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    UNITED NATIONS ENVIRONMENT PROGRAMME
    INTERNATIONAL LABOUR ORGANISATION
    WORLD HEALTH ORGANIZATION


    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 190





    XYLENES



    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 P. Lundberg (National Institute of Working
    life, Solna, Sweden), Mr P.D. Howe and Dr S. Dobson (Institute of
    Terrestrial Ecology, Monk's Wood, United Kingdom) and Mr M.J. Crookes
    (Building Research Establishment, Watford, United Kingdom).


    Published under the joint sponsorship of the United Nations
    Environment Programme, the International Labour Organisation, and the
    World Health Organization, and produced within the framework of the
    Inter-Organization Programme for the Sound Management of Chemicals.


    World Health Organization
    Geneva, 1997

         The International Programme on Chemical Safety (IPCS) is a joint
    venture of the United Nations Environment Programme (UNEP), the
    International Labour Organisation (ILO), and the World Health
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    sound management of chemicals in relation to human health and the
    environment.



    WHO Library Cataloguing in Publication Data

    Xylenes.

    (Environmental health criteria ; 190)

       1.Xylenes - adverse effects   2.Xylenes - toxicity
       3.Environmental exposure    I.Series

    ISBN 92 4 157190 X        (NLM Classification: QD 341.H9)
    ISSN 0250-863X


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    (c) World Health Organization 1997

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    proprietary products are distinguished by initial capital letters.

    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR XYLENES

    Preamble

    1. SUMMARY

    2. IDENTITY, PROPERTIES AND ANALYTICAL METHODS
         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. In air
              2.4.2. In water
              2.4.3. In biological media
                     2.4.3.1  In blood
                     2.4.3.2  In urine
                     2.4.3.3  In exhaled air
                     2.4.3.4  In human milk

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
         3.1. Production processes
         3.2. Production levels
         3.3. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
         4.1. Transport and distribution between media
              4.1.1. Volatilization
              4.1.2. Rain-out
              4.1.3. Adsorption
         4.2. Transformation
              4.2.1. Biodegradation
                     4.2.1.1  Aerobic degradation
                     4.2.1.2  Anaerobic degradation
              4.2.2. Abiotic degradation
                     4.2.2.1  Photolysis
                     4.2.2.2  Atmospheric oxidation
                     4.2.2.3  Hydrolysis
              4.2.3. Bioaccumulation

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
         5.1. Environmental levels
              5.1.1. Ambient air
              5.1.2. Water and sediment
                     5.1.2.1  Surface water
                     5.1.2.2  Groundwater
                     5.1.2.3  Precipitation
                     5.1.2.4  Leachate
                     5.1.2.5  Sediment

              5.1.3. Soil
              5.1.4. Biota
         5.2. General population exposure
              5.2.1. Source of exposure
                     5.2.1.1  Air
                     5.2.1.2  Food
                     5.2.1.3  Drinking-water
                     5.2.1.4  Other source of exposure
              5.2.2. Xylene levels in human biological samples
         5.3. Occupational exposure during manufacture, formulation or use

    6. KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS
         6.1. Absorption
              6.1.1. In humans
              6.1.2. In laboratory animals
         6.2. Distribution
              6.2.1. In humans
              6.2.2. In laboratory animals
         6.3. Metabolic transformation
              6.3.1. In humans
              6.3.2. In laboratory animals
         6.4. Elimination and excretion
              6.4.1. In humans
              6.4.2. In laboratory animals
         6.5. Factors affecting toxicokinetics in humans and animals
         6.6. Biological monitoring

    7. EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS
         7.1. Single exposure
              7.1.1. Inhalation studies
                     7.1.1.1   o-Xylene
                     7.1.1.2   m-Xylene
                     7.1.1.3   p-Xylene
                     7.1.1.4  Technical or undefined xylene
              7.1.2. Other exposure routes
         7.2. Short-term exposure
              7.2.1. Inhalation studies
                     7.2.1.1   o-Xylene
                     7.2.1.2   m-Xylene
                     7.2.1.3   p-Xylene
                     7.2.1.4  Technical or undefined xylene
              7.2.2. Other exposure routes
         7.3. Long-term exposure
         7.4. Skin and eye irritation; sensitization
         7.5. Reproductive and developmental toxicology
         7.6. Mutagenicity and related end-points
         7.7. Carcinogenicity
         7.8. Other effects

    8. EFFECTS ON HUMANS
         8.1. Acute and accidental exposure
         8.2. Controlled human studies
         8.3. Occupational exposure

    9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
         9.1. Laboratory experiments
              9.1.1. Microorganisms
              9.1.2. Aquatic organisms
                     9.1.2.1  Algae
                     9.1.2.2  Higher plants
                     9.1.2.3  Protozoa
                     9.1.2.4  Invertebrates
                     9.1.2.5  Vertebrates
              9.1.3. Terrestrial organisms

    10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
         10.1. Evaluation of human health risks
              10.1.1. Exposures
              10.1.2. Effects
              10.1.3. Guidance value

         10.2. Evaluation of effects on the environment
              10.2.1. Exposure
              10.2.2. Effects
              10.2.3. Risk evaluation

    11. CONCLUSIONS

    12. RECOMMENDATIONS

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    REFERENCES

    RESUME

    RESUMEN
    

    NOTE TO READERS OF THE CRITERIA MONOGRAPHS

         Every effort has been made to present information in the criteria
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    Criteria monographs, readers are requested to communicate any errors
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         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
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         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.

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    FIGURE 1

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    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR XYLENES

     Members

    Dr E. Frantik, Centre for Industrial Hygiene and Occupational
       Diseases, National Institute of Public Health, Prague, Czech
       Republic

    Dr U. Hass, Department of Toxicology and Biology, National Institute
       of Occupational Health, Copenhagen, Denmark

    Mr P. Howe, Institute of Terrestrial Ecology, Monks Wood Experimental
       Station, Abbots Ripton, Huntingdon  Cambridgeshire, United Kingdom
        (Co-Rapporteur)

    Dr Young Lee, Contaminants Standards, Monitoring and Programs Branch,
       Centre for Food Safety and Applied Nutrition, US Food and Drug
       Administration, Washington DC, USA

    Mr G. Long, Health and Welfare Canada, Environmental Health Centre,
       Tunney's Pasture, Ottawa, Ontario, Canada

    Dr P. Lundberg, Department of Toxicology, National Institute for
       Working Life, Solna, Sweden  (Co-Rapporteur)

    Dr Choon-Nam Ong, Department of Community, Occupational and Family
       Medicine, National University of Singapore, Singapore

    Dr V. Riihimäki, Institute of Occupational Health, Helsinki, Finland
        (Chairman)

     Observer

    Dr C.J. Bevan, Exxon Biomedical Sciences Inc., East Millstone, New
       Jersey, USA

     Secretariat

    Dr B.H. Chen, International Programme on Chemical Safety, World Health
       Organization, Geneva, Switzerland  (Secretary)

    ENVIRONMENTAL HEALTH CRITERIA FOR XYLENES

         A WHO Task Group on Environmental Health Criteria for Xylenes met
    in Geneva from 6 to 9 November 1995. Dr B.H. Chen, IPCS, opened the
    meeting and welcomed the participants on behalf of the Director, IPCS,
    and the three IPCS cooperating organizations (UNEP/ILO/WHO).  The Task
    Group reviewed and revised the draft criteria monograph and made an
    evaluation of the risks for human health and the environment from
    exposure to xylenes.

         The first draft of this monograph was prepared by Dr P. Lundberg,
    Mr P.D. Howe, Mr M.J. Crookes and Dr S. Dobson.  The second draft was
    prepared by Dr P. Lundberg and Mr P.D. Howe incorporating comments
    received following the circulation of the first draft to the IPCS
    Contact Points for Environmental Health Criteria monographs.  Dr P.
    Lundberg and Mr P.D. Howe contributed to the final text of the health
    and environmental sections, respectively.

         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 document are gratefully acknowledged.

    ABBREVIATIONS

    ATPase    adenosine triphosphatase
    BCF       bioconcentration factor
    BTX       benzene, toluene, xylene
    CNS       central nervous system
    DMP       dimethylphenol
    DMSO      dimethylsulfoxide
    EEG       electroencephalograph
    FID       flame-ionization detector
    i.m.      intramuscular
    i.p.      intraperitoneal
    i.v.      intravenous
    LOAEL     lowest-observed-adverse-effect level
    NADPH     reduced nicotinamide adenosine dinucleotide
    NOAEL     no-observed-adverse-effect level
    PB        phenobarbital
    PMBA       p-methylbenzyl alcohol
    POCP      photochemical ozone-creation potential
    RMA       reflex modification audiometry
    s.c.      subcutaneous
    TCE       1,1,1-trichloroethylene

    1.  SUMMARY

         Xylene is an aromatic hydrocarbon which exists in three isomeric
    forms: ortho, meta and para.  Technical grade xylene contains a
    mixture of the three isomers and also some ethylbenzene.  The
    estimated world production in 1984 was 15.4 million tonnes.  Xylene is
    a colourless liquid at room temperature with an aromatic odour.  The
    vapour pressure lies between 0.66 and 0.86 kPa for the three isomers. 
    Approximately 92% of mixed xylenes is blended into petrol.  It is also
    used in a variety of solvent applications, particularly in the paint
    and printing ink industries.

         The majority of xylene released into the environment enters the
    atmosphere directly.  In the atmosphere the xylene isomers are readily
    degraded, primarily by photooxidation.  Volatilization to the
    atmosphere from water is rapid for all three isomers.  In soil and
    water, the meta and para isomers are readily biodegraded under a wide
    range of aerobic and anaerobic conditions, but the ortho isomer is
    more persistent.  The limited evidence available suggests that
    bioaccumulation of the xylene isomers by fish and invertebrates is
    low.  Elimination of xylene from aquatic organisms is fairly rapid
    once exposure has ceased.

         Typically, mean background levels of all three xylene isomers in
    ambient air are around 1 µg/m3, but in suburban areas they are 
    around 3 µg/m3.  Higher levels have been measured in urban and
    industrialized areas, mean concentrations ranging up to 500 µg/m3. 
    However, concentrations are generally below 100 µg/m3.

         Estimated daily exposure of the general population through
    inhalation is 70 µg in rural areas and less than 2000 µg in urban
    areas.  The concentration in drinking-water ranges from not detectable
    to 12 µg/litre.  The data on the level in food are too limited to
    estimate daily oral exposure.

         Mean background concentrations of xylenes in surface water are
    generally below 0.1 µg/litre.  However, much higher values have been
    measured in industrial areas and areas associated with the oil
    industry (up to 30 µg/litre in polluted waters and up to 2000 µg/litre
    near to discharge pipes).  Similar background levels have been
    reported for groundwater although high levels have been reported due
    to localized pollution from underground storage tanks and pipes.

         After inhalation exposure the retention in the lungs is about 60%
    of the inhaled dose.  Xylene is efficiently metabolized.  More than
    90% is biotransformed to methylhippuric acid, which is excreted in
    urine.  Xylene does not accumulate significantly in the human body.

         Acute exposure to high concentrations of xylene can result in CNS
    effects and irritation in humans.  However, there have been no
    long-term controlled human studies or epidemiological studies.  The
    chronic toxicity appears to be relatively low in laboratory animals. 
    There is suggestive evidence, however, that chronic CNS effects may
    occur in animals at moderate concentrations of xylene.

         Xylene appears not to be a mutagen or a carcinogen.

         The critical end-point is developmental toxicity, which has been
    demonstrated at an exposure level of 870 mg/m3 (200 ppm) in rats. 
    Based on this end-point, the recommended guidance value for xylene in
    air is 0.87 mg/m3 (0.2 ppm).

         The xylene isomers are of moderate to low toxicity for aquatic
    organisms.  For invertebrates the lowest LC50 value, based on
    measured concentrations, is for  o-xylene at 1 mg/litre  (Daphnia
     magna).  The lowest LC50 values recorded for fish are 7.6 mg/litre
    for  o-xylene (rainbow trout;  based on measured concentrations), and
    7.9 and 1.7 mg/litre for  m- and  p-xylenes respectively (both for
    striped bass; based on nominal concentrations).  Limited information
    is available regarding chronic exposure of aquatic organisms to
    xylenes;  however, rapid volatilization makes chronic exposure in
    water unlikely.  The acute toxicity of xylene to birds is low.

    2.  IDENTITY, PROPERTIES AND ANALYTICAL METHODS

    2.1  Identity

    Xylene exists in three isomeric forms,  ortho-,  meta- and
     para-xylene.  The commercial product is a mixture of all three
    isomers with  m-xylene predominating, usually 60-70%.  The technical
    product, "mixed xylenes", contains approximately 40%  m-xylene and
    20% each of ethylbenzene,  o-xylene and  p-xylene.  Small quantities
    of toluene and C9 aromatic fractions may also be present (Fishbein,
    1988).


    Chemical formula

         C8H10                C8H10                 C8H10

    Chemical structure

    CHEMICAL STRUCTURE 1


    Chemical name

          ortho-xylene           meta-xylene           para-xylene

    Synonyms

         1,2-dimethyl-           1,3-dimethyl-          1,4-dimethyl-
         benzene                 benzene                benzene
         o-methyltoluene         m-methyltoluene        p-methyltoluene
         1,2-xylene              1,3-xylene             1,4-xylene
         o-xylol                 m-xylol                p-xylol
         ortho-xylene            meta-xylene            para-xylene

    Relative molecular mass

         106.16                  106.16                 106.16

    CAS registry number

         95-47-6                 108-38-3               106-42-3

    RTECS registry number

         ZE 2450000              ZE 2275000             ZE 2625000

    CAS registry number (mixed xylenes)   1330-20-7

    RTECS registry number (mixed xylenes) ZE 210000 

    2.2  Physical and chemical properties

         Some physical and chemical properties are given in Table 1.
        Table 1.  Some physical and chemical properties of xylenesa

                                                                                            

                                             o-Xylene          m-Xylene          p-Xylene
                                                                                            

    Physical state (20°C; 101.3 kPa)         liquid            liquid            liquid

    Colour                                   colourless        colourless        colourless

    Boiling point (°C; 101.3 kPa)            144.4             139.1             138.3

    Melting point (°C; 101.3 kPa)            -25.2             -47.9             13.3

    Relative density (25°/4°C)               0.876             0.860             0.857

    Vapour pressure (kPa at 20°C)            0.66              0.79              0.86

    Flash point (°C) (closed cup)            30                25                25

    Saturation % in air (101.3 kPa)          1.03 (32°C)       1.03 (28°C)       1.03 (27°C)

    Explosion limits (vol-% in air)          1.0-6             1.1-7             1.1-9

    Autoignition temp (°C)                   465               525               525

    Octanol/water partition coefficient
     (log P)                                 3.12              3.2               3.15

    Solubility in water (mg/litre)           142               146               185

                                                                                            

    a    Data from Sandmeyer (1981); Verschueren (1983); ECETOC (1986); IARC, (1989);
         DECOS (1991); Bell (1992)
    
         All three isomers of xylene are soluble in organic solvents such
    as ethanol, diethyl ether, acetone and benzene (ECETOC, 1986; IARC,
    1989; DECOS, 1991).  At room temperature the xylenes are colourless
    liquids with an aromatic odour (DECOS, 1991).  The odour threshold for
    mixed xylene in air is approximatively 4.35 mg/m3 (1 ppm) (Carpenter
    et al., 1975; Amoore & Hautala, 1983; DECOS, 1991).

    2.3  Conversion factors

         1 ppm = 4.35 mg/m3 at 25°C, 101.3 kPa

         1 mg/m3 = 0.23 ppm at 25°C, 101.3 kPa

    2.4  Analytical methods

    2.4.1  In air

         US NIOSH has presented a method for measuring aromatic
    hydrocarbons including xylene, in air.  Xylene is adsorbed to coconut
    shell charcoal, eluated with carbon disulfide and determined using gas
    chromatography with a flame-ionization detector (FID) (Eller, 1984).

         A similar method has been described by the International Agency
    for Research on Cancer (IARC) (Brown, 1988a) concerning airborne
    vapours of benzene, toluene and xylenes, or mixtures thereof. The
    concentration range is about 1-1000 mg/m3 (approximately 0.2-200 ppm)
    in 12-litre air samples.  In another method described by IARC (Brown,
    1988b) hydrocarbons are adsorbed on a porous polymer, desorbed with
    heat and transferred with an inert carrier gas into a gas
    chromatograph equipped with a FID.  For a 5-litre air sample the
    concentration range is approximately 0.5-50 mg/m3 (0.1-10 ppm).  With
    the use of a gas chromatography and mass spectrometry (GC/MS)
    technique, the detection limit can be as low as 0.2 µg/m3 (Bevan et
    al., 1991).

         IARC also presented a method for determinating gasoline
    hydrocarbons (Brown, 1988c).  The air is drawn through two adsorbent
    tubes in series, containing Chemosorb 106 and charcoal, respectively. 
    The vapour after heat desorption is transferred to a gas chromatograph
    equipped with a capillary column and FID.  The method is suitable for
    airborne vapours of full-range gasoline over a concentration range of
    approximately 0.2-100 mg/m3 (0.04-20 ppm) in a 2.5-litre air sample.

         There are commercially available badges based on passive charcoal
    sampling.  After extraction with carbon disulfide the xylenes can be
    detected by gas chromatography (Van der Wal & Moerkerken, 1984;
    Triebig & Schaller, 1986).  Xylene can also be detected with infrared

    analysers with a minimum concentration of 9.6 mg/m3 (2.2 ppm) at a
    wavelength of 13.1 µm and a pathlength of 20.25 m.  This method is
    only suitable when no other compounds that absorb in the same region
    are present (DECOS, 1991).

         Earlier methods for determinating xylenes have been reviewed by
    Fishbein et al. (1988).

    2.4.2  In water

         A head-space technique coupled to capillary column gas
    chromatography has been described by Drozd & Novak (1978).  The
    detection limit is at the ppb level.  The detection limits could be
    lowered if the xylenes were extracted from the water by an air stream
    and condensed in a refrigerated column.  In another method, the sample
    is extracted with hexane or heated in a water bath at 25°C for 1 h. 
    Aliquots are then determined by gas chromatography with FID or mass
    spectometry.  The detection limit is 1 µg/litre (Otson & Williams,
    1981; Otson et al., 1982).  Recent studies have suggested that with
    the use of GC/MS the detection limits for xylene in water can be in
    the range of 0.001 to 0.01 µg/litre (Kenrick et al., 1985; MAFF,
    1991).

    2.4.3 In biological media

         A review of biological monitoring of exposure to xylene has been
    produced; methods include measuring methylhippuric acid in urine,
    xylene in blood and xylene in expired air (Lauwerys &  Buchet, 1988).

    2.4.3.1 In blood

         A method using capillary head-space gas chromatography with FID 
    has been developed for the simultaneous determination of xylene and
    other aromatic hydrocarbons, such as benzene, xylenes and ethyl-
    benzene, in blood.  The limit of detection is 5 µg/litre and the
    response is linear between 5 and 4000 µg/litre of blood.

         A head-space gas chromatographic method for determinating xylenes
    in blood has also been described (Engström & Riihimäki, 1988a).  This
    method is suitable for the determination of xylene isomers in blood
    specimens.  The detection limit is 53 µg/litre.  Ethylbenzene, which
    normally accompanies xylenes in technical xylene, does not interfere
    with the determination of xylene.

    2.4.3.2 In urine

         In humans, xylene is metabolized to methylhippuric acids (see
    section 6.3), which are not normally present in the urine of
    non-exposed people.  The urine methylhippuric acid level has been
    measured by gas chromatography (Engström & Bjurström, 1978),
    colorimetry (Ogata & Hobara, 1979), thin-layer chromatography (Bieniek
    et al., 1982) and high performance liquid chromatography (Ogata &
    Taguchi, 1986).

         A suitable gas chromatographic method for the determination of
    methylhippuric acids in urine has been presented by Engström &
    Riihimäki (1988b).  The range of application is 10-2120 mg/litre.  No
    interference from the normal constituents of urine is seen in the
    specified range.  Another method using HPLC allows methylhippuric
    acids, phenyl glyoxylic acid and mandelic acid to be determined
    together with hippuric acid in one run (Angerer, 1988b).  The limit of
    detection is 50 mg/litre of urine and the response is linear up to
    2000 mg/litre.  The aromatic carboxylic acids excreted in urine do not
    interfere with the hippuric acid determination.

    2.4.3.3 In exhaled air

         There is a method for determinating benzene, toluene and xylene
    in breath samples by gas chromatography/mass spectrometry (Pellizzari
    et al., 1988).  The detection limit for xylene is 0.5 µg/m3 and the
    quantification limit is 2.5 µg/m3.  No interference has been
    observed.  The linear range for quantification using fused silica
    capillaries on a gas chromatograph/mass spectrometer/computer is
    generally three orders of magnitude.

    2.4.3.4 In human milk

         A purge and trap technique using gas chromatography and electron
    impact mass spectrometry has been developed by Pellizari et al. (1982)
    for the detection of xylene and various volatile compounds in human
    milk.

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Production processes

         Before 1940 virtually all of the aromatic solvents, including
    xylene, were produced from coal.  Thereafter production of xylene from
    petroleum started.  Most mixed xylene is currently produced by
    catalytic reforming of petroleum.  It is also obtained from pyrolysis
    gasoline as a by-product of olefin manufacture during the cracking of
    hydrocarbons.  Small amounts of mixed xylenes are also obtained from
    coal-derived coke-oven light oil and from disproportionation of
    toluene (Fishbein, 1988).

         There are some differences in the composition of commercial
    xylenes produced from petroleum and from coal-tar.  The general
    composition of xylenes from petroleum is 44%  m-xylene, 20%
     o-xylene, 20%  p-xylene and 15% ethylbenzene.  The xylenes from
    coal-tar consists of 45-70%  m-xylene, 23%  p-xylene, 10-15%
     o-xylene and 6-10% ethylbenzene.  Commercial xylene may also contain
    small amounts of toluene, trimethylbenzene (pseu documene), phenol,
    thiophene, pyridine and non-aromatic hydrocarbons and has frequently
    been contaminated with benzene (WHO, 1981; Fishbein, 1988).

    3.2  Production levels

         Approximately 3.9 million tonnes of mixed xylenes were isolated
    in the USA in 1978.  The non-isolated mixed xylenes (containing
    benzene and toluene) are blended into gasoline, while the isolated
    mixed xylenes are used primarily for the production of the individual
    isomers and for solvent applications (Fishbein, 1988).

         World production of  p-xylene in 1983 was 3.9 million tonnes of
    which the USA accounted for 48%, Europe 23% and Japan 16%.  The world
    production of  o-xylene in 1983 was 1.3 million tonnes of which
    western Europe produced 30% and the USA 18%.  Eastern Europe was the
    other large producer of  o-xylene (Fishbein, 1988).

         The approximate world production of  o-, p- and mixed xylenes in
    1984 was 15.4 million tonnes (ECETOC, 1986).  The production of mixed
    xylenes in 1984 in the USA was 2.78 million tonnes and that of
     p-xylene was 1.94 million tonnes (Fishbein, 1988).  During the same
    year the production of  o-xylene was 316 000 tonnes.  The production
    of mixed xylene and  p-xylene in 1994 was 4.1 and 2.8 million tonnes,
    respectively (Kirschner, 1995).  The production of xylenes in some
    western European countries in 1984 was  estimated to be: France 85 000
    tonnes, Italy 395 000 tonnes and Federal Republic of Germany 455 000
    tonnes.  In 1987 the figures were: (in thousands of tonnes) Canada
    345, France 129, Federal Republic of Germany 501,  India 28, Italy
    491, Japan 1767, Republic of Korea 552, Mexico 381 and USA 2772 (IARC,
    1989).

    3.3  Uses

         Approximately 92% of the mixed xylenes produced is blended into
    gasoline.  The remainder is used in a variety of solvent applications
    as well as to produce the individual isomers of xylene.  Xylenes are
    used as solvents, particularly in the paint and printing ink
    industries.  The single largest end-use of mixed xylenes is in the
    production of the  p-xylene isomer.  The major derivatives produced
    from  p-xylene are dimethylterephthalate and terephthalic acid used
    in the production of polyester fibre, film and fabricated items
    (ECETOC, 1986; Fishbein, 1988).

         The  o-xylene is almost exclusively used to produce phthalic
    anhydride for phthalate plasticizers, and  m-xylene is used for the
    production of isophthalic acid, an intermediate in the manufacture of
    polyester resins (ECETOC, 1986; Fishbein, 1988).

         Mixed xylenes are also used in the manufacture of perfumes,
    pesticide formulations, pharmaceuticals and adhesives, and in the 
    painting, printing, rubber, plastics and leather industries (IARC,
    1989).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION

    4.1  Transport and distribution between media

         The majority of xylene released into the environment enters the
    atmosphere directly.  This results mainly from its use as a solvent
    and its release in motor vehicle exhausts.  A small proportion is also
    likely to enter water and soil due to oil/petrol spillages etc.  Once
    in the environment a number of physical processes can affect its
    distribution.  Jori et al. (1986) calculated that more than 99% of the
    xylene released ultimately partitions to the atmosphere; the
    calculations were based on the Mackay fugacity model (Mackay et al.,
    1985).

    4.1.1  Volatilization

         Owing to the relatively high vapour pressure and low water
    solubility of xylenes, volatilization from water bodies to the
    atmosphere is likely to be an important distribution process.  The
    half-life for evaporation of  o-xylene from water bodies at a depth
    of 1 metre has been estimated to be around 5.6 h (Mackay & Leinonen,
    1975).  It is expected that both  m-xylene and  p-xylene will behave
    similarly.

         No information has been reported on the volatilization rate of
    xylenes from soils, but it is expected to be a fairly rapid process,
    at least from near to the surface, owing to the reasonably high
    volatility of xylenes.

    4.1.2  Rain-out

         Xylenes are only slightly soluble in water (see section 2).  This
    means that only a very small proportion of xylene in the atmosphere is
    likely to be removed by precipitation (rain-out).  This is supported
    by the fact that xylenes have been detected in rainwater samples at
    only very low levels (2 ng  m-xylene/litre and 9 ng  p-xylene/litre;
    see section 5.1.2.3).  It is also possible that a small amount of
    xylene in soil may leach out into aquatic systems.

    4.1.3 Adsorption

         Xylenes are likely to be adsorbed to a small extent onto both
    aquatic sediments and soil, based on their partition coefficients. 
    However, adsorption is dependent on such factors as the organic carbon
    content and the water content.

         Sediment-water partition coefficients of 8.9 for  o-xylene and
    10.5 for  p-xylene have been measured.  These were for surface
    sediment from the Tamar Estuary, United Kingdom, which has an organic
    carbon content of 4.02% (Vowles & Mantoura, 1987).

          m-Xylene has been shown to adsorb onto soil to a small extent. 
    Using three soils with organic carbon contents ranging between 0.2 and
    3.7%, soil organic carbon-water partition coefficient (Koc) values of
    129, 158 and 289 (2.1, 2.2 and 2.5 log values) were measured (Seip et
    al., 1986).  A similar Koc of 219 has been quoted for  o-xylene
    (Pussemier et al., 1990).

          p-Xylene has been shown to adsorb onto minerals and soils to a
    small extent from the vapour phase (Rhue et al., 1988).

         In the absence of water, soils and clay minerals exhibit a large
    capacity to adsorb  p-xylene, owing primarily to adsorption on
    mineral surfaces.  However, such dry conditions are rarely encountered
    in the environment and may only exist at the soil surface or in arid
    climates.  When the relative humidity is increased to 67% or 90%, the
    sorption of  p-xylene vapour decreases significantly (Pennell et al.,
    1992).

    4.2 Transformation

    4.2.1  Biodegradation

         In soil and water,  o- and  p-xylene are readily biodegraded
    under a wide range of aerobic and anaerobic conditions, but  o-xylene
    is much more persistent under similar conditions.

    4.2.1.1  Aerobic degradation

    Bacteria of the genus  Pseudomonas have been shown to be capable of
    growing using either  m-xylene or  p-xylene as the sole carbon
    source (Davis et al., 1967; Omori et al., 1967; Omori & Yamada, 1970;
    Davey & Gibson, 1974).  The main initial metabolites appear to be
     m-toluic acid from  m-xylene and  p-toluic acid from  p-xylene. 
    Similarly, cultures of three strains of  Nocardia have been shown to
    metabolize  p-xylene to  p-toluic acid and 2,3-dihydroxy- p-toluic
    acid (Raymond et al., 1969).

         In contrast to this, many of the bacteria that have been shown to
    be capable of growing on either  m-xylene or  p-xylene as sole
    carbon source do not appear to be capable of growing on  o-xylene as
    sole carbon source (Omori et al., 1967; Davey & Gibson, 1974).

          o-Xylene has been shown to undergo biodegradation in the
    presence of other carbon sources.  Using hexadecane as growth
    substrate,  o-xylene was co-oxidized to  o-toluic acid by  Nocardia. 
    A similar oxidation was observed with  Pseudomonas using hexane as
    the growth substrate (Jamison et al., 1976).

         The biodegradation of xylenes by the autochthonous microflora in
    groundwater in the presence of the water soluble fraction of gas oil
    has been demonstrated by Kappeler & Wuhrmann (1978a, 1978b).  After a
    lag period of 3 to 4 days, individual hydrocarbon concentrations were
    found to decrease at a measurable rate.  The removal of  m-xylene and
     p-xylene was complete after 7 days.   o-Xylene was shown to degrade
    at a significantly slower rate than the meta and para isomers, removal
    being complete after 11-12 days.  In each case, the first step in the
    degradation appears to be oxidation to the corresponding methylbenzyl
    alcohol.

         Both  m-xylene and  p-xylene have been shown to be readily
    degraded within 13 days using a microbial inoculum from an activated
    sludge wastewater treatment plant.  The initial concentration of
    xylene was 100 mg/litre and 30 mg/litre of sludge biomass was used. 
    Degradation of xylene was monitored by comparing the oxygen uptake of
    the system with that of controls (Tabak et al., 1989).

