dawley (CD) rats. Export,
    Pennsylvania, Bushy Run Research Center (Project report 51-634)
    (Unpublished data submitted to the Chemical Manufacturers Association
    Cresols Panel, Washington).

    Bulich AA & Isenberg DL (1980) Use of the luminescent bacterial system
    for the rapid assessment of aquatic toxicity. Adv Instrum,
    35(2): 35-40.

    Bulich AA & Isenberg DL (1981) Use of the luminescent bacterial system
    for the rapid assessment of aquatic toxicity. ISA Trans, 20(1): 29-33.

    Bulich AA, Greene MW, & Isenberg DL (1981) Reliability of the
    bacterial luminescence assay for determination of the toxicity of pure
    compounds and complex effluents. Philadelphia, Pennsylvania, American
    Society for Testing and Materials, pp 338-347 (ASTM Special Technical
    Publication No. 737).

    Campbell I (1941) Petroleum cresylic acids: A study of their toxicity
    and the toxicity of cresylic disinfectants. Soap Sanit Chem,
    17(4): 103.

    Carter WPL, Winer AM, & Pitts JN Jr (1981) Major atmospheric sink for
    phenol and the cresols: Reaction with the nitrate radical. Environ Sci
    Technol, 15(7): 829-831.

    Cason JS (1959) Report on three extensive industrial chemical burns.
    Br Med J, 1: 827-829.

    Cautreels W & van Cauwenberghe K (1978) Experiments on the
    distribution of organic pollutants between airborne particulate matter
    and the corresponding gas phase. Atmos Environ, 12: 1133-1141.

    Chambers CW, Tabak HH, & Kabler PW (1963) Degradation of aromatic
    compounds by phenol-adapted bacteria. J Water Pollut Contr Fed,
    35: 1517-1528.

    Chan TK, Mak LW, & Ng RP (1971) Methemoglobinemia, Heinz bodies and
    acute massive intravascular hemolysis in Lysol poisoning. Blood,
    38: 739-744.

    Cheng M & Kligerman AD (1984) Evaluation of the genotoxicity of
    cresols using sister-chromatid exchange (SCE). Mutat Res,
    137(1): 51-55.

    Chudyk WA, Carrabba MN, & Kenny JE (1985) Remote detection of
    groundwater contaminants using far-UV laser-induced fluorescence. Anal
    Chem 57(7): 1237-1242.

    CIIT (1983) Preliminary results of  in vivo and  in vitro sister
    chromatid exchange assays on cresol isomers and of an immunological
    evaluation of  o-cresol. Research Triangle Park, North Carolina,
    Chemical Industry Institute of Toxicology (Report to the US
    Environmental Protection Agency, Office of Pesticides and Toxic
    Substances) (CIIT Docket No. 12283).

    Clark RM, Goodrich JA, & Deininger RA (1986) Drinking water and cancer
    mortality. Sci Total Environ, 53(3): 153-172.

    Cooper WE & Stout RJ (1982) Assessment of transport and fate of toxic
    materials in an experimental stream ecosystem. In: Dickson KL ed.
    Modelling the fate of chemicals in the aquatic environment. Pellston
    Conference III. Ann Arbor, Michigan, Ann Arbor Science Publications,
    pp 347-378.

    Cote MA, Lyonnais J, & Leblond PF (1984) Acute Heinz-body anemia due
    to severe cresol poisoning: Successful treatment with
    erythrocytapheresis. Can Med Assoc J, 130(10): 1319-1322.

    Czuczwa J, Leuenberger C, Tremp J, & Giger W (1987) Determination of
    trace levels of phenol and cresols in rain by continuous liquid-liquid
    extraction and high-performance liquid chromatography. J Chromatogr,
    403: 233-241.

    Daugherty JP & Franks H (1986) Effect of monocyclic derivatives on DNA
    repair in human lymphocytes. Res Commun Chem Pathol Pharmacol,
    54(1): 133-136.

    Davis JA (1981) Comparison of static-replacement and flow-through
    bioassays using duckweed, lemna gibba G-3. Washington, DC, US
    Environmental Protection Agency (EPA 560/6-81-003; NTIS PB81-187650).

    DeGraeve GM, Geiger DL, Meyer JS, & Bergman HL (1980) Acute and
    embryo-larval toxicity of phenolic compounds to aquatic biota. Arch
    Environ Contam Toxicol, 9(5): 557-568.

    DeWolf WE Jr, Carr SA, Varrichio A, Goodhart PJ, Mentzer MA, Roberts
    GD, Southan C, Dolle RE, & Kruse LI (1988) Inactivation of dopamine
    beta-hydroxylase by  p-cresol: Isolation and characterisation of
    covalently modified active site peptides. Biochemistry, 27: 9093-9102.

    Deichmann W & Keplinger ML (1981) Phenols and phenolic compounds. In:
    Clayton GD & Clayton FE ed. Patty's industrial hygiene and toxicology,
    3rd ed. New York, John Wiley and Sons, vol 2A, pp 2567-2627.

    Deichmann WB & Witherup S (1944) Phenolic studies. VI: The acute and
    comparative toxicity of phenol and  o-,  m-, and  p-cresols for
    experimental animals. J Pharmacol Exp Ther, 80: 233-240.

    DeRosa E, Bartolucci GB, Sigon M, Callegaro R, Perbellini L, &
    Brugnone F (1987) Hippuric acid and  ortho-cresol as biological
    indicators of occupational exposure to toluene. Am J Ind Med,
    11(5): 529-537.

    Devillers J (1988) Acute toxicity of cresols, xylenols and trimethyl
    phenols to  Daphnia magna straus 1820. Sci Total Environ, 76: 79-83.

    Dietz F & Traud J (1978) [Odour and taste thresholds. Concentration of
    phenol bodies.] GWF-Wasser/Abwasser 119(6) (in German).

    Dobbins DC & Pfaender FK (1988) Methodology for assessing respiration
    and cellular incorporation of radiolabeled substrates by soil
    microbial communities. Microbiol Ecol, 15: 257-273.

    Dobson KR, Stephenson M, Greenfield PF, & Bell PRF (1985)
    Identification and treatability of organics in oil shale retort water.
    Water Res 19: 849-856.

    Douglas GR, Nestmann ER, Betts JL, Mueller JC, Lee EGH, Stich HF, San
    RHC, Brouzes RJP, Chmelauskas AL, Paavile HD, & Walden CC (1980)
    Mutagenic activity in pulp mill effluents. Water Chlorination: Environ
    Impact Health Eff, 3: 865-880.

    Dow Chemical (1978) Acute toxicological properties and industrial
    handling hazards of cresol (ortho, meta, para isomers).  Midland,
    Michigan, Dow Chemical Company (Unpublished data submitted to the US
    Environmental Protection Agency, Office of Toxic Substances)
    (Fiche No. OTS206146).

    Dreibelbis WG, Ealy JA, & Porter WE (1985) Industrial hygiene
    monitoring for evaluation of employee exposure and control measures in
    coal conversion program at Oak Ridge National Laboratory.  In: Cooke M
    & Dennis AJ ed.  Polynuclear aromatic hydrocarbons: Mechanisms,
    methods and metabolism.  Columbus, Ohio, Battelle Press, pp 351-363.

    Druyan EA (1974) [Separate determination of phenol and  o-,  m-, and
     p-cresol in air with the aid of thin-layer chromatography.] Gig i
    Sanit, 8: 51-53 (in Russian).

    Eisenreich SJ, Looney BB, & Thornton JD (1981) Airborne organic
    contaminants in the Great Lakes ecosystem. Environ Sci Technol,
    15: 30-38.

