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.

    Published under the joint sponsorship of
    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    First draft prepared by Dr R.B. Williams,
    United States Environmental Protection Agency

    World Health Orgnization
    Geneva, 1993

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    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    WHO Library Cataloguing in Publication Data

    Methyl ethyl ketone.

        (Environmental health criteria ; 143)

        1.Butanones - adverse effects  2.Butanones - toxicity
        3.Occupational exposure    I.Series

        ISBN 92 4 157143 8        (NLM Classification: QV 633)
        ISSN 0250-863X

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    1. SUMMARY

         1.1. Properties and analytical methods
         1.2. Sources of exposure and uses
                1.2.1. Production and other sources
                1.2.2. Uses and loss to the environment
         1.3. Environmental transport and distribution
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism
         1.6. Effects on experimental species
         1.7. Effects on humans
                1.7.1. MEK alone
                1.7.2. MEK in solvent mixtures
         1.8. Enhancement of the toxicity of other solvents


         2.1. Identity
         2.2. Chemical and physical properties
         2.3. Conversion factors
         2.4. Sampling and analytical methods
                2.4.1. General considerations
                2.4.2. Air
                2.4.3. Water
                2.4.4. Solids
                2.4.5. Biological materials


         3.1. Natural occurrence
         3.2. Production levels, processes and uses
                3.2.1. World production
                3.2.2. Production processes
                3.2.3. Other sources
                3.2.4. Uses
         3.3. Release into the environment


         4.1. Transport in the environment
         4.2. Bioaccumulation and biodegradation


         5.1. Environmental levels
                5.1.1. Air
                5.1.2. Water
                5.1.3. Foodstuffs
         5.2. General population exposure
         5.3. Occupational exposure
         5.4. Peri-occupational exposure


         6.1. Absorption
                6.1.1. Percutaneous absorption
                6.1.2. Inhalation absorption
                6.1.3. Ingestion absorption
                6.1.4. Intraperitoneal absorption
         6.2. Distribution
         6.3. Metabolic transformation
                6.3.1. Animal studies
                6.3.2. Human studies
         6.4. Elimination and excretion
         6.5. Turnover
         6.6. Metabolic interactions
         6.7. Mechanisms of action


         7.1. Acute exposure
                7.1.1. Lethal doses
                7.1.2. Non-lethal doses
                7.1.3. Skin and eye irritation
         7.2. Repeated exposures
         7.3. Neurotoxicity
                7.3.1. Behavioural testing
                7.3.2. Histopathology
         7.4. Developmental toxicity
         7.5. Mutagenicity and related end-points
         7.6. Carcinogenicity


         8.1. General population exposure
         8.2. Effects of short-term exposure
         8.3. Skin irritation and sensitization
         8.4. Occupational exposure
                8.4.1. MEK alone
                8.4.2. MEK in solvent mixtures
         8.5. Carcinogenicity


         9.1. Microorganisms
         9.2. Aquatic organisms
         9.3. Terrestrial organisms
                9.3.1. Animals
                9.3.2. Plants


         10.1. Hexacarbon neuropathy
                10.1.1. Introduction
                10.1.2. Animal studies
                10.1.3. Human studies
                Solvent abuse
                Occupational exposure
         10.2. Haloalkane solvents
                10.2.1. Studies in animals
                10.2.2. Potentiation of haloalkane toxicity in humans


         11.1. Human health risks
                11.1.1. Non-occupational exposure
                11.1.2. Occupational exposure
                11.1.3. Relevant animals studies
         11.2. Effects on the environment


         12.1. Human heath protection
         12.2. Environmental protection



    APPENDIX 1. Conversion factors for various solvents





    Professor E.A. Bababunmi, Postgraduate Institute for Medical Research
         and Training, College of Medicine, Ibadan, Nigeria

    Dr P.E.T. Douben, Department of Ecotoxicology, Institute for Forestry
         and Nature Research, Arnhem, The Netherlands

    Professor C.L. Galli, Toxicology Laboratory, Institute of
         Pharmacological Sciences, University of Milan, Milan, Italy

    Dr R.F. Hertel, Fraunhofer Institute of Toxicology and Aerosol
         Research, Hanover, Germany

    Dr H.P.A. Illing, Head of Toxicology, Health and Safety Executive,
         Bootle, United Kingdom

    Professor A. Massoud, Department of Community, Environmental &
         Occupational Health, Faculty of Medicine, Ain Shams University,
         Abbassia, Egypt  (Joint Rapporteur)