         The degradation of mixtures of benzene, toluene and  p-xylene
    has been studied using pure cultures of either  Pseudomonas sp.
    strain CFS-215 or  Arthrobacter sp. strain HCB, or a mixed culture
    indigenous to a shallow sandy aquifer.  In the mixed culture, the
    presence of  p-xylene was found to increase the lag period before the
    degradation of benzene and toluene commenced, and also appeared to
    decrease the rate of toluene degradation compared to the rate obtained
    without added  p-xylene.  Degradation of  p-xylene occurred in the
    mixed culture, although a long lag period was observed before
    degradation commenced.  When toluene was also present in the culture,
    the lag period for the degradation of  p-xylene was reduced and the
    degradation rate was increased, but after all the toluene had been
    degraded, the  p-xylene degradation rate again slowed.  In the
    experiments with  Pseudomonas sp., the degradation of  p-xylene was
    slow; no degradation was observed in the first 3 weeks when  p-xylene
    alone was present.  Again, the degradation rate of  p-xylene was
    found to increase when toluene was also being degraded.  Also, the
    presence of  p-xylene again increased the lag period for benzene and
    toluene degradation.  In the experiments with  Arthrobacter sp.,
    degradation of  p-xylene was found to occur only in the presence of
    benzene and at a slow rate (Alvarez & Vogel, 1991).

         The biodegradation of  o-xylene and  m-xylene has been studied
    in three core samples of subsurface soil: uncontaminated soil, soil
    that had previously been contaminated with unleaded gasoline and soil
    from an area that had previously undergone biostimulation using
    hydrogen peroxide.   m-Xylene was rapidly degraded in all three core
    types, although the rate was faster in the previously biostimulated
    sample due to a higher bacterial cell count ( m-xylene disappeared to
    below the analytical detection limit within 3 weeks in the previously
    biostimulated samples, whereas some remained after 3 weeks in the
    previously contaminated samples).   o-Xylene was found to be
    recalcitrant in all of the samples (Thomas et al., 1990).

          p-Xylene and  o-xylene were shown to be degraded in aquifer
    material collected from the contaminant plume after a large gasoline
    spill.  The degradation occurred fastest in material from the aerobic
    degrading zone of the plume, but also occurred rapidly in
    uncontaminated material (Wilson et al., 1990).

         In a study using laboratory aquifer columns that simulated
    saturated-flow conditions typical of a river/groundwater infiltration
    system, all three xylene isomers were shown to undergo degradation
    under aerobic conditions.  Both  m-xylene and  p-xylene were
    degraded to concentrations below the analytical limit of detection
    within 17 days.  The rate of transformation was significantly lower
    for  o-xylene but degradation still occurred readily (Kuhn et al.,
    1985).

         The rate of biodegradation of benzene, toluene and xylene (BTX)
    in groundwater/soil slurries has been shown to be highly dependent on
    the dissolved oxygen concentration (Chiang et al., 1989).  At a
    dissolved oxygen concentration of between 2 and  8 mg/litre, BTX
    (initial concentrations between 120 and 16000 µg/litre) was 80-100%
    degraded in 30-40 days with a half-life of 5-20 days.  When the
    dissolved oxygen concentration was 1 or 2 mg/litre, the BTX was
    incompletely degraded (20-60%) in 30-40 days.  Little or no
    degradation was observed at dissolved oxygen concentrations of 0, 0.1
    and 0.5 mg/litre.

         The xylenes have been shown to be 100% degraded after 192 h
    incubation at 13°C with natural flora in groundwater in the presence
    of other components of high-octane gasoline (Jamison et al., 1976).

    4.2.1.2  Anaerobic degradation

          o-Xylene, along with other alkylbenzene compounds, has been
    shown to undergo degradation under anaerobic methanogenic conditions.
    No significant degradation of  o-xylene occurred over the first 20
    weeks, but after 40 weeks the concentration was reduced to 22% of the
    original.  Less than 1% remained after 120 weeks (Wilson et al.,
    1986).

         In anoxic suspensions of  Pseudomonas sp. strain T cells grown 
    anaerobically with toluene,  m-xylene and  p-xylene were partially
    oxidized to 3- and 4-methylbenzoate, respectively.   o-Xylene was not
    oxidized to 2-methylbenzoate.  Suspensions of strain T cells grown
    anaerobically with  m-xylene and incubated with  m-xylene at 5°C
    accumulated 3-methylbenzaldehyde (3.5 µM after 20 min) and
    3-methylbenzoate (5 µM after 20 min).  After further incubation at
    room temperature, the three aromatic compounds were completely
    oxidized within 3 h (Seyfried et al., 1994).

         Experiments have been carried out using aquifer material from a
    site containing areas that were either contaminated or uncontaminated
    with JP-4 jet fuel.  Both mixed xylene and the individual isomers were
    incubated with the aquifer material at 12°C under a nitrogen
    atmosphere.  Both  o-xylene and  m-xylene were slowly degraded in
    the uncontaminated aquifer material when added individually, although
     m-xylene (at 16 mg/litre) also appeared to inhibit the basal rate of
    denitrification.  Using mixed xylenes, a lag period of 30 days was
    required before biodegradation commenced in the uncontaminated
    material.   m-Xylene and  p-xylene were degraded to below the
    analytical limit of detection within the next 26 days, but the
    degradation of  o-xylene was found to be much slower.  In the
    contaminated aquifer material, much longer lag periods and decreased
    rates of biodegradation were observed,  o-xylene not being
    significantly degraded over a 6-month period (Hutchins et al., 1991a). 
    In further laboratory experiments using a mixture of benzene and
    alkylbenzenes, both  o-xylene and  m-xylene were found to be
    degraded under nitrate-reducing and nitrous oxide-reducing conditions,
    but degradation of  o-xylene was found to cease once the other
    alkylbenzenes had been degraded (Hutchins, 1991).  In field
    experiments in the same aquifer,  m-xylene and  p-xylene were shown
    to be degraded under denitrifying conditions when nitrate was injected
    into the aquifer, but no evidence of biodegradation of  o-xylene was
    found (Hutchins et al., 1991b).

         The three xylene isomers have been shown to be completely
    mineralized by aquifer-derived microorganisms under sulfate-reducing
    conditions.  The source of the inoculum was a gasoline-contaminated
    sediment.  All microcosms were initially fed a mixture of benzene,
    toluene, ethylbenzene,  o-xylene and  p-xylene (about 5 mg/litre of
    each component).   p-Xylene was found to be > 80% degraded within 72
    days and  o-xylene was > 80% degraded within 104 days.  After this
    initial adaptation period,  o-xylene,  m-xylene and  p-xylene were
    rapidly degraded by the system without any lag period ( m-xylene
    co-elutes with  p-xylene and, therefore,  m-xylene was not added
    initially) (Edwards et al., 1992).

         Edwards & Grbic-Galic (1994) reported that  o-xylene is
    completely mineralized by aquifer-derived microorganisms under
    anaerobic conditions.  However, an adaptation period of 200 to 255
    days was required before the onset of degradation.  Anaerobic
    degradation was found to be inhibited by the presence of some natural
    organic substrates and co-contaminants.

          p-Xylene and  o-xylene have been shown to be degraded in
    anaerobic aquifer material collected from the contaminant plume after
    a large gasoline spill (Wilson et al., 1990).

         All three xylene isomers have been shown to undergo degradation
    under anaerobic denitrifying conditions.  The rate was much lower  for
     o-xylene than for the other isomers.  Long lag periods were observed
    in all cases before degradation commenced (Kuhn et al., 1985).

         Degradation of  o-xylene under anaerobic conditions has been
    hypothesized to explain the distribution of  o-xylene in a landfill
    leachate plume (Reinhard et al., 1984).   m-Xylene has been shown to
    be rapidly mineralized to carbon dioxide in laboratory aquifer columns
    operated under continuous flow conditions with nitrite as an electron
    acceptor.  The degradation occurred simultaneously with the reduction
    of nitrite.  In contrast to this, the concentrations of  o-xylene and
     p-xylene were only slightly reduced in the experiment.  The author
    noted, however, that the experiments were carried out over a 6-day
    period after the addition of the new substrate and therefore may not
    have allowed a build-up of other microorganisms capable of degrading
    these substrates (Kuhn et al., 1988).

         The biodegradation of BTX has been shown to occur under
    anaerobic, denitrifying conditions using shallow aquifer material that
    had previously been exposed to BTX.   o-Xylene and  m-xylene were
    found to be degraded to 15% and 12%, respectively, of the initial
    concentration (3 mg/litre) after 62 days with added nitrate (Major et
    al., 1988).  Much less degradation occurred under anaerobic conditions
    in the absence of added nitrate (73%  o-xylene remained after 62 days
    and 59%  m-xylene remained after 62 days).  These losses were not
    considered to be significant when compared with sterile controls.

         Up to 0.4 mM (42.5 mg/litre)  m-xylene was found to be rapidly
    mineralized in a  laboratory aquifer column operated in the absence of
    molecular oxygen with nitrate as an electron acceptor.  Quantitative
    (80%) oxidation of  m-xylene to carbon dioxide occurred with
    concomitant reduction of nitrate.  The column was inoculated with
    denitrifying river sediment that had been continuously fed  m-xylene
    for several months (Zeyer et al., 1986).

    4.2.2  Abiotic degradation

         The xylene isomers are readily degraded in the atmosphere,
    photooxidation being the most important degradation process.

    4.2.2.1  Photolysis

         Xylenes do not absorb UV-visible radiation appreciably at
    wavelengths longer than 290 nm.  This means that they are unlikely to
    be directly photolysed in the troposphere or in solution, as the ozone
    layer absorbs wavelengths shorter than 290 nm.  Experiments using
    xylenes adsorbed on silica gel have shown that the photomineralization
    rates for all three isomers are low using radiation with a wavelength
    longer than 290 nm (Gab et al., 1977).

    4.2.2.2  Atmospheric oxidation

         Atmospheric oxidation of xylenes is rapid and proceeds via
    free-radical chain processes.  The most important oxidant is the
    hydroxyl radical, but xylenes will also react with other species found
    in the atmosphere, such as alkoxy radicals, peroxy radicals, ozone and
    nitrogen oxides.  The most likely reaction pathways occurring in the
    atmosphere are hydroxyl radical addition to the aromatic ring and
    hydrogen abstraction from the alkyl groups by hydroxyl radicals (Gery
    et al., 1987), although reaction with nitrate radicals may become
    important at night (Grosjean, 1990).

         Estimates for the lifetime of xylenes in the atmosphere have been
    made from smog chamber experiments and from knowledge of the rate
    constant for reaction with hydroxyl radicals.  Atkinson (1985)
    reviewed the available hydroxyl radical reaction rate constant data
    and recommended kOH values at 25°C of 1.47 × 10-11 cm3 × molecule-1
    × s-1 for reaction with  o-xylene, 2.45 × 10-11 cm3 × molecule-1 ×
    s-1 for reaction with  m-xylene and 1.52 × 10-11 cm3 × molecule-1 ×
    s-1 for reaction with  p-xylene.

         Based on hydroxyl radical reaction rate constant data,
    atmospheric lifetimes of 2.6 h for  o-xylene, 1.5 h for  m-xylene
    and 2.4 h for  p-xylene have been calculated in south-east England
    (Brice & Derwent, 1978).

         Lifetimes in the boundary layer of the atmosphere have been
    calculated by Singh et al. (1986).  Using hydroxyl radical reaction
    rate constants, lifetimes of 9 sunlight hours for  o-xylene, 5
    sunlight hours for  m-xylene and 10 sunlight hours for  p-xylene
    were estimated.  Singh et al. (1983) estimated that around 71.3% loss
    of  o-xylene, 87% loss of  m-xylene and 67% loss of  p-xylene would
    occur per day (12 sunlight hours) as a result of reaction with
    hydroxyl radicals.

         An important point to consider with this data is that the
    calculated lifetime depends on several factors, including temperature,
    and also the actual concentration of hydroxyl radicals.  It is known
    that the concentration of hydroxyl radicals depends greatly on the
    amount of sunlight available.  Thus typical figures are around 2 ×
    106 molecules/cm3 in summer months, falling by approximately a
    factor of 2 in the winter months (Singh et al., 1986).  At night the
    concentration of hydroxyl radicals is negligible.  Even so, it can be
    seen that xylenes are removed from the atmosphere quite readily by
    reaction with hydroxyl radicals.

         It is possible that xylenes will be removed from aquatic systems
    by similar types of reactions, as hydroxyl radicals are known to exist
    in aquatic systems (Mansour et al., 1985).

         The reaction of xylene isomers with NO3 radicals has been
    studied.  The second-order reaction rate constants measured were:
     o-xylene, k = 3.74 × 10-16 cm3 × molecule-1 × s-1;  m-xylene,
    k = 2.49 × 10-16 cm3 × molecule-1 × s-1; and  p-xylene, k = 4.49 ×
    10-16 cm3 × molecule-1 × s-1.  NO3 radicals have been measured in
    the lower troposphere during night time hours but photodecomposition
    occurs during daylight at a wavelength of 600 nm.  Typical
    concentrations of NO3 radicals found during the night are 2.4 × 108
    molecules/cm3 in a clean atmosphere and 2 × 109 molecules/cm3 in a
    moderately polluted atmosphere (Sabljic & Güsten, 1990).  Using these
    concentrations, the following half-lives for the reaction of xylene
    with NO3 radicals at night have been estimated:  o-xylene, 15-89
    days;  m-xylene, 23-194 days; and  p-xylene, 13-107 days.  These
    half-lives are much longer than those for the daylight reaction with
    hydroxyl radicals, but indicate that removal of xylenes from the
    atmosphere could still occur at night by this route, especially in
    polluted atmospheres.

         The xylenes are sufficiently susceptible to photochemical
    oxidation in the lower atmosphere that they may contribute to
    tropospheric ozone formation.  Derwent & Jenkin (1990) calculated
    POCPs (Photochemical Ozone Creation Potentials) for xylenes of 41
    ( o-xylene), 78 ( m-xylene) and 63 ( p-xylene).  The POCP values
    reflect the ability of a substance to form low-level ozone as a result
    of its atmospheric degradation reactions, the POCP values being
    calculated relative to ethylene (a chemical that is thought to be
    important in low-level ozone formation and is given a POCP of 100) on
    a unit mass emission basis.

    4.2.2.3  Hydrolysis

         It is considered unlikely that xylenes will hydrolyse under the
    conditions found in the natural environment.

    4.2.3  Bioaccumulation

         Octanol-water partition coefficients of 3.12, 3.20 and 3.15
    (log values) have been determined for  o-xylene,  m-xylene
    and  p-xylene, respectively.  These values indicate that slight
    bioaccumulation could take place in the environment.  Using these
    values, bioconcentration factors (BCFs) of 138 (2.14) for  o-xylene,
    158.5 (2.20) for  m-xylene and 144.5 (2.16) for  p-xylene (log
    values are given in parentheses) can be estimated using the formula of
    Veith et al. (1980).

         Bioconcentration factors (BCFs) of 21.4 (1.33 log value) for
     o-xylene and 23.6 (1.37 log value) for combined  m-xylene and
     p-xylene have been measured in the eel  (Anguilla japonica).  The
    half-life for elimination of  m-xylene and  p-xylene from the flesh
    after exposure had ceased was 2.6 days (Ogata & Miyake, 1979).

         Bioconcentration factors have been measured for all three isomers
    in the goldfish.  The reported BCFs were 14.1 (1.15) for  o-xylene,
    14.8 (1.17) for  m-xylene and 14.8 (1.17) for  p-xylene (log values
    are in parentheses) (Ogata et al., 1984).

         After exposure to the water-soluble fraction of Cook Inlet crude
    oil ( o-xylene concentration 0.14 mg/litre;  m-xylene concentration
    0.15 mg/litre) for 8 days, concentrations of 0.87 mg/kg  o-xylene
    and 0.90 mg/kg  m-xylene were found in the Manila clam  (Tapes
    semidecussata).  The concentrations in the clam were found to
    decrease rapidly during the first 7 days after exposure ceased (Nunes
    & Benville, 1979).

         A BCF of 9 for mixed xylenes was measured in both the thorax and
    abdomen of the adult spot shrimp  (Pandelus platyceros) when it was
    exposed to a water-soluble fraction of Prudhoe Bay crude oil (Sanborn
    & Malins, 1980).

         The low BCFs indicate that biomagnification of xylenes through
    the aquatic food chain is unlikely.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

         Owing to analytical difficulties it is often not possible to
    quantify  m-xylene and  p-xylene individually in environmental
    samples.  As a result, a large proportion of the measured levels of
    these two isomers refer to the combined total of the two.

    5.1.1  Ambient Air

         Measured levels of  o-xylene and the combined  m-xylene and
     p-xylene levels are shown in Table 2.  Levels of xylene for indoor
    air are given in section 5.2.

         Typically, background levels of all three xylene isomers are
    around 1 µg/m3.  Higher levels have been measured in urban areas,
    showing that vehicle emissions are a significant source of xylenes.

         Six studies giving measured levels for  m-xylene and  p-xylene
    as individual compounds have been reported.  One study gave measured
    levels in Florida, USA, of < 0.09 to 5.5 µg/m3 for  m-xylene and
    < 0.09 to 2.4 µg/m3 for  p-xylene (Lonneman et al., 1978).  Another
    gave levels of 0.019 to 2.66 µg/m3 for  m-xylene and 0.018 to 1.19
    µg/m3 for  p-xylene in the Black Forest, Germany (Jüttner, 1988a),
    while another reported levels of 92.6 µg/m3 for  m-xylene and 39.7
    µg/m3 for  p-xylene in Zurich, Switzerland (Grob & Grob, 1971). 
    Levels of 11.94-25.74 µg/m3  m-xylene and 5.33-11.14 µg/m3
     p-xylene were reported for two cities in Taiwan (Hung & Liao, 1991). 
    Average values of 1.5-6.2 µg/m3  m-xylene and 0.44-2.6 µg/m3
     p-xylene were found in the Netherlands, with maximum values of 11-70
    µg/m3  m-xylene and 4.9-15.9 µg/m3  p-xylene (Guicherit &
    Schulting, 1985).  Kawata & Fujieda (1993) monitored xylene
    concentrations in the air of Niigata, Japan, in 1991 and 1992.  At an
    urban location, mean  m-xylene and  p-xylene concentrations were 4.8
    and 2 µg/m3, respectively.  The  m-xylene and  p-xylene
    concentrations at a rural location were 1.8 and 0.7 µg/m3,
    respectively.

         Svanberg et al. (1995) measured xylene levels in the air of 17
    Swedish towns during the winters of 1992-1993 and 1993-1994.  Mean
    concentrations ranged from 17 to 47 µg/m3 and from 11 to 41 µg/m3
    for  m/p-xylene for the two winters, respectively, and from 18 to 53
    µg/m3 and 12 to 44 µg/m3 for  o-xylene.

         High levels of total xylene have been measured in air samples
    from within landfill sites in the United Kingdom (Young & Parker,
    1983).  Levels of between 36 and 77 mg/m3 were reported in domestic
    landfills, with higher levels (actual levels not reported) being found
    in some industrial waste landfills.

        Table 2.  Mean measured levels of o-xylene and m/p-xylenes in ambient air

                                                                                              

    Location                    o-Xylene          m/p-Xylene       Reference
                               levels           levels
                               (µg/m3)          (µg/m3)
                                                                                              

    Sydney, Australia          6.63             17.2             Nelson & Quigley (1982)

    Sweden

      near car factory         38               264              Petersson (1982)
      1 km from the factory    11.6             85.1
      background               0.21             0.58

    Stockholm, Sweden

      busy streets                              251 and 91       Jonsson et al. (1985)
      calm streets                              28.3 and
                                                15.9

    The Netherlands            0.88 - 3.1                        Guicherit & Schulting
                               max                               (1985)
                               7.5 - 22.5

    Black Forest, Germany      0.024-1.77                        Jüttner (1988a)

    Hamburg, Germany

     12 sites                  4.5-15.2                          Bruckmann et al. (1988)

    Los Angeles, USA           28.7                              Altshuller et al. (1971)

    USA

      car painting planta      52               158              Sexton & Westberg (1980)
      9 miles from the plant   4.5              14.5
      background               0.5              2.5

    USA, 10 cities             2.48-8.35        4.11-19.95       Singh et al. (1983)

    USA, 5 cities              ND-5.24b         1.03-14.64       Sheldon et al. (1988)
                                                                                              

    Table 2.  (Cont'd)

                                                                                              

    Location                    o-Xylene          m/p-Xylene       Reference
                               levels           levels
                               (µg/m3)          (µg/m3)
                                                                                              

    Raleigh, USA, near to      1.9-7.6          5-19.9           Chan et al. (1991b)
    roads

    USA, 6 cities              2.78-25.25       1.9-13.1         Singh et al. (1986)

    USA

     urban                     5.2              1.2              Brodzinsky & Singh (1983)
     rural                     0.41             0.38

    Taiwan

     2 cities                  7.14 and 15.17                    Hung & Liao (1991)

    Niigata, Japan

      urban                    2                                 Kawata & Fujida (1993)
      rural                    0.83

    Finland

      industrial               207              568              Kroneld (1989)
      urban                    0.143            0.392

    Grenoble, France

      winter                   1.9              22.9             Foster et al. (1991)
      summer                   2.4              28.7

    Vienna, Austria

      streets                  24.0             50.8             Lanzerstorfer & Puxbaum (1990)
      suburbs                  6.2              10.4
      backgrounds              1.9              3.9
                                                                                              

    Table 2.  (Cont'd)

                                                                                              

    Location                    o-Xylene          m/p-Xylene       Reference
                               levels           levels
                               (µg/m3)          (µg/m3)
                                                                                              

    United Kingdom

      urban                    5.43             12.2             Clark et al. (1984)
      rural                    0.75             2.2

    Southampton, United Kingdom

      urban                    12               27               Bevan et al. (1991)
      busy roads               33               69
      common land              5                6

    Harwell, United Kingdom    2.4              3.9              Jones (1988)
                               max 15.8         max 34.4
                                                                                              

    a    Based on individual samples
    b    ND not detectable (detection limits not states)
        5.1.2  Water and sediment

    5.1.2.1  Surface water

         Levels of the individual xylene isomers measured in surface water
    are shown in Table 3.  Typically, background levels of xylenes in
    surface waters are low (< 0.1 µg/litre).  Much higher levels have
    been measured in some industrial areas and areas associated with the
    oil industry. Wiesenburg et al. (1981) measured xylenes in brine from
    an oil production platform in the Gulf of Mexico.  Two samples
    contained 480 and 1800 µg/litre of  m/p-xylene and 500 and 1900
    µg/litre of  o-xylene.  Samples were taken from an underwater vent
    plume from offshore oil production operations in the same region. 
    Xylene concentrations in the surface water were 0.270 µg/litre for
     m/p-xylene and 0.06 µg/ litre for  o-xylene.  Water from the
    discharge pipe contained 2060 µg/litre of  m/p-xylene and 1510
    µg/litre of  o-xylene.

         It has been reported that motor boats could be a significant
    source of xylenes in surface water.  Measurements were carried out in
    an entrance canal to a harbour on Lake Constance both before (early
    morning) and during boat movement on the lake.  Levels recorded before

    boat movements were  o-xylene 18 ng/litre,  m-xylene 17 ng/litre and
     p-xylene 39 ng/litre.  Levels recorded during the rest of the day
    were  o-xylene 57-481 ng/litre,  m-xylene 76-750 ng/litre and
     p-xylene 62-416 ng/litre.  In general, the levels of xylene
    increased as the number of boats passing the sampling point increased
    (Jüttner, 1988b).

         Xylenes were surveyed in surface water in Japan in 1977, 1985 and
    1986.  No xylene isomers were detected in 1977 (detection limit = 2
    µg/litre).  In 1985 one out of 21 samples contained xylene at
    concentrations of 0.021, 0.042 and 0.037 µg/litre for  o-, m- and
     p-xylene, respectively (detection limit = 0.02 µg/litre).  In 1986,
    the concentrations of  o- and  m-xylene ranged from 0.04 to 1.2
    µg/litre in 12 out of 137 samples and 15 out of 126 samples, for the
    two isomers respectively.   p-Xylene was detected in 4 out of 122
    samples at concentrations ranging from 0.06 to 0.48 µg/litre
    (detection limit = 0.03 µg/litre) (EAJ, 1993).

    5.1.2.2  Groundwater

         Table 3 shows levels of xylene measured in groundwater. 
    Typically, background levels of xylenes in aquifers are low (< 0.1
    µg/litre).  High levels have been reported in contaminated aquifers. 
    The migration of petroleum products from leaking underground storage
    tanks and pipelines poses a groundwater contamination problem. 
    Gasoline-contaminated groundwater in Los Angeles, USA, contained
    xylene at a concentration of 153 µg/litre (Karlson & Frankenburger,
    1989).

         Very high levels of  o-xylene (4001 µg/litre) and  m/ p-xylene
    (5385 µg/litre) have been measured in a polluted aquifer in Italy. 
    Water was taken from a well at a depth of 30 m and the pollution was
    thought to be due to leakage from underground solvent storage tanks
    (Botta et al., 1984).

    5.1.2.3  Precipitation

         Kawamura & Kaplan (1983) measured xylene in rainwater in Los
    Angeles, USA, during 1982.  An  m-xylene concentration of 0.002
    µg/litre and a  p-xylene concentration of 0.009 µg/litre were
    reported.

        Table 3.  Levels of xylene in water

                                                                                            

    Location                      Isomera    Level (µg/litre)b      References
                                                                                            

    Surface water

    River Lee, UK                 T          detected at a level    Waggot (1981)
                                             of > 0.1

    River Besós, Spain            m/p        24                     Gomez-Belinchon et al.
    (polluted)                    ortho      8.1                    (1991)

    River Llobregat, Spain        m/p        4.7                    Gomez-Belinchon et al.
    (polluted)                    ortho      0.83                   (1991)

    Seawater

    Off River Humber, UK          T          < 0.001-29.0           MAFF (1991)
    Dredged spoil disposal site   T          < 0.001-0.330
    Sewage sludge disposal site   T          < 0.001

    North Sea, off UK coast       T          < 0.01-0.250           Hurford et al. (1990)

    River Tees estuary, UK        m/p        < 0.05-1.1             Harland et al. (1985)
                                  ortho      < 0.05-1.1

    Coastal site, USA             m/p        0.0045-0.066           Gschwend et al. (1982)
                                  ortho      0.0018-0.025

    Barcelona, Spain              m/p        0.015-0.072            Gomez-Belinchon et al.
                                  ortho      0.004-0.210            (1991)

    Gulf of Mexico:               T          0.002-0.056            McDonald et al. (1988)
    river mouth

    Gulf of Mexico:                          0.001
    chemical outfall

    Inner harbour of the          T          0.04-0.2               McFall et al. (1985)
    navigation canal of
    Lake Pontchartrain, USA
                                                                                            

    Table 3.  (Cont'd)

                                                                                            

    Location                      Isomera    Level (µg/litre)b      References
                                                                                            

    Wastewater

    Effluent samples from a       T          1.82                   Kennicut II et al. (1984)
    Barceloneta waste
    treatment facility, Puerto
    Rico (mainly pharmaceutical
    in origin)

    Wastewater treatment          para       influent = 4.40        Michael et al. (1991)
    plant, Great Lakes Basin                 effluent = < 1

    Groundwater

    British aquifers              para       occasionally           Kenrick et al. (1985)
    (uncontaminated sites                    detected at
    thought to represent                     0.001-0.02
    background levels)            ortho      detected in 19
                                             out of 32 samples.
                                             highest = 0.02
                                             mean = 0.011

    Groundwater, near             para       ND-0.5c                Barker et al. (1988)
    landfill site, Hamilton,      ortho      0.03-0.5
    Ontario, Canada

    Edwards aquifer, Texas,       T          up to 0.08             Buszka et al. (1990)
    USA

    Groundwater near              m/p        NDd-50                 Slain & Baker (1990)
    bituminous layers of          ortho      NDd-21
    shale in rock, near a
    sanitary landfill site,
    Ontario, Canada
                                                                                            

    Table 3.  (Cont'd)

                                                                                            

    Location                      Isomera    Level (µg/litre)b      References
                                                                                            

    Groundwater near an           m/p        240-830                Stuermer et al. (1982)
    underground coal              ortho      260-590
    gasification site in                     (background was
    the USA                                  below the limit of
                                             detection of
                                             0.5 µg/litre)

    Groundwater, New Jersey/      T          59-300                 Rao et al. (1985)
    New York, USA
                                                                                            

    a    m/p = combined m-xylene and p-xylene;  T = total xylene
    b    ND = not detected
    c    detection limit not stated
    d    detection limit = 2 µg/litre
        5.1.2.4  Leachate

         Barker et al. (1988) measured  o- and  p-xylene in the leachate
    from a landfill in Hamilton, Ontario, Canada.  Xylene concentrations
    ranged from 30.8 to 123 µg/litre for the ortho isomer and from 12.5 to
    191 µg/litre for the para isomer.  Leachate from a landfill in
    Minnesota, USA, contained  m-xylene concentrations ranging from 21 to
    150 µg/litre and  o/p-xylene concentrations ranging from 12 to 170
    µg/litre.  Both xylene isomers were presented in all six samples
    collected (Sabel & Clark, 1984).

    5.1.2.5  Sediment

         Tynan et al. (1991) measured levels of xylene in sediment samples
    taken in Wales, United Kingdom, of up to 23.4 µg/kg and 21.2 µg/kg for
     o-xylene and  p-xylene, respectively.  Harland et al. (1985)
    reported  o-xylene levels of 0.6-3.9 µg/kg and combined  m/p-xylene
    levels of 3.4-250 µg/kg in sediment from the River Tees estuary,
    England.

         Xylenes were surveyed in sediment in Japan in 1977, 1985 and
    1986.  No xylene isomers were detected in 1977 (detection limit = 4
    µg/kg).  In 1985 one out of 21 samples contained  o- or  m-xylene at
    concentrations of 1.1 and 2 µg/kg respectively;  no  p-xylene was
    detected (detection limits = 0.6 µg/kg for  o-xylene, 1 µg/kg for

     m-xylene and 2 µg/kg for  p-xylene).  In 1986   o-,  m- and
     p-xylene concentrations ranged from 0.5 to 7 µg/kg (detected in 24
    out of 111 samples), 0.5 to 15 µg/kg (detected in 33 out of 118
    samples) and 0.5 to 3.8 µg/kg (detected in 12 out of 105 samples), for
    the three isomers respectively (detection limit = 0.5 µg/kg) (EAJ,
    1993).