    Ellis MM (1937) Detection and measurement of stream pollution.
    Washington, DC, US Department of Commerce, Government Printing Office,
    pp 365-437 (Bureau of Fisheries Bulletin No. 22).

    Ellis DD, Jone CM, Larson RA, & Schaeffer DJ (1982) Organic
    constituents of mutagenic secondary effluents from wastewater
    treatment plants. Arch Environ Contam Toxicol, 11: 373-382.

    Emery RM (1970) The comparative acute toxicity of cresol to two
    benthic crustaceans. Water Res, 4: 485-491.

    Evangelista RA, Allen HL, & Mandel RM (1990) Treatment of phenol and
    cresol contaminated soil. In: Characterization and cleanup of chemical
    waste sites. Symposium of the 197th National Meeting of the American
    Chemical Society, Dallas, TX, April 10, 1989. J Hazard Mater,
    25(3): 343-360.

    Falk-Petersen IB, Kjorsvik E, Lonning S, Naley AM, & Sydnes LK (1985)
    Toxic effects of hydroxylated aromatic hydrocarbons on marine embryos.
    Sarsia, 70: 11-16.

    Faust BC & Hoigné J (1987) Sensitized photooxidation of phenols by
    fulvic acid in natural waters. Environ Sci Technol, 21: 957-964.

    FDRL (1975) Acute toxicity studies of  ortho-cresol in rats and
    rabbits. Saddle Brook, New Jersey, Food and Drug Research Laboratories
    (Unpublished data submitted to the US Environmental Protection Agency,
    Office of Toxic Substances) (Fiche No. OTS206095).

    Fedorak PM & Hrudey SE (1984) The effects of phenol and some alkyl
    phenolics on batch anaerobic methanogenesis. Water Res, 18: 361-367.

    Fedorak PM & Hrudey SE (1986) Nutrient requirements for the
    methanogenic degradation of phenol and  p-cresol in anaerobic draw
    and feed cultures.  Water Res, 20(7): 929-933.

    Fiege H & Bayer AG (1987) Cresols and xylenols.  In: Gerharte W ed. 
    Ullman's encyclopedia of industrial chemistry, 5th ed. New York, VCH
    Publishers, vol 8A, pp 25-59.

    Finzer KH (1961) Lower nephron nephrosis due to concentrated Lysol
    vaginal douches: A report of two cases. Can Med Assoc J, 84: 549.

    Fiserova-Bergerova V, Pierce JT, & Droz PO (1990) Dermal absorption
    potential of industrial chemicals: Criteria for skin notation. Am J
    Ind Med, 17(5): 617-636.

    Florin I, Rutberg L, Curvall M, & Enzell CR (1980) Screening of
    tobacco smoke constituents for mutagenicity using the Ames' test.
    Toxicology, 15(3): 219-232.

    Flyvbjerg J, Arvin E, Jensen BK, & Olsen SK (1993) Microbial
    degradation of phenols and aromatic hydrocarbons in
    creosote-contaminated groundwater under nitrate-reducing conditions. J
    Contam Hydrol, 12 :133-150.

    Freitag D, Geyer H, Kraus A, Viswanathan R, Kotzias D, Attar A, Klein
    W, & Korte F (1982) Ecotoxicological profile analysis: VII. Screening
    chemicals for their environmental behavior by comparative evaluation.
    Ecotoxicol Environ Saf, 60: 60-81.

    Gadaskina ID & Filov VA (1971) Transformations and determination of
    industrial poisons in the human body. Leningrad, Meditsina,
    pp 202-205.

    Gaffney JS, Streit GE, Spall WD, & Hall JH (1987) Beyond acid rain: Do
    soluble oxidants toxins interact with SO2 and NOx to increase
    ecosystem effects? Environ Sci Technol, 21(6): 519-523.

    Gantzer CJ, Kollig HP, Rittmann BE, & Lewis DL (1988) Predicting the
    rate of trace-organic compound removal by natural biofilms. Water Res,
    22: 191-200.

    Garrett JS (1975) Association between bladder tumors and chronic
    exposure to cresols and cresote (letter). J Occup Med, 17: 492.

    Gaur JP (1988) Toxicity of some oil constituents to Selenastrum
    capricornutum. Acta Hydrochim Hydrobiol, 16(6): 617-620.

    Geiger DL, Poirier SH, Brooke LT, & Call DJ (1986) Acute toxicities of
    organic chemicals to fathead minnows  (Pimephales promelas). Superior,
    Wisconsin, Center for Lake Superior Environmental Studies, University
    of Wisconsin, vol 3, pp 1-24, 165-166.

    Geiger DL, Brooke LT, & Call DJ (1990) Acute toxicities of organic
    chemicals to fathead minnows  (Pimephales promelas). Superior,
    Wisconsin, Center for Lake Superior Environmental Studies, University
    of Wisconsin, vol 5, pp 1-24, 157-160.

    Giabbai MF, Cross WH, Chian ESK, & DeWalle FB (1985) Characterization
    of major and minor organic pollutants in wastewaters from coal
    gasification processes. Int J Environ Anal Chem, 20: 113-129.

    Goerlitz DF, Troutman DE, Godsy EM, & Franks BJ (1985) Migration of
    wood-preserving chemicals in contaminated groundwater in a sand
    aquifer at Pensacola, Florida. Environ Sci Technol, 19: 955-961.

    Goodley PC & Gordon M (1976) Characterization of industrial organic
    compounds in water. Trans Ky Acad Sci, 37: 11-15.

    Gosselin RE, Hodge HC, Smith RP, & Gleason MN (1976) Clinical
    toxicology of commercial products. Baltimore, Maryland, Williams
    Wilkins & Co.

    Great Lakes Water Quality Board (1983) An inventory of chemical
    substances identified in the Great Lakes ecosystem. Volume 1: Summary,
    pp 1-195 (Report to the Great Lakes Water Quality Board, Windsor,
    Ontario, Canada).

    Green MA (1975) A household remedy misused-fatal cresol poisoning
    following cutaneous absorption (a case report). Med Sci Law,
    15: 65-66.

    Grosjean D (1984) Atmospheric reactions of ortho cresol: Gas phase and
    aerosol products. Atmos Environ, 18: 1641-1652.

    Grosjean D (1985) Reactions of  o-cresol and nitrocresol with NOx
    in sunlight and with ozone-nitrogen dioxide mixtures in the dark.
    Environ Sci Technol, 19(10): 968-974.

    Hampton CV, Pierson WR, Harvey TM, Upolegrove WS, & Marano RS (1982)
    Hydrocarbon gases emitted from vehicles on the road: I. A qualitative
    gas chromatography/mass spectrometry survey. Environ Sci Technol,
    16: 287-298. Hansch C & Leo AJ (1985) Medchem Project: Issue 26.
    Claremont, California, Pomona College.

    Hassan SM, Salem FB, & El-Salam NA (1987) Colorimatric determination
    of phenols in water samples. Anal Lett, 20(5): 677-688.

    Haworth S, Lawlor T, Mortelmans K, Speck W, & Zeiger E (1983)
     Salmonella mutagenicity test results for 250 chemicals. Environ
    Mutagen, 1(Suppl): 3-142.

    Hawthorne SB & Sievers RE (1984) Emission of organic air pollutants
    from shale oil wastewaters. Environ Sci Technol, 18: 483-490.

    Hawthorne SB, Miller DJ, Barkley RM, & Krieger MS (1988)
    Identification of methoxylated phenols as candidate tracers for
    atmospheric wood smoke pollution. Environ Sci Technol,
    22(10): 1191-1196.