    Dr K. Morimoto, Division of Chem-Bio Informatics, National Institute
         of Hygienic Sciences, Setagaya-ku, Tokyo, Japan

    Dr V. Riihimäki, Institute of Occupational Health, Helsinki, Finland

    Dr E. de Souza Nascimento, University of Sao Paulo, Sao Paulo, Brazil

    Dr H. Tilson, Neurotoxicology Division, Health Effects Research
         Laboratory, US Environmental Protection Agency, Research Triangle
         Park, USA

    Dr R.B. Williams, Office of Research and Development, US Environmental
         Protection Agency, Washington D.C., USA  (Joint Rapporteur)


    Dr P.G. Jenkins, International Programme on Chemical Safety, World
         Health Organization, Geneva, Switzerland

    Dr E. Smith, International Programme on Chemical Safety, World Health
         Organization, Geneva, Switzerland


         Every effort has been made to present information in the criteria
    monographs as accurately as possible without unduly delaying their
    publication. In the interest of all users of the Environmental Health
    Criteria monographs, readers are kindly requested to communicate any
    errors that may have occurred to the Director of the International
    Programme on Chemical Safety, World Health Organization, Geneva,
    Switzerland, in order that they may be included in corrigenda.

                                    * * *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Palais des
    Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or


         A WHO Task Group on Environmental Health Criteria for Methyl
    Ethyl Ketone (MEK) met at the World Health Organization, Geneva, from
    9 to 13 September 1991. Dr E. Smith welcomed the participants on
    behalf of Dr M. Mercier, Director, IPCS, and on behalf of the heads of
    the three IPCS cooperating organizations (UNEP/ILO/WHO). The Task
    Group reviewed and revised the draft monograph and made an evaluation
    of the risks for human health and the environment from exposure to

         The first draft of this monograph was prepared by Dr R.B.
    Williams, Office of Research and Development, US Environmental
    Protection Agency. Dr E. Smith and Dr P.G. Jenkins, both members of
    the IPCS Central Unit, were responsible for the scientific content and
    technical editing, respectively.

         The efforts of all who helped in the preparation and finalization
    of the monograph are gratefully acknowledged.


    ALT         alanine transferase

    BEI         biological exposure index

    DCB         dichlorobenzene

    DMA         dimethylamine

    DMF         dimethylformamide

    DNPH        2,4-dinitrophenyl hydrazine

    EBK         ethyl  n-butyl ketone

    ECD         electron-capture detection

    FID         flame ionization detection

    FT-IR       Fourier transform infrared

    GC          gas chromatography

    GLDH        glutamate dehydrogenase

    GPT         glutamic-pyruvic transaminase

    GST         glutathione-S-transferase

    2,5-HD      2,5-hexanedione

    2,5-Hpdn    2,5-heptanedione

    HPLC        high-performance liquid chromatography

    HS          headspace

    IR          infrared

    LC50        median lethal concentration

    LDQ         lowest detectable quantity

    MAC         maximum allowable concentration

    MBK         methyl  n-butyl ketone

    MEK         methyl ethyl ketone

    MIBK        methyl isobutyl ketone

    MS          mass spectrometry

    NADPH       reduced nicotinamide adenine dinucleotide phosphate

    OCT         ornithine carbamyl transferase

    PID         photo-ionization detection

    SRT         simple reaction time

    STEL        short-term exposure limit

    TLV         threshold limit value

    TWA         time-weighted average

    UV          ultraviolet

    1.  SUMMARY

    1.1  Properties and analytical methods

         Methyl ethyl ketone (MEK) is a clear, colourless, volatile,
    highly flammable liquid with an acetone-like odour. It is stable under
    ordinary conditions but can form peroxides on prolonged storage; these
    may be explosive. MEK can also form explosive mixtures with air. It is
    very soluble in water, miscible with many organic solvents, and forms
    azeotropes with water and many organic liquids. In the atmosphere MEK
    produces free radicals, which may lead to the formation of
    photochemical smog. 