    5.1.3  Soil

         Levels of 0.15 g/kg ( o-xylene) and 0.4 g/kg ( m- and
     p-xylene) have been measured at a depth of 75-250 cm in soil
    from a gasoline station.  The soil was thought to be contaminated
    as a result of leakage from an underground storage tank (Morgan &
    Watkinson, 1990).

    5.1.4  Biota

         Xylenes have been measured at levels of 16 µg/kg wet weight in
    oysters from Lake Pontchartrain, Louisiana, USA (Ferrario et al.,
    1985).  Levels of combined  m- and  p-xylene have been measured in
    fish and shellfish from three estuarine sites in the USA (Reinert et
    al., 1983).  The levels found were: silverside  (Menidia menidia) 100
    and 180 µg/kg, ribbed mussel  (Modiolus demissus) 100 µg/kg, and
    grass shrimp  (Palaemonetes pugio) 200 µg/kg.

         Xylenes were monitored in fish during 1986 in Japan.   o-Xylene
    concentrations ranged from 0.8 to 5 µg/kg in 41 out of 137 samples,
     m-xylene concentrations ranged from 0.86 to 9.2 µg/kg in 45 out of
    124 samples and  p-xylene concentrations ranged from 0.8 to 3 µg/kg
    in 28 out of 127 samples (detection limit = 0.8 µg/kg for all three
    isomers) (EAJ, 1993).

    5.2  General population exposure

    5.2.1  Source of Exposure

    5.2.1.1  Air

         Otson et al. (1993) pooled aliquots of individual air sample
    extracts from 757 randomly selected Canadian residences.  The
    composite sample contained  o-,  m- and  p-xylene concentrations of
    8, 7 and 6 µg/m3, respectively.  Fellin & Otson (1993) studied the
    seasonal trends of xylene concentrations in the indoor air of 754
    randomly selected Canadian homes.  Lowest mean concentrations were
    found in the summer and the highest in the autumn.  Mean
    concentrations ranged from 3.73 to 9.12 µg/m3 for  p-xylene, from
    6.81 to 26.03 µg/m3 for  m-xylene and from 3.03 to 8.19 µg/m3 for
     o-xylene.  Lioy et al. (1991) monitored indoor and outdoor air at

    three homes in New Jersey, USA during 1987.  Indoor concentrations
    ranged from 6.0 to 20.5 µg/m3 for  o-xylene and from 15.2 to 57.5
    µg/m3 for  p-xylene.  Outdoor concentrations ranged from 1.6 to 12.7
    µg/m3 for  o-xylene and from 4.6 to 36.9 µg/m3 for  p-xylene.

         Weschler et al. (1990) monitored xylene concentrations in the air
    of a building with a history of occupant health and comfort
    complaints.   o-Xylene concentrations ranged from 2.1 to 9 µg/m3 and
     m/p-xylene concentrations ranged from 3.9 to 25 µg/m3.  The highest
    xylene concentrations were associated with the lift shaft.

         The California Total Exposure Assessment Methodology (TEAM) study
    conducted in 1984 monitored xylenes in outdoor air, personal air and
    breath samples for 188 people in Los Angeles  County (urban) and
    Contra Costa County (rural area).  The 12-h arithmetic means of the
    xylene concentrations are summarized in Table 4.  A second TEAM study
    was carried out in 1987 with 51 residents of Los Angeles, California. 
    The 24-h arithmetic means of the xylene concentrations in this study
    are also summarized in Table 4.  Daisey et al. (1994) reported the
    concentrations of xylenes in the air in 12 office buildings in
    California.  The concentration of  o-xylene ranged from 1.3 to  6.1
    µg/m3 (0.30 to 1.40 ppb) and that of  m/p-xylene from 4.0 to 20.0
    µg/m3 (0.93 to 4.60 ppb).

         Levels measured during winter were higher than summer levels for
    all types of air.  Smoking was determined to be the major determinant
    for the presence of xylene in breath and personal air; concentrations
    in the breath of smokers were more than double those of nonsmokers. 
    At petrol stations, exposure to vehicle exhaust and the type of
    employment contributed significantly to increased concentrations of
    xylene in breath and personal air (Wallace et al., 1988).  Higgins et
    al. (1983) reported that the gas-phase delivery of  p-xylene in
    ultra-low tar delivery cigarette smoke ranged  from < 0.01 to 8
    µg/cigarette, while the ranges for  m- and  o-xylene were < 0.01 to
    20 µg/cigarette and < 0.005 to 10 µg/cigarette, respectively.

        Table 4.  Mean xylene concentrations in personal air, outdoor air and breath samples
              (Wallace et al., 1988, 1991)

                                                                                             

    Location           Date               Sample type              m/p-Xylene      o-Xylene
                                                                   (µg/m3)         (µg/m3)
                                                                                             

    Los Angelesa       February 1984      personal airc            28              13
                                          outdoor air              24              11
                                          breath                   3.5             1.0

    Los Angelesa       June 1984          personal air             24              7.2
                                          outdoor air              9.4             2.7
                                          breath                   2.8             0.7

    Contra Costaa      June 1984          personal air             11              4.4
                                          outdoor air              2.2             0.7
                                          breath                   2.5             0.6

    Los Angelesb       February 1987      personal air             43              16
                                          indoor aird              30              12
                                          outdoor aire             18              6.5
                                          breath (median value)    2.5             0.8

    Los Angelesb       July 1987          personal air             27              9.2
                                          indoor aird              12              4.3
                                          outdoor aire             7.4             2.8
                                          breath (median value)    0.7             0.25
                                                                                             

    a    12-h arithmetic means of xylene concentration
    b    24-h arithmetic means of xylene concentration
    c    Air sample collected at the breathing level of the subjects
    d    samples collected in living room-kitchen area
    e    samples collected in backyards of homes
             Weisel et al. (1992) analysed air within automobiles whilst
    idling, driving on a suburban route in New Jersey and commuting into
    New York City.  During a 30-min idling period, mean  m/ p-xylene
    concentrations ranged from 1.3 to 42 µg/m3 and  o-xylene
    concentrations ranged from 0.5 to 18 µg/m3.  The highest values were
    recorded during the summer and the lowest during the winter.  The mean
     m/ p-xylene concentrations for the suburban route were 23 and 16
    µg/m3 for low and high ventilation, respectively; for  o-xylene mean
    concentrations were 8.6 and 7.5 µg/m3.  Xylene concentrations of 23
    µg/m3 for  m/p-xylene and 8.8 µg/m3 for  o-xylene were recorded

    whilst commuting into New York City; mean xylene levels of 37 µg/m3
    ( m/ p-xylene) and 12 µg/m3 ( o-xylene) were measured whilst
    travelling through a tunnel.  Chan et al. (1991) studied exposure of
    commuters in Boston, USA, to xylenes and found that the highest
    exposures were associated with commuting by car ( m/ p-xylene = 20.9
    µg/m3;  o-xylene = 7.3 µg/m3).

         The levels of xylenes in samples of air in the vicinity of petrol
    pumps in five Canadian cities were monitored between June and August
    1985 and between January and March 1986.  Measured mean concentrations
    of all the isomers of xylene in the immediate vicinity of self-service
    pumps were 0.716 mg/m3 in the winter and 0.973 mg/m3 in the summer,
    and ranged from 0.678 to 3.77 mg/m3 and 0.001 to 6.9 mg/m3,
    respectively (PACE 1987; 1989).   p-Xylene represented more than 70%
    of the mean concentrations for all isomers.

         van Wijnen et al. (1995) monitored ambient air for traffic-related
    pollutants in Amsterdam.  Maximum mean time-weighted concentrations
    were as high as 193 µg/m3 for car drivers, 46 µg/m3 for cyclists
    and 41 µg/m3 for pedestrians.

         A mean total xylene level of 65 µg/m3 (15.06 ppb) in ambient air
    was measured in Turin, Italy, throughout 1991 (Gilli et al., 1994). 
    Within a 10-day sampling period, mean concentrations of 85 and 57
    µg/m3 (19.50 and 13.13 ppb) were measured in indoor air for day-
    and night-time sampling, respectively.  The corresponding mean
    concentrations for outdoor air were 82 and 54 µg/m3 (18.82 and 12.31
    ppb) for day- and night-time sampling respectively.  The mean personal
    exposure of the volunteers was 84 µg/m3 (19.30 ppb).

         Monitoring for xylene has been carried out at filling stations
    in Rome, Italy (Lagorio et al., 1993).  The range of measured
    concentrations from 703 personal samples among 111 workers was 0.003
    to 15.37 mg/m3 (mean: 0.32 mg/m3).

         Bostrom et al. (1994) calculated the average exposure dose for
    xylenes  (o, m and  p) to be 11 µg/m3, based on the relationship
    between nitrogen oxides (NOx) and xylenes, and a mean exposure for
    the Swedish population of 23 µg/m3 for nitrogen oxides.

         The exposure of students commuting to school in Taipei City,
    Taiwan, in 1992 has been reported by Chan et al. (1993).  Students
    commuting by bus were exposed to 222.8 µg/m3 of  o-xylene and 418.1
    µg/m3 of  m/p-xylene.  Students commuting by motorcycle were exposed
    to 524.5 µg/m3 of  o-xylene and 926.9 µg/m3 of  m/p-xylene.  The
    air in school classrooms was also monitored;  the mean concentration
    of  o-xylene was 26.3 µg/m3 and that of  m/p-xylene was 46.4 µg/m3.

    5.2.1.2  Food

          o-Xylene has been detected at levels up to 25 µg/kg (mean level
    9 µg/kg) in seven samples of dried beans, at a level of 8 µg/kg in
    split peas and at a level of 3 µg/kg in lentils from the USA (Lovegren
    et al., 1979).  Xylenes have been identified but not quantified in
    various other food items including cheese from Italy (Meinhart &
    Schreier, 1986), dry red beans from the USA (Buttery et al., 1975),
    winged beans and soybeans from the Philippines (del Rosario et al.,
    1984) and tomatoes and tomato products from Japan (Chung et al.,
    1983).  All three isomers were detected in the volatile compounds from
    roasted turkeys fed on a basal diet supplemented with tuna oil
    (Crawford & Kretsch, 1976).

    5.2.1.3  Drinking-water

         All three xylene isomers were detected in all of 14 samples of
    United Kingdom drinking-water derived from rivers, lowland reservoirs
    and groundwater (detection limit not stated) (Fielding et al., 1981). 
    Xylenes have been shown to pass through a drinking-water treatment
    plant unaltered in concentration (Dowty et al., 1975).

         Otson et al. (1982) monitored 30 Canadian potable water treatment
    facilities.  Mean total xylene concentrations in both raw and treated
    water were less than the detection limit in this study (1 µg/litre). 
    Maximum values were less than 1 µg/litre for raw water and 8 µg/litre
    for treated water.

         When Williams et al. (1982) sampled 12 Great Lakes (Canada)
    municipal drinking-water supplies,  o- and  m-xylenes ( m-isomers)
    were not detected at five of the sites and in 50% of the 22 samples. 
    Detectable concentrations ranged from 1.1 to 12 µg/litre.

         The concentration of  m- and  p-xylene in tap water, Toronto,
    Canada, was reported to be 0.06 µg/litre (City of Toronto, 1990).  The
    concentrations of xylene in seven samples of bottled water ranged from
    less than the detection limit to 0.07 µg/litre.

    5.2.1.4  Other source of exposure

         The US EPA (Sack et al., 1992) carried out analyses of 1159
    household products.  The results of the analyses, according to product
    category, are presented in Table 5.

    5.2.2  Xylene levels in human biological samples

         Xylenes have been detected in human blood at levels of between
    0.5 and 160 µg/litre (mean = 5.2 µg/litre) (Antoine et al., 1986). 
    The level was found to be significantly elevated in 7 out of 250
    people sampled.   m-Xylene has been determined in human whole blood
    at levels of 10-20 ng/litre (Cramer et al., 1988).

        Table 5.  Mean xylene concentrations in various products

                                                                                                                                          

                                                                    m-Xylene                                   o/p-Xylene

    Product category             Number of          Products containing   Mean concentration    Products containing   Mean concentration
                                 products tested    analyte (%)           (% w/w)               analyte (%)           (% w/w)
                                                                                                                                          

    Automotive                   167                26.7                  10.6                  10.0                  31.0

    Household cleaners and       111                33.3                  1.4                   -                     -
    polishers

    Paint-related products       463                60.3                  4.2                   58.2                  2.8

    Fabric and leather           91                 -                     -                     33.3                  0.1
    treatments

    Cleaners from electronic     69                 -                     -                     -                     -
    equipment

    Oils, greases, lubricants    111                9.3                   0.2                   11.9                  0.2

    Adhesive-related products    76                 9.1                   0.2                   9.1                   0.2

    Miscellaneous:               71                 -                     -                     -                     -
    specialized cleaners, rust
    remover, correction fluid
                                                                                                                                          
             Ashley et al. (1994) monitored blood samples from more than 600
    people in the USA third national health and nutrition examination
    survey.  None of the subjects were occupationally exposed to xylenes. 
    Mean concentrations were 0.37 µg/litre for  m/ p-xylene and 0.14
    µg/litre for  o-xylene.

         Fustinoni et al. (1995) reported that the mean blood
    concentration of  m/p-xylene in non-smoking traffic wardens in Milan,
    Italy, was 853 ng/litre before the shift and 683 ng/litre at the end
    of the shift.  The level in non-smokers of the clerical environment
    from the same area was 809 and 629 ng/litre, respectively.

         Xylenes were detected, but not quantified, in 8 out of 12 samples
    of breast milk (Pellizzari et al., 1982).

         Xylenes have been detected in the axilla odour from humans
    (Labows et al., 1979).  Placental transfer of xylene has been shown to
    occur (Dowty & Laseter, 1976).

    5.3  Occupational exposure during manufacture, formulation or use

         Occupational exposure to xylenes alone is rare.  There is usually
    simultaneous exposure to other compounds, often organic solvents. In
    one study, however, 10 female laboratory workers had been exposed to
    xylene (vapour as well as liquid) for about 4 h daily for up to 16
    years.  Exposure levels, determined by only one measurement in the
    breathing zone and by only one in the workroom air, were 139 mg/m3
    (32 ppm) and 62 mg/m3 (14 ppm), respectively (Proust et al., 1986).

         A number of studies have been performed on workers occupationally
    exposed to solvent mixtures including xylenes (e.g. Seppäläinen et
    al., 1978; Elofsson et al., 1980; Husman, 1980; Lindström et al.,
    1982; Valciukas et al., 1985; Maizlish et al., 1987; Van Vliet et al.,
    1987).

         In a study on spray varnishers (Angerer & Wulf, 1985) 35 male
    workers were exposed to 2.2-14.8 mg/m3 (0.5-3.4 ppm)  o-xylene,
    13.9-50.1 mg/m3 (3.2-11.7 ppm)  m-xylene, 3.9-18.7 mg/m3 (0.9-4.3
    ppm)  p-xylene, 1.4-7.5 ppm ethylbenzene, < 1.5 ppm toluene, <1.2
    ppm n-butanol, < 35.5 ppm 1,1,1-trichloroethane and several C9
    aromatic compounds.

         Mean 8-h xylene concentrations of 21.7 and 27.8 mg/m3 (5 and 6.4
    ppm) were measured in a lacquer/resin spraying operation in a
    woodworking facility in the USA (Fairfax, 1995).

         In a study on workers engaged in dip-coating of metal parts the
    mean xylene vapour concentration was 16.5 mg/m3 (3.8 ppm).  The
    concentration of the isomers were 3.5 mg/m3 (0.8 ppm)  o-xylene, 9.1
    mg/m3 (2.1 ppm)  m-xylene and 3.9 mg/m3 (0.9 ppm)  p-xylene (Kawai
    et al., 1991a).

         In a study on workers employed in printing, painting or the
    manufacture of plastic coated wires, there was an exposure to mixtures
    of toluene and xylenes.  Personal air samples were collected and
    analysed for toluene and the three isomers of xylene.  Maximum
    exposures to xylenes were > 435 mg/m3 (100 ppm) with a time-weighted
    average of 17.4 mg/m3 (4 ppm).  About half of the xylene was
     m-xylene (Huang et al. 1994).

         Concentrations of xylenes ranging from 0.4 to 7.0 mg/m3 (0.1 to
    1.6 ppm) were measured during full-shift personal exposure monitoring
    at an axle painting operation in Newark, Ohio, USA (NIOSH, 1991).

         Breathing zone samples were collected from workers in the liquid
    inks and paste inks departments of a small printing ink manufacturing
    factory.  The mean full shift concentration of xylene in the liquid
    inks department was 314 mg/m3 and in the paste inks department 24
    mg/m3.  Other solvents in the factory were toluene, ethyl acetate,
    ethanol, isopropanol and  n-hexane (Lewis, 1994).

         During paint operations in an aeronautical factory xylene
    concentrations (sum of the three isomers) of 14.3 to 167.0 mg/m3 were
    measured by personal air monitoring.  Other solvents present were
    methyl ethyl ketone, ethyl acetate,  n-butyl alcohol, methyl isobutyl
    ketone, toluene,  n-butyl acetate, ethylbenzene, ethylene glycol and
    monoethylether acetate (Vincent et al., 1994).  Similarly,
    concentrations of xylene (isomer not specified) among printers have
    been measured to be between 5.6 and 91.3 mg/m3 (1.3 and 21 ppm). 
    Other solvents were acetone, ethyl acetate, methyl ethyl ketone, white
    spirit, toluene and trichloroethylene (Nasterlack et al., 1994).

         Levels of xylene to which workers have been exposed in
    histological laboratories, measured as 8-h time-weighted average, are
    from about 10.9 mg/m3 (2.5 ppm) to over 304.5 mg/m3 (70 ppm)
    (Angerer & Lehnert, 1979; Kilburn et al, 1985; IARC, 1989).  In a
    hospital laboratory, levels of up to 1740 mg/m3 (400 ppm) have been
    measured (Klaucke et al, 1982).  In lithographical processes in Poland
    the mean value in 1968 was 119 mg/m3 and ten years later 130 mg/m3
    (Moszczynski & Lisiewicz, 1985), and in a chemical plant in Hungary
    the mean concentration in air was 47-56 mg/m3 (Pap & Varga, 1987).

         In a NIOSH study involving conducted environmental monitoring of
    xylene in various worksites, the concentrations where workers were
    exposed to gasoline and exhaustion emissions ranged from < 0.08 to
    68.3 mg/m3 (0.02 to 15.7 ppm) (NIOSH, 1993a).  The concentration in
    the air in the cab ranged up to 8.7 mg/m3 (2 ppm) (NIOSH, 1993b). 
    The personal breathing zone samples of an indoor parking garage, a
    medical taxi cab, an automobile dealership/repair shop and a state
    highway maintenance garage in New York State ranged from < 0.08 to
    1.87 mg/m3 (0.02 to 0.43 ppm) (NIOSH, 1993c).  The concentration in
    personal breathing zone samples from workers in automotive maintenance

    facilities/dealers, repair shops) in Stamford, Connecticut, USA,
    ranged from < 0.08 to 1.39 mg/m3 (0.02-0.32 ppm) (NIOSH, 1993d). 
    The highest full-shift exposure at an oil refinery in Colombia was
    22.2 mg/m3 (5.1 ppm), and all short-term exposures were below the
    quantifiable concentration of 1.3 mg/m3 (0.3 ppm) (NIOSH, 1994).

         Kawai et al. (1991b) monitored the exposure of tank truck drivers
    to xylenes in Japan.  Maximum concentrations were 26.5 to 94.8 mg/m3
    (6.1 to 21.8 ppm) during loading and 3.9 to 5.96 mg/m3 (0.90 to 1.37
    ppm) during a delivery trip.

         Fustinoni et al. (1995) measured the exposure of traffic wardens
    to xylenes in Milan, Italy, in 1994.  During a 10-day period, the
    concentration of  o-xylene was 48 µg/m3 and of  m/p-xylene was 108
    µg/m3.  Concurrent monitoring of policemen in clerical environments
    was also carried out; the concentration of  o-xylene in indoor air
    was 32 µg/m3 and of  m/p-xylene was 53 µg/m3.

    6.  KINETICS AND METABOLISM IN LABORATORY ANIMALS AND HUMANS

    6.1  Absorption

    6.1.1  In humans

         In humans, absorption of xylenes has been investigated following
    inhalation of the vapour or dermal application of the liquid.

         Pulmonary retention of  m-xylene became relatively constant at
    about 60% after the first 5-10 min of exposure to 430 mg/m3 (100 ppm)
    (Riihimäki et al., 1979a).  The determination was made by measurement
    of atmospheric and exhaled concentrations.  In a previous study
    (Sedivec & Flek, 1976) a pulmonary retention of 62-64% was reported
    for each xylene isomer at exposure levels of 196-391 mg/m3 (45-90
    ppm) for up to 7 h.

         A relatively constant retention, average 59%, was reported in
    individuals exposed to varying  m-xylene concentrations in the range
    of 304-957 mg/m3 (70-220 ppm), both at rest and while undergoing
    intermittent physical exercise (Riihimäki et al., 1979b).  A slight
    reduction in retention was noted when resting individuals subsequently
    underwent moderately heavy physical exercise.  Increased pulmonary
    ventilation during exercise was found to be associated with a 
    corresponding increase in total uptake of xylenes (Riihimäki et al.,
    1979b; Åstrand et al., 1978).

         In resting individuals exposed to 870 mg/m3 (200 ppm) xylene
    (8.8%  o-xylene, 49.4%  m-xylene, 1.4%  p-xylene, and 40.4%
    ethylbenzene) the alveolar air level was about 15% of that in inspired
    air, while 36% was recorded for individuals undergoing heavy exercise
    (Åstrand et al., 1978).  The ratio of  m/p-xylene to ethylbenzene was
    found to be similar in alveolar air and inspired air.  This indicates
    similar rates of pulmonary absorption for xylenes and ethylbenzene. 
    In this study,  o-xylene was not measured (Engström & Bjurström,
    1978).

         During inhalation exposure in resting subjects, a levelling of
    the blood xylene concentration began after about 15 min of exposure to
    435-870 mg/m3 (100-200 ppm) xylene.  Light exercise increased the
    blood level of xylene and indications of plateauing were noted after
    about 2 h (Åstrand et al., 1978).  In another study, an exposure to
    435-1261 mg/m3 (100-290 ppm)  m-xylene revealed a rapid rise in
    xylene blood levels during the first hour.  Repeated exposure to 430
    mg/m3 for 4.5 days (6 h/day) gave rising pre-exposure morning blood
    levels, indicating some accumulation of  m-xylene (Riihimäki et al.,
    1979a; Riihimäki et al., 1982a,b).

         Dermal absorption of xylenes has been studied after exposure to
    the vapour or the liquid.  Liquid xylenes (about 0.2 ml of the
    individual isomers) were applied to the forearm.  Uptake into the skin
    was calculated by measuring the remained material after 5-15 min
    (Dutkiewicz & Tyras, 1968).  Uptake values of 50-160 µg/cm2 per min
    were reported.  However, it should be noted that not all the xylene
    taken up necessarily penetrated the skin and was absorbed.  In more
    recent studies, dermal absorption has been studied following hand
    immersion in liquid  m-xylene for 15-20 min.  Absorption, estimated
    from the urinary level of the metabolite  m-methylhippuric acid, was
    recorded to be about 2 µg/cm2 per min in eight volunteers (Engström
    et al., 1977).  The amount absorbed (about 35 mg) through both hands
    was estimated to be equal to the amount absorbed through inhalation of
    435 mg/m3 (100 ppm) during the same time.  Another group (Lauwerys et
    al., 1978) obtained a similar value for dermal absorption (2.45
    µg/cm2 per min) based on urinary levels of  m-methylhippuric acid
    and  m-xylene levels in exhaled breath.

         Dermal exposure of  m-xylene vapour has been investigated in
    volunteers exposed to 1305 mg/m3 (300 ppm) (two men) or 2610 mg/m3
    (600 ppm) (three men) for 3.5 h.  Inhalation was excluded by means of
    a full facepiece supplied-air respirator with overpressure inside the
    mask. The volunteers were dressed in pyjamas and performed exercise to
    raise the skin temperature and perspiration (Riihimäki & Pfäffli,
    1978).  Dermal absorption appeared to be directly dependent on vapour
    concentration.  At 2610 mg/m3 the absorption was calculated to be
    approximately 0.01 µg/cm2 per min. In a further experiment, three
    subjects were exposed to 87 mg/m3 (20 ppm) without respirator.  In
    this case both pulmonary and dermal absorption could occur.  The total
    absorption of  m-xylene in this experiment was calculated to be of
    the same order of magnitude as after dermal-only exposure to 2610
    mg/m3.

    6.1.2  In laboratory animals

         Absorption of xylene was recorded following whole-body exposure
    of mice to ring-labelled 14C- m-xylene vapour for 10 min.  Based on
    autoradiograms the absorption was primarily through respiration
    (Bergman, 1979; Bergman, 1983). All xylenes are well-absorbed orally
    by rats, based on urinary metabolites. Peak blood levels were reported
    4 h after an oral dose of 0.5-4 g  m-xylene/kg body weight or 1.1 g
     p-xylene/kg body weight (Gut & Flek, 1981).

         The rate of absorption of liquid  o-xylene across excised rat
    skin has been calculated to be 0.103 µg/cm2 per min at steady state
    (Tsuruta, 1982).

    6.2  Distribution

    6.2.1  In humans

         Little information is available on the distribution of xylenes in
    humans.  A peritoneal fat/air partition coefficient of 3605 has been
    determined for  m-xylene  in vitro  (Sato et al., 1974).  The times
    required to reach equilibrium in tissues have been calculated from
    physiological parameters.  It is estimated to be a few minutes for
    well-perfused parenchymal organs, a few hours for muscles and several
    days for adipose tissue (Riihimäki & Savolainen, 1980).

         Postmortem analysis on a woman who had swallowed xylene 4 days
    prior to death, revealed xylene to be present in all tissues
    investigated (Takatori et al., 1982).  The ratios of the three isomers
    (ortho: meta: para) were 3:5:2 in the stomach content, 3:6:1 in blood
    and 4:4:2 in adipose tissue.  In the brain, liver, spleen, kidney and
    myocardium, however, the  o-xylene accounted for about 80%.

         When volunteers were exposed to 435 to 870 mg/m3 (100 to 200
    ppm) mixed xylenes for 2 h, the ratio of  m/p-xylene to ethylbenzene
    was similar in subcutaneous fat and inspired air up to 22 h
    post-exposure (Engström & Bjurström, 1978).  In another study
    volunteers were exposed to 391-870 mg/m3 (90-200 ppm)  m-xylene 6 h
    per day 5 days per week (plus an additional day after the weekend)
    (Engström & Riihimäki, 1979).  The proportion of absorbed  m-xylene
    distributed to subcutaneous fat was calculated to be about 4% in
    resting individuals and 8% in those undergoing exercise.

         Two adult male and two adult female volunteers were exposed by
    inhalation to < 108-217 mg/m3 (25-50 ppm) of  m-xylene (Laparé,
    1993).  Doubling the exposure concentration led to a proportional
    increase in the concentrations of unchanged solvents in alveolar air
    and blood at the end of a 7-h exposure period.  Cumulative urinary
    excretion of the metabolites exhibited a nearly proportional increase. 
    It is also suggested that alveolar air solvent concentration is a
    reliable index of exposure to  m-xylene.

    6.2.2  In laboratory animals

         The distribution of xylene has been studied in male rats exposed
    to about 217 mg/m3 (50 ppm) 14C-labelled  p-xylene for 8 h
    (Carlsson, 1981).  The highest concentrations were present in the
    kidneys (up to about 1000 nmol/g tissue) and subcutaneous fat (up to
    more than 250 nmol/g tissue).  Higher concentrations than in blood
    were also found in the ischiatic nerve.  Lower concentrations than in
    blood were found in the cerebrum, cerebellum, muscle and spleen.
    Elimination half-times from fat were estimated to be 2-7 h.  In

    pregnant rats,  o-xylene has been shown to cross the placenta.  The
    concentrations in fetal blood were 25-30% of that in maternal blood
    after a 2-h exposure (Ungvary et al., 1980).   o-Xylene was also
    detected in amniotic fluid.

         The concentration of  m-xylene in perirenal fat and cerebrum was
    positively correlated to exposure levels in rats exposed to 217 to
    3262 mg/m3 (50 to 750 ppm)  m-xylene 6 h/day, 5 days/week for 1-2
    weeks (Savolainen & Pfäffli, 1980; Elovaara et al., 1982). 
    Accumulation in perirenal fat has also been shown in rats exposed to
    1305 mg/m3 (300 ppm) xylene (80%  m-xylene, 12%  p-xylene) 6 h/day,
    5 days/week for 1-2 weeks (Savolainen et al., 1979a,b).  In a similar
    study with 1305 mg/m3 m-xylene, no accumulation in perirenal fat or
    brain tissue was recorded after one week (Elovaara et al., 1982). 
    When rats were exposed to 1305 mg/m3 xylene (19.2%  o-xylene, 43.0%
     m-xylene, 19.5%  p-xylene, 18.3% ethylbenzene) during 6 h/day, 5
    days/week for 18 weeks, a progressive increase of xylene levels in
    perirenal fat was demonstrated over the first 2 weeks followed by a
    decline (Elovaara et al., 1980).  The decline was attributed to xylene
    inducing its own metabolism.  Similar results were obtained in a study
    where rats were exposed to 1305 mg/m3 xylene (85%  m-xylene, 15%
     o-xylene) (Savolainen et al., 1979a,b).