    Hawthorne SB, Krieger MS, Miller DJ, & Mathiason MB (1989) Collection
    and quantitation of methoxylated phenol tracers for atmospheric
    pollution from residential wood stoves. Environ Sci Technol,
    23(4): 470-475.

    HAZDAT (1992) Hazardous substances database. Atlanta, Georgia, Agency
    for Toxic Substances and Disease Registry, Exposure and Disease
    Registry Branch, Office of External Affairs.

    Hazleton Labs (1988a) Mutagenicity tests on  o-,  m-, and  p-cresol
    in an  in vitro cytogenetic assay measuring chromosomal aberration
    frequencies in CHO cells. Kensington, Maryland, Hazleton Laboratories
    (Unpublished data submitted to the US Environmental Protection Agency,
    Office of Toxic Substances) (Fiche No. OTS0517691).

    Hazleton Labs (1988b) Mutagenicity tests on  o-cresol in the
     in vitro transformation of BALB/C-3T3 cells assay in the presence of
    rat liver cell activation system. Kensington, Maryland, Hazleton
    Laboratories (Unpublished data submitted to the US Environmental
    Protection Agency, Office of Toxic Substances) (Fiche No. OTS0517697).

    Hazleton Labs (1988c) Mutagenicity tests of  p-cresol and  m-cresol
    in a mouse lymphoma mutation assay. Kensington, Maryland, Hazleton
    Laboratories (Unpublished data submitted to the US Environmental
    Protection Agency, Office of Toxic Substances) (Fiche No. OTS0517693).

    Hazleton Labs (1988d) Mutagenicity tests on  meta-cresol and
     para-cresol in the  in vitro transformation of BALB/C-3T3 cells
    assay. Kensington, Maryland, Hazleton Laboratories (Unpublished data
    submitted to the US Environmental Protection Agency, Office of Toxic
    Substances) (Fiche No. OTS0517694).

    Hazleton Labs (1988e) Mutagenicity tests on  meta-cresol in a rat
    primary hepatocyte unscheduled DNA synthesis assay. Kensington,
    Maryland, Hazleton Laboratories (Unpublished data submitted to the US
    Environmental Protection Agency, Office of Toxic Substances)
    (Fiche No. OTS0517692).

    Hazleton Labs (1988f) Mutagenicity tests on  m-cresol in the
     in vitro transformation of BALB/C-3T3 cells assay. Kensington,
    Maryland, Hazleton Laboratories (Unpublished data submitted to the US
    Environmental Protection Agency, Office of Toxic Substances)
    (Fiche No. OTS0517698).

    Hazleton Labs (1989a) Dominant lethal assay in mice:  ortho-Cresol
    CRE-9.1-DL-HLA (HLA study No. 10004-0-471). Kensington, Maryland,
    Hazleton Laboratories (Unpublished data submitted to the Chemical
    Manufacturers Association, Washington).

    Hazleton Labs (1989b) Dominant lethal assay in mice:  para-Cresol
    CP945 (HLA study No. 10003-0-471). Kensington, Maryland, Hazleton
    Laboratories (Unpublished data submitted to the Chemical Manufacturers
    Association, Washington).

    Hazleton Labs (1989c) Mutagenicity test on cresol program panel sample
    #2  meta-cresol in the mouse bone marrow cytogenetic assay (HLA study
    No. 10002-0-451). Kensington, Maryland, Hazleton Laboratories
    (Unpublished data submitted to the Chemical Manufacturers Association,
    Washington).

    Hazleton Labs (1989d) Mutagenicity test on  ortho-cresol (lot number
    RC645A)  Drosophila melanogaster sex-linked recessive lethal test
    (HLA study No. 10004-0-461). Kensington, Maryland, Hazleton
    Laboratories (Unpublished data submitted to the Chemical Manufacturers
    Association, Washington).

    Hazleton Labs (1989e) Mutagenicity test on  para-cresol (lot number
    1206, batch 807)  Drosophila melanogaster sex-linked recessive lethal
    test (HLA study No. 10003-0-461). Kensington, Maryland, Hazleton
    Laboratories (Unpublished data submitted to the Chemical Manufacturers
    Association, Washington).

    Heikkila PR, Hameila M, Pyy L, & Raunu P (1987) Exposure to creosote
    in the impregnation and handling of impregnated wood. Scand J Work
    Environ Health, 13: 431-437.

    Herwick RP & Treweek DN (1933) Burns from anesthesia mask sterilized
    in compound solution of cresol. J Am Med Assoc, 100: 407-408.

    Hine J & Mookerjee PK (1975) The intrinsic hydrophilic character of
    organic compounds: Correlations in terms of structural contributions.
    J Org Chem, 40: 292-298.

    Hinz RS, Lorence CR, Hodson CD, Hansch C, Hall LL, & Guy RH (1991)
    Percutaneous penetration of  para-substituted phenols  in vitro. Fundam
    Appl Toxicol, 17: 575-583.

    Hirose M, Inoue T, Asamoto M, Tagawa Y, & Ito N (1986) Comparison of
    the effects of 13 phenolic compounds in induction of proliferative
    lesions of the forestomach and increase in the labelling indices of
    the glandular stomach and urinary bladder epithelium of Syrian golden
    hamsters. Carcinogenesis, 7(8): 1285-1289.

    Hites RA (1979) Sources and fates of industrial organic chemicals: A
    case study. In: Proceedings of the 8th National Conference on
    Municipal Sludge Management. Silver Spring, Maryland, Information
    Transfer, Inc., pp 107-119.

    Ho CT, Lee KN, & Jin QZ (1983) Isolation and identification of
    volatile flavor compounds in fried bacon. J Agric Food Chem,
    31: 336-342.

    Hoffman WA Jr & Tanner RL (1986) Detection of organic acids in
    atmosphere precipitation. Upton, New York, Brookhaven National
    Laboratory, Environmental Chemistry Division, Department of Applied
    Science (Report to the US Department of Energy) (BNL-51922;
    NTIS DE8 005294).

    Hopper DJ (1976) The hydroxylation of  p-cresols and its conversion
    to  p-hydroxybenzaldehydreu in  Pseudomonas putida. Biochem Biophys
    Res Commun,  69(2): 462-468.

    Hopper DJ (1978) Incorporation of [18O] Water in the formation of
     p-hydroxybenzyl alcohol by the  p-cresol methylhydroxylase from
    Pseudomonas putida. Biochem J, 75: 345-347.

    Hopper DJ & Taylor DG (1977) The purification and properties of
     p-cresol-(acceptor) oxidoreductase (hydroxylating), a
    flavocytochrome from Pseudomonas putida. Biochem J, 167(1): 155-162.

    Hornshaw TC, Aulerich RJ, & Ringer RK (1986) Toxicity of  o-cresol to
    mink and European ferrets. Environ Toxicol Chem, 5(8): 713-720.

    Horowitz A, Shelton DR, Cornell CP, & Tiedje JM (1982) Anaerobic
    degradation of aromatic compounds in sediments and digested sludge.
    Dev Ind Microbiol, 23: 435-444.

    Hoshika Y & Muto G (1978) Gas-liquid-solid chromatographic
    determination of phenols in air using Tenax-GC and alkaline
    precolumns. J Chromatogr, 187: 277-284.

    Huang JC & Gloyna EF (1968) Effect of organic compounds on
    photosynthetic oxygenation: I. Chlorophyll destruction and suppression
    of photosynthetic oxygen production. Water Res, 2: 347-366.

    Hwang HM, Hodson RE, & Lewis DL (1989) Microbial degradation kinetics
    of toxic organic chemicals over a wide range of concentrations in
    natural aquatic systems. Environ Toxicol Chem, 8: 65-74.

    ILO (1991) Occupational exposure limits for airborne toxic substances.
    Geneva, International Labour Office.