         Several analytical methods exist for the measurement of MEK at
    environmental levels in air, water, biological samples, waste and
    other materials. In the more sensitive methods, MEK is trapped and
    concentrated either on a solid sorbant or as a derivative of
    2,4-dinitrophenylhydrazine (DNPH). Absorbed MEK and other volatile
    organic compounds are desorbed, separated by gas chromatography and
    measured with a mass spectrometer or flame ionization detector.
    Derivatized MEK is separated from related compounds by high
    performance liquid chromatography and measured by ultraviolet
    absorption. In media such as solid waste and biological materials, MEK
    must first be separated from the substrate by methods such as solvent
    extraction or steam distillation. High concentrations of MEK in air
    can be monitored continuously by infrared absorption. Detection limits
    are 3 µg/m3 in air, 0.05 µg/litre in drinking-water, 1.0 µg/litre in
    other types of water, 20 µg/litre in whole blood and 100 µg/litre in

    1.2  Sources of exposure and uses

    1.2.1  Production and other sources

         Recent values for annual industrial manufacture (in thousands of
    tonnes) are: USA, 212 to 305; western Europe, 215; Japan, 139. In
    addition to its manufacture, sources of MEK in the environment are
    exhaust from jet and internal combustion engines, and industrial
    activities such as gasification of coal. It is found in substantial
    amounts in tobacco smoke. In the USA, production of MEK by engines is
    no more than 1% of its deliberate manufacture. In smog episodes,
    photochemical production of MEK and other carbonyls from free radicals
    can be far greater than direct anthropogenic emission. MEK is produced
    biologically and has been identified as a product of microbial
    metabolism. It has also been detected in a wide diversity of natural
    products including higher plants, insect pheromones, animal tissues,
    and human blood, urine and exhaled air. It is probably a minor product
    of normal mammalian metabolism.

    1.2.2  Uses and loss to the environment

         The major use of MEK, application of protective coatings and
    adhesives, reflects its excellent characteristics as a solvent. It
    also is used as a chemical intermediate, as a solvent in magnetic tape
    production and the dewaxing of lubricating oil, and in food
    processing. In addition to industrial applications, it is a common
    ingredient in consumer products such as varnishes and glues. In most
    applications MEK is a component of a mixture of organic solvents.
    Losses to the environment are mainly to the air and result principally
    from solvent evaporation from coated surfaces. MEK is released into
    water as a component of the waste from its manufacture and from a
    variety of industrial operations. It has been detected in natural
    waters and could have originated from microbial activities and from
    atmospheric input, as well as from anthropogenic pollution.

    1.3  Environmental transport and distribution

         MEK is highly mobile in the natural environment and subject to
    rapid turnover. It is very soluble in water and evaporates readily
    into the atmosphere. In air MEK is subject to rapid photochemical
    decomposition and is also synthesized by photochemical processes. In
    water containing free halogens or hypohalites, it reacts to form a
    haloform that is more toxic than the original compound. MEK is
    distributed by both air and water, but does not accumulate in any
    individual compartment, and does not persist long where there is
    microbial activity. It is rapidly metabolized by microbes and mammals.
    There is no evidence of bioaccumulation. MEK occurs naturally in some
    clover species and is produced by fungi to concentrations that affect
    the germination of some plants.

    1.4  Environmental levels and human exposure

         General population exposure to low levels of MEK is widespread.
    In minimally polluted air, the concentration is less than 3 µg/m3
    (< 1 ppb), but a level of 131 µg/m3 (44.5 ppb) has been measured
    under conditions of heavy air pollution. Away from industrial areas
    where MEK is manufactured or used, major sources may be vehicle
    exhaust and photochemical reactions in the atmosphere. Cigarettes and
    other tobacco products that are burned contribute to individual
    exposure (20 cigarettes contain up to 1.6 mg). Volatilization of MEK
    from building materials and consumer products can pollute indoor air
    to levels far above adjacent outdoor air. MEK concentrations in
    exposed natural waters are rarely above 100 µg/litre (100 ppb) and are
    usually below a detectable level. Trace amounts of MEK, however, have
    been detected widely in drinking-water (approximately 2 µg/litre) and
    presumably originated as solvent leached from cemented joints of
    plastic pipe. Although MEK is a normal component of many foods,
    concentrations are low and food consumption cannot be considered a
    significant source of population exposure. Average daily per capita
    intake in the USA via foodstuffs is estimated to be 1.6 mg, most

    coming from white bread, tomatoes and Cheddar cheese. In addition to
    MEK present naturally, foods may contain MEK from cheese ripening,
    aging of poultry meat, cooking or food processing, or by absorption
    from plastic packaging materials.