         The tissue distribution of 14C-labelled xylenes has been studied
    in mice by low-temperature whole body autoradiography (Bergman, 1979;
    Bergman, 1983; Ghantous & Danielsson, 1986).  When male mice were
    exposed to about 1435 mg/m3 (330 ppm)  m-xylene for 10 min, high
    levels of radioactivity was found immediately post-exposure in body
    fat, bone-marrow, brain (white matter), spinal cord, spinal nerves,
    liver and kidney.  Radioactivity in the nervous system and fatty
    tissues was due to xylene alone and was present for 1 and 8 h,
    respectively.  High levels of xylene metabolites were recorded in
    blood, lung, liver and kidney for up to 8-h post-exposure and in
    intestinal contents, bronchi and nasal mucosa up to 24 h (Bergman,
    1979; Bergman, 1983).

         Autoradiography of male mice following 10 min inhalation of
    radioactively labelled  p-xylene revealed an accumulation of
    non-volatile metabolites in the nasal mucosa and the olfactory bulb of
    the brain.  It was assumed that the activity represented aromatic
    acids (methyl hippuric acid and toluic acid) (Ghantous et al., 1990).

         The same technique has been used to study distribution of
    radioactivity after exposure of pregnant mice to about 8700 mg/m3
    (2000 ppm) 14C-labelled  p-xylene for 10 min (Ghantous & Danielsson,
    1986).  High concentrations of xylene were recorded in the adult brain
    and lung with lesser amounts in kidney and liver. At all stages of
    gestation studied (days 11, 14, 17)  p-xylene appeared to pass

    immediately from dam to embryo/fetus. The concentration in fetus,
    however, was low; 2% of that in maternal brain. Xylene was evenly
    distributed in the fetus following exposure on day 11. After exposure
    on day 17 the xylene was located primarily in the liver (Ghantous &
    Danielsson, 1986).

         In a study where rabbits were exposed to xylene (27%  o-xylene,
    52%  m-xylene, 21%  p-xylene) for several months, the concentration
    was reported to be higher than in blood in the adrenals, bone-marrow
    and spleen (Fabre et al., 1960).  Due to the limited nature of the
    study it is impossible to draw any firm conclusions.

         Partition coefficients have been determined  in vitro for
     m-xylene using tissue homogenates and blood (Sato et al., 1974). 
    The following blood/air values were reported: 20 (pig blood), 21
    (rabbit plasma) and 37 (rabbit blood).  Tissue/blood partition
    coefficients reported were 1.6-2.1 (muscle, kidney, heart and lung),
    3.0-3.3 (liver and brain), 42 (bone-marrow) and 146 (peritoneal fat). 
    The relatively low value for brain tissue has been attributed to the
    content of phospholipids in which xylenes are less soluble than in
    neutral fat (Riihimäki & Savolainen, 1980).

    6.3  Metabolic transformation

    6.3.1  In humans

         Fig. 1 shows schematically the metabolic pathways for xylene
    ( m-xylene is used as an example) in humans.

         Metabolism of xylenes by humans consists primarily of side-chain
    oxidation to form methylbenzoic acid (Sedivec & Flek, 1976; Riihimäki
    et al., 1979a; Riihimäki et al., 1979b).  Methylbenzoic acid is
    conjugated principally with glycine and excreted in urine as
    methylhippuric acid.  It has been estimated that glycine conjugation
    would be saturated in humans exposed to about 1174 mg/m3 (270 ppm)
    xylene while working and to about 3393 mg/m3 (780 ppm) while resting
    (Riihimäki, 1979a).  A small amount of the glucuronide ester of
    methylbenzoic acid and trace levels of methylbenzyl alcohol have been
    detected in human urine (Ogata et al., 1980; Engström et al., 1984;
    Campbell et al., 1988).

         Hydroxylation of the aromatic ring with the formation of
    dimethylphenols seems to be a minor pathway in humans.  The following
    dimethylphenol isomers have been identified in human urine: 2,3- and
    3,4-dimethylphenol (with  o-xylene), 2,4-dimethylphenol (with
     m-xylene) and 2,5-dimethylphenol (with  p-xylene) (Sedivec & Flek,
    1976; Engström et al., 1984).

    FIGURE 2

    6.3.2  In laboratory animals

         Most studies on metabolism of xylenes have been performed on rat. 
    The principal pathway involves side-chain oxidation to methylbenzoic
    acid via methylbenzyl alcohol and methylbenzyl aldehyde. 
    Methylbenzoic acid is then conjugated with glycine or glucuronic acid
    (Sugihara & Ogata, 1978; Ogata et al., 1980; Elovaara et al., 1984). 
    Conjugation with glycine to form methylhippuric acid predominates for
     m- and  p-xylene (Sugihara, 1979; Ogata & Fujii, 1979; Elovaara et
    al., 1984).  In the case of  o-xylene, glucuronide formation has been
    reported to predominate (Ogata et al., 1980).

         A separate minor pathway resulting in urinary excretion of
    thioethers has been studied (Van Doorn et al., 1980; Van Doorn et al.,
    1981).  This pathway appears to be more important for  o-xylene than
    for the other isomers.  Hydroxylation of the aromatic ring with the
    formation of dimethylphenols has been reported to be another minor
    metabolic pathway in rats (Bakke & Scheline, 1970; Elovaara et al.,
    1984).

         Methylbenzoic acid and dimethylphenols are present in urine of
    guinea-pigs and rabbits exposed to xylene isomers (Fabre et al.,
    1960).  After oral dosing of rabbits with xylenes the main metabolite
    was methylbenzoic acid (Bray et al., 1949).  The acid was considered
    to be mostly present as the glycine conjugate, methylhippuric acid.

         Studies with isolated perfused livers and lungs from rabbit
    indicate  differences in the metabolic pathways between these two
    organs (Smith et al., 1982).  In the liver  p-methylhippuric acid was
    the major metabolite detected.  In the lung  p-methylbenzyl alcohol
    and  p-methylbenzoic acid were the main metabolites detected.  There
    was formation of 2,5-dimethylphenol in the lungs but not in the liver. 
    Metabolism of  m- and  p-xylenes to  m- and  p-methylbenzyl alcohols
    has been found to be greater with hepatic than with pulmonary
    microsomes (Harper, 1975; Toftgård et al., 1986).  Further metabolism
    to methylbenzoic acid occurred in the presence of hepatic but not
    pulmonary cytosolic fraction.  Daily exposures to xylene increased the
    activities of liver microsomal enzymes and concentrations of
    cytochrome P450 (Elovaara et al., 1982; Pathiratne et al., 1986).
    Metabolism of  m-xylene by cerebral microsomal preparations was
    reported to be very slow (Elovaara et al., 1982).

         No definitive studies have been reported showing which microsomal
    P-450 enzymes are involved in xylene metabolism.  However when rats
    were given  m-xylene (1.0-1.4 ml/kg body weight) by gastric
    intubation once daily for 3 consecutive days and killed 24 h after the
    last treatment, xylene caused an induction of CYP2B and CYP2E1 in
    liver microsomes (Raunio et al., 1990).  Exposure of male Wistar rats

    to each of the xylene isomers by inhalation at a concentration level
    of 4000 mg/m3 for 20 h/day over 4 days similarly induced hepatic
    CYP2B1, while CYP2E1 was reduced, as estimated by Western blots (Gut
    et al., 1993).

    6.4  Elimination and excretion

    6.4.1  In humans

         Absorbed xylenes are excreted mainly as metabolites in urine. 
    Small amounts are excreted unchanged in exhaled air.  Excretion in
    faeces appears to be unimportant.  The rate of clearance of  p-xylene
    from blood has been calculated to be 2.6 litres/kg per hour at 87
    mg/m3 (20 ppm) and 1.6 litres/kg per hour at 304 mg/m3 (70 ppm)
    (Wallén et al., 1985).

         When volunteers were exposed to a constant concentration of 
    about 391-870 mg/m3 (90-200 ppm)  m-xylene over 5 days, at least 97%
    was calculated to be excreted as  m-methylbenzoic acid conjugates. 
    2,4-Dimethylphenol conjugates accounted for 1-2% of the metabolites
    (Riihimäki et al., 1979a; Riihimäki et al., 1979b).  When volunteers
    were exposed to about 195 mg/m3 (45 ppm) of  o-,  m- or  p-xylene
    for 8 h, about 95-99% of the dose was excreted as methylhippuric acid
    in urine.  Dimethylphenol excretion was estimated to be 0.1 to 2% of
    the dose absorbed (Sedivec & Flek, 1976).  About 90% of the absorbed
    dose of  m-xylene was excreted as methylhippuric acid after exposure
    to 435 mg/m3 (100 ppm) for 4 h (Lauwerys et al., 1978; Campbell et
    al., 1988).  On the other hand, after exposure to 600 mg/m3 (138 ppm)
    of  o-xylene, only 46% was excreted in urine as methylhippuric acid
    and only trace amounts of the  o-methylbenzoyl glucuronide were
    detected (Ogata et al., 1980).

         In a study of 121 male workers engaged in dip-coating of metal
    parts, the mean concentration was 3.48 mg/m3 (0.8 ppm)  o-xylene,
    9.1 mg/m3 (2.1 ppm)  m-xylene and 3.91 mg/m3 (0.9 ppm)  p-xylene. 
    The workers were also exposed to 0.8 ppm toluene and 0.9 ppm
    ethylbenzene.  At the end of the 8 h-shift urine samples were
    collected and methylhippuric acid was determined.  There was a linear
    relationship between the intensity of exposure to xylenes and the
    concentration of methylhippuric acid in urine.  The methylhippuric
    acid concentration as a function of increasing xylene concentration
    was 17.8 mg/litre per ppm (Kawai et al., 1991a).

         In workers occupationally exposed to an average of 17.4 mg/m3
    (4 ppm) xylene (combination of all three isomers), with a maximum of
    more than 430 mg/m3 (100 ppm), the urinary excretion of
    methylhippuric acid was linearly correlated with the air exposure
    (Huang et al., 1994).

         The urinary methylhippuric acid excretion of xylene-exposed
    painters at the end of the working week showed two distinct phase of
    excretion.  Half-times for urinary excretion of methylhippuric acid
    were estimated to be 3.6 h for the first 10 h and 30.1 h for the next
    2 days after exposure (Engström et al., 1978).  A positive association
    between the degree of obesity and the length of half-time was seen. 
    In volunteers exposed to  m-xylene the urinary excretion of
     m-methylbenzoic acid was described as triphasic with half-times of
    1-2, 10 and 20 h (Riihimäki et al., 1979a).  The observed elimination
    half-time in the subcutaneous adipose tissue was about 58 h (Engström
    & Riikimäki, 1979).

         After oral administration of  o-xylene (39 mg/kg body weight)
    maximum urinary levels of glycine and glucuronide conjugates of
     o-methylbenzoic acid were reported to be 33.1 and 1.0% of the 
    administered dose, respectively.  Similar values were obtained after
    an oral dose of 78 mg/kg body weight (Ogata et al., 1979; Ogata et
    al., 1980).

         About 4-5% of the dose absorbed in the lungs is exhaled unchanged
    after exposure to 870 mg/m3 (200 ppm) xylene (Sedivec & Flek, 1976,
    Åstrand et al., 1978, Riihimäki et al., 1979a, Riihimäki et al.,
    1979b).  Elimination in exhaled breath is reported to follow a similar
    triphasic profile to that for urinary excretion of methylbenzoic acid
    conjugates (Riihimäki et al, 1979).  An initial half-time of about one
    hour was obtained in a study by Campbell et al., 1988.

    6.4.2  In laboratory animals

         Exhalation of unchanged  m-xylene has been described in one
    study on rats.  Exhalation was greatest 4 h after an intraperitoneal
    injection, and 13% of the dose was exhaled unchanged within 10 h
    (Sugihara, 1979).  In mice 3.4% of the dose was exhaled within 8 h
    (Bergman, 1979; Bergman, 1983).

         In rats a total of 46% of the  m-xylene dose (5 mmol/kg body
    weight) was excreted as  m-methylbenzoic acid within 24 h, and
    phenobarbital (PB) treatment increased it to 70% of the dose.  PB
    treatment increased the elimination of  m-methylbenzoic acid after
    oral administration about 4-fold in the first 3 h, more then 2-fold in
    the first 12 h, and 1.5-fold within 24 h compared to untreated but
     m-xylene-exposed rats (Gut & Flek, 1981).

         Wistar rats were pretreated with PB for 3 days (80 mg/kg body
    weight per day) and then given  m-xylene orally or intraperitoneally
    at a small (0.081 mmol/kg) or a large (0.81 mmol/kg) dose or by
    inhalation (6 h) at a low (174 mg/m3, 40 ppm) or high (1740 mg/m3,
    400 ppm) concentration.  PB treatment had a significant effect on the
    metabolism of inhaled  m-xylene (decreased blood  m-xylene and

    increased urinary excretion of  m-methylhippuric acid), but only at
    the high dose.  The PB-induced enzyme induction had an effect at both
    dose levels on the metabolism of orally administered  m-xylene.  The
    effect on intraperitoneally administered  m-xylene was more similar
    to that of inhaled than that of orally administered  m-xylene (Kaneko
    et al., 1995).

         After an intraperitoneal injection of 87-348 mg/kg body weight
     m-xylene to rats, 53-75% of the dose was excreted as  m-methyl-
    hippuric acid in urine during 24 h (Ogata & Fujii, 1979).  After
    an intraperitoneal dose of 319 mg/kg body weight the proportion
    excreted as mercapturic acids was calculated to be 10% for  o-xylene
    and 0.6-1.3% for  m- and  p-xylene (Van Doorn et al., 1980).

         Male rats were exposed to soil-adsorbed (sandy soil or clay soil)
    or pure 225 µl of  m-xylene containing 20 µCi of  m-[14C]-xylene
    through the skin (Skowronski et al., 1990).  The major route of
    excretion in the pure and sandy groups was via expired air followed by
    urine.  However, in the presence of clay soil, the percentage of the
    initial dose in expired air was similar to that in urine.  In the
    presence of clay soil, an increase in  m-xylene was observed in
    adipose tissue.  Methyl hippuric acid was the main urinary metabolite.

         Turkall et al. (1992) reported the bioavailability of
    soil-adsorbed  m-xylene in male and female rats.  The rats were
    gavaged with an aqueous suspension of 5% of gum acacia containing 150
    µl of  m-xylene with 5 µCi  m-[14C]-xylene alone or adsorbed to
    sandy or clay soil.  While ingested soil contaminated with  m-xylene
    produced a higher bioavailability than the chemical alone in females,
    no effects of soil was observed in males.  No differences in the
    bioavailability of  m-xylene alone were observed between the sexes. 
     m-Xylene was primarily metabolized and excreted in urine,
    methylhippuric acid being the main urinary metabolite in all groups.

    6.5  Factors affecting toxicokinetics in humans and animals

         In humans, co-exposure of  m-xylene and ethylbenzene and
    consumption of ethanol or aspirin (acetylsalicylic acid) prior to
    inhalation has been shown to reduce urinary excretion of one or more
    xylene metabolites, including methylhippuric acid (Riihimäki et al.,
    1982a,b; Engström et al., 1984; Campbell et al., 1988).  In the case
    of ethanol consumption an increase in concentration of  m-xylene in
    blood was described (Riihimäki et al., 1982a,b).  Co-exposure to
    toluene decreased the ratio of the concentration of  p-xylene in
    venous blood to that in exhaled air (Wallén et al., 1985).  The dermal
    absorption of liquid  m-xylene was reduced in the presence of
    isobutanol (Riihimäki, 1979a).

         Volunteers given ethanol on two evenings (total dose 137 g)
    preceding exposure by inhalation to either 435 or 1740 mg/m3 (100 or
    400 ppm)  m-xylene for 2 h enhanced the metabolism of  m-xylene but
    only at 1740 mg/m3 (Tardif et al., 1994).  Ethanol pretreatment
    decreased the concentration of  m-xylene in blood and alveolar air
    during and after exposure and increased urinary excretion of
     m-methylhippuric acid at the end of exposure to 1740 mg/m3.

         Five male volunteers were exposed for 7 h/day over 3 consecutive
    days to 50 ppm toluene, 174 mg/m3 (40 ppm) xylene (15%  o-xylene,
    25%  m-xylene and 60%  p-xylene) or a combination of both.  To study
    high-level exposure four men were exposed for 4 h to 95 ppm toluene or
    348 mg/m3 (80 ppm) xylene or a combination of both.  Mixed exposure
    (low-level) did not alter the concentration of the solvents in blood
    or exhaled air, nor did it modify the excretion of urinary
    metabolities.  High-level mixed exposure, however, increased the
    concentration of solvents in blood and exhaled air and caused a delay
    in the urinary excretion of hippuric acid (Tardif et al., 1991).

         Simultaneous exposure by inhalation to toluene and xylene (15%
     o-xylene, 60%  m-xylene and 25%  p-xylene) has been studied in
    Sprague-Dawley rats.  Exposure time was 5 h and the concentrations
    were 75 ppm toluene plus 979 mg/m3 (225 ppm) xylene, 150 ppm  toluene
    plus 652 mg/m3 (150 ppm) xylene or 225 ppm toluene plus 326 mg/m3
    (75 ppm) xylene.  Compared to exposure to a single solvent,
    simultaneous exposure resulted in lower amounts of excreted urinary
    hippuric and methylhippuric acids over 24 h.  Increased concentrations
    of solvents in blood and brain were found immediately post-exposure. 
    Simultaneous exposure also enhanced the pulmonary elimination of both
    solvents (Tardif et al., 1992).

         From a toxicokinetic modelling study it was concluded that there
    is competitive metabolic inhibition between  m-xylene and toluene in
    the rat (Tardif et al., 1993a).  The interaction is likely to be
    observed when exposure exceeds 50 ppm of each solvent (Tardif et al.,
    1993b).

         Inhalation exposure of rats for 4 h to 2436 mg/m3 (560 ppm)
     m-xylene or 320 ppm of ethylbenzene alone, or in combination,
    indicated that in the combined exposure blood and brain  m-xylene
    concentrations increased by 52 and 40%, respectively, whereas there
    was no corresponding effect on ethylbenzene concentrations (Frantik &
    Vodickova, 1995).

         In a study of metabolic interaction, Wistar rats were exposed
    for 6 h to 1305 mg/m3 (300 ppm)  m-xylene, 600 ppm methyl ethyl
    ketone (MEK) or a mixture of both.  After mixed exposure the
    cytochrome P-450-dependent monooxygenase activities were additively or

    synergistically induced.  In the presence of MEK the overall
    metabolism of  m-xylene was inhibited, as shown by an increase in 
    xylene concentration in blood and fat and a decrease in the 24-h
    excretion of xylene metabolites (Liira et al., 1991).

         Male Wistar rats were exposed by inhalation for 4 h to 1000
    mg/m3 (230 ppm)  of  o-xylene or 1700 ppm of acetone alone, or in
    combination.  In the combination exposure, blood xylene immediately
    after the exposure was increased by 40% whereas the blood acetone
    level was decreased by 15%.  In a corresponding study, H-strain mice
    were exposed for 2 h to 1392 mg/m3 (320 ppm) of  o-xylene or 6655
    mg/m3 (1530 ppm) of acetone alone or in combination.  The combination
    exposure was accompanied by a 33% increase of the blood xylene
    concentration whereas the blood acetone level was decreased by 18%
    (Vodickova et al., 1995).

    6.6  Biological monitoring

         More than 90% of xylene is transformed in human metabolism to
    methylhippuric acid and excreted in urine.  Urinary methylhippuric
    acid has proved a robust measure of the amount of xylene taken up in
    the body over some preceding hours.  The measurement has been
    routinely used in some countries for assessment of individual exposure
    to xylene in the occupational setting.  About 1.5-2 g methylhippuric
    acid per g creatinine in the post-shift urine sample corresponds to
    exposure to 435 mg/m3 (100 ppm) xylene over a full workday (Lauwerys
    & Buchet, 1988).  Different workloads cause variation in the excreted
    amounts of methylhippuric acid at a given exposure level since the
    lung uptake of xylene is directly proportional to pulmonary
    ventilation.  Biotransformation of xylene to methylhippuric acid is
    inhibited in the presence of ethanol and acetylsalicylic acid (see
    section 6.5); these interfering factors need to be controlled when the
    method is applied.

         The analysis of xylene in blood and exhaled air can be used for
    assessment of exposure (Lauwerys & Buchet, 1988).  These methods may
    be particularly suitable for estimating xylene body burden caused by
    the low and relatively stable background exposure in the general
    population, or, in case of accidental exposure, for measuring levels
    for a clinical toxicological evaluation.

    7.  EFFECTS ON LABORATORY MAMMALS AND  IN VITRO TEST SYSTEMS

    7.1  Single exposure

    7.1.1  Inhalation studies

    7.1.1.1  o-Xylene

         The LC50 value for  o-xylene in Sprague-Dawley rats (12
    males/group) was calculated to be 4330 ppm (95% confidence limits
    4247-4432 ppm) for a 6-h exposure.  The reported signs of intoxication
    were hypotonia and somnolence.  Autopsy on surviving animals 14 days
    later revealed no macroscopic lesions of lung, liver or kidneys
    (Bonnet et al., 1982).  Under similar conditions the LC50 value for
    mice (OF-1) was 4595 ppm (4468-4744 ppm) (Bonnet et al., 1979).

         Rats (probably Wistar, sex not stated, 10 animals/group) were
    exposed to 1531, 3062 or 6125 ppm for 24 h.  No deaths occurred at
    1531 ppm, one death at 3062 ppm and 8 deaths at 6125 ppm (Cameron et
    al., 1938).  In the same study one group was exposed to 12 250 ppm
     o-xylene for 12 h.  Two deaths occurred, one after 2 h.  Autopsy of
    those animals that died did not reveal any macroscopic or microscopic
    lesions in the organs studied (Cameron et al., 1938).  In the same
    study mice (10 animals/group) were exposed to the same concentrations
    for the same period of time as the rats.  There were no deaths at 1531
    ppm, four deaths at 3062 ppm and nine  deaths at 6125 ppm.  In the
    group exposed to 12 250 ppm for 12 h there were two deaths, one after
    9 h.  The organs of animals that died after exposure showed no
    characteristic changes (Cameron et al., 1938).

         In a study of the effect on prenarcotic motor behaviour, groups
    of eight male rats (CFY) were exposed to  o-xylene (dose not stated)
    for 1, 2, 3 or 4 h.  No significant effects on group motor activity
    were observed.  Narcosis occurred at higher concentrations with a
    threshold of 2180 ppm for a 4-h exposure (Molnar et al., 1986).  Mice
    (strain, sex and numbers not stated) were exposed for 2 h to
     o-xylene in order to determine the minimum concentration needed for
    an animal to fall on its side and die.  The minimum concentration for
    falling was 3400-4600 ppm and for death 6900 ppm (Lazarew, 1929).

         In a study of subnarcotic effects of solvents in Wistar rats and
    H-strain mice, using electrically evoked seizures, the lowest
    effective concentration of  o-xylene was 170 ppm.  The criterion used
    was a significant suppression by 10% of the generation and maintenance
    of the seizure discharge after 4 h (rats) or 2 h (mice) of inhalation
    (Frantik et al., 1994).  A 30% suppression was induced by  o-xylene
    at a concentration of 390 ppm, corresponding to a blood concentration
    of 62 µmol/litre (Frantik et al., 1993).

         In order to determine the RD50 value (exposure level reducing
    the respiratory rate by 50%), groups of male mice (OF-1) were exposed
    to  o-xylene.  The RD50 value was calculated to be 1467 ppm
    (1406-1530 ppm).  The onset of response was rapid and the maximum
    decrease in respiratory rate was reached within a few minutes (De
    Ceaurriz et al., 1981).

         In a study of conditioned behaviour in mice, an increased
    response rate was observed after a 30-min exposure to 1400-2000 ppm
     o-xylene.  At higher concentrations there was a decrease in response
    rate with an EC50 of 5179 ppm.  The biphasic response indicates that
    there was excitation of the central nervous system at low
    concentrations and depression at higher concentrations (Moser et al.,
    1985).

         In a study to observe effects in the "behavioural despair"
    swimming test, groups of 10 mice (OF-1) were exposed to 0, 1010, 1101,
    1207 or 1234 ppm  o-xylene for 4 h.  The ID50 (50% decrease in
    immobility) value was calculated to be 1127 ppm (1068-1182 ppm) (De
    Ceaurriz et al., 1983).  The study demonstrated subnarcotic effects by
     o-xylene on the CNS.

    7.1.1.2  m-Xylene

         After a 6-h exposure to  m-xylene the LC50 in rats and mice was
    reported to be 5984 ppm (5796-6181 ppm) and 5267 ppm (5025-5490 ppm),
    respectively (Bonnet et al., 1979; Bonnet et al., 1982).  The signs of
    toxicity consisted of hypotonia, somnolence, narcosis, and clonic
    spasms leading to death due to respiratory failure (Lazarew, 1929;
    Cameron et al., 1938, Bonnet et al., 1982; Moser et al., 1985; Molnar
    et al., 1986).

         In the comparative study by Frantik et al., (1994) described in
    section 7.1.1.1, the lowest effective air concentration for  m-xylene
    was 210 ppm.

         A biphasic CNS response occurred at similar exposure levels to
    those seen for  o-xylene (section 7.1.1.1) (Moser et al., 1985).  The
    narcotic threshold in rats of about 2100 ppm  m-xylene determined in
    prenarcotic behaviour studies was similar to that observed for
     o-xylene (Molnar et al., 1986).  During a 4-h exposure to 8000 ppm
     m-xylene, 10 out of 12 rats (Carwoth-Wistar) died (Smyth et al.,
    1962).

         When groups of rats (Wistar; 6 males/group) were exposed for 24 h
    to 0, 75, 150 or 300 ppm  m-xylene, there was a significant decrease
    in cytochrome P-450 concentrations at all doses, and a dose-related

    decrease in 7-ethoxycoumarin-O-deethylase activity in the lung.  No
    abnormalities of the lungs, as determined by scanning electron
    microscopy, were seen in two animals exposed to 300 ppm (Elovaara et
    al., 1987).

         When male Wistar rats were exposed for 4 h to a 1:1 mixture of
     m-xylene and  n-butyl alcohol or to the single substances at
    500-4000 ppm, there were disturbances of rotarod performance.  The
    medial effective concentrations (EC50) were calculated to be 3080 ppm
    (mixture), 6530 ppm ( n-butyl alcohol) and 1980 ppm (xylene)
    respectively.  The combined exposure gave less than additive effects
    (Korsak et al., 1993).

         A concentration-dependent decrease in respiratory rate in mice
    was demonstrated in a study where mice were exposed to 500-4000 ppm of
     n-butyl alcohol,  m-xylene or a 1:1 mixture of both.  The RD50 was
    calculated to be 3010 ppm, 1360 ppm and 3140 ppm, respectively.  The
    combined exposure gave less than additive effects (Korsak et al.,
    1993).

         The acute neurobehavioural effect of  m-xylene was evaluated
    after 20 min inhalation exposure using a functional observations
    battery in mice.  In the concentration range of 2000-8000 ppm, these
    effects included changes in posture, decreased arousal and rearing,
    increased ease of handling, disturbances of gait, mobility and
    righting reflex, decreased forelimb grip strength, increased landing
    foot splay and impaired psychomotor coordination.  The response to
    various sensory stimuli was also decreased.  These acute effects were
    short-lived, recovery beginning within minutes of removal from the
    exposure chamber (Tegeris & Balster, 1994).

    7.1.1.3  p-Xylene

         A 4-h LC50 value in rats (female Sprague-Dawley) of 4740 ppm
     p-xylene has been reported (Drew & Fouts, 1974).  The corresponding
    6-h value was 4591 ppm (4353-5049 ppm) (Bonnet et al., 1982), and for
    mice (OF-1) was 3907 ppm (3747-4015 ppm) (Bonnet et al., 1979).  The
    signs of toxicity were similar to those reported for the other two
    isomers.

         Like the other two isomers, exposure to  p-xylene gave a
    biphasic CNS response (Moser et al., 1985).  In another study (Molnar
    et al., 1986), marked activation and tremor were observed at
    concentrations between 400 and 1500 ppm  p-xylene in rats.  The
    narcotic threshold was 1940 ppm.

         When Sprague-Dawley rats (16 females/group) were exposed for 4 h
    to 0, 1000, 1500 or 2000 ppm  p-xylene, a dose-dependent increase in
    serum enzymes activites was observed.  This was taken as a sign of

    hepatocellular and hepatobiliary damage (Patel et al., 1979).  In
    other studies at higher exposure levels, no microscopic hepatic
    lesions were seen in rats or mice (Cameron et al., 1938; Furnas &
    Hine, 1958; Bonnet et al., 1982).

         When Long Evans rats were exposed for 4 h to 0, 800 or 1600 ppm
     p-xylene, the  flash-evoked potential of the visual system was
    reduced at the highest  exposure level (Dyer et al., 1988).  The
    authors suggested that this may have been secondary to changes in
    arousal or excitability.  In a study of the effect on learning tasks
    and motor activity, rats (Long Evans) were exposed to 0 or 1600 ppm
     p-xylene for 4 h.  Signs of toxicity (unsteadiness and fine tremor)
    disappeared 30 min post-exposure.  The results indicate an effect on
    motor control rather than on cognitive capacity (Bushnell, 1989).

         In the comparative study by Frantik et al. (1994) described above
    (section 7.1.1.1), where rats and mice were exposed, the lowest
    effective air concentration for  p-xylene was 220 ppm.

         After a 4-h exposure to 1000 ppm  p-xylene there was a 
    decrease in pulmonary cytochrome P-450 in rabbits and a decrease in
    NADPH-cytochrome  c-reductase and mixed-function oxidase activity in
    rats (Patel et al., 1976; Patel et al., 1978).

         When Sprague-Dawley rats were exposed to 3400 ppm  p-xylene for
    4 h and killed 12 h later, an induction of cytochrome P-450 activities
    (CYP2B) in liver microsomes was observed.  On the other hand, the
    pulmonary cytochrome P-450 activities were inhibited (Day et al.,
    1992).

         In rats (Sprague-Dawley)  p-xylene (2800 ppm for 4 h) has been
    shown to potentiate hepatotoxicity induced by bromobenzene, while the
    effect of bromobenzene on pneumotoxicity was unaffected by  p-xylene,
    indicating differences in xylene metabolism between the liver and the
    lung (Day et al., 1992).