    Isaacs R (1922) Phenol and cresol poisoning. Ohio State Med J,
    18: 558-561.

    Izard PA, Fail PA, George JD, Grizzle TB, & Heindel JJ (1992)
    Reproductive toxicity of cresol isomers administered in feed to mouse
    breeding pairs.  Toxicologist, 12: 198 (Abstract).

    James RH, Adams RE, Finkel JM, Miller HC, & Johnson LD (1984)
    Evaluation of analytical methods for the determination of POHC on
    combustion products.  In: Proceedings of the 77th Annual Meeting of
    the Air Pollution Control Association, San Francisco, California,
    24-29 June. Research Triangle Park, North Carolina, Industrial
    Research Laboratory, pp 1-25 (NTIS/PB84-246289).

    Johnson LD, Midgett MR, James RH, Thomason MM, & Manier ML (1989)
    Screening approach for principal organic hazardous constituents and
    products of incomplete combustion. J Air Pollut Control Assoc,
    39(5): 709-713.

    Jouglard J, Aquaron R, Gatua-Pelanchon J, Trigano A, & Bel JG (1971)
    Intoxications aiguës par un antiseptique ménager: le crésyl. Mars Méd,
    108: 425-431.

    Jungclaus GA, Lopez-Avila, & Hites RA (1978) Organic compounds in an
    industrial waste water: A case study of their environmental impact.
    Environ Sci Technol, 12: 88-96.

    Junk GA & Ford CS (1980) A review of organic emissions from selected
    combustion processes. Chemosphere, 9: 187-230.

    Kavlock RJ (1990) Structure-activity relationships in the
    developmental toxicity of substituted phenols:  In vivo effects.
    Teratology, 41: 43-49.

    Kawamura K & Kaplan IR (1986) Compositional change of organic matter
    in rainwater during precipitation events. Atmos Environ,
    20(3): 527-536.

    Keat MJ & Hopper DJ (1978) The aromatic alcohol dehydrogenase in
     Pseudomonas putida N.C.I.B. 9869 grown on 3,5-xylenol and  p-cresol.
    Biochem J, 175(2): 959-967.

    Khalal KD, Hasan BA, Moralesrubio A, & Delaguardia M (1993)
    Flow-injection spectrophotometric determination of cresol compounds in
    water by raction with  p-aminophenol. Mikrochim Acta,
    112(1-4): 99-111.

    Klecka GM, Davis JW, Gray DR, & Madsen SS (1990) Natural
    bioremediation of organic contaminants in ground water: Cliffs-Dow
    Superfund Site. Ground Water, 28(4): 534-543.

    Klinger ME & Norton JF (1945) Toxicity of cresylic acid-containing
    solvent.  US Navy Med Bull, 44(2): 438-439.

    Koch R & Nagel M (1988) Quantitative structure activity relationships
    in soil ecotoxicology. Sci Total Environ, 77(2-3): 269-276.

    Koerber SC, McIntire W, Bohmont C, & Singer TP (1985)  Resolution of
    the flavocytochrome  p-cresol methylhydroxylase in subunits and
    reconstitution of the enzyme. Biochemistry, 24: 5276-5280.

    Kollig HP, Parrish RS, & Holm HW (1987) An estimate of the variability
    in biotransformation kinetics of xenobiotics in natural waters by
    Aufwuchs communities. Chemosphere, 16: 49-60.

    Krotoszynski BK & O'Neill HJ (1982) Involuntary bioaccumulation of
    environmental pollutants in nonsmoking heterogenous human population.
    J Environ Sci Health Part A Environ Sci Eng, 17(6): 855-883.

    Kühn R & Pattard M (1990) Results of the harmful effects of water
    pollutants to green algae  (Scenedesmus subspicatus) in the cell
    multiplication inhibition test. Water Res, 24(1): 31-38.

    Kühn EP, Zeyer J, Eicher P, & Schwarzenbach RP (1988) Anaerobic
    degradation of alkylated benzenes in denitrifying laboratory aquifer
    columns. Appl Environ Microbiol, 54: 490-496.

    Kühn R, Pattard M, Pernak KD, & Winter A (1989a)  Results of the
    harmful effects of water pollutants to  Daphnia magna in the 21 day
    reproduction test. Water Res, 23(4): 501-510.

    Kühn R, Pattard M, Pernak KD, & Winter A (1989b) Results of the
    harmful effects of selected water pollutants (anilines, phenols,
    alphatic compounds) to  Daphnia magna. Water Res, 23(4): 495-499.

    Kurlyandsky BA, Partsef DP, & Chernomorskiy AR (1975) [A procedure for
    determining the mean daily maximum permissible concentration of
    tricresol in atmospheric air.] Gig i Sanit, 5: 85-87 (in Russian).

    Kushi A & Yoshida D (1987)  Antimutagenic effects of phenols on MNNG -
    induced mutagenesis in  Escherichia coli. Agric Biol Chem,
    51: 1439-1440.

    Kuwata K & Tanaka S (1988) Liquid chromatographic determination of
    traces of phenols in air. J Chromatogr, 442: 407-411.

    Kuwata K, Uebori M, & Yamazaki Y (1981) Reversed-phase liquid
    chromatographic determination of phenols in auto exhaust and tobacco
    smoke as  p-nitrobenzeneazophenol derivatives. Anal Chem,
    53(9): 1531-1534.

    Kwasniewski K & Kaiser KLE (1983) Toxicities of selected phenols to
    fermentative and oxidative yeasts. Bull Environ Contam Toxicol,
    31(2): 188-194.

    Labram C & Gervais P (1968) Un cas d'intoxication massive par le
    crésyl. Sem Hop Paris, 44: 3029-3031.

    Larcan A, Lambert H, & Laprevote-Heully MC (1974) Intoxication aiguë
    par le crésyl, à propos d'une observation avec hémolyse aiguë massive,
    méthémoglobinémie et corps de Heinz. Eur J Toxicol, 7: 5-8.

    Lee WY & Nicol JAC (1978) Individual and combined toxicity of some
    petroleum aromatics to the marine amphipod  Elasmopus pectenicrus.
    Mar Biol, 48(3): 215-222.

    Lehtonen M (1983) Gas-liquid chromatographic determination of volatile
    phenols in matured distilled alcoholic beverages. J Assoc Off Anal
    Chem, 66(1): 62-70.

    Leone JA, Flagan RC, Grosjean D, & Seinfeld JH (1985) An outdoor smog
    chamber and modeling study of toluene-NOx photooxidation. Int J Chem
    Kinet, 17(2): 177-216.

    Leuenberger C, Ligocki MP, & Pankow JF (1985) Trace organic compounds
    in rain.  4.  Identities, concentrations, and scavenging mechanisms
    for phenols in urban air and rain. Environ Sci Technol,
    19(11): 1053-1058.

    Lewis DL, Holm HW, & Hodson RE (1984) Application of single and
    multiphasic Michaelis-Menten kinetics to predictive modeling for
    aquatic ecosystems.  Environ Toxicol Chem, 3: 563-574.

    Lewis DL, Kollig HP, & Hodson RE (1986) Nutrient limitation and
    adaptation of microbial populations to chemical transformations. Appl
    Environ Microbiol, 51: 598-603.

    Liberti A, Goretti G, & Russo MV (1983) PCDD and PCDF formation in the
    combustion of vegetable wastes. Chemosphere, 12: 661-663.

    Litton Bionetics (1980) Sister chromatid exchange assay, Ames assay,
    mouse lymphoma forward mutation assay, and transformation assay for a
    sample containing 33-1/3% each  ortho-,  meta-, and  para-cresol.
    Kensington, Maryland, Litton Bionetics, Inc. (Unpublished data
    submitted to the US Environmental Protection Agency, Office of Toxic
    Substances) (Fiche No. OTS0517528).