    7.1.1.4  Technical or undefined xylene

         In rats LC50 values of 6350, 6700 and 10 950 ppm have been
    reported after 4-h exposure (Hine & Zuidema, 1970; Carpenter et al.,
    1975; Lundberg et al., 1983).  Deaths occurred during the exposure
    period.  No LC50 values for mice have been found, although
    experiments have been carried out at up to 7000 ppm for 30 min (Moser
    et al., 1985).  Signs of toxicity were the same as those produced by
    the individual isomers.

         No signs of toxicity were reported when rats and dogs were
    exposed for 4 h to 580 and 530 ppm, respectively.  The composition was
    7.63%  o-xylene, 65.01%  m-xylene, 7.84%  p-xylene and 19.27%
    ethylbenzene (Carpenter et al., 1975).  The same type of response at

    similar exposure levels as for the three individual isomers was
    observed in mice in a conditioned behavioural study (Moser et al.,
    1985).  In rats effects of xylene were studied on an operant behaviour
    maintained by a fixed-ratio liquid reinforced  schedule.  A decrease
    in the reinforcement rate was seen after exposure to 113 ppm for 2 h
    (Ghosh et al., 1987; Ghosh & Pradhan, 1987).

         When rats (Fischer F-344) were exposed to 1450 ppm xylene for 8
    h, a slight increase in the auditory response threshold at 20 kHz was
    noted (Pryor et al., 1987).  The xylene composition was 10%
     o-xylene, 80%  m-xylene and 10%  p-xylene.

         In mice (Swiss-Webster) exposed to 1300 ppm xylene for one
    minute, a decrease in respiratory rate as an indication of respiratory
    tract irritation was seen (Carpenter et al., 1975).  This effect was
    not seen at an exposure level of 460 ppm.  No histological
    abnormalities were seen on histological examination of livers from
    rats exposed to 5480 ppm for 4 h, nor were there any changes in serum
    activities of an indicator enzyme (sorbitol dehydrogenase) for
    hepatotoxicity after exposure to > 340 ppm  (Lundberg et al.,
    1986).  No histological abnormalities were seen in cat livers after
    exposure to about 9500 ppm for up to 2 h (Carpenter et al., 1975).  In
    dogs (Beagle) 1200 ppm xylene for 4 h caused lacrimation but there was
    no noticeable effect at 530 ppm (Carpenter et al., 1975).

         When groups of cats (five animals/group) were exposed for 5740,
    6900 or 9200 ppm for up to 6 h, there was a concentration-dependent
    decrease in time to onset of staggering and mild narcosis.  There was,
    however, a large individual variation.  Deep narcosis was seen in four
    animals at 9200 ppm xylene (Engelhardt & Estler, 1935).

    7.1.2 Other exposure routes

         The oral LD50 values in rat have been reported to be 3608 mg/kg
    body weight for  o-xylene, 5011 mg/kg body weight for  m-xylene and
    4029 mg body weight for  p-xylene (Smyth et al., 1962).  For various
    mixtures of xylenes oral LD50 values in rat have been reported to be
    between 3523 and 8700 mg/kg body weight (Wolf et al., 1956; Hine & 
    Zuidema, 1970; NTP, 1986).  In mice the corresponding values were
    reported to be 5627 mg/kg body weight for male and 5251 mg/kg body
    weight for females (NTP, 1986).  Signs of toxicity at lethal doses
    were CNS depression and congestion of cells in liver, kidney and
    spleen, seen by histological examination.

         A dermal LD50 value for rabbits (New Zealand White) of 12 180
    mg/kg has been reported for a 24-h exposure to  m-xylene (Smyth et
    al., 1962).  From studies with intraperitoneal (i.p.), intravenous
    (i.v.), subcutaneous (s.c.) and intramuscular (i.m.) administration in
    rats and mice the acute toxicity of xylene is low (Bell et al., 1992).

         All three isomers have been found to interfere with the
    modulation of the vestibular-oculomotor pathways in the rat.  The
    blood threshold levels for this effect were 170-200 µg/ml following
    administration by the i.v. route (Tham et al., 1984).  Similar effects
    have also been reported for  m-xylene in rabbit.  The
    vestibular-oculomotor effects were seen at blood levels of 30 µg/ml
    and some deaths due to respiratory stress were recorded at 100 µg/ml
    (Larsby et al., 1976; Aschan et al., 1977; Ödkvist et al., 1979;
    Ödkvist et al., 1980).

         A dose-dependent depletion of hepatic glutathione, following i.p.
    administration, has been demonstrated in rats.  With  o-xylene the
    effect was seen from 50 mg/kg and with the other two isomers from 425
    mg/kg (Van Doorn et al., 1980).  A decrease in pulmonary cytochrome
    P-450 levels has been observed with the three isomers, when
    administered (i.p.) at 531 mg/kg (Pyykkö et al., 1987).

         The CYP2B1 and CYP1A1 isoenzyme activities, benzyloxy-resorufin
     O-deethylation and ethoxyresorufin  O-deethylation, respectively,
    were studied in nasal, pulmonary and hepatic tissues of rats injected
    intraperitoneally with  m-xylene.  Tissues taken at 2, 12 and 24 h
    after injection showed inhibition of these activities in both nasal
    and pulmonary microsomes, but increased activities in hepatic
    microsomes (Blanchard & Morris, 1994).

         The effects of intraperitoneal administration of  o-xylene
    (1g/kg body weight) on: (a) rat hepatic and pulmonary mixed-function
    oxidase content and activity; and (b) microsomal membrane structural
    parameters were studied 1, 3, 6 and 12 h after administration (Park et
    al., 1994).  The pulmonary cytochrome P-450 content and aryl
    hydrocarbon hydroxylase activity were decreased, a maximal inhibition
    occurring 3 h after dosing.  Reduced pulmonary activity for both
    ethoxyresorufin  O-dealkylation and benzyloxyresorufin
     O-dealkylation was noted.  In contrast, increased hepatic cytochrome
    P-450 content was noted, with slightly increased ethaxyresorufin
     O-dealkylation and markedly increased benzyloxyresorufin
     O-dealkylation.  An increase in pulmonary microsomal phospholipid
    content and cholesterol content was noted even 1 h after dosing.  In
    liver the phospholipid content increased although there was no change
    in cholesterol content; this suggested an increase in membrane
    fluidity.

         Sprague-Dawley rats were given  m-xylene (1 g/kg body weight)
    intraperitoneally and killed one hour after treatment.  Microsomes
    from the lung were then prepared.  Compared to controls,  m-xylene
    administration decreased the CYP2B1 activity but did not alter the
    CYP1A1 activity or epoxide hydrolase activity.  In total,  m-xylene
    administration resulted in an inhibition of benzo (a)pyrene
    detoxication and increased production of toxic metabolites in the
    pulmonary microsomal preparations (Stickney et al., 1991).

         Xylenes have been shown to inhibit the hypotonic haemolysis of
    erythrocytes  in vitro at low concentrations.  The EC50 values were
    29, 39 and 44 µg/ml for  o-xylene,  m-xylene and  p-xylene,
    respectively (Holmberg et al., 1974).

    7.2  Short-term exposure

    7.2.1  Inhalation studies

    7.2.1.1  o-Xylene

         In a study on the noradrenaline and dopamine levels in various
    parts of the forebrain and hypothalamus, Sprague-Dawley rats (six
    males/group) were exposed to 0 or 2000 ppm  o-xylene 6 h/day for 3
    days. The animals were killed within 18 h after final exposure.  There
    was a significant increase in catecholamine levels and turnover in
    various parts of the hypothalamus and a decrease in the dopamine
    turnover in the forebrain of exposed animals (Andersson et al., 1981).

         In order to study the effects on cytochrome P-450 and enzyme
    activities Sprague-Dawley rats (four males/group) were exposed to 0 or
    2000 ppm  o-xylene, 6 h/day for 3 days.  There was a significant
    increase in relative liver weight and cytochrome P-450 content in
    exposed animals.  Furthermore, there were increases in some liver
    enzyme activities.  In lungs, there was a decrease in cytochrome P-450
    activity (Toftgård & Nilsen., 1982).

         When guinea-pigs (15 per group) were exposed to 0 or 780 ppm
     o-xylene, 8 h/day, 5 days/week for 6 weeks, there was a marked
    decrease in body weight gain in exposed animals.  No effects on the 
    liver, kidney, heart, spleen or lung were observed upon histological
    examination (Jenkins et al., 1970).  In the same study beagle dogs
    were exposed for the same period of time.  One dog out of two
    experienced tremors throughout the exposure period.  No other signs of
    toxicity were reported (Jenkins et al., 1970).  Squirrel monkeys were
    also exposed in the same manner.  One monkey out of three died on day
    seven.  No other signs of toxicity were reported (Jenkins et al.,
    1970).

    7.2.1.2  m-Xylene

         In a study of levels of noradrenaline and dopamine in various
    parts of the forebrain and hypothalamus, Sprague-Dawley rats (six
    males/group) were exposed to 0 or 2000 ppm  m-xylene, 6 h/day for 3
    days.  The animals were killed within 18 h after the last exposure. A
    significant increase in catecholamine levels and turnover was observed
    in various parts of the hypothalamus of exposed animals.  There was no
    effect on dopamine levels (Andersson et al., 1981).

         In another study, Sprague-Dawley rats (four males/group) were
    exposed to 0 or 2000 ppm  m-xylene for 3 days.  The effect on
    cytochrome P-450 and enzyme activities in liver, kidney and lung were
    studied.  In exposed animals there was a significant increase  in
    relative liver weight, in cytochrome P-450 content in liver and
    kidney, and in some enzyme activities in these two organs.  The
    content of pulmonary cytochrome P-450 was decreased (Toftgård &
    Nilsen, 1982).

         In a study of the effect on xenobiotic metabolism in Wistar rats,
    10 males per group were exposed to 0, 50, 400 or 750 ppm  m-xylene, 6
    h/day, 5 days/week for one week.  At the two highest doses there
    was a significant increase in hepatic microsomal protein and
    NADPH-cytochrome c reductase levels, and a decrease in hepatic
    glutathione levels.  There was no effect on hepatic cytochrome P-450
    levels or on renal glutathione levels.  At all dose levels there was a
    significant increase in renal cytochrome P-450 and some enzyme
    activities.  When the animals were exposed to the same regimen for 2
    weeks similar results were obtained.  There were no abnormalities upon
    histological examination of the liver (Elovaara, 1982). When Wistar
    rats (20 males/group) were exposed to 0 or 300 ppm  m-xylene 6 h/day,
    5 days/week for one week there was, in exposed groups, a significant
    increase in hepatic and renal 7-ethoxycoumarin  O-deethylase activity 
    and in renal UDP-glucuronyl transferase.  When exposure time was 2
    weeks there was also a significant increase in hepatic cytochrome
    P-450 and NADPH-cytochrome c reductase activities (Elovaara et al.,
    1982).

         In order to study the effect on lung cytochrome P-450 in rats,
    six male Wistar rats/group were exposed to 0 or 300 ppm  m-xylene 7
    h/day, 4 days/week for 5 weeks.  The only effects seen were a
    significant decrease in cytochrome P-450 content and 7-ethoxycoumarin
     O-deethylase activity (Elovaara et al., 1987).  When the effects on
    cerebral biochemistry was studied, groups of Wistar rats (15
    males/group) were exposed to 0, 50, 400 or 750 ppm  m-xylene 6 h/day,
    5 days/week for 1 or 2 weeks.  The only effect seen after one week of
    exposure was a significant decrease in glutathione levels at all
    concentrations.  After 2 weeks there were also a dose-dependent
    decrease in superoxide dismutase activity, a significant increase in
    NADPH-diaphorase activity at all concentrations and a significant
    increase in azoreductase activity at the two highest concentrations
    (Savolainen & Pfäffli, 1980).

    7.2.1.3  p-Xylene

         In a study of levels of noradrenaline and dopamine in the
    forebrain and hypothalamus, Sprague-Dawley rats (six males/group) were
    exposed to 0 or 2000 ppm  p-xylene 6 h/day for 3 days.  The animals
    were killed 16-18 h after the last exposure.  In exposed animals there

    was a significant increase in catecholamine levels and turnover in
    various parts of the hypothalamus.  There was no effect on dopamine
    levels or turnover in the forebrain (Andersson et al., 1981).

         In order to study the effect on cytochrome P-450 and enzyme
    activities in the liver, kidney and lung, Sprague-Dawley rats (four
    males/group) were exposed to 0 or 2000 ppm 6 h/day for 3 days.  In
    exposed animals there were significant increases in relative liver
    weight, in hepatic cytochrome P-450 content, in NADPH-cytochrome c
    reductase activity in the liver and kidney, and in 7-ethoxyresorufin
     O-deethylase activity in the kidney.  There was also a decrease in
    pulmonary cytochrome P-450 content (Toftgård & Nilsen, 1982).  To
    study the lung microsomal activity, rabbits (New Zealand White; four
    males/group) were exposed to 0 or 1000 ppm  p-xylene 4 h/day for 2
    days.  In exposed animals there was a significant decrease in
    microsomal cytochrome P-450 concentration and in NADPH-cytochrome c
    reductase activity (Patel et al., 1978).  Inhibition of CYP2B1 has
    been observed in the lungs of rats dosed with  p-xylene (Verschoyle
    et al. 1993).

         Rats exposed to 300 ppm  p-xylene, 6 h/day for 1, 3 or 5 days
    exhibited alterations in pulmonary microsomal membrane structural and
    metabolic parameters (Silverman & Schatz, 1991).  Following 1 day of
    exposure, conjugated diene levels were elevated while total
    phospholipid levels, cytochromes P-450 content, benzyloxyresorufin
     O-dealkylase activity and 2-aminofluorene  N-hydroxylase activity
    were decreased.  Core membrane fluidity was increased following 3 days
    of exposure.  After 5 days of exposure all parameters returned to
    control levels with the exception of aryl hydrocarbon hydroxylase
    activity, which was increased by 41%.  Extracellular surfactant levels
    were also decreased after 1 and 3 days of exposure but returned to
    control values after 5 days.  The increase in aryl hydrocarbon
    hydroxylase activity after 5 days of exposure could have important
    consequences on the metabolism of co-administered xenobiotics.

         Male Fischer-344 rats exposed to 0 or 1600 ppm  p-xylene by
    inhalation, 6 h/day, for 1 or 3 days did not produce overt
    hepatotoxicity but resulted in a significant increase in the
    concentration of hepatic cytochrome P-450 (Simmons et al., 1991). 
    However, the concentration of hepatic cytochrome P-450 had returned to
    control levels within 2 to 3 days after exposure.

          p-Xylene has been shown to decrease axonal transport of
    proteins and glycoproteins in rats (Long-Evans) exposed by inhalation
    to 1600 ppm for 6 h/day, 5 days/week, for 8 days.  When ethanol (10%
    in drinking-water) was given during 6 days prior to inhalation of
     p-xylene, the treatment prevented the decreased axonal transport. 
    Ethanol  per se did not decrease the axonal transport (Padilla et
    al., 1992).

         When 10 Wistar rats and 10 mice (strain not given) were exposed
    to 1226 ppm  p-xylene 8 h/day for 14 days, no animals died.  No other
    results were reported (Cameron et al., 1938).

         When mice were exposed to 1200 ppm  p-xylene 6 h/day for 4 days
    and infected with a sublethal dose of murine cytomegalovirus, 34%
    mortality occurred, whereas no deaths occurred among uninfected,
     p-xylene-exposed mice or infected, air-exposed mice (Selgrade et
    al., 1993).  Although  p-xylene potentiated liver damage caused by
    the virus, the magnitude of serum enzyme activities indicated that
    this damage was not the probable cause of death.  Enhanced mortality
    was related to enhanced xylene toxicity due to suppression of
    cytochrome P-450, although additive or synergistic damage to tissues
    other than liver could not be ruled out.  There was no indication that
     p-xylene had caused immune suppression.

    7.2.1.4  Technical or undefined xylene

         When rats (strain not defined) were exposed to 620, 980 or 1600
    ppm xylene 18-20 h/day for 7 days, instability, incordination and
    narcosis were observed at the two highest concentrations. Signs of
    mucous membrane irritation occurred, and congestion and cloudy
    swelling of kidneys was reported at 980 ppm (Batchelor, 1927). 
    Similar results were reported in another study (Winslow, 1927).

         Groups of Harlan-Wistar rats (25 males/group) were exposed to 0,
    180, 460 or 810 ppm xylene 6 h/day, 5 days/week for 13 weeks.  The
    xylene consisted of 7.63%  o-xylene, 65.01%  m-xylene, 7.84%
     p-xylene and 19.27% ethylbenzene.  At 3, 7 and 13 weeks 3, 3 and 4
    animals, respectively, were killed.  No treatment-related
    histopathology was seen (Carpenter et al., 1975).

         In a study of levels of noradrenaline and dopamine in the
    forebrain and hypothalamus of rats, the xylene mixture used was 2.0%
     o-xylene, 64.5%  m-xylene, 10.0%  p-xylene and 23.0% ethylbenzene.
    Sprague-Dawley rats (6 males/group) were exposed to 0 or 2000 ppm
    xylene 6 h/day for 3 days.  The animals were killed 16-18 h after the
    last exposure.  There was a significant increase in catecholamine
    levels and turnover in the hypothalamus and a significant increase in
    dopamine levels and turnover in the forebrain (Andersson et al.,
    1981).

         In order to study the effect on levels of neurotransmitters in
    the rat brain, five to six Sprague-Dawley rats/group were exposed to
    0, 200, 400 or 800 ppm xylene (mixture not defined) for 30 days. 
    Acetylcholine levels in the striatum were decreased at > 400 ppm. 
    Noradrenaline levels in the hypothalamus were increased significantly
    at the highest dose.  From 400 ppm the cAMP levels were decreased in
    the striatum, and at 800 ppm the glutamine levels in the midbrain were
    increased.  At all concentrations glycine and GABA levels in the
    midbrain were increased (Honma et al., 1983).

         When 12 male Fischer F-344 rats/group were exposed to 0 or 1450
    ppm xylene 8 h/day for 3 days, there was, in exposed animals, an
    increase in the auditory response threshold at 12 and 20 kHz.

         Rats (Long Evans) were exposed to 2500 ppm of mixed xylenes 6
    h/day for 5 days.  Testing of auditory function was conducted 5 to 8
    weeks after exposure using reflex modification audiometry (RMA).  The
    results indicated increased RMA thresholds for the mid-frequency tones
    (e.g., 8, 16 and 24 kHz) but not for higher or lower tones (Crofton et
    al., 1994).

         In another study Sprague-Dawley rats (four males/group) were
    exposed to 0 or 630 ppm xylene 6 h/day, 5 days/week for 4 weeks.  The
    animals were killed the morning after the last exposure.  In exposed
    animals there was a significant decrease in body weight gain, while
    the absolute and relative liver weights were increased.  There was an
    increase in hepatic cytochrome P-450 and the xylene was shown to act
    as a phenobarbital-like inducer of cytochrome P-450.  The xylene used
    was 2.0%  o-xylene, 64.5%  m-xylene, 10.0%  p-xylene and 23.0% 
    ethylbenzene (Toftgård et al., 1981).

         When male Sprague-Dawley rats (8-12 animals/group) were exposed
    to 0, 75, 250, 500, 1000 or 2000 ppm xylene 6 h/day for 3 days there
    was a dose-dependent increase in the concentration of liver microsomal
    cytochrome P-450.  When animals were exposed to the two highest
    concentrations for 5 days, there was a dose-dependent increase in the
    surface area of smooth endoplasmic reticulum but not in rough
    endoplasmic reticulum.  Based on their results the authors concluded
    that xylene causes phenobarbital-type induction in the liver.  The
    xylene used was the same as that in the previous paragraph (Toftgård
    et al., 1983).

         The same type of xylene was also used in a study where four male
    Sprague-Dawley rats/group were exposed to 0 or 2000 ppm xylene 6 h/day
    for 3 days.  In exposed animals there were significant increases in
    hepatic and renal cytochrome P-450 content, in NADPH-cytochrome c
    reductase activities and 7-ethoxyresorufin  O-deethylase activities
    in liver and kidney.  The pulmonary cytochrome P-450 content was
    decreased. Increased enzyme activity in liver and kidney and decreased
    activity in the lung were thus observed (Toftgård &  Nilsen, 1982).

         Groups of male Wistar rats (20 animals/group) were exposed to 0
    or 300 ppm xylene 6 h/day, 5 days/week for up to two weeks.  In each
    group 10 animals had 15% v/v ethanol in the drinking-water.  There was
    a significant decrease in motor activity in exposed animals.  In 
    addition, there was a significant increase in brain DT-diaphorase
    activity, in acid proteinase and in hepatic and renal 7-ethoxycoumarin
     O-deethylase activities.  Concurrent dosing with ethanol had a
    marked synergistic effect on hepatic and renal 7-ethoxycoumarin
     O-deethylase activities.  The xylene used was 80%  m-xylene and 12%
     p-xylene (Savolainen et al., 1979a,b).

         In a study of the effect of simultaneous exposure to xylene
    (undefined) and noise on metabolic activity in the myocardium, male
    rats (strain not specified) were exposed to 0 or 69 ppm xylene 4 h per
    day, 5 days per week for 6 weeks, and simultaneously to a noise level
    of 0, 46, 85 or 95 dB.  There were changes in some enzyme activities,
    but the brief reporting makes the study impossible to evaluate
    (Ivanovich et al., 1985).

         When Beagle dogs (four males per group) were exposed to 0, 180,
    460 or 810 ppm xylene 6 h per day, 5 days per week for 13 weeks, no
    treatment-related effects were reported.  The xylene used was 7.63%
     o-xylene, 65.01%  m-xylene, 7.84%  p-xylene and 19.27% ethylbenzene
    (Carpenter et al., 1975).

    7.2.2  Other exposure routes

         Decreased body weight compared to controls was noted in rats
    (Sprague-Dawley) administered orally 1062 mg  m-xylene/kg body weight
    for 3 days (Pyykkö, 1980), and reduced terminal body weight was
    observed in rats (Fischer F-344) administered 500 mg  m-xylene/kg
    body weight, 5 days per week, for 4 weeks (Halder et al., 1985). 
    Three days administration of 1062 mg  m-xylene/kg body weight
    resulted in significant increases in liver weight, liver cytochrome
    P-450 and cytochrome b5 levels and NADPH cytochrome c reductase and
    MFO enzymes activities.  The same range of increases was also seen in
    the kidney (Pyykkö, 1980).  In another study, however, there were no
    effects on kidney weight and no treatment-related abnormalities
    histopathologically in Fischer rats given 500 or 2000 mg/kg body
    weight 5 days per week for 4 weeks (Dési et al., 1967).

         Upon oral administration of 0, 125, 250, 500, 1000 or 2000 mg
    xylene per kg body weight to rats (F-344/N), in a 14-day study, a high
    mortality was seen in the highest dose group.  The xylene used was
    9.1%  o-xylene, 60.2%  m-xylene, 13.6%  p-xylene and 17.0%
    ethylbenzene.  The body weight gain was reduced in  males at > 250
    mg/kg body weight and in females at 125 mg/kg body weight and
    > 1000 mg/kg body weight.  There were no treatment-related
    abnormalities at gross necropsy (NTP, 1986).  In the same study xylene
    was administered at 0, 62.5, 125, 250, 500 or 1000 mg per kg body
    weight, 5 days per week, for 13 weeks.  No treatment-related
    abnormalities were seen during gross necropsy or histopathological
    examination (NTP, 1986).

         Daily administration (s.c.) of xylene (undefined) for up to 4
    weeks to rats (strain not given) resulted in significant mortality at
    870 mg/kg body weight but not at 435 or 174 mg/kg body weight. 
    Repeated administration of 435 mg/kg body weight resulted in decreased
    learning rate (Dési et al., 1967).  When Sprague-Dawley rats were

    given 0 or 3123 mg/kg body weight for 3 days, there was a significant
    increase in liver weight, cytochrome P-450 levels, NADPH cytochrome c
    reductase and activity of MFO enzymes.  The xylene used was 30%
     o-xylene, 55%  m-xylene and 15%  p-xylene (Pathiratne et al.,
    1986).

         In order to study further the effects of  p-xylene, rats were
    given  p-methylbenzyl alcohol (PMBA) or 2,5-dimethylphenol (DMP)
    (300 mg/kg body weight and 150 mg/kg body weight, respectively)
    intraperitoneally once a day for 3 days.  It was concluded that of the
    two metabolites, PMBA may have a significant role in the inhibition of
    pulmonary cytochrome P-450 caused by  p-xylene (Day & Carlson, 1992).

         Male Sprague-Dawley rats (n=10) were given xylene (isomer not
    stated) intraperitoneally, as a single dose per day, for 3 consecutive
    days.  The dose given was equal to half the LD50 (1.6 ml/kg body
    weight per day).  Only slight somnolence was observed.  After the last
    dosing the animals were killed and aminopeptidase activities in
    several regions of the brain were measured.  The activities were
    largely unaffected, compared to those of controls (De Gandarias et
    al., 1993).

         Brain cell cultures enriched in astroglial cells were prepared
    from neonatal Sprague-Dawley rats.  The cultures were exposed for 1 h
    to 3, 6 or 9 mmol  o-xylene/litre.  The ATPase activity was reduced
    in a dose-dependent manner (Naskali et al., 1994).

    7.3 Long-term exposure

         A short summary of long-term studies is presented in Table 6.

         In Wistar rats exposed to 1000 ppm  m-xylene for 6 h/day,
    5 days/week for 3 months or to 100 ppm for 6 months, slight
    ultrastructural changes (proliferation of smooth endoplasmic
    reticulum) were found in hepatocytes.  When rats were exposed to a 1:1
    combination of  m-xylene and toluene (500 plus 500 ppm or 50 plus 50
    ppm), the changes were a combination of those of each single solvent
    (Rydzynski et al., 1992).  The combined exposure at both exposure
    levels gave more pronounced disturbances in a rotarod performance test
    and decrease in spontaneous motor activity compared to single solvent
    exposure.  In animals exposed to 500 plus 500 ppm for 3 months a
    decrease in red blood cell count and an increase in rod neutrophil
    cell count were observed (Korsak et al., 1992).

         In a six-week study, groups of rats (Sprague-Dawley or
    Long-Evans; 15 animals/group) were exposed to 0 or 780 ppm  o-xylene
    (8 h/day, 5 days/week) or to 78 ppm continously for 90 days.  There
    was no effect on body weight gain, leukocyte count, haemoglobin level
    or heamatocrit. Histological examination of the liver, kidney, heart,
    spleen and lung revealed no effects (Jenkins et al., 1970).

        Table 6.  Effects of xylenes in long-term studies

                                                                                                                                      

    Compound        Species        Exposure      NOEL    LOEL     End-point                                 Reference
                                                 (ppm)   (ppm)
                                                                                                                                      

    Inhalation exposure

    o-Xylenea       rat, dog,      13 weeks      780     -                                                  Jenkins et al., 1970
                    guinea-pig

    o-Xylenea       monkey         13 weeks +    78      -                                                  Jenkins et al., 1970

    m-Xylenea       rat            3 months      -       1000     liver cell changes (i.e. inc. smooth      Rydzynski et al., 1992
                                                                  endoplasmic reticulum, lysosomes)

    m-Xylenea       rat            6 months      -       100      liver cell changes (i.e. inc. smooth      Rydzynski et al., 1992
                                                                  endoplasmic reticulum, lysosomes)

    m-Xylenea       rat            3 months      -       100      dec. lymphocyte/monocyte count;           Korsak et al., 1992
                                                                  dec. rotorod, performance

    m-Xylenea       rat            6 months      -       100      dec. rotorod, performance                 Korsak et al., 1992
                                                                  dec. spontaneous motor activity

    Xylenes         rat            3 months      50      100      dec. rotorod performance                  Korsak et al., 1994
                                                                  dec. spontaneous motor activity

    Xylenes         rat            6 months      346     923      liver effects (inc. liver weight inc.     Ungvary, 1990
                                                                  smooth endoplasmic reticulum, inc.
                                                                  P-450 activity)
                                                                                                                                      

    Table 6.  (Cont'd)

                                                                                                                                      

    Compound        Species        Exposure      NOEL    LOEL     End-point                                 Reference
                                                 (ppm)   (ppm)
                                                                                                                                      

    Inhalation exposure

    Xylenes         rat            13 weeks      810     -                                                  Carpenter et al., 1975

    Xylenes         dog            13 weeks      810     -                                                  Carpenter et al., 1975

    Xylenes         rat            6 weeks       -       800      ototoxicity                               Pryor et al., 1987
                                   (14h/day)

    Xylenes         rat            61 days       -       1000     ototoxicity                               Nylen & Hagman, 1994
                                   (18 h/day)

    Xylenes         rat            18 weeks      -       300      liver microsomes activity                 Elovaara et al., 1980

    Xylenes         rat            18 weeks      -       300      brain superoxide dismutase activity       Savolainen et al., 1979

    Xylenes         rat            13 weeks +    -       320      brain lipid composition changes           Kyrklund et al., 1987

    Xylenes         gerbil         3 months      160     320      change in astroglial cell marker          Rosengren et al., 1986
                                                                  proteins
                                                                                                                                      

    Table 6.  (Cont'd)

                                                                                                                                      

    Compound        Species        Exposure      NOEL    LOEL     End-point                                 Reference
                                                 (ppm)   (ppm)
                                                                                                                                      

    Oral exposure

    Xylenes         rat            13 weeks      1000    -                                                  NTP, 1986

    Xylenes         mouse          13 weeks      2000    -                                                  NTP, 1986

    Xylenes         rat            13 weeks      -       150      increased liver weights (males);          Condie et al., 1988
                                                                  hyaline droplet nephropathy (males)

    Xylenes         rat            2 years       250     500      mortality                                 NTP, 1986

    Xylenes         mouse          2 years       500     -                                                  NTP, 1986
                                                                                                                                      

    a    Only one dose was used
    b    Continous exposure
             The effects of combined exposure to  m-xylene and  n-butyl
    alcohol have been studied in rats exposed to the individual solvents
    at 50 and 100 ppm and their 1:1 mixture at 50 plus 50 ppm and 100 plus
    100 ppm, 6 h/day, 5 days/week for 3 months (Korsak et al., 1994).  The
    results indicate less than an additive toxic effect (motor
    coordination disturbances) of combined exposure to  m-xylene and
     n-butyl alcohol.  For xylene alone an effect was seen at 100 ppm but
    not at 50 ppm.

         Rats (CFY) were exposed to xylene (10%  o-xylene, 50%
     m-xylene, 20%  p-xylene and 20% ethylbenzene) for 8 h/day up to 6
    months at  concentrations of 600, 1500 or 4000 mg/m3.  No macroscopic
    changes were seen but the relative liver weight was increased at 4000
    mg/m3.  At 4000 mg/m3 hypertrophy of the centrilobular zone in
    the liver, including a change in the amount of smooth and rough
    endoplasmic reticulum, was seen.  As a result of xylene exposure the
    hexobarbital sleeping time decreased.  Liver enzymatic activities were
    increased during the first 6 weeks.  After the 4-week exposure-free
    period the changes described above could no longer be seen.  The same
    type of changes could also be seen when xylene was applied orally,
    subcutaneously or intraperitoneally for a short period of time (4-7
    day).  Essentially the same changes as those described for rat liver
    were also seen in livers from mice and rabbits (Ungvary, 1990).

         Groups of 50 male and 50 female Fischer-344/N rats received 0,
    250 or 500 mg xylene/kg body weight.  The xylene used was 9.1%
     o-xylene, 60.2%  m-xylene, 13.6%  p-xylene and 17.0% ethylbenzene. 
    The doses were given (in corn oil) by stomach tube on 5 days per week
    for 103 weeks.  The animals were killed within 14 days after the last
    dosing.  Body weights of high-dose (500 mg/kg body weight) males were
    5 to 8% lower than those of vehicle controls.  Results for low-dose
    males and both female groups were comparable to those of controls. 
    Gross observation and histopathological results showed no incidences
    of non-neoplastic effects in dosed groups, related to the
    administration of xylene, at any sites (NTP, 1986; Huff et al., 1988). 
    In the same study groups of 50 male and 50 female B6C5F1 mice
    received 0, 500 or 1000 mg xylene/kg body weight.  The same type of
    technical xylene was used.  The doses were given, in corn oil, by
    stomach tube 5 days per week for 103 weeks, after which the animals
    were killed within 14 days.  No significant difference in mean body
    weights or survival was observed between treated animals and controls. 
    Gross observation and histopathological results indicated that at no
    site were the incidences of non-neoplastic effects in dosed groups
    related to the administration of xylene (see also section 7.7).

         Male Fischer-344 rats were exposed to 0, 800, 1000 or 1200 ppm
    xylene 14 h/day, 7 days/week for 6 weeks.  At the highest dose level
    there was a slight impairment of auditory (but not of visual or
    somatosensory) conditioned avoidance response.  All animals had

    increased auditory response thresholds compared to controls at the
    same frequencies.  At 1000 and 800 ppm the thresholds were elevated at
    16 kHz and 8 kHz and at 1200 ppm the brainstem auditory-evoked
    response thresholds were elevated at 4, 8 and 16 kHz tone frequency. 
    The xylene used in these two studies was 10%  o-xylene, 80%
     m-xylene and 10%  p-xylene (Pryor et al., 1987).

         Wistar rats (60 males/group) were exposed to 0 or 300 ppm xylene
    6 h per day, 5 days per week, for up to 18 weeks, and 50% of the
    animals had 15-20% ethanol in the drinking water.  The xylene used was
    19.2%  o-xylene, 43.0%  m-xylene,  19.5%  p-xylene and 18.3%
    ethylbenzene.  It was concluded that concurrent ethanol intake
    increased hepatic and renal microsomal enzyme activities.  Stearosis
    in the liver was more marked in co-exposed animals than in animals
    exposed only to ethanol.  No treatment-related abnormalities were
    observed during histopathological examination of animals exposed only
    to xylene (Elovaara et al., 1980).

         Exposure to 1000 ppm xylene (not defined) 18 h per day, 7 days
    per week, for 61 days caused a slight loss of auditory sensitivity in
    Sprague-Dawley rats.  Co-exposure to  n-hexane (1000 ppm) caused
    a persistent loss of auditory sensitivity, which was less than
    additively enhanced.  Xylene inhibited  n-hexane-induced impulse
    velocity reduction in peripheral nerves (Nylén & Hagman, 1994).

         In a study to investigate the effect on brain lipid composition,
    Sprague-Dawley rats were exposed to 0 or 320 ppm xylene continuously
    for 30 or 90 days.  The xylene (undefined) produced only limited
    transient changes (Kyrklund et al., 1987).  In another study to
    investigate the effect on brain with and without co-exposure to
    ethanol, Wistar rats (20 males/group) were exposed to 0 or 300 ppm
    xylene 6 h per day, 5 days per week, for up to 18 weeks.  In each
    group were 10 animals also exposed to 15% v/v ethanol in the
    drinking-water.  There was a significant increase in cerebral
    microsomal superoxide dismutase activity by week 18, but no effect on
    cerebral protein or RNA levels.  Co-exposure to ethanol reduced the
    effect caused by xylene exposure.  The xylene used was 7.5%
     o-xylene, 85.0%  m-xylene and 7.5%  p-xylene (Savolainen et al.,
    1979a,b).

         In a study of the effect on spinal cord axon membrane, Wistar
    rats (five animals per group) were exposed to 0 or 300 ppm xylene
    (undefined) 6 h per day, 5 days per week, for 18 weeks.  In exposed
    animals there was a decrease in the amount of membrane lipid per mg of
    protein but no change in the cholesterol/lipid phosphorus ratio. 
    Ethanol (15% v/v) in the drinking-water enhanced the decrease and also
    decreased the cholesterol/lipid phosphorus ratio (Savolainen &
    Seppäläinen, 1979).

         In a neurotoxicity study, changes in two astroglial cell marker
    proteins (S-100 and GFA) and DNA were measured.  Mongolian gerbils
    (four of each sex per group) were exposed to 0, 160 or 320 ppm xylene
    continously (24 h/day) for 3 months, followed by a 4-month
    exposure-free period.  The xylene used was 18%  o-xylene, 70%
     m-xylene, 12% p-xylene and < 3% ethylbenzene.  The exposure to
    xylene resulted in brain damage which was manifest as an increase in
    astroglial cells.  Effects were seen in particular parts of the brain
    at both exposure levels but were only significant at 320 ppm
    (Rosengren et al., 1986).

         Ageing Long-Evans rats fed 200 ppm  o-xylene for up to 6 months
    showed formation of vacuolar structures in hepatocytes when examined
    ultrastructurally (Bowers & Cannon, 1982).

         Groups of 10 male and 10 female Sprague-Dawley rats were exposed
    to mixed xylenes by gavage (in corn oil) for 90 consecutive days at
    dose levels of 150, 750 and 1500 mg/kg body weight per day (Condie et
    al., 1988).  The most significant findings were increased relative
    liver and kidney weights.  Histopathology evaluation of liver and
    kidney tissues revealed an increased incidence of minimal chronic
    renal disease in females only.  Treatment-related hepatic
    histopathological changes were not detected in either sex.  Hyaline
    droplet formation was observed in male rats in all treated groups.  In
    females, there was an increased incidence of kidney effects, which
    were thought to represent onset of progressive nephropathy (Condie et
    al., 1988).

         Mice (B6C3F1) were given orally 0, 250, 500, 1000 or 2000 mg
    xylene per kg body weight for 14 days or 0, 125, 250, 500, 1000 or
    2000 mg per kg body weight, 5 days per week, for 13 weeks.  The xylene
    used was 9.1%  o-xylene, 60.2%  m-xylene, 13.6%  p-xylene and 17.0%
    ethylbenzene.  Mean body weight gain was reduced in males at > 250
    mg/kg body weight.  No treatment-related abnormalities were observed
    at gross necropsy or histopathological examination (NTP, 1986).

    7.4  Skin and eye irritation; sensitization

         Erythema and oedema were induced following a single application
    (amount not stated) of xylene (not defined) to rabbit or guinea-pig
    skin.  There was a rapid onset and epithelial desquamation, with some
    evidence of necrosis occurring after several days (Rigdon, 1940;
    Steele & Wilhelm, 1966).  After 24 h of exposure to 0.5 ml xylene
    (undefined) under semi-occlusive conditions, irritation of rabbit skin
    was observed.  The irritation was graded as moderate by the authors
    (Hine & Zuidema, 1970).

         Application of 0.5 ml  p-xylene, under a Teflon chamber, to
    rabbit skin for 4 h produced a response which would be classified as
    irritant using European Union criteria (Jacobs et al., 1987).  In
    another study, following 10 to 20 applications of xylene (not defined)
    to open or semi-occluded rabbit skin for up to four weeks, a moderate
    to marked irritation and moderate necrosis was reported, as was
    blistering of the skin under the semi-occlusive dressing (Wolf et al.,
    1956).

         Application of approximately 0.05 to 0.5 ml of liquid xylenes
    (individual isomers or undefined composition) to the rabbit eye was
    reported to cause immediate discomfort and blepharospasm followed by
    slight conjunctival irritation and very slight, transient corneal
    necrosis (Wolf et al., 1956).  Application of 0.1 ml liquid xylene
    (not defined) was mildly irritant to rabbit eye.  The lesions were not
    described (Kennah et al., 1989).

         No skin sensitization studies have been reported.

    7.5  Reproductive and developmental toxicity

         A summary of reproductive and developmental toxicity studies is
    shown in Table 7.

         Groups of female rats (CFY) were exposed to 0, 34, 345 or 690 ppm
     o-xylene 24 h/day from day 7 to day 14 of gestation.  The dams were
    killed on day 21.  Some ultrastructural changes in the liver and
    decreased weight gain during the exposure period were observed in the
    dams exposed to 345 or 690 ppm.  At these concentrations lower fetal
    body weight was observed, and at the highest dose level delayed
    skeletal ossification was noted.  There was no evidence of
    malformations.  Similar results were obtained when the animals were
    exposed to  m-xylene.  With  p-xylene there were signs of delayed
    skeletal ossification at exposure levels showing no maternal toxicity
    (at 34 and 345 ppm).  At 690 ppm, increased postimplantation loss of
    fetuses and more retarded fetuses were observed (Ungvary et al.,
    1980).

        Table 7. Reproductive and developmental effects (inhalation studies)

                                                                                                                                      

    Compound          Species   Exposure       Duration    NOEL          LOEL           Endpoint                   Reference
                                                                                                                                      

    o, m, p-Xylene    rat       0, or 1000     24 h/day;                                Fused sternebrae,          Hudak & Ungvary
                                mg/m3          days 9-14                                extra ribs                 (1978)

    Xylene            rat       0, 10, 50 or   6 h/day;                                 Maternal toxicity not      Mirkova et al.
    (not specified)             500 mg/m3      days 1-21                                addressed                  (1983)

    Xylene            rat       0, 250, 1900   24 h/day;                 250 mg/m3      Skeletal retardation       Ungvary & Tatrai
    (not specified)             or 3400        days 7-15                 (mothers and                              (1985)
                                mg/m3                                    offspring)

    o-xylene          rat       0, 150, 1500   24 h/day;   150 mg/m3     150 mg/m3      Decreased fetal weight,    Ungvary et al.
                                or 3000        days 7-14   offspring     (dams)         skeletal retardation       (1980)
                                mg/m3                                    1500 mg/m3
                                                                         (offspring)

    m-xylene          rat       0, 150, 1500   24 h/day;   1500 mg/m3    3000 mg/m3     Maternal: reduced food     Ungvary et al.
                                or 3000        days 7-14   (dams and     (dams and      consumption, reduced       (1980)
                                mg/m3                      offspring)    offspring)     weight gain
                                                                                        Offspring: reduced fetal
                                                                                        weight

    p-xylene          rat       0, 150, 1500   24 h/day;                 150 mg/m3      Reduced mean litter        Ungvary et al.
                                or 3000        day 7-15                  (dams and      size; reduced fetal        (1980)
                                mg/m3                                    offspring)     weight; skeletal
                                                                                        retardation

    p-xylene          rat       0 or 3000      10th day,                                Decreased fetal weight     Ungvary et al.
                                mg/m3          24 h                                                                (1981)
                                                                                                                                      

    Table 7. (Cont'd)

                                                                                                                                      

    Compound          Species   Exposure       Duration    NOEL          LOEL           Endpoint                   Reference
                                                                                                                                      

    p-xylene          rat       0, 3500 or     6 h/day;    7000          7000 mg/m3     Maternal: reduced          Rosen et al.
                                7000 mg/m3     days 7-16   mg/m3         (dams)         weight gain                (1986)
                                                           (offspring),
                                                           3500
                                                           mg/m3
                                                           (dams)

    Xylene            rat       0 or 600       24 h/day;                                Decreased maternal         Ungvary (1985)
    (not defined)               mg/m3          day 7-15                                 weight gain.
                                                                                        Delayed fetal
                                                                                        development; extra ribs

    Xylene            rat       870 mg/m3      6 h/day;                                 No maternal toxicity;      Hass & Jakobsen
    (not defined)                              days 4-20                                delayed ossification       (1993)

    o, m, p-Xylene    rat       2175 mg/m3     6 h/day;                                 Delayed righting reflex;   Hass et al. (1995)
                                               days 7-20                                reduced absolute brain
                                                                                        weight; impaired
                                                                                        neuromotor ability

    Xylene            mouse     0, 500 or      24 h/day;   500 mg/m3     1000 mg/m3     Skeletal retardation and   Ungvary & Tatrai
    (not specified)             1000 mg/m3     days 6-15   offspring     (offspring)    increased incidence of     (1985)
                                                                                        weight-retarded fetuses

    Xylene            rabbit    0, 500 or      24 h/day;                 500 mg/m3      Maternal: decreased        Ungvary & Tatrai
    (not specified)             1000 mg/m3     days 7-20                 (offspring)    weight gain                (1985)
                                                                         1000 mg/m3     Offspring: delayed
                                                                         (dams)         skeletal development
                                                                                                                                      
             Rats (CFY) were exposed to 0.58, 437 or 782 ppm 24 h/day on days
    7 to 15 of gestation and the dams were killed on day 21.  Data
    concerning maternal toxicity was not given.  There was delayed
    skeletal ossification at all dose levels, while decreased fetal
    bodyweight, increased postimplantation loss and increased frequency of
    skeletal variants (extra ribs) were observed at 782 ppm.  Mice (CFLP)
    were exposed to 0 or 115 ppm  o-xylene for 4 h, 3 times per day on
    day 6 to day 15 of gestation, and the dams were killed on day 18. 
    Data concerning maternal toxicity were not reported.  There was
    evidence of delayed weight gain and skeletal ossification in the
    fetuses of exposed animals.  Similar results were obtained with
     m-xylene and  p-xylene (Ungvary & Tatrai, 1985).  When rabbits (New
    Zealand White) were exposed to 0 or 115 ppm  o-xylene 24 h/day from
    day 7 to day 20 of gestation, no maternal toxicity or incidence of
    delayed development was observed in the exposed group.  Similar
    results were observed with  m-xylene, but an increased incidence of
    post-implantation loss was observed.  Exposure to 115 ppm  p-xylene
    gave the same results as with  o-xylene, but exposure to 230 ppm
     p-xylene 24 h/day resulted in no live fetuses (one dam died, three
    aborted and in four there was total resorption or fetal death  in
     utero) (Ungvary & Tatrai, 1985).

         In a study to validate a developmental toxicity screen, mice
    (ICR/SIM) were exposed orally to 0 or 2000 mg  m-xylene/kg body
    weight from day 8 to day 12 of gestation.  No effects were seen on
    mothers or young (Seidenberg et al., 1986).  In another study
    Sprague-Dawley rats were exposed to 0, 800 or 1600 ppm  p-xylene, 6 h
    per day from day 7 to day 16 of gestation.  The dams were allowed to
    deliver their young.  In the highest dose group the maternal weight
    gain was significantly reduced.  Exposure to  p-xylene had no effects
    on postnatal viability, offspring growth or function of the nervous
    system (activity level and acoustic startle response) at any of the
    doses tested (Rosen et al., 1986).

         In an attempt to study the effect of xylene on sex steroids
    during pregnancy, rats (CFY) were exposed to 0 or 681 ppm  p-xylene
    for 24 h on day 10 of gestation or continuously on days 9 and 10 of
    gestation.  The animals were killed on day 11.  Data on maternal
    toxicity were not reported.  Sex hormone levels in the uterine and
    femoral veins were decreased in the exposed group.  The authors
    (Ungvary et al., 1981) suggested that this may play a role in the
    embryotoxicity.

         Rats (CFY) were exposed to 0 or 230 ppm xylene for 24 h/day from
    day 9 to day 14 of gestation, and the dams were killed on day 21.  The
    xylene used was 10%  o-xylene, 50%  m-xylene, 20%  p-xylene and 20%
    ethylbenzene.  No maternal effects were seen in exposed animals. 
    There was an increased incidence of skeletal variants such as extra
    ribs and fused sternebrae.  Three malformations were found (2
    agnathia, 1 fissura sterni), but there was no significant increase in
    the frequency of malformations (Hudak & Ungvary, 1978).

         In another study rats (CFY) were exposed to 0 or 138 ppm xylene
    (not defined) 24 h/day from day 7 to day 15 of gestation.  The dams
    were killed on day 21.  In the exposed group, decreased maternal
    weight gain, delayed fetal development and increased incidence of
    skeletal variants (extra ribs) were observed, but there was no
    evidence of malformations (Ungvary, 1985).

         In a report issued by the American Petroleum Institute in 1983,
    described by Bell et al. (1992), Sprague-Dawley rats were exposed to a
    xylene mixture of 20.4%  o-xylene, 44.2%  m-xylene, 20.3%  p-xylene
    and 12.8% ethylbenzene.  There were 30 males and 60 females in the
    control group, while 10 males and 20 females per group were exposed to
    60 or 250 ppm xylene and 20 males and 40 females were exposed to 500
    ppm xylene.  Exposures were 6 h per day, 7 days per week, for a
    131-day pre-mating period and a 20-day mating period.  Mated females
    were also exposed during days 1-20 of gestation and days 5-20 of
    lactation.  For males there were no effects on body weight gain, but
    for females the mean body weight gain was significantly greater than
    that of controls in the 60 and 250 ppm groups during the mating
    period.  This was not considered indicative of an adverse effect of
    treatment.  Mating indices were significantly lower than control
    values at 250 ppm (both sexes treated) and at 500 ppm (females treated
    only), but mating indices were comparable to control values at 500 ppm
    when both sexes were treated or when males alone were treated.  There
    were no treatment-related effects on mean duration of gestation, mean
    litter size or pup survival.  The mean pup weight in the group where
    both parents had been exposed to 500 ppm xylene was significantly
    lower than for controls.  In the teratogenicity part of the study
    there was no evidence of an increased incidence of malformations in
    exposed groups.  The mean fetal weights for the 500 ppm group were
    lower than the control value, but, the difference was statistically
    significant for only the female fetuses.

         Groups of Wistar rats were exposed to 0, 2, 11 or 114 ppm xylene
    (mixed, not defined) for 6 h per day from day 1 to day 21 of
    gestation.  The maternal toxicity was not reported.  The incidence of
    post-implantation loss and fetal death was significantly increased in
    the 11 ppm and 114 ppm groups.  At the highest dose an increase in
    some malformations was noted but no incidence was given.  The results
    of the study cannot be evaluated because of insufficient reporting of
    exposure conditions and results (Mirkova et al., 1983).  In an attempt
    to repeat this study, groups of 36 Wistar rats were exposed to 200 ppm
    technical xylene 6 h per day on days 4 to 20 of gestation.  There were
    no signs of maternal toxicity.  No exposure-related differences were
    found except for delayed ossification of maxillary bone.  The
    xylene-exposed pups had a slightly higher body weight and impaired
    performance in a motor ability test, which was most marked in female
    offspring (Hass & Jakobsen, 1993).

         In a follow-up study (Hass et al., 1995), Wistar rats were
    exposed to 500 ppm technical xylene (19%  o-xylene, 45%  m-xylene,
    20%  p-xylene and 15% ethylbenzene) for 6 h per day on gestation days
    7-20.  The dose level was selected so as not to induce maternal
    toxicity or decrease the viability of offspring.  There were 15
    exposed litters and 13 control litters.  A delay in the development of
    the air righting reflex, a lower absolute brain weight and impaired
    performance in behavioural tests for neuromotor abilities, learning
    and memory were found in the offspring of the exposed rats. 
    Generally, the effects were most marked in the female offspring.  The
    alterations were long-lasting, as they were still apparent in adult
    rats at the age of 4 months.

         A composition of 9.1%  o-xylene, 60.2%  m-xylene, 13.6%
     p-xylene and 17.0% ethylbenzene was given orally to CD-1 mice.  The
    doses were 0, 520, 1030, 2060, 2580, 3100 or 4130 mg per kg body
    weight daily from day 6 to day 15 of gestation.  All animals in the
    highest dose group died and so did 50% of the animals in the 3100
    mg/kg group.  In this group there was a significant increase in the
    incidence of dams with complete resorptions.  There was a significant
    increase in the incidence of cleft palate at > 2060 mg/kg, as well
    as decreased mean fetal weight (Marks et al., 1982).

         In order to study the teratogenic and embryotoxic effects of
    xylene (60%  p-xylene, 22%  o-xylene, 18% ethylbenzene; no
     m-xylene) embryos of Sprague-Dawley rats were explanted on day 9.5
    of gestation and cultured in rat serum to which xylene (0.1, 0.5 or
    1.0 ml/litre) dissolved in DMSO was added.  The embryos were cultured
    for 48 h.  There were no observable teratogenic effects in terms of
    malformations.  However, dose-dependent embryotoxicity in terms of
    retardation on growth and development was observed (Brow-Woodman et
    al., 1991).  In a similar study (Brown-Woodman et al., 1994) rat
    embryos were incubated  in vitro with up to 2.7 µmol xylene/ml for
    40 h.  Concentrations of > 1.89 µmol/ml retarded embryo growth and
    development.  The no-observed-effect level (NOEL) was 1.08 µmol/ml. 
    No gross morphological malformations were observed.  Combined exposure
    to toluene, xylene and benzene caused additive embryotoxic effects
    with no evidence of synergistic action (Brown-Woodman et al., 1994).

         When Sprague-Dawley rats were exposed to 1000 ppm xylene (not
    defined) 18 h per day, 7 days per week, for 61 days, testicular
    atrophy or loss of nerve growth factor-immunoreactive germ cell line
    was not observed.  Xylene also was found to protect from
     n-hexane-induced testicular atrophy (Nylén et al., 1989).

         Wistar rats were exposed for 7 days to xylene (isomer not stated)
    twice a day until disappearance of righting reflex (xylene
    concentration not given).  Anaesthesia was achieved in about 10 min. 
    On day 8 the rats were killed.  A decrease in body weight and weights
    of testes and accessory reproductive organs, as well as reduced acid

    phosphate activity in the prostate and reduced plasma testosterone
    levels, was observed in xylene-exposed animals.  There was also a
    decrease in spermatozoan count in the epididymis (Yamada, 1993).

    7.6  Mutagenicity and related end-points

         Technical grade xylene did not produce differential killing in
    DNA-repair-proficient compared to repair-deficient strains of
     Bacillus subtilis rec+/- (McCarroll et al., 1981a) or  Escherichia
     coli (McCarroll et al., 1981b).  Xylene (type not specified) did not
    induce SOS activity in  Salmonella typhimurium TA1535/pSK 1002
    (Nakamura et al., 1987).  For  E. coli  WP2 uvr A  p-xylene was not
    mutagenic in the presence or absence of an exogenous metabolic system
    from PCB-induced rat liver (Shimizu et al., 1985).  None of the
    isomers nor unspecified xylene was mutagenic to  S. typhimurium
    TA1535, TA1537, TA98, TA100, UTH 8413 or UTH8414 in the presence or
    absence of a metabolic system from uninduced or Arochlor-induced rat
    and hamster livers (Lebowitz et al., 1979; Bos et al., 1981; Haworth
    et al., 1983; Connor et al., 1985; Shimizu et al., 1985; Zeiger et
    al., 1987).

         Exposure to technical grade xylene containing 18.3% ethylbenzene
    caused recessive lethal mutations in  Drosophila melanogaster but not
    exposure to  m-xylene, or  o-xylene (Donner et al., 1980).  The same
    report stated that exposure to rats for 300 ppm, 6 h per day, 5 days
    per week for 9, 14 and 18 weeks did not induce chromosomal aberrations
    in bone-marrow cells (Donner et al., 1980).  Xylene (unspecified) did
    not induce mutations in mouse lymphoma L5178Y TK+/- cells  in vitro
    or chromosomal aberrations in rat bone marrow cells (Lebowitz et al.,
    1979).  Xylene (unspecified) did not induce sister chromatid exchange
    or chromosomal aberrations in human lymphocytes  in vitro.  No
    exogenous metabolic system was used in this study (Gerner-Smidt &
    Friedrich, 1978).

         None of the isomers induced micronuclei in the bone marrow of
    male NMRI mice after two i.p. administrations of 105-650 mg/kg body
    weight at a 24-h interval, but they did, however, enhance the
    induction of micronuclei by toluene (Mohtashamipur et al., 1985).

         When Sprague-Dawley rats were given 440 or 1320 mg  o-xylene/kg
    body weight intraperitoneally, a significant increase in the
    percentage of abnormal sperm was reported when the animals were housed
    at 24-30°C (but not at 20-24°C).  The authors (Washington et al.,
    1983) interpreted this as a synergistic effect between  o-xylene and
    temperature.

    7.7  Carcinogenicity

         Group of Sprague-Dawley rats, 40 of each sex, received 500 mg
    mixed xylenes (composition not specified) per kg body weight in olive
    oil by stomach tube on 4 to 5 days per week for 104 weeks.  Fifty
    animals of each sex received olive oil only.  The animals were
    maintained until natural death.  All animals had died by week 141.  At
    that time thymomas were reported in 1/34 treated males and 0/36
    treated females (compared to 0/45 and 0/49, respectively, in
    controls).  Other haemolymphoreticular tumours (not specified) were
    reported in 4/34 treated males and 3/36 treated females (compared to
    3/45 and 1/49, respectively, in controls).  The authors (Maltoni et
    al., 1983; Maltoni et al., 1985) reported an increase in the total
    number of animals with malignant tumours (type not specified) at 141
    weeks, e.g., as 13/38 in treated males and 22/40 in treated females
    (compared to 11/45 and 10/49, respectively, in control animals). 
    Combining all tumours is, however, not an acceptable basis for
    analysis particularly in aged animals.  No data were provided to allow
    an analysis on an individual tumour-type basis.

         In a carcinogenicity study, groups of 50 B6C3F1 mice of each sex
    were given 0, 500 or 1000 mg xylene/kg body weight in corn oil by
    stomach tube on 5 days per week for 103 weeks.  The xylene used was
    9.1%  o-xylene, 60.2%  m-xylene, 13.6%  p-xylene and 17.0%
    ethylbenzene. The surviving animals were killed within 2 weeks after
    the last administration.  Survival at the termination of the study for
    males was: 27 controls, 35 low-dose and 36 high-dose; and for females
    was: 36 controls, 35 low-dose and 31 high-dose.  No treatment-related
    increase in the incidence of any tumour was seen in either sex (NTP,
    1986; Huff et al., 1988).

         The NTP also performed a carcinogenicity study on Fischer-344
    rats with the same type of technical xylene.  Groups of 50 rats of
    each sex were given 0, 250 or 500 mg xylene/kg body weight in corn oil
    by stomach tube 5 days per week for 103 weeks.  The surviving animals
    were killed within 2 weeks following the last administration.  At the
    termination of the experiment, the survival for males was: 36
    controls, 25 low-dose and 20 high-dose animals, and for females was:
    38 controls, 33 low-dose and 35 high-dose.  For the males survival
    appeared to be dose-related, but many of the early deaths were related
    to gavage trauma or corn oil-xylene aspiration (3/14, 8/25, 11/30). 
    The incidences of tumours in treated animals of either sex were not
    significantly higher than in the control group (NTP, 1986; Huff et
    al., 1988).

         Two studies have investigated whether exposure to xylenes alters
    the incidence of experimentally induced skin neoplasia in mice (Pound
    & Withers, 1963; Pound, 1970).  The reporting does not allow any firm
    conclusions.

    7.8  Other effects

         No effects were observed upon  in vitro exposure of human
    lymphocytes at concentrations up to 2 mM xylene for 72 h.  However, at
    higher concentrations, cell mortality only was significantly increased
    (Richer et al., 1993).

    8.  EFFECTS ON HUMANS

    8.1  Acute and accidental exposure 

         Acute poisoning and deaths have been reported after overexposure
    or oral ingestion of substantial amounts of xylene.  The exposure
    level required for loss of consciousness has been estimated to be
    10 000 ppm (Morley et al., 1970).  At autopsy pulmonary congestion and
    oedema have been observed after inhalation or oral intake (Morley et
    al., 1970; Abu Al Ragheb et al., 1986).  Among survivors coma, EEG
    changes, amnesia, mental confusion and ocular nystagmus have been
    reported.  Evidence of gastrointestinal and respiratory symptoms as
    well as impaired renal and hepatic function have also been observed
    (Ghislandi & Fabiani, 1957; Recchia et al., 1985; Bakinson & Jones,
    1985).  After exposure to about 700 ppm (calculated) for up to one
    hour, headache, nausea, irritation of the eyes, nose and throat,
    dizziness, vertigo and vomiting have been reported (Klaucke et al.,
    1982).  Recovery seems to be complete in most non-fatal cases although
    dizziness and vision problems have been observed 24 h after ingestion
    of xylene (quantity unknown) (Recchia et al., 1985).  In a suicidal
    attempt a 30-year-old man injected 8 ml of xylene intravenously. 
    After 10 min he developed a life-threatening acute pulmonary failure,
    but survived through medical treatment (Sevcik et al., 1992).