    Litton Bionetics (1981) Sister chromatid exchange assay, Ames assay,
    mouse lymphoma forward mutation assay, and cell transformation on
     o-cresol.  Unpublished data submitted to EPA/OTS
    (Fiche no. OTS0517531).

    Liu D & Pacepavicius G (1990) A systematic study of the aerobic and
    anaerobic biodegradation of 18 chlorophenols and 3 cresols. Toxic
    Assess Int J, 5(4): 367-388.

    Ludzack FJ & Ettinger MB (1960) Chemical structures resistant to
    aerobic biochemical stabilization. J Water Pollut Control Fed,
    32: 1173-2000.

    Lund FA & Rodriguez DS (1984) Acclimation of activated sludge to
     mono-substituted derivatives of phenol and benzoic acids. J Gen Appl
    Microbiol, 30: 53-61.

    Lyman WJ, Reehl WF, & Rosenblatt DH ed (1982) Handbook of chemical
    property estimation methods. New York, McGraw Hill Book Co.,
    chapter 15.

    Lyman WJ, Reehl WF, & Rosenblatt DH ed (1990) Handbook of chemical
    property estimation methods: environmental behavior of organic
    compounds.  Washington, DC, American Chemical Society, pp 15-16.

    Ma L & Wang CC (1989) [Case report of cresol burn and poisoning.] Chin
    J Ind Hyg Occup Dis, 7: 219-220  (in Chinese).

    Ma SH, Ma CS & Lin RC (1982) [Clinical studies 83 cases of chemical
    burns.]  Chin J Dermatol, 15(1): 9-10  (in Chinese).

    McCreary JJ, Jackson JG, & Zoltek J Jr (1983) Toxic chemicals in an
    abandoned phenolic waste site. Chemosphere, 12: 1619-1632.

    McIntire W & Singer TP (1982) Resolution of  p-cresol
    methylhydroxylase into catalytically active subunits and
    reconstitution of the flavocytochrome. FEBS Lett, 143(2): 316-318.

    McIntire W, Edmonson DE, Hopper DJ, & Singer TP (1981) 8
     alpha-(O-Tyrosyl)flavin adenine dinucleotide, the prosthetic group
    of bacterial  p-cresol methylhydroxylase. Biochemistry,
    20(11): 3068-3075.

    McIntire W, Hopper DJ, Craig JC, Everhart ET, Webster RV, Causer MJ, &
    Singer TP (1984) Stereochemistry of 1-(4'-hydroxyphenyl)ethanol
    produced by hydroxylation of 4-ethylphenol by  p-cresol
    methylhydroxylase. Biochem J, 224(2): 617-621.

    McIntire W, Hopper DJ, & Singer TP (1985)  p-Cresol
    methylhydroxylase. Assay and general properties. Biochem J,
    228(2): 325-335.

    McKinney RE, Tomlinson HD, & Wilcox RL (1956) Metabolism of aromatic
    compounds by activated sludge. Sew Ind Wastes, 28: 547-557.

    McKnight DM, Pereira WE, Ceazan ML, & Wissmar RC (1982)
    Characterization of dissolved organic materials in surface waters
    within the blast zone of Mount St. Helens, Washington. Org Geochem,
    4: 85-92.

    McIntire W, Singer TP, Smith AJ, & Matthews FS (1986)  Amino acid and
    sequence analysis of the cytochrome and flavoprotein subunits of
     p-cresol methylhydroxylase. Biochemistry, 25:5975-5981.

    McLeese DW, Zitko V, & Peterson MR (1979) Structure-lethality
    relationships for phenols, anilines and other aromatic compounds in
    shrimp and clams.  Chemosphere, 8(2): 53-57.

    Malaney GW (1960) Oxidative abilities of aniline-acclimated activated
    sludge. J Water Pollut Control Fed, 32: 1300-1311.

    Malaney GW & McKinney RE (1966) Oxidative abilities of
    benzene-acclimated activated sludge. Water Sew Works, 113: 302-309.

    Manita MD (1966) [Analysis of the vapors of monohydric phenols
    (phenol,  o-,  m-, and  p-cresol) in atmospheric air by the
    ultraviolet spectrophotometric method.] Gig i Sanit 8: 60-63
    (in Russian).

    Masunaga S, Urushigawa Y, & Yonezawa Y (1983) Microbial transformation
    of  o-cresol to dihydroxytoluenes by phenol acclimated activated
    sludge.  Chemosphere, 12: 1075-1082.

    Masunaga S, Urishigawa Y, & Yonezawa Y (1986) Biodegradation pathway
    of  o-cresol by heterogeneous culture.  Phenol activated sludge.
    Water Res, 20: 477-484.

    Matsumoto H, Kuwabara K, Murakami Y, Nishimune T, & Sueki K (1989)
    Cresol isomers contaminating beef on the market. J Food Hyg Soc Jpn,
    30(3): 250-253.

    Mattsson JL, Albee RR, & Gorzinski SJ (1989) Similarities of toluene
    and  o-cresol neuroexcitation in rats. Neurotoxicol Teratol,
    11(1): 71-75.

    Mattson VR, Arthur JW, Walbridge CT (1976) Acute toxicity of selected
    organic compounds to fathead minnows. Duluth, Minnesota, US
    Environmental Protection Agency, Environmental Research Laboratory
    (EPA 600/3-76-097).

    MBA (1988a) Subchronic toxicity of  ortho-cresol in Sprague Dawley
    rats.  Bethesda, Maryland, Microbiological Associates (Unpublished
    data submitted to the US Environmental Protection Agency).

    MBA (1988b) Subchronic toxicity of  para-cresol in Sprague Dawley
    rats.  Bethesda, Maryland, Microbiological Associates (Unpublished
    data submitted to US Environmental Protection Agency).

    MBA (1988c)  Subchronic toxicity of  meta-cresol in Sprague Dawley
    rats.  Bethesda, Maryland, Microbiological Associates (Unpublished
    data submitted to the US Environmental Protection Agency).

    Medvedev VA & Davidov VD (1981a) The influence of isomers on the
    transformation rate of phenols in Chernozem soil. In: Overcash MR ed.
    Decomposition of toxic and nontoxic organic compounds in soil. Ann
    Arbor, Michigan, Ann Arbor Scientific Publishers, pp 175-181.

    Medvedev VA & Davidov VD (1981b) The transformation of various coke
    industry products in Chernozem soil. In: Overcash MR ed. Decomposition
    of toxic and nontoxic organic compounds in soil. Ann Arbor, Michigan,
    Ann Arbor Scientific Publishers, pp 245-254.

    Mellon Institute (1949) The acute toxicity of  m-cresol. Pittsburgh,
    Pennsylvania, Mellon Institute of Industrial Research (Unpublished
    data submitted to the US Environmental Protection Agency, Office of
    Toxic Substances) (Fiche No. OTS0517523).

    Minami M, Katzumata M, & Tomoda A (1990) Methemoglobinemia with
    oxidized hemoglobins and modified hemoglobins found in bloods of
    workers handling aromatic compounds and in those of man who drank
    cresol solution. Biomed Biochim Acta, 49(2-3): 5327-5333.

    Molodkina NN, Gabulgalimova RR, Umarova SI, & Matveev AA (1985)
    Hygienic evaluation of the combined effect of some organic solvents
    (chlorobenzene and tricresol). In: Kasparova AA ed. Methodological
    principles for ensuring healthier working conditions at industrial
    plants with a leading chemical factor. Moscow, Research Institute of
    Labor Hygiene and Occupational Diseases, Academy of Medical Sciences,
    pp 82-88.

    Moore SP & Coohill TP (1983) An SV40 mammalian inductest for putative
    carcinogens. Prog Nucleic Acid Res Mol Biol, 29: 149-153.

    Murray KE & Adams RF (1988) Determination of simple phenols in feces
    and urine by high performance liquid chromatography. J Chromatogr
    Biomed Appl, 431(1): 143-149.

    Namkoong W, Loehr RC, & Malina JF Jr (1988) Kinetics of phenolic
    compounds removal in soil. Hazard Waste Hazard Mater, 5(4): 321-328.

    Needham LL, Head SL, & Cline RE (1984) Determination of phenols and
    cresols in urine by gas chromatography. Anal Lett, 17(B14): 1555-1565.

    Neiminen E & Heikkila P (1986) Simultaneous determination of phenol,
    cresols and xylenols in workplace air, using a
    polystyrene-divinylbenzene column and electrochemical detection. J
    Chromatogr, 360(1): 271-278.

    Neufeld RD, Debes MR, Moretti C, Mayernik J, Keleti G, Sykora J, &
    Bender J (1985) Cooling tower evaporation of treated coal gasification
    wastewaters.  J Water Pollut Control Fed, 57(9): 955-964.

    Niwa T (1993)  Phenol and  p-cresol accumulated in uremic serum
    measured by HPLC with fluorescence detection. Clin Chem, 39:108-111.

    Oglesby LA, Ebron-McCoy MT, Logsdon TR, Copeland F, Beyer PE, &
    Kavlock RJ (1992)  In vitro embryotoxicity of a series of
     para-substituted phenols: Structure, activity, and correlation with
     in vivo data. Teratology, 45(1): 11-34.

    Oliveira DP & Sitar N (1985) Ground water contamination from
    underground solvent storage tanks, Santa Clara, California. In:
    Proceedings of the 5th National Symposium on Aquifer Restoration and
    Ground Water Monitoring. Richmond, California, Cooper Engineers, Inc.
    and Berkeley, California, Department of Civil Engineering, University
    of California, pp 691-708.

    Palumbo AV, Pfaender FK, & Paerl HW (1988) Biodegradation of NTA and
     m-cresol in coastal environments. Environ Toxicol Chem, 7: 573-585.

    Paris DF, Wolfe NL, Steen WC, & Baughman GL (1983) Effect of phenol
    molecular structure on bacterial transformation rate constants in pond
    and river samples. Appl Environ Microbiol, 45: 1153-1155.

    Parker JG (1984) The effects of selected chemicals and water quality
    on the marine polychaete  Ophryotrocha diadema. Water Res,
    18(7): 865-868.

    Parkhurst BR, Bradshaw AS, Forte JL, & Wright GP (1979) An evaluation
    of the acute toxicity to aquatic biota of a coal conversion effluent
    and its major components. Bull Environ Contam Toxicol, 23(3): 349-356.

    Parrish CF (1983) Solvents, industrial. In: Grayson M ed.
    Kirk-Othmer's encyclopedia of chemical technology, 3rd ed. New York,
    John Wiley & Sons, vol 21, pp 386-387.

    Pashkova GA (1972) [Special effects of cresol and phosphoryl chloride
    on the endocrine glands.] Kuibyshev, USSR, Research Institute of
    Epidemiology, Microbiology and Hygiene, pp 203-204 (Scientific
    Publication No. 7) (in Russian).

    Pashkova GA (1973) [Comparative evaluation of the gonadotrophic and
    general toxic effect of tricresol, phosophoryl chloride and
    tricresylphosphate.] In: [Problems in labour hygiene, occupational
    pathology and toxicology in the production and testing of
    phosphor o-organic plasticizers.]  Moscow, pp 86-90.

    Pauli O & Franke G (1971) Behaviour and degradation of technical
    preservatives in the biological purification of sewage. Biodeterior
    Mater Proc Int Biodeterior Symp 2nd, 1971: 52-60.

    Pegg SP & Campbell DC (1985) Children's burns due to cresol. Burns,
    11(4): 294-296.

    Pereima VL (1975) Inhalational effect of cresol isomers at low
    concentrations and means for improving detoxication processes in
    experiments on white rats. Lvov Univesity, pp 86-90 (Dissertaton).

    Pickering QH & Henderson C (1966) Acute toxicity of some important
    petrochemicals to fish. J Water Pollut Control Fed, 38(9): 1419-1429.

    Pitter P (1976) Determination of biological degradability of organic
    substances. Water Res, 10: 231-235.

    Pool BL & Lin PZ (1982) Mutagenicity testing in the  Salmonella
     typhimurium assay of phenolic compounds and phenolic fractions
    obtained from smokehouse smoke condensates. Food Chem Toxicol,
    20(4): 383-391.

    Pool BL, Yalkinoglu AO, Klein P, & Schlehofer JR (1989) DNA
    amplification in genetic toxicology. Mutat Res, 213:61-72.

    Presley JA & Brown WE (1956) Lysol-induced criminal abortion. Obstet
    Gynecol, 8: 368-370.

    Ram NM, Exner P, Bell R, & Santos S (1985) Feasibility of treating
    contaminated ground water at a hazardous waste site. In: Proceedings
    of the NWWA/API Conference on Petroleum Hydrocarbons and Organic
    Chemicals in Ground Water Prevention, Detection and Restoration,
    Houston, Texas, 13-15 November 1985. Dublin, Ohio, National Water Well
    Association, pp 513-534.

    Reimann SP (1933) "Sensitivity" to sylphydryl. Am J Clin Pathol,
    3(2): 167-170.

    Renwick AG, Thakrar A, Lawrie CA, & George CF (1988) Microbial amino
    acid metabolites and bladder cancer: No evidence of promoting activity
    in man.  Hum Toxicol, 7(3): 267-272.

    Ribo JM, Kaiser KLE.  1983.  Effects of selected chemicals to
    photoluminescent bacteria and their correlations with acute and
    sublethal effects on other organisms. Chemosphere,
    12(11-12): 1421-1442.

    Riddick JA, Bunger WB, & Sakano TK (1986) Organic solvents. New York,
    Chichester, Brisbane, Toronto, John Wiley and Sons, Inc., pp 224-229.

    Risner CH (1993) The quantification of hydroquinone, catechol, phenol,
    3-methylcatechol, scopoletin,  m+p-cresol and  o-cresol in indoor
    air sample by high performance liquid chromatography. J Liq
    Chromatogr, 16:4117-4140.

    Roberts MS, Anderson RA, & Swabrick J (1977) Permeability of human
    epidermis to the phenolic compounds. J Pharm Pharmacol, 29: 677-683.

    Roberts DJ, Fedorak PM, & Hrudey SE (1987) Comparison of the fates of
    the methyl carbons of  m-cresol and  p-cresol in methanogenic
    consortia. Can J Microbiol, 33: 335-338.

    Rogers JE, Li SW, & Felice LJ (1984) Microbiological transformation
    kinetics of xenobiotics in aquatic environment. Richland, Washington,
    Battelle Pacific Northwest Laboratories, p 105 (NTIS PB84-162866).

    Sabljic A (1987) [The prediction of fish bioconcentration factors of
    organic pollutants from the molecular connectivity model.] Z Gesamte
    Hyg Grenzgeb, 33: 493-496 (in Yugoslavian).

    Savolainen H (1979) Toxic effects of peroral  o-cresol intake on rat
    brain.  Res Commun Chem Pathol Pharmacol, 25(2): 357-364.