    8.2  Controlled human studies

         A number of volunteer studies have been performed predominantly
    at the Finnish Institute of Occupational Health.  Effects on the
    sensory motor and information process functions of the central nervous
    system (CNS) have been investigated.  Usually  m-xylene has been
    used, but  p-xylene and mixed xylenes have also been studied
    (Savolainen & Linnavuo, 1979; Savolainen, 1980; Savolainen et al.,
    1980; Seppäläinen et al., 1981; Savolainen & Riihimäki, 1981;
    Savolainen et al., 1981; Savolainen et al., 1982a, Savolainen et al.,
    1982b; Savolainen et al., 1984; Savolainen et al., 1985a, Savolainen
    et al., 1985b).  In these studies no significant effects on vestibular
    or visual function, reaction times, coordination or peripheral senses
    were observed during a 4-h exposure to a constant concentration of up
    to 160 ppm.  Slight impairment of vestibular and visual function and
    reaction time was noted at exposure levels from 200 to 300 ppm.  There
    was adaption to the impairment over five successive daily exposures. 
    In another study (Anshelm Olson et al., 1985), volunteers (n=16) were
    exposed for 4 h to  p-xylene alone (300 mg/m3: 70 ppm) or in
    combination with toluene (200 mg/m3 toluene plus 100 mg/m3
     p-xylene).  Heart rate, subjective symptoms, simple reaction time,
    choice reaction time and short-term memory were unaffected by
    exposure.

         In another study nine male volunteers were exposed for 4 h to 200
    ppm (TWA)  m-xylene.  Short-term peak exposures were up to 400 ppm. 
    The effects of xylene on electroencephalography (EEG) were minor and
    no deleterious effects were noted (Seppäläinen et al., 1991).

         Healthy male subjects were exposed to technical xylene,
    containing 40% ethylbenzene, for 2 h with or without a working load of
    100 watts.  The air concentration was 435 or 1300 mg/m3.  During work
    at the higher exposure level evidence of performance decrement was
    observed in three of the five performance tests: reaction time
    addition test (p < 0.05), short-term memory (p < 0.05) and choice
    reaction time (p < 0.10) (Gamberale et al., 1978).

         Dizziness was reported by four of six volunteers exposed to 690
    ppm  p-xylene for 15 min (Carpenter et al., 1975).  Nine volunteers
    were exposed for about 4 h to either a constant or a fluctuating
    pattern of  m-xylene with a time-weighted average exposure
    concentration of 200 ppm in both cases (Laine et al., 1993). 
    Prolonged simple visual and auditive choice reaction times were
    observed after exposure to the peaks of 400 ppm  m-xylene.  Exposure
    to  m-xylene at a constant level of 200 ppm did not affect the ratio
    of "active" to "quiet" sleep during the following night, but decreased
    slightly the number of body movements in bed.

         Studies on coexposure to  m-xylene and ethanol (Savolainen,
    1980; Seppäläinen et al., 1981; Savolainen & Riihimäki, 1981;
    Riihimäki et al., 1982a,b;  Riihimäki et al., 1982a,b),  m-xylene and
    1,1,1-trichloroethane (TCE) (Savolainen et al., 1981; Savolainen et
    al., 1982) or  p-xylene and toluene (Anshelm-Olson et al., 1985) have
    been performed.  Exposure to 145-150 ppm xylene and 0.8 g ethanol/kg
    body weight had an additive disturbing effect on vestibular function. 
    At higher xylene concentrations (275-290 ppm) there was evidence of
    functional tolerance, and xylene appeared to antagonize the effect of
    ethanol on vestibular function. In a study where volunteers were
    exposed to 200 ppm  m-xylene, minor effects on vestibular and visual
    functions and reaction time were reported.  Simultaneous exposure to
    400 ppm TCE had no further effect.  Combined exposure to 60 ppm
     p-xylene and 30 ppm toluene had no effect on reaction time,
    short-term memory or heart rate.

         Ten male volunteers were exposed to 100 ppm xylene (not
    specified) or 100 ppm toluene or a mixture of 50 ppm of each. 
    Exposure time was 4 h and each person participated in four exposure
    sessions.  Changes in CNS functions were tested by nine psychological
    tests.  Xylene had the most adverse effect on simple reaction time and
    choice reaction time, while the combined exposure gave weaker effects
    than xylene alone but stronger than toluene alone (Dudek et al.,
    1990).

         A summary of acute effects from inhalation exposure is presented
    in Table 8.

         In studies on skin irritation, both hands of subjects were
    immersed in pure  m-xylene (Engström et al., 1977; Lauwerys et al.,
    1978; Riihimäki, 1979a).  A burning sensation was soon noticed and an
    erythematous reaction was observed in the exposed skin.  Of six
    subjects tested, four reported eye irritation after exposure to 460 or
    690 ppm xylene for 15 min.  The xylene contained 7.6%  o-xylene,
    65.0%  m-xylene, 7.8%  p-xylene and 19.3% ethylbenzene.  One subject
    reported eye irritation at 230 ppm but none at 110 ppm (Carpenter et
    al., 1975).  In another study, no irritation in the eyes, nose or
    throat was reported after exposure to 98, 196 or 392 ppm mixed xylenes
    for 30 min (Hastings et al., 1984).  In an older study exposure to 200
    ppm xylene (undefined) for 3-5 min caused irritation of the eyes, nose
    and throat (Nelson et al., 1943).

         The skin sensitization potential was investigated using a
    non-adjuvant maximization test.  The xylene used was not defined. 
    None of 24 subjects tested showed evidence of sensitization (Kligman,
    1966).

         Five adult, healthy, white men were exposed for 7 h per day for 3
    days to 40 ppm xylene.  This exposure was repeated three times at
    intervals of 2 weeks.  Blood samples were taken before and after each
    exposure.  No significant effects were observed on sister-chromatid
    exchange frequency, cell cycle time or cell mortality in lymphocytes
    (Richer et al., 1993).

    8.3  Occupational exposure

         In workers exposed to xylene or solvent mixtures containing large
    amounts of xylene, subjective symptoms have been reported (Joyner &
    Leak Pegues, 1961; Glass, 1961; Hipolito, 1980; Kilburn et al., 1983;
    Kilburn et al., 1985).  Depression, fatigue, headache, anxiety,
    feeling of drunkenness and sleep disorders were the most common
    symptoms reported, but exposure levels and duration were often missing
    in these reports.

         Workers occupationally exposed to solvent mixtures including
    xylene have been reported to have neurophysiological and psychological
    disorders (Lindström, 1973; Seppäläinen et al., 1978; Elofsson et al.,
    1980; Husman, 1980;  Husman & Karli, 1980; Arlien-Soborg et al., 1981;
    Lindström et al., 1982; Valciukas et al., 1985; Maizlish et al., 1987;
    Van Vliet et al., 1987; Ruijten et al., 1994).  In these studies there
    was no exposure to xylene alone.  Xylene was not the main solvent in
    the mixture.  No conclusions concerning effects of xylenes as such can
    be drawn from these studies.

        Table 8. Single inhalation exposure to xylene in humans

                                                                                                         

    Exposure         Time      Effect                                    Reference
    concentration
    (mg/m3)
                                                                                                         

    3 000            1 h       Dizziness, irritation                     Klaucke et al. (1982)

    3 000            15 min    Dizziness                                 Carpenter et al. (1975)

    1300a            2 h       Performance decrement                     Gamberale et al. (1978)

    900b             4 h       Prolonged reaction times                  Laine et al. (1993)

    900              4 h       Impairment of vestibular and visual       Savolainen et al.
                               function and prolonged reaction time      (1979, 1981, 1982, 1985)

    900              4 h       Minor effect on EEG                       Seppäläinen et al. (1991)

    600              4 h       No effect on reaction time                Savolainen et al. (1980, 1981)

    450              4 h       Prolonged reaction time                   Dudek et al. (1990)

    300              4 h       No effects in psychophysiological test    Anshelm - Olson et al. (1985)
                                                                                                         

    a    during exercise
    b    peak values of 1800 mg/m3
    
         Liver effects have been reported in some studies on workers
    occupationally exposed to solvents containing xylene (Dössing et al.,
    1981; Edling, 1982; Sotaniemi et al., 1982; Dössing et al., 1983;
    Fischbein et al., 1983, Lundberg et al., 1994) but these were not
    confirmed in other studies (Craveri et al., 1982; Kurppa & Husman,
    1982; Lundberg & Håkansson, 1985).  Recent findings seem to support
    the concept that the hepatotoxicity of xylene is low (Riihimåki &
    Hännien, 1987).

         Some case studies and epidemiological studies have addressed a
    possible association between occupational exposure to hydrocarbons
    (including xylene) and proliferative glomerulonephritis (Beirne & 
    Brennan, 1972; Zimmerman et al., 1975;  Lagrue, 1976).  Exposures
    have, however, been so diverse that the  role of xylene is impossible
    to assess.  A Swedish group of researchers reported a higher
    concentration of albumin, erythrocytes and leukocytes in the urine of
    workers exposed predominantly to xylenes and toluene than among
    controls (Askergren et al., 1981a,b,c; Askergren, 1981).  Franchini et
    al. (1983) found that painters exposed to toluene and xylenes at
    relatively low concentrations had a higher excretion of kidney tubular
    enzymes in their urine than the controls.  They suggested that the
    mixed solvents may exert a slight adverse effect on the kidney
    tubules.

         One case of contact urticaria due to occupational exposure to
    airborne xylene has been reported.  The level of xylene in air
    exceeded 100 ppm.  Direct skin contact with the solvent appeared to
    have been negligible.  The contact urticaria seemed likely to be an
    immunological type (Palmer & Rycroft, 1993).

         Thirty-five male spray varnishers were exposed to 0.5-3.4 ppm
     o-xylene, 3.2-11.7 ppm  m-xylene, 0.9-4.3 ppm  p-xylene, 1.4-7.5
    ppm ethylbenzene, < 1.5 ppm toluene, < 1.2 ppm  n-butanol, < 35.5
    ppm 1,1,1-trichloroethane and several C9 aromatics. In addition, some
    of the lacquers contained lead pigments.  The mean peripheral
    erythrocyte counts and haemoglobin levels were decreased in the
    exposed men compared to controls.  Whether these effects were due to
    xylene or the solvent mixture is uncertain (Angerer & Wulf, 1985).

         The health effects on 175 factory workers in China exposed to
    xylene vapour with a mixture of three isomers at a concentration of up
    to 175 ppm (with time-weighted average geometric mean concentration of
    14 ppm and arithmetic mean of 21 ppm) were studied.  There was an
    increased prevalence of subjective symptoms in the exposed workers;
    these were apparently related to effects on the central nervous system
    and to local effects on the eye, nose and throat (Uchida et al.,
    1993).  In workers exposed to a maximum concentration of 103 ppm
    xylene (geometric mean 4 ppm) and 203 ppm toluene (geometric mean 3

    ppm), the prevalence of some subjective CNS-related symptoms was
    higher than in the controls (Chen et al., 1994).  No effects on
    haematology or serum biochemistry with respect to liver and kidney
    functions were observed in these two studies.

         Sister-chromatid exchanges (SCE) in peripheral lymphocyte
    cultures have been studied in two groups of 23 workers who had been
    exposed for between 4 months and 23 years to mixed xylenes (including
    ethylbenzene).  The exposure levels for the two groups were 11 and 13
    ppm, respectively.  No differences in SCE frequency was seen (Pap &
    Varga., 1987).  A few other reports have described increased incidence
    of chromosomal aberrations or effects on sister-chromatid exchange
    frequencies (Funes-Cravioto et al., 1977; Haglund et al., 1980).  In
    both these studies the exposure to xylene (not defined) was
    accompanied by exposure to other solvents, including benzene.

         No data on carcinogenic effects resulting from exposure to
    xylenes have been found in the literature.

         In an investigation into the effect on reproduction, the outcome
    of pregnancy was studied among university laboratory employees exposed
    to xylene (not defined) during the first trimester of pregnancy. 
    Exposure levels were not given.  There was no difference in
    miscarriage rate when compared to controls not exposed to solvents
    (Axelsson et al., 1984).

         A similar case control study on associations between laboratory
    work and pregnancy outcome revealed that use of xylene for 3 or more
    days a week during the first trimester was significantly associated
    with an elevated risk of spontaneous abortion.  The authors pointed
    out, however, that laboratory workers were often exposed to several
    solvents and chemicals simultaneously; only two cases and two controls
    were exposed to xylene alone (Taskinen et al., 1994).  About half of
    the women exposed to xylene worked in pathology/histology laboratories
    where there was concomitant exposure to  formaldehyde vapour. 
    Formaldehyde (formalin) also appeared to be a  significant risk factor
    for spontaneous abortion.  Exposure to xylene was also noted to be
    associated with an increase in birth weight (Taskinen et al., 1994).

    9.  EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD

    9.1  Laboratory experiments

    9.1.1  Microorganisms

         Bringmann & Kuhn (1977, 1978) exposed the bacterium  Pseudomonas
     putida for 16 h and the blue-green alga  Microcystis aeroginosa for
    8 days to xylene.  They found a reduction in  cell multiplication at
    concentrations of >200 mg/litre.

         Walton et al. (1989) studied the effect of  p-xylene on the
    microbial respiration of two soil types, a silt loam (1.49% organic
    carbon) and a sandy loam (0.66% organic carbon).  The chemical was
    applied at a rate of 1000 µg/g (dry weight).  Microbial respiration,
    as measured by CO2 efflux, of the silt loam was unaffected.  In the
    sandy loam, the CO2 efflux initially decreased and then increased,
    but returned to control levels within the 6-day exposure period.

         All three isomers have been shown to inhibit the respiration of
    sewage sludge utilizing biogenic substrates.  Two screening tests were
    used, RIKA (respiration inhibition kinetic analysis) and OECD 209. 
    The concentration of each compound used was at the limit of the
    solubility in the medium (approx. 175-198 mg/litre).  Inhibitions in
    the respiration rate of 100% were found for all three isomers in the
    RIKA screening test, and inhibitions of 22% ( o-xylene) and 43%
    ( p-xylene) were measured in the OECD 209 screening test.   m-Xylene
    was only tested at a concentration of 0.3 mg/litre in the OECD 209
    screening test, which resulted in 5% inhibition (Volskay & Grady,
    1990).

         The toxicity of xylene to three species of environmental bacteria
    has been determined using assays in sealed serum bottles to prevent
    loss of chemical by volatilization.  Activity of the bacteria was
    measured by either gas production over 48 h (methanogens), oxygen
    consumption over 15 h (aerobic heterotrophs) or ammonia use over 24 h
     (Nitrosomonas).  IC50 values (the concentration required to inhibit
    the bacterial activity by 50%, as compared with controls) for xylene
    were 250 mg/litre for methanogens, 1100 mg/litre for aerobic
    heterotrophs and 100 mg/litre for  Nitrosomonas (Blum & Speece,
    1991).

    9.1.2  Aquatic organisms

         Xylene isomers are highly volatile and disappear rapidly from
    solution.  For example, Mackay & Wolkoff (1973) found that in agitated
    water, 1m deep and with a 1m2 surface for evaporation, the half-life
    for  o-xylene was 39 min.  When Benville & Korn (1977) monitored the
    loss of xylene from solution during LC50 tests, average percentage

    losses for the four time intervals studied (24, 48, 72 and 96 h) were
    29, 61, 84 and > 99% respectively.  These losses mean that the
    exposure can be difficult to determine.  For example, many of the 24-h
    and 96-h LC50 values are the same or similar, suggesting that most of
    the xylene had been lost during the test.  Galassi et al. (1988),
    using a closed static system, found mean measured concentrations of
    xylene and other aromatics to fluctuate by only 10% during the test
    period of up to 96 h.  Care must therefore be taken when interpreting
    data from open static tests over longer periods than 24 h, especially
    those based on nominal concentrations.  Overall it can be stated that
    xylene has moderate to low acute toxicity for aquatic organisms.

    9.1.2.1 Algae

    Bringmann & Kühn (1977) exposed the green alga  Scenedesmus
     quadricauda for 8 days to xylene.  They found reduction in cell
    multiplication at concentrations of > 200 mg/litre.  Brooks et al.
    (1977) studied the effect of xylene on photosynthesis in a mixed ocean
    culture of phytoplankton.  They found that exposure to a concentration
    of 3 mg/litre xylene for 8 h caused a 50% reduction in photosynthesis.

         Galassi et al. (1988) calculated the 72-h EC50 for growth
    inhibition in the alga  Selenastrum capricornutum to be 4.7, 4.9 and
    3.2 mg/litre for the ortho, meta and para isomers, respectively. 
    Similar results were obtained by Herman et al. (1990).  Using the same
    species of algae, they obtained 8 day EC50 values for growth
    inhibition of 4.2, 3.9 and 4.4 mg/litre for the ortho, meta and para
    isomers, respectively.  Sheedy et al. (1991) reported a 14-day EC50
    for growth inhibition of  Selenastrum capricornutum of 72 mg/litre
    for xylene (composition not stated).

         Hutchinson et al. (1980) exposed the algae  Chlamydomonas
     angulosa and  Chlorella vulgaris to  p-xylene for 3 h.  EC50
    values for inhibition of photosynthesis (measured using 14CO2
    uptake) were 45.7 and 105.1 mg/litre for the two species,
    respectively.  Kauss et al. (1973) exposed the green alga  Chlorella
    vulgaris to  o-xylene and studied growth over a 10-day period in an
    open system.  At nominal concentrations of between 25 and 100
    mg/litre, a short-term toxic effect was observed.  However, the algal
    culture recovered within 2 days.  The authors pointed out that
    recovery was probably due to volatilization of the chemicals.  A
    near-saturation concentration of 171 mg  o-xylene/litre proved to be
    acutely toxic and the alga did not recover.  Concentrations of 25 and
    50 mg  o-xylene/litre progressively increased the lag period between
    initial inoculation and growth.  An  o-xylene concentration of 100
    mg/litre delayed the onset of growth for 4 days and a near-saturation
    concentration of 171 mg/litre caused complete inhibition of growth
    during the 10-day exposure period (Kauss & Hutchinson, 1975).

         Dunstan et al. (1975) exposed marine microalgae, the diatom
     Skeletonema costatum, the dinoflagellate  Amphidinium carterae, the
    coccolithophorid  Cricosphaera and the green flagellate  Dunaliella
     tertiolecta, to xylene for 3 days.  A xylene concentration of 10
    mg/litre inhibited the growth of all species.  Inhibition was most
    marked in  A carterae and  S. costatum.

    9.1.2.2  Higher plants

         Frank et al. (1961) exposed the angiosperm pondweeds  Elodea
     canadensis,  Potamogeton nodosus and  P. pectinatus to xylene
    (plus 2% emulsifying agent) under static, open conditions for a period
    of four weeks.  A concentration of 100 mg/litre was found to be toxic
    (8.6 on an injury scale of 0 to 10) but 5 mg/litre was not.  Both 300
    and 600 mg/litre were similarly toxic after 30-min exposures in
    flowing water.

    9.1.2.3  Protozoa

         Bringmann et al. (1980) exposed the flagellate protozoan
     Chilomonas paramaecium to xylene for 48 h and found an initial
    reduction (5%) in cell multiplication at concentrations of > 80
    mg/litre.  Rogerson et al. (1983) exposed the ciliate protozoan
     Colpidium colpoda to xylene in an "open" system consisting of a
    covered watchglass with an air space.  Toxicity thresholds were 1.75
    mg/litre (16.5 mmol/m3) for  o-xylene and 162 mg/litre (1530
    mmol/m3) for  m-xylene; no threshold was calculated for  p-xylene. 
    The same authors exposed the protozoan  Tetrahymena ellioti to xylene
    isomers in a closed system with no air space.  Toxicity thresholds for
     o-, p- and  m-xylene were 18.5, 16.9 and 55.7 mg/litre (174, 159
    and 525 mmol/m3), respectively.

    9.1.2.4  Invertebrates

         The LC50 values of xylene to aquatic invertebrates are
    summarized in Table 9.

         Le Gore (1974)  exposed Pacific oyster larvae  (Crassostrea
     gigas) to  o- and  p-xylene for 48 h.  LC50 values were 0.17 and
    0.58 mg/litre for the two isomers, respectively, suggesting that this
    organism is one of the more sensitive invertebrates to xylene
    exposure.  However, no experimental details were given for these
    toxicity tests, which makes them difficult to interpret.

        Table 9.  LC50 values of xylenes to aquatic invertebrates

                                                                                                                                      

    Organisms        Size/        Static/  Open/     Temp.   Hardness      Isomer  Duration   Concentration   Reference
                     life-stage   flowa    closeda   (°C)    (mg/litre)c                      (mg/litre)d
                                                                                                                                      

    Estuarine and marine invertebrates

    Pacific oyster   larvae                                                ortho   48 h       0.17            Le Gore (1974)
    (Crassostrea     larvae                                                para    48 h       0.58            Le Gore (1974)
    gigas)

    Grass shrimp                  static   c         21      15s                   96 h       7.4             Neff et al. (1976)
    (Palaemonetes                 static   c         21      15s                   24 h       14.0            Tatem et al. (1978)
     pugio)                                                                        96 h       7.4             Tatem et al. (1978)

    Bay shrimp       adult        static   o         16      25s           ortho   24 h       4.7 n           Benville & Korn (1977)
    (Crago           adult        static   o         16      25s           ortho   96 h       1.1 n           Benville & Korn (1977)
     franciscorum)   adult        static   o         16      25s           meta    24 h       4.1 n           Benville & Korn (1977)
                     adult        static   o         16      25s           meta    96 h       3.2 n           Benville & Korn (1977)
                     adult        static   o         16      25s           para    24 h       1.7 n           Benville & Korn (1977)
                     adult        static   o         16      25s           para    96 h       1.7 n           Benville & Korn (1977)

    Dungeness crab   zoeae        static+            13      30s           ortho   48 h       38 n            Caldwell et al. (1977)
    (Cancer          zoeae        static+            13      30s           ortho   96 h       6 n             Caldwell et al. (1977)
     magister)       zoeae        static+            13      30s           meta    48 h       33 n            Caldwell et al. (1977)
                     zoeae        static+            13      30s           meta    96 h       12 n            Caldwell et al. (1977)
                                                                                                                                      

    Table 9.  (Cont'd)

                                                                                                                                      

    Organisms        Size/        Static/  Open/     Temp.   Hardness      Isomer  Duration   Concentration   Reference
                     life-stage   flowa    closeda   (°C)    (mg/litre)c                      (mg/litre)d
                                                                                                                                      

    Freshwater invertebrates

    Water flea                    static   o                                       24 h       >100<1000 n     Dowden & Bennett (1965)
    (Daphnia magna)               static                                           24 h       165 n           Brigmann & Kühn (1982)
                                  static   c                               ortho   24 h       1 m             Galassi et al. (1988)
                                  static   c                               meta    24 h       4.7 m           Galassi et al. (1988)
                                  static   c                               para    24 h       3.6 m           Galassi et al. (1988)
                     4-6 days     static   c                               ortho   48 h       3.2 n           Bobra et al. (1983)
                     4-6 days     static   c                               meta    48 h       9.6 n           Bobra et al. (1983)
                     4-6 days     static   c                               para    48 h       8.5 n           Bobra et al. (1983)
                     < 24 h       flow     o         17      44.7          ortho   48 h       3.82 m          Holcombe et al. (1987)

    Mosquito         larvae       static   o         24-26                         24 h       13.9            Berry & Brammer (1977)
    (Aedes aegypti)

    Snail
    (Aplexa          adult        flow     o         17      44.7          ortho   96 h       >22.4 m         Holcombe et al. (1987)
     hypnorum)
                                                                                                                                      

    a    static = static conditions (water unchanged for duration of test);                          b    o = open; c = closed
         static+ = semi-static conditions (water renewed at 24 hour intervals);                      c    s = salinity (%)
         flow = flow-through conditions (xylene concentration in water continuously maintained)      d    m = measured; n = nominal
             Berry & Brammer (1977) exposed mosquito larvae  (Aedes aegypti)
    to xylene under static, open conditions at 25°C.  Larvae were exposed
    for 24 h, since no detectable levels of any water-soluble component
    remained after that period.  A non-lethal concentration of 7.92
    mg/xylene litre was reported.  However, the authors found that
    bioassays using different volumes of solution and different sized
    containers demonstrated the significant effect that surface area,
    volume and depth can have on the results of experiments with volatile
    hydrocarbons such as xylenes.

         Falk-Petersen et al. (1985) exposed sea urchin  (Strongy
     locentrotus droebachiensis) eggs to  o-xylene from fertilization
    and monitored deaths, pathology, inhibition of cleavage and
    differentiation, and pigment effects. Eggs were maintained in test
    beakers covered with aluminium foil.  They calculated a 96-h EC50,
    based on all these parameters, of 4.1 mg/litre.

         Freshwater mussels  (Dreissena polymorpha) were exposed to
    various concentrations of xylene, and the behaviour of the mussels in
    terms of shell valve movements was monitored.  At the start of the
    experiment, all valves were gaping continuously.  After a certain
    period of toxicant addition, a gradual increase in valve closure
    period was observed.  Finally, total closure of shell valves was
    observed.  Effects were first seen at a xylene concentration of
    11.9-19.4 mg/litre (nominal) (Slooff et al., 1983).

    9.1.2.5  Vertebrates

         The LC50 values of xylene to fish are summarized in Table 10.

         Morrow et al. (1975) found that 100 mg xylene/litre killed 100%
    of young coho salmon  (Oncorhynchus kisutch) within 24 h under
    static, closed conditions.  Concentrations of 1 and 10 mg/litre did
    not cause significant mortality within the 96-h exposure period. 
    Toxicity included rapid, violent and erratic swimming, "coughing",
    loss of equilibrium and death.

         Rainbow trout  (Oncorhynchus mykiss) significantly avoided
    xylene (plus 2% emulsifying agent) at a nominal concentration of 0.1
    mg/litre during a 1-h test.  Fish exposed to 0.001 mg/litre did not
    show significant avoidance and those exposed to 0.01 mg/litre were
    significantly attracted to the xylene (Folmar, 1976).  Maynard & Weber
    (1981) found that juvenile coho salmon were able to significantly
    avoid  o-xylene concentrations of > 0.2 mg/litre water.

         Slooff (1979) exposed rainbow trout  Oncorhynchus mykiss to
    various concentrations of xylene in a flow-through, closed system and
    monitored any effects of the chemical on their breathing.  The lowest
    concentration at which a toxic condition developed within 24 h after
    toxicant administration was 2 mg/litre.

        Table 10.  LC50 values of xylenes to fish

                                                                                                                                      

    Organisms        Size/      Static  Open/    Temp.   Hardness     Isomer     Duration     Concentration  Reference
                     lifestage  /flowa  closedb  °C      (mg/litre)c                          (mg/litre)d
                                                                                                                                      

    Freshwater fish

    Fathead minnow   1-2 g      static  o        25      20                      24 h         28.8 n         Pickering & Henderson
     (Pimephales     1-2 g      static  o        25      20                      48 h         27.7 n         (1966)
     promelas)       1-2 g      static  o        25      20                      96 h         26.7 n
                     1-2 g      static  o        25      360                     24 h & 96 h  28.7 n

                     0.3 g      flow    o        17      44.7         ortho      96 h         16.1 m         Holcombe et al. (1987)

    Bluegill         1-2 g      static  o        25      20                      24 h         24 n           Pickering & Henderson
     (Lepomis        1-2 g      static  o        25      20                      48 h         24 n           (1966)
     macrochirus)    1-2 g      static  o        25      20                      96 h         20.9 n

                     1.1 g      flow    o        17      44.7         ortho      96 h         16.1 m         Holcombe et al. (1987)

    Goldfish         1-2 g      static  o        25      20                      24 h & 96 h  36.8 n         Pickering & Henderson
     (Carassius                                                                                              (1966)
     auratus)
                     20-80 g    flow             17-19   80                      24 h         30.6 m         Weber et al. (1975)
                     20-80 g    flow             17-19   80                      96 h         16.9 m

                     3.3 g      static  o        19-21                ortho      24 h         13 m           Bridie et al. (1979)
                     3.3 g      static  o        19-21                meta       24 h         16 m
                     3.3 g      static  o        19-21                para       24 h         18 m

                     2.5 g      flow    o        17      44.7         ortho      96 h         16.1 m         Holcombe et al. (1987)
                                                                                                                                      

    Table 10.  (Cont'd)

                                                                                                                                      

    Organisms        Size/      Static  Open/    Temp.   Hardness     Isomer     Duration     Concentration  Reference
                     lifestage  /flowa  closedb  °C      (mg/litre)c                          (mg/litre)d
                                                                                                                                      

    Guppy            0.1-0.2 g  static  o        25      20                      24 h & 96 h  34.7 n         Pickering & Henderson
     (Poecilia                                                                                               (1966)
     reticulata)
                                static                                meta       14 days      305            Könemann (1981)
                                static                                ortho      7 days       291
                                static                                para       7 days       285

                                static  c        20-22                ortho      96 h         12 m           Galassi et al. (1988)
                                static  c        20-22                meta       96 h         12.9 m
                                static  c        20-22                para       96 h         8.8 m

    Rainbow trout               static  c        11-13                ortho      96 h         7.6 m          Galassi et al. (1988)
     (Oncorhynchus              static  c        11-13                meta       96 h         8.4 m
     mykiss)                    static  c        11-13                para       96 h         2.6 m

                                flow    o        9-13    89.5                    96 h         10e            Folmar (1976)

                     13.1 g     flow    o        17      44.7         ortho      96 h         8.05 m         Holcombe et al. (1987)

                     0.9 g      flow    o        12      40-48        technical  24 h & 96 h  13.5           Walsh et al. (1977)

    Zebra fish                  flow    c                                        48 h         20             Sloff (1979)
     (Brachydanio
     rerio)
                                                                                                                                      

    Table 10.  (Cont'd)

                                                                                                                                      

    Organisms        Size/      Static  Open/    Temp.   Hardness     Isomer     Duration     Concentration  Reference
                     lifestage  /flowa  closedb  °C      (mg/litre)c                          (mg/litre)d
                                                                                                                                      

    Golden orfe      1.2-1.8 g  static                                           48 h         86f            Juhnke & Lüdemann
     (Leuciscus      1.2-1.8 g  static                                           48 h         308f           (1978)
     idus
     melanotus)

    White sucker     2.4 g      flow    o        17      44.7         ortho      96 h         16.1 m         Holcombe et al. (1987)
     (Catostomus
     commersoni)

    Marine fish

    Coho salmon      young      static  c        8       30s                     24 h         > 10 < 100     Morrow et al. (1975)
     (Oncorhynchus
     kisutch)

    Striped bass     6 g        static  o        16      25s          ortho      24 h & 96 h  9.7 n          Benville & Korn (1977)
     (Morone         6 g        static  o        16      25s          meta       24 h & 96 h  7.9 n
     saxatilis)      6 g        static  o        16      25s          para       24 h & 96 h  1.7 n
                                                                                                                                      

    a    static = static conditions (water unchanged for duration of test);
         flow = flow-through conditions (xylene concentration in water continuously maintained)
    b    o = open; c = closed
    c    s = salinity (°/oo)
    d    m = measured; n = nominal
    e    included 2% emulsifying agent
    f    results from two different laboratories
             When Walsh et al. (1977) exposed rainbow trout (average weight
    165 ± 86 g) to xylene concentrations of 0.31, 0.65 and 1.1 mg/litre in
    artificial streams for 56 days, no adverse effects on the fish were
    noted at any concentration.  Using the same artificial streams, all
    rainbow trout exposed to xylene concentrations of 14.2 or 22.5
    mg/litre for 2 h died.  Fish exposed to xylene concentrations of 3.2
    and 6.2 mg/litre for 2 h showed symptoms similar to anaesthesia.