    Sawahata T & Neal NA (1983) Biotransformation of phenol t-hydroquinone
    and catechol by rat liver microsomes. Mol Pharmacol, 23: 453-460.

    Sawhney BL & Kozloski RP (1984) Organic pollutants in leachates from
    landfill sites. J Environ Qual, 13: 349-352.

    Sax NI & Lewis RJ (1987) Hawley's condensed chemical dictionary, 11th
    ed. New York, Van Nostrand Reinhold Co, pp 320-321.

    Schafer EW Jr, Bowles WA Jr, & Hurlbut J (1983) The acute oral
    toxicity, repellency, and hazard potential of 998 chemicals to one or
    more species of wild and domestic birds. Arch Environ Contam Toxicol,
    12(3): 355-382.

    Schultz TW (1987) The use of the ionization constant (pKa) in
    selecting models of toxicity in phenols. Ecotoxicol Environ Saf,
    14(2): 178-813.

    Schultz TW & Riggin GW (1985) Predictive correlations for the toxicity
    of allkyl- and halogen-substituted phenols. Toxicol Lett, 25: 47-54.

    Scientific Associates (1976) Skin corrosiveness test in rabbits. St.
    Louis, Missouri, Scientific Associates, Inc. (Unpublished data
    submitted to the US Environmental Protection Agency, Office of Toxic
    Substances) (Fiche No. OTS206095).

    Shah JJ & Heyerdahl EK (1989) National ambient volatile organic
    compound (VOCs) data base update. Research Triangle Park, North
    Carolina, US Environmental Protection Agency, Atmospheric Science
    Research Laboratory (EPA 600/3-88/010(a)).

    Shamala N, Lim LW, Mathews FS, McIntire W, Singer TP, & Hopper DJ
    (1985) Preliminary X-ray study of  p-cresol methylhydroxylase
    (flavocytochrome c) from  Pseudomonas putida N.C.I.B. 9869. J Mol
    Biol, 183(3): 517-518.

    Shamala N, Lim LW, Mathews FS, McIntire W, Singer TP, & Hopper DJ
    (1986) Structure of an intermolecular electron-transfer complex:
     p-cresol methylhydroxylase at 6.0-A resolution. Proc Natl Acad Sci
    (USA), 83(13): 4626-4630.

    Sheldon LS & Hites RA (1978) Organic compounds in the Delaware River. 
    Environ Sci Technol, 12: 1188-1194.

    Sheldon LS & Hites RA (1979) Sources and movement of organic chemicals
    in the Delaware River. Environ Sci Technol, 13: 574-579.

    Shelley WB (1974)  p-Cresol: Cause of ink-induced hair depigmentation
    in mice. Br J Dermatol, 90: 169-174.

    Shelton DR & Tiedje JM (1981) Development of test for determining
    anaerobic biodegradation potential. Washington, DC, US Environmntal
    Protection Agency, Office of Toxic Substances.

    Shimp RJ & Pfaender FK (1985a) Influence of easily degradable
    naturally occurring carbon substrates on biodegradation of
    monosubstituted phenols by aquatic bacteria. Appl Environ Microbiol,
    49: 394-401.

    Shimp RJ & Pfaender FK (1985b) Influence of naturally occurring humic
    acids on biodegradation of monosubstituted phenols by aquatic
    bacteria.  Appl Environ Microbiol, 49: 402-407.

    Singer PC, Lamb JC III, Pfaender FK, & Goodman R (1979) Treatability
    and assessment of coal conversion wastewaters: Phase I. Research
    Triangle Park, North Carolina, US Environmental Protection Agency,
    Industrial Environmental Research Laboratory.

    Slooff W (1983) Benthic macroinvertebrates and water quality
    assessment: Some toxicological considerations. Aquat Toxicol,
    4: 73-82.

    Slooff W & Baerselman R (1980) Comparison of the usefulness of the
    Mexican Axolol  (Ambystoma mexicanum) and the clawed toad  (Xenopus
     laevis) in toxicological bioassays. Bull Environ Contam Toxicol,
    24(3): 439-443.

    Slooff W, Canton JH, & Hermens JLM (1983) Comparison of the
    susceptibility of 22 freshwater species to 15 chemical compounds: I.
    (Sub)acute toxicity tests. Aquat Toxicol, 4(2): 113-128.

    Smith JH, Mabey WR, Bohonos N, Holt BR, Lee SS, Chou T-W, Bomberger
    DC, & Mill T  (1978) Environmental pathways of selected chemicals in
    freshwater systems. Part II: Laboratory studies.  Research Triangle
    Park, North Carolina, US Environmental Protection Agency,
    Environmental Research Laboratory.

    Smolenski WJ & Suflita JM (1987) Biodegradation of cresol isomers in
    anoxic aquifers. Appl Environ Microbiol, 58: 710-716.

    Snider EH & Manning FS (1982) A survey of pollutant emission levels in
    waste waters and residuals from the petroleum refining industry.
    Environ Int, 7: 237-258.

    Southworth GR & Keller JL (1986) Hydrophobic sorption of polar
    organics by low organic carbon soils. Water Air Soil Pollut,
    28(3-4): 239-248.

    Spain JC & van Veld PA (1983) Adaptation of natural microbial
    communities to degradation of xenobiotic compounds: Effects of
    concentration, exposure time, inoculum, and chemical structure. Appl
    Environ Microbiol, 45(2): 428-435.

    Stone AT (1987) Reductive dissolution of manganese (III/IV) oxides by
    substituted phenols. Environ Sci Technol, 21: 979-988.

    STORET (1993) Online retrieval from data base. Washington, DC, US
    Environmental Protection Agency.

    Stout J & Kilham SS (1983) Effects of  p-cresol on photosynthetic and
    respiration rates of a filamentous green alga  (Spirogyra). Bull
    Environ Contam Toxicol, 30(1): 1-5.

    Stout RJ & Cooper WE (1983) Effect of  p-cresol on leaf decomposition
    and invertebrate colonization in experimental outdoor streams. Can J
    Fish Aquat Sci, 40(10): 1647-1657.

    Stuermer DH, Ng DJ, & Morris CJ (1982) Organic contaminants in
    groundwater near an underground coal gasification site in northeastern
    Wyoming. Environ Sci Technol, 16: 582-587.

    Suflita JM, Gibson SA, & Beeman RE (1988) Anaerobic biotransformations
    of pollutant chemicals in aquifers. J Ind Microbiol, 3(3): 179-194.

    Suflita JM, Liang LN, & Saxena A (1989) The anaerobic biodegradation
    of  o-,   m-, and  p-cresol by sulfate-reducing bacterial
    enrichment cultures obtained from a shallow anoxic aquifer. J Ind
    Microbiol, 4(4): 255-266.

    Swann RL, Laskowski DA, McCall PJ, & Vander Kuy K (1983) A rapid
    method for the estimation of the environmental parameters
    octanol/water partition coefficient, soil sorption constant, water to
    air ratio, and water solubility. Residue Rev, 85: 17-28.

    Swindoll CM, Aelion CM, Dobbins DC, Jiang O, Long SC, & Pfaender FK
    (1988) Aerobic biodegradation of natural and xenobiotic organic
    compounds by subsurface microbial communities. Environ Toxicol Chem,
    7(4): 291-299.

    Syrovadko ON & Malysheva ZV (1977) Working conditions and their effect
    on some specific functions of women engaged in the manufacture of
    enamel-insulated wires. Gig Tr Prof Zabol, 4: 25-28.

    Tabak HH, Chambers CW, & Kabler PW (1964) Microbial metabolism of
    aromatic compounds: I. Decomposition of phenolic compounds and
    aromatic hydrocarbons by phenol-adapted bacteria. J Bacteriol,
    87: 910-919.

    Thompson DC, Perera K, Fisher R, & Brendel K (1994)  Cresol isomers: 
    comparison of toxic potency in rat liver slices. Toxicol Appl
    Pharmacol,  125:51-58.

    TRL (1986) Subchronic neurotoxicity study in rats of orth o-,  meta-,
    and  para-cresol. Research Triangle Park, North Carolina, Toxicity
    Research Laboratories (Unpublished data submitted to the US
    Environmental Protection Agency).

    US EPA (1982) Assessment of testing needs: Cresols support document. 
    Washington, DC, US Environmental Protection Agency, Office of Toxic
    Substances, Test Rule Development Branch, Assessment Division, p 373.

    US EPA (1986) Test methods for evaluating solid waste: SW-846. Vol.
    II: Field manual physical/chemical methods, 3rd ed. Washington, DC, US
    Environmental Protection Agency, Office of Solid Waste and Emergency
    Response.

    US EPA (1988) US EPA contract laboratory program statement of work for
    organic analysis: Semi-volatile compounds. Washington, DC, US
    Environmental Protection Agency, pp D1/SV-D45/SV.

    US EPA (1989) Toxics release inventory. Washington, DC, US
    Environmental Protection Agency, Office of Pesticides and Toxic
    Substances.

    USITC (1990) Synthetic organical chemicals, United States production
    and sales, 1989. Washington, DC, United States International Trade
    Commission, p 3-2 (Publication No 2338).

    USITC (1991) Synthetic organical chemicals, United States production
    and sales, 1990. Washington, DC, United States International Trade
    Commission, p 3-2 (Publication No. 2470).

    US NIOSH (1989) Manual of analytical methods, 3rd ed. Cincinnati,
    Ohio, National Institute for Occupational Safety and Health.

    US NTP (1992) Toxicity studies of cresols (CAS nos. 95-48-7, 108-39-4,
    106-44-5) in F344/N rats and B6C3F1 mice (feed studies). Research
    Triangle Park, Noth Carolina, National Toxicology Program.

    Uzhdavini ER, Astaf'yeva IK, Mamayeva AA, & Bakhtizina GZ (1972)
    [Inhalation toxicity of  o-cresol.] Tr Ufimskogo
    Nauchno-Issledovatel'skogo Inst Gig Prof Zabol, 7: 115-119
    (in Russian).

    Uzhdavini ER & Gilev VG (1976) Toxicity of the lower phenols in the
    case of epicutaneous applications. Tr Bashkir Med Inst, 19: 162-167.

    Uzhdavini ER, Astafeva IK, & Mamaeva AA (1974) Acute toxicity of the
    lower phenols. Gig Tr Prof Zabol, 2: 58-59.

    Uzhdavini ER, Astafeva IK, Mamaeva AA, & Gilev VG (1976) Materials for
    establishing the limiting dose of dicresol in the air at production
    premises. Gig Tr Prof Zabol, 9: 53-55.

    Vance BM (1945) Intrauterine injection of Lysol as an abortifacient:
    Report of a fatal case complicated by oil embolism and Lysol
    poisoning. Arch Pathol, 40: 395-398.

    Vecera Z & Janak J (1987) Continuous aerodispersive enrichment unit
    for trace determination of pollutants in air. Anal Chem,
    59(11): 1494-1498.

    Verchuesen K (1983)  Handbook of environmental data on organic
    chemicals.  2nd edition. New York, Van Nostrand Reinhold Company,
    pp 403-410.

    Vernot EH, MacEwen JD, Haun CC, & Kinkead ER (1977) Acute toxicity and
    skin corrosion data from some organic and inorganic compounds and
    aqueous solutions. Toxicol Appl Pharmacol, 42: 417-423.

    Visser SA, LaMontagne G, Zoulalian V, & Tessier A (1977) Bacteria
    active in the degradation of phenols in polluted waters of the St.
    Lawrence River.  Arch Environ Contam Toxicol, 6: 455-469.

    Wallen IE, Greer WC, & Lasater R (1957) Toxicity to Gambusia affinis
    of certain pure chemicals in turbid waters. Sew Ind Wastes,
    29(6): 695-711.

    Wang YT, Suidan MT, Pfeffer JT, & Najm I (1988) Effects of some alkyl
    phenols on methanogenic degradation of phenol. Appl Environ Microbiol,
    54(5): 1277-1279.

    Wang YT, Suidan MT, Pfeffer JT, & Najm I (1989) The effect of
    concentration of phenols on their batch methanogenesis. Biotechnol
    Bioeng J, 33(10): 1353-1357.

    Weast RC, Astle MJ, & Beyer WH (1988) CRC handbook of chemistry and
    physics, 69th ed. Boca Raton, Florida, CRC Press, Inc, pp C/218-C/220.

    Weber AS & Matsumoto MR (1987) Feasibility of intermittent biological
    treatment for hazardous wastes. Environ Prog, 6(3): 166-171.

    Williams RA, MacRae R, & Shepherd MJ (1989) Non-aqueous size-exclusion
    chromatography coupled online to reversed-phase high-performance
    liquid chromatography interface development and applications to the
    analysis of low-molecular-weight contaminants and additives in foods.
    J Chromatogr, 477(2): 315-326.

    Williams RT (1938) CXVIII: Studies in detoxication: I. The influence
    of (a) dose and (b)  o-,  m- and  p-substitution on the sulfate
    detoxication of phenol in the rabbit. Biochem J, 32: 878-887.

    Windholz M, Budavini S, Blumetti RF & Otterbein ES ed. (1983) The
    Merck index: an encyclopedia of chemicals, drugs, and biologicals,
    10th ed.  Rahway, New Jersey, Merck and Co., Inc.

    Wiseman HW, Turner WH, & Volans GW (1980) Acute poisoning due to
    Wright's vaporizing fluid. Postgrad Med J, 56(653): 166-168.

    Wu HY & Kwan Y (1984) [Case report of an acute renal failure
    complicated by cresol burns.] Chin J Prev Med, 18:145-149
    (in Chinese).

    Wynder EL & Hoffmann D ed. (1967) Tobacco and tobacco smoke. New York,
    London, San Francisco, Academic Press, pp 387, 499-500.

    Yalkowsky SH, Valvani SC, & Kun W (1987) Arizona database of aqueous
    solutions.

    Yanysheva NYA, Balenko NV, Chernichenko IA, & Babiy VF (1993)
    Peculiarities of carcinogenesis under simultaneous oral administration
    of benzo( a)pyrene and  o-cresol in mice. Environ Health Perspect,
    101(Suppl. 3): 341-344.

    Yashiki M, Kojima T, Miyazaki T, Ohikasne F, & Ohtani M (1989) Gas
    chromatographic determination of cresols in the biological fluids of a
    non-fatal case of cresol intoxication.  Forensic Sci Int, 47: 21-29.

    Yasuhara A (1987) Identification of volatile compounds in poultry
    manure by gas chromatography-mass spectrometry. J Chromatogr,
    387: 371-378.

    Yasuhara AO, Shiraishi H, Tsuji M, & Okuno T (1981) Analysis of
    organic substances in highly polluted river water by mass
    spectrometry. Environ Sci Technol, 15: 570-573.

    Yoshikawa M, Arashidani K, Kodama Y (1986) [A simple determination of
    phenol in urine by high performance liquid chromatography.] San Igaku,
    27(2): 83-89 (in Japanese, with English abstract).

    Young LY & Rivera MD (1985) Methanogenic degradation of four phenolic
    compounds. Water Res, 19: 1325-1332.

    Young RHF, Ryckman DW, & Buzzell JC Jr (1968) An improved tool for
    measuring biodegradability. 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)