         Kjorsvic et al. (1982) exposed cod eggs ( Gadus morhus L.) to
    xylene isomers in covered glass dishes and monitored the effects both
    during fertilization and during early cleavage of fertilised eggs. 
    Both  m-xylene and  p-xylene induced significant decreases in the
    fertilization rate at concentrations above 10 mg/litre.   o-Xylene
    had no significant effect on the fertilization rate at concentrations
    of 16-35 mg/litre.  Fertilized eggs were exposed to xylene for 3 or 6
    h before first cleavage.  No significant difference was observed
    between the individual xylene isomers or between the two exposure
    periods.  Effects on the early cleavage pattern were significant for
    xylene concentrations between 2 and 7 mg/litre.  The effects seen
    included inhibition of formation of the cleavage furrow.  Small cells
    or a total absence of cleavage occurred on exposure to all isomers at
    concentrations of 16-35 mg/litre, while incomplete or uneven cleavage
    was found at exposures of 8-15 mg/litre.

         Black et al. (1982) exposed embryo-larval stages of the leopard
    frog  Rana pipiens and rainbow trout  (Oncorhynchus mykiss) to
     m-xylene from 30 min after fertilization to 4 days after hatching in
    a closed, flow-through system (hatching times were 5 days for the frog
    and 23 days for the trout).  LC50 values of 3.53 and 3.77 mg/litre
    were calculated for the two species,  respectively.

    9.1.3  Terrestrial organisms

         Hill & Camardese (1986) exposed Japanese quail  (Coturnix
     coturnix japonica) to xylene in 5-day dietary toxicity tests.  The
    LC50 was found to be greater than 20 000 mg/kg diet.  No overt signs
    of toxicity occurred at 5000 mg/kg.

         No studies on terrestrial plants, terrestrial invertebrates or
    field effects of xylenes have been reported.

    10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

    10.1  Evaluation of human health risks

    10.1.1  Exposures

         In the general environment humans are exposed to xylenes mainly
    by inhalation.  Absorption through the skin may also occur in the
    working environment.  The retention in the lungs is about 60% of the
    inhaled dose.  Xylene is efficiently metabolized.  More than 90% is
    biotransformed to methylhippuric acid, which is excreted in urine. 
    Xylene does not accumulate significantly in the human body.

         Typically, mean background levels of all three xylene isomers in
    ambient air are around 1 µg/m3 with levels of 3 µg/m3 in suburban
    areas.  Higher levels have been measured in urban and industrialized
    areas with mean concentrations ranging up to 500 µg/m3; however,
    concentrations are generally below 100 µg/m3.

         The estimated daily exposure of the general population through
    inhalation is 70 µg in rural areas and less than 2000 µg in urban
    areas.  The concentration in drinking-water ranges from not detectable
    to 12 µg/litre.  Data on the levels in food are too limited to
    estimate daily oral exposure.

    10.1.2  Effects

         Based on experimental human studies, xylene may have an acute
    impairing effect on the sensory-motor and information-processing
    functions of the central nervous system (CNS).  Exposure to 435-870
    mg/m3 (100-200 ppm) of xylene over 4 h caused slight impairments in
    reaction time performance and vestibular functions.  There was
    adaptation at 200 ppm  m-xylene to the impairment over five 
    successive days.  The LOAEL of xylene for acute CNS effects, based on
    one study, is 470 mg/m3 (108 ppm).  It should be noted, however,
    that other identical studies found significant effects only at
    concentrations of 870 mg/m3 (200 ppm) or more.  According to a study
    by a different research group, exposure to 304 mg/m3 (70 ppm)  p-
    xylene for 4 h did not cause impairment of corresponding psycho-
    physiological functions; 304 mg/m3 (70 ppm) xylene can therefore
    be regarded as the NOAEL for acute CNS effects.

         Xylene vapour becomes irritating at relatively high levels. 
    Among six volunteer subjects, four reported eye irritation after
    exposure to 2000 or 3000 mg/m3 (460 or 690 ppm) xylene for 15 min
    while one subject reported eye irritation at 1000 mg/m3 (230 ppm) and
    none at 478 mg/m3 (110 ppm).  According to another study, no
    irritation of  the eyes, nose or throat was reported after exposure to
    423, 852 or 1705 mg/m3 (98, 196 or 392 ppm) mixed xylenes for 30 min.

    These human findings are consistent with mouse studies showing that
    strong irritancy (respiratory rate decrease by 50%) occurs at about
    5960 mg/m3 (1370 ppm) xylene.  The odour threshold for xylene is
    about 1 ppm.

         Subjective symptoms have been reported among workers exposed to
    solvent mixtures containing large amounts of xylene.  Long-term
    exposure to xylene is suspected to affect the nervous system adversely
    because chronic toxic encephalopathy and milder functional
    disturbances of the brain have sometimes been found among exposed
    painters and other workers.  Likewise, slight changes in kidney
    tubular function may occur.  The specific role of xylene in these
    effects cannot, however, be ascertained.

         When human data are sparse, especially data from chronic studies,
    animal data are used as a substitute.  An assessment of the risk to
    human health of exposure to xylene must rely on animal studies.

         Apparently irreversible effects on the CNS were found 4 months
    after a 3-month inhalation exposure (24 h per day) of Mongolian
    gerbils to xylene at concentrations of 696 or 1392 mg/m3 (160 or 320
    ppm).  At the lower level the effects were not statistically
    significant in any individual part of the brain but the changes were
    all of the same nature.  The study disclosed an increased
    concentration of astroglial proteins in most brain regions studied,
    which may indicate that glial proliferation is characteristic to
    various neurodegenerative and neurotoxic states.  In the light of
    similar findings in animals exposed to other solvents (e.g.,
    trichloroethylene, ethanol and tetrachloroethylene), the results are
    estimated to be an important piece of evidence for potential
    xylene-induced neurotoxicity at > 696 mg/m3 (160 ppm) (the LOAEL). 
    Functional changes, similar to acute effects on nervous functions,
    were described after exposure to 435 mg/m3 (100 ppm), but they cannot
    be discriminated from the acute effects of the last exposure.  The
    exposure level is consistent with the levels giving acute effects in
    humans, as stated above.

         No adequate studies of reproduction and development toxicity in
    humans exposed to xylene alone have been published.  Placental
    transfer of xylene has been shown in humans and in experimental
    animals.

         Teratogenicity studies in pregnant animals exposed to technical
    xylene or xylene isomers during organogenesis indicate that xylene may
    cause reduced fetal weight and delayed ossification, but not 
    malformations, at dose levels causing no or only slight maternal
    toxicity.  LOAEL values of 500-2175 mg/m3 (115-500 ppm) have been
    reported, depending on the length of the daily exposure periods (6-24
    h/day).  Signs of delayed ossification in the absence of lower fetal

    body weight have been reported at lower dose levels.  However, these
    findings cannot be properly evaluated owing to incomplete description
    of the criteria for assessing ossification.  A NOAEL for delayed fetal
    development cannot therefore be established.

         In a study of postnatal development in rat offspring prenatally
    exposed to 870 or 2175 mg/m3 (200 or 500 ppm) technical xylene,
    behavioural impairments indicating effects on the development of the
    central nervous system were detected.  There was no maternal toxicity,
    and the effects at 2175 mg/m3 (500 ppm) were long-lasting as they
    were apparent in adult offspring.  As 870 mg/m3 (200 ppm) was the
    lowest dose level investigated for this effect a NOAEL could not be
    established.

         In several short-term and long-term animal studies, effects on
    the activities of various metabolic enzymes in different organs have
    been observed.  Exposure to 217 mg/m3 (50 ppm)  m-xylene 6 h/day for
    5 days induced renal cytochrome P-450.  At 1305  mg/m3 (300 ppm)
    xylene (6 h/day for 14 days) an increase in hepatic and renal enzyme
    activities was observed.  At > 1740 mg/m3 (400 ppm) increases in
    hepatic and renal metabolic enzyme levels, as well as increased
    relative liver and kidney weights, have been reported.  At the same
    exposure levels the pulmonary P-450 content and pulmonary enzyme
    activities were decreased.  When rats were orally given 150 mg
    xylene/kg body weight per day for 90 days, increased relative liver
    weights were seen.

         These changes in metabolic enzyme activities and increased
    relative liver weight could be taken as an indication of metabolic
    adaptation rather than toxicity.

         When rats were exposed to 3480 mg/m3 (800 ppm) xylene, 14 h/day,
    7 day/week for 6 weeks, an increased auditory response threshold was
    reported.  Thus, 3480 mg/m3 (800 ppm) is the LOAEL for ototoxicity. 
    For this effect no NOAEL could be established as 3480 mg/m3 (800 ppm)
    was the lowest dose level used.

         Xylene appears not to be a mutagen or a carcinogen.

    10.1.3  Guidance value

         The definition and aim of guidance values for the general
    population have been described by IPCS (1994).

         Although some differences in action between the three isomers
    exist, there is no clear evidence that they (or mixture of them) have
    totally different effects.

         There have been no long-term controlled human studies or
    epidemiological studies from which a guidance value may be calculated.

         Epidemiological data from the occupational setting do not allow
    an estimation of xylene-specific chronic nervous system effects,
    neither can the neuropsychological impairment seen among
    solvent-exposed workers be attributed to any specific level of xylene
    in air.

         On the basis of human volunteer studies (Anshelm Olson, 1985),
    one may conclude that the NOAEL for acute CNS effects in humans is
    about 304 mg/m3 (70 ppm) for a 4-h exposure.  The use of an
    uncertainty factor of 10 for intraspecies variability (the study
    subjects were healthy male research workers) and an additional factor
    of 6 (4-h exposure versus 24-h general population exposure) leads to a
    guidance value of 4.8 mg/m3 (1.1 ppm).  It should be noted, however,
    that the acute CNS effect observed probably has no predictive value
    for chronic CNS toxicity by xylene.  The guidance value of 4.8 mg/m3
    (1.1 ppm) is close to the odour threshold of xylene.  It should be
    noted that a subset of the human population may be sensitive enough to
    experience the odour as annoying.  The Task Group considered that
    there was no need to add another uncertainty factor for the lack of
    data from chronic exposure.

         On the basis of animal studies on developmental toxicity, one may
    conclude that the LOAEL for reduced fetal body weight is 500 mg/m3
    (115 ppm) (Ungvary & Tatrai, 1985) and that for developmental
    neurotoxicity is 870 mg/m3 (200 ppm) (Hass & Jakobsen, 1993). 
    Developmental neurotoxicity is a serious effect that may be
    long-lasting and is therefore considered the critical effect.  An
    uncertainty factor of 10 for use of a LOAEL rather than a NOAEL seems
    justified based on the evidence of lower fetal body weight at 500
    mg/m3 (115 ppm) and limited evidence of delayed ossification at even
    lower exposure levels.  The use of additional factors of 10 for
    interspecies variation and 10  for inter-individual variation leads to
    a guidance value of 0.87 mg/m3 (0.2 ppm).

         Using the hearing loss (Pryor et al., 1987) detected in animals
    after exposure to 3480 mg/m3 (800 ppm) xylene for 6 weeks as a
    starting point, an uncertainty factor of 10 for use of a LOAEL rather
    than a NOAEL, a factor of 10 for interspecies variation and an
    additional factor of 10 for inter-individual variation results in a
    guidance value of 3.48 mg/m3 (0.8 ppm).

         A neurotoxicity study in animals exposed continuously for 3
    months to 696 or 1392 mg/m3 (160 or 320 ppm) xylene (Rosengren et
    al., 1986) provided suggestive biochemical evidence of an apparently
    irreversible adverse effect on the nerve cells of the brain even at
    the lower level.  Although there may be uncertainty concerning the
    biological significance and interpretation of the findings, the Task
    Group considered them potentially important and recommended further
    confirmatory  studies.  With respect to animal-human extrapolation and

    relatively short exposure, the estimate of the critical level for
    life-long exposure in humans is 1.6 ppm.  A guidance value of 0.87
    mg/m3 (0.2 ppm) covers another uncertainty factor of approximate 10
    in this respect.

         Based on the above considerations, the Task Group recommended
    0.87 mg/m3 (0.2 ppm) as a guidance value for the general population. 
    This value was derived from the LOAEL reported for developmental
    neurotoxic effects in laboratory animals.

    10.2  Evaluation of effects on the environment

    10.2.1  Exposure

         The majority of xylene released into the environment will enter
    the atmosphere directly.  In the atmosphere the xylene isomers are
    readily degraded.  Volatilization to the atmosphere from water is
    rapid for all three isomers.  Although the meta and para isomers are
    readily biodegraded, in soil and water the ortho isomer is more
    persistent.  Bioaccumulation of xylene isomers by aquatic organisms is
    low.

         Typically, mean background levels of all three xylene isomers in
    ambient air are around 1 µg/m3.  Mean background concentrations of
    xylenes in surface waters are generally below 0.1 µg/litre.  However,
    higher values have been measured in industrial areas.  In areas
    associated with the oil industry even higher levels have been reported
    but only associated with discharge pipes.  Similar background levels
    have been reported for groundwater, although localized pollution can
    lead to higher levels.

    10.2.2  Effects

         The xylene isomers are of moderate to low toxicity to aquatic
    organisms.  The variation between each individual isomer with respect
    to aquatic toxicity is generally small.  The lowest LC50 value, based
    on measured concentrations, is for a 24-h exposure of  Daphnia magna
    to 1 mg  o-xylene/litre.

         There is limited information regarding chronic exposure of
    aquatic organisms to xylenes and none of the observed effect levels
    were lower than those summarized under the acute studies.

         The acute toxicity of xylene to birds is low.

    10.2.3  Risk evaluation

         Xylenes are rapidly degraded in the environment.  However, the
    photooxidation reactions of the xylene isomers in the atmosphere may
    contribute to photochemical smog.

         High levels of xylenes have been reported in groundwater
    associated with localized pollution from underground tanks and pipes,
    but the environmental significance of such values is difficult to
    assess.

         For the aquatic environment, the most sensitive toxicity test,
    based on  measured  concentrations, yielded an LC50 for  Daphnia
     magna of 1 mg/litre ( o-xylene).  This value is more than 10 000
    times higher than mean background concentrations in surface water,
    which are generally less than 0.1 µg/litre for each isomer.  The
    lowest LC50 is still over 30 times higher than the highest single
    measured concentration of total xylenes in the most polluted area. 
    The exposure/toxicity ratio will be much higher for mean
    concentrations in polluted areas.

         On the basis of rapid volatilization and degradation of xylenes
    and their low to moderate toxicity, the overall risk to the aquatic
    environment can therefore be considered low.  It should be noted,
    however, that very much higher levels have been measured around
    discharges from oil production sites, and higher levels are also
    possible if spillage occurs.

         The likely route of exposure for birds in the environment is via
    food such as fish.  The only acute toxicity test on birds was carried
    out on 14-day old Japanese quail and gave a 5-day LC50 of > 5000
    mg/kg diet.  Based on food consumption and body weight, an LD50 for
    the quail of > 1746 mg/kg body weight can be calculated.  Using this
    data an estimated LC50 for a fish-eating bird (kingfisher) based on
    body weight and food consumption can be calculated.

    LC50 (mg/kg dry weight diet) =

    Test species LD50 (mg/kg) × body wt (kg)
                                             
            food consumption (kg)

         The estimated LC50 for the fish-eating bird is > 7990 mg/kg
    diet.  The highest water  concentration (30 µg/litre) multiplied by
    the highest theoretical bioconcentration factor (158) gives a worst
    case residue level in fish of 4.7 mg/kg.  It should be noted that the
    bioconcentration factor does not take into account degradation or
    metabolism.  Comparing this value to the estimated LC50 value gives a
    Toxicity Exposure Ratio (TER) of > 1700.  Therefore, the risk to
    fish-eating birds is very low.

    11.  CONCLUSIONS

         Humans are exposed to xylene mainly by inhalation.  This compound
    does not accumulate significantly in the human body.  Acute exposure
    to high concentrations can result in CNS effects in human.  There have
    been no long-term controlled studies or epidemiological studies with
    exposure to xylene alone.  The chronic toxicity appears to be
    relatively low in laboratory animals.  There is suggestive evidence,
    however, that chronic CNS effects may occur in animals at moderate
    concentrations of xylene.  Xylene appears not to be a mutagen or a
    carcinogen.  The critical end-point is developmental toxicity.  Based
    on this end-point, the recommended guidance value for xylene in air
    for the general population is 0.87 mg/m3 (0.2 ppm).  This value is
    higher than the concentrations to which the general population is
    exposed.

         The xylene isomers are non-persistent chemicals, being readily
    degraded in the atmosphere, soil and water.  It should be noted that
     o-xylene appears to biodegrade only in the presence of other carbon
    sources and at a reduced rate compared to the other isomers.  The
    photooxidation reactions of the xylene isomers in the atmosphere may
    contribute to photochemical smog.

         It can be concluded that xylenes are unlikely to cause problems
    in aquatic ecosystems except near to localized industrial discharges
    and spillage incidents.  The risk to birds from xylene exposure is
    low.

    12.  FUTURE RESEARCH

         There is little information on the long-term effects of xylene in
    humans and, specifically, no dose-response or dose-effect data are
    available.  Epidemiological studies of populations occupationally
    exposed to xylene should be encouraged.  In this context the use of
    xylene metabolites in urine as a marker of exposure can be of special
    value because the method determines the internal doses that
    individuals receive via all routes of exposure.  Because xylene has
    acute effects on CNS, epidemiological studies should address the CNS
    as a potential target organ.  Moreover, since ethylbenzene is almost
    invariably one of the components in solvent mixtures at the workplace,
    study designs that address possible interactions between xylene and
    other solvent components are desirable.

         Animal studies are needed to address biochemical, functional and
    morphological evidence of chronic neurotoxicity and potential effects
    on fertility.  In addition, there is a need for further studies on
    developmental toxicity to assess the dose-response relationship and to
    estimate the NOAEL, especially for developmental neurotoxicity.

         Further studies are needed to determine the effect on hearing
    impairment in order to determine the NOAEL.  The relationship between
    the dose level and the length of the exposure period should also be
    investigated.  The effect of exposure to xylene together with noise
    should be studied.

    13. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

         The International Agency for Research on Cancer (IARC) has
    evaluated the carcinogenicity of xylene.  There was inadequate
    evidence for the carcinogenicity of xylene in humans as well as in
    experimental animals.  The overall evaluation was that xylene is not
    classifiable as to its carcinogenicity in humans (IARC, 1989).

         The European Commission (1991-1992) recommended an 8-h
    time-weighted average occupational exposure limit for xylene of 217
    mg/m3 (50 ppm).  To limit peaks of exposure that could result in
    irritation, a short-term exposure level (STEL) of 435 mg/m3 (100 ppm)
    was recommended.

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    RESUME

         Le xylčne est un hydrocarbure aromatique qui existe sous trois
    formes: les isomčres ortho, méta et para.  Le xylčne de qualité
    technique est un mélange des trois isomčres qui contient en outre un
    peu d'éthylbenzčne.  En 1984, la production mondiale de xylčne était
    estimée ą 15,4 millions de tonnes.  A la température ambiante, le
    xylčne se présente sous la forme d'un liquide incolore d'odeur
    aromatique.  La tension de vapeur est comprise entre 0,66 et 0,86 kPa
    pour les trois isomčres.  Environ 92% des mélanges de xylčnes sont
    incorporés ą l'essence.  On les utilise aussi comme solvants, en
    particulier dans les peintures et les encres d'imprimerie.

         La majeure partie du xylčne libéré dans l'environnement passe
    directement dans l'atmosphčre.  Les trois isomčres y sont rapidement
    décomposés, principalement par photooxydation.  Ils se volatilisent
    tous les trois rapidement ą partir de l'eau.  Dans le sol et dans
    l'eau, les isomčres méta et para subissent une biodégradation aisée
    dans des conditions variées d'aérobiose et d'anaérobiose; en revanche,
    l'isomčre ortho est plus persistant.  Les données limitées dont on
    dispose indiquent que les xylčnes isomčres s'accumulent peu chez les
    poissons et les invertébrés.  Une fois que l'exposition a cessé, ils
    sont assez rapidement éliminés par les organismes aquatiques.

         Les concentrations moyennes de fond des trois xylčnes dans l'air
    ambiant se situent autour de la valeur caractéristique de 1 µg/m3,
    mais dans les banlieues elles atteignent 3 µg/m3 environ.  On a
    mesuré des valeurs plus élevées en zone urbaine et industrielle, les
    moyennes allant cette fois jusqu'ą 500 µg/m3.  Toutefois, la
    concentration est en général inférieure ą 100 µg/m3.

         On estime que l'exposition journaličre de la population par la
    voie respiratoire est de 70 µg en milieu rural et de 2 000 µg en
    milieu urbain.  Dans l'eau de boisson, la concentration varie de zéro
    ą 12 µg/litre.  Les données concernant la concentration dans les
    denrées alimentaires sont trop limitées pour que l'on puisse évaluer
    l'exposition journaličre par voie orale.

         Dans les eaux superficielles, la concentration moyenne de fond
    des xylčnes est généralement inférieure ą 0,1 µg/litre.  Cependant, on
    a mesuré des valeurs beaucoup plus élevées dans des zones
    industrielles et plus particuličrement celles oł sont implantées des
    industries pétroličres (jusqu'ą 30 µg/litre dans les eaux polluées et
    jusqu'ą 2 000 µg/litre ą proximité des conduites de décharge).  Des
    valeurs analogues ont été observées dans les eaux souterraines, ces
    valeurs élevées pouvant źtre attribuées dans certains cas ą une
    pollution locale par des réservoirs et des canalisations enterrées.

         Aprčs exposition par la voie respiratoire, la dose inhalée est
    retenue ą 60% environ dans les poumons.  La métabolisation est
    efficace puisque le xylčne est transformé ą 90% en acide
    méthylhippurique, lequel est ensuite excrété dans les urines.  Le
    xylčne ne s'accumule pas en quantité importante dans l'organisme
    humain.

         Chez l'homme, une exposition aiguė ą du xylčne sous forte
    concentration peut avoir des effets sur le systčme nerveux central et
    provoquer une irritation.  Ces effets n'ont toutefois pas donné lieu ą
    des études contrōlées ni ą des études épidémiologiques ą long terme. 
    Chez les animaux de laboratoire, la toxicité chronique se révčle
    faible.  On a cependant de bonnes raisons de penser que sous
    concentration modérée, le xylčne pourrait avoir des effets sur le SNC
    chez l'animal.

         Le xylčne ne s'est révélé ni mutagčne ni cancérogčne.

         Le point d'aboutissement toxicologique essentiel concerne l'effet
    nocif que le xylčne exerce sur le développment.  On l'a mis en
    évidence chez le rat ą partir d'une concentration de 870 mg/m3 (200
    ppm).  Compte tenu de cela, la valeur-guide recommandée pour la
    concentration maximale de xylčne dans l'air a été fixée ą 0,87 mg/m3
    (0,2 ppm).

         Les xylčnes isomčres sont faiblement ą modérément toxiques pour
    les organismes aquatiques.  Chez les invertébrés, c'est l' o-xylčne
    qui a la Cl50 la plus faible (1 mg/litre pour  Daphnia magna).  Chez
    les poissons, la CL50 la plus faible est également celle de
    l' o-xylčne (7,6 mg/litre chez la truite arc-en-ciel, par mesure de
    concentration).  Des valeurs de 7,9 et 1,7 mg/litre ont été obtenues,
    respectivement pour le  m- et le  p-xylčne, dans le cas de la perche
    commune (d'aprčs la concentration nominale).  On ne dispose que de
    données limitées au sujet de l'exposition chronique des organismes
    aquatiques aux xylčnes, mais, quoi qu'il en soit, la volatilisation
    rapide de ces composés la rend peu probable.  Le xylčne ne présente
    qu'une faible toxicité aiguė pour les oiseaux.

    RESUMEN

         El xileno es un hidrocarburo aromįtico del que hay tres formas
    isoméricas: orto, meta y para.  El xileno de calidad técnica contiene
    una mezcla de los tres isómeros y algo de etilbenceno.  Se estima que
    la producción mundial fue de 15,4 millones de tone-ladas en 1984.  La
    presión de vapor estį comprendida entre 0,66 y 0,86 kPa para los tres
    isómeros. Aproximadamente un 92% de las mezclas de xilenos se combinan
    con el petróleo.  El producto se emplea también en diversos
    disolventes, en particular en las industrias de fabricación de
    pinturas y de tintas de imprenta.

         La mayor parte del xileno liberado en el medio ambiente pasa
    directamente a la atmósfera.  En ésta los isómeros de xileno se
    degradan con facilidad, principalmente por fotooxidación.  Los tres
    isómeros se volatilizan rįpidamente en la atmósfera a partir del agua. 
    En el suelo y el agua los isómeros meta y para se biodegradan
    fįcilmente en una amplia variedad de condiciones aerobias y
    anaerobias, pero el isómero orto es mįs persistente. Las limitadas
    pruebas disponibles parecen indicar que la bioacumulación de los
    isómeros de xileno por los peces y los invertebrados es baja.  La
    eliminación del xileno de los organismos acuįticos es bastante rįpida
    a partir del momento en que se interrumpe la exposición.

         Normalmente los niveles basales medios de los tres isómeros de
    xileno en el aire ambiente son de aproximadamente 1 µg/m3, pero en
    zonas suburbanas se hallan en torno a 3 µg/m3. Se han detectado
    concentraciones mayores en zonas urbanas e industrializadas, con
    niveles medios de hasta 500  µg/m3. No obstante, las concentraciones
    son por lo general inferiores a 100 µg/m3.

         La exposición diaria por inhalación estimada en la población
    general es de 70 µg en zonas rurales y de menos de 2000 µg en zonas
    urbanas. La concentración en el agua potable estį comprendida entre
    valores indetectables y 12 µg/litro. Los datos disponibles sobre la
    concentración en los alimentos son insuficientes para poder estimar la
    exposición oral diaria.

         Las concentraciones basales medias de xilenos en aguas
    superficiales son generalmente inferiores a 0.1 µg/litro. Sin embargo
    se han hallado valores mucho mįs altos en zonas industriales y en
    zonas vinculadas a la industria petrolera (hasta 30 µg/litro en aguas
    contaminadas y hasta 2000 µg/litro en las proximidades de tuberķas de
    desagüe).  Se ha informado del hallazgo de niveles basales similares
    en aguas subterrįneas, aunque se han detectado también concentraciones
    elevadas, atribuidas a contaminación localizada a partir de tanques de
    almacenamiento y tuberķas subterrįneos.

         Tras la exposición por inhalación la retención pulmonar es de un
    60% de la dosis inhalada.  El xileno es metabolizado eficientemente. 
    Mįs del 90% se biotransforma en įcido metilhipśrico, que se excreta
    por la orina.  El xileno no se acumula de forma significativa en el
    organismo humano.

         La exposición aguda a altas concentraciones de xileno puede
    afectar al SNC y causar irritación en el hombre.  Sin embargo, no se
    han llevado a cabo ni estudios controlados a largo plazo en el ser
    humano ni estudios epidemiológicos.  La toxicidad crónica parece
    relativamente baja en animales de laboratorio.  Hay indicios, no
    obstante, de que concentraciones moderadas de xileno pueden tener
    efectos crónicos sobre el SNC en animales.

         El xileno no parece tener efectos mutįgenos ni carcinógenos.

         El parįmetro crķtico es la toxicidad para el desarrollo,
    demostrada a niveles de exposición de 870 mg/m3 (200 ppm) en la rata. 
    Teniendo en cuenta este parįmetro, la concentración indicativa
    recomendada para el xileno en el aire es de 0.87 mg/m3 (0,2 ppm).

         Los isómeros de xileno poseen una toxicidad entre moderada y baja
    para los organismos acuįticos. En invertebrados la CL50 mįs baja,
    calculada a partir de las concentraciones medidas, es de 1 mg/litro
    para el  o-xileno  (Daphnia magna). Los valores mįs bajos de CL50
    detectados en peces son de 7,6 mg/litro para el  o-xileno (trucha
    arco iris; segśn las concentraciones medidas), y de 7,9 y 1,7 mg/litro
    para los  m- y  p-xilenos respectivamente (ambos para la lubina
    estriada; segśn las concentraciones nominales).  La información
    disponible respecto a la exposición crónica de organismos acuįticos a
    los xilenos es limitada; no obstante, su rįpida volatilización hace
    improbable la exposición crónica en el agua.  La toxicidad aguda del
    xileno para las aves es baja.
    


    See Also:
       Toxicological Abbreviations
       Xylenes (IARC Summary & Evaluation, Volume 71, 1999)