         Industrial exposure to moderate levels of MEK is widespread.
    However, in some regions workers in small factories (e.g., shoe
    factories, printing plants and painting operations) are exposed to
    much higher concentrations due to inadequate ventilation. In these
    factories, exposure is usually to a mixture of solvents including

    1.5  Kinetics and metabolism

         Absorption of MEK is rapid via dermal contact, inhalation,
    ingestion and intraperitoneal injection. It is rapidly transferred
    into the blood and thence to other tissues. The solubility of MEK
    appears similar for all tissues. The clearance of MEK and its
    metabolites in mammals is essentially complete in 24 h. It is
    metabolized in the liver where it is mainly oxidized to
    3-hydroxy-2-butanone and subsequently reduced to 2,3-butanediol. A
    small portion may be reduced to 2-butanol, but 2-butanol is rapidly
    oxidized back to MEK. The bulk of MEK taken into the mammalian body
    enters the general metabolism and/or is eliminated as simple compounds
    such as carbon dioxide and water. Excretion of MEK and its
    recognizable metabolites is mainly through the lungs, although small
    amounts are excreted via the kidneys.

         MEK increases microsomal cytochrome P-450 enzyme activities. This
    enhancement of enzymatic activity and thus of the body's potential for
    metabolic transformation may well be the mechanism by which MEK
    potentiates the toxicity of haloalkane and aliphatic hexacarbon

    1.6  Effects on experimental species

         MEK has low to moderate acute, short-term and chronic toxicity
    for mammals. LD50 values for adult mice and rats are 2 to 6 g/kg
    body weight, death occurring within 1 to 14 days following a single
    oral dose. Average vapour concentrations producing lethality in rats
    following a single exposure are around 29 400 mg/m3 (10 000 ppm),
    although guinea-pigs survived a 4-h exposure to this concentration.
    The lowest acute oral dose modifying body structure is 1 g/kg body
    weight, which damaged kidney tubules in the rat. Inhalation by rats of
    74 mg/m3 (25 ppm) for 6 h produced measurable changes in behaviour
    which persisted for several days. Repeated exposure of rats to 14 750
    mg/m3 (5000 ppm) (6 h/day, 5 days/week) produced no lethality, had
    only minor effects on growth and structure, and there were no
    neuropathological changes. There was no evidence that MEK produced
    neuropathological changes in chickens, cats or mice exposed to 3975
    mg/m3 (1500 ppm) for periods of up to 12 weeks. Transient effects on

    behaviour or neurophysiology were detected following repeated exposure
    of rats and baboons to concentrations as low as 295-590 mg/m3 (100
    to 200 ppm).

         There is evidence for a low level of fetotoxicity without any
    maternal toxicity at 8825 mg/m3 (3000 ppm), but no evidence for
    embryotoxic or teratogenic effects at lower exposure levels. Repeated
    exposure of pregnant rats to 8825 mg/m3 induced in their offspring
    a small but significant increase in skeletal abnormalities of types
    that occurred at low incidences among the unexposed population.

         Although examined in a number of conventional mutagenicity test
    systems, the only evidence of mutagenicity was provided by a study on
    aneuploidy in the yeast  Saccharomyces cerevisiae.

         MEK is not acutely toxic to fish or aquatic invertebrates and
    LC50 values range from 1382 to 8890 mg/litre. 

         MEK has an inhibiting effect on the germination of several plant
    species, even at levels occurring naturally. The growth of aquatic
    algae is inhibited.

         Compared with natural background levels, relatively high
    concentrations of MEK have been used for fumigation under experimental
    conditions. It is moderately effective as a fumigant against the
    Caribbean fruit fly and is a very effective attractant for tsetse
    flies. Levels of MEK up to 20 mg/litre retard biodegradation but do
    not stop the process entirely. At levels of up to 100 mg/litre, MEK is
    biostatic to a variety of bacteria. At higher concentrations (1000
    mg/litre or more) inhibition of the growth of bacteria and protozoa

    1.7  Effects on humans

    1.7.1  MEK alone

         Exposure to 590 mg/m3 (200 ppm) had no significant effect in a
    variety of behavioural and psychological tests. Short-term exposure to
    MEK alone does not appear to be a significant hazard, either
    occupationally or for the general public. Experimental exposure to a
    concentration of 794 mg/m3 (270 ppm) for 4 h/day had little or no
    effect on behaviour, and a 5-min contact with liquid MEK produced no
    more than a temporary whitening of the skin. There is only one
    non-occupational report of acute toxicity to MEK. This resulted from
    accidental ingestion and appeared to produce no lasting harm. There is
    no evidence that occupational MEK exposure has resulted in death.
    There have been two reports of chronic occupational poisoning and one
    questionable report of acute occupational poisoning. In one of the
    chronic cases, exposure to 880-1770 mg/m3 (300-600 ppm) resulted in
    dermatoses, numbness of fingers and arms, and various symptoms such as
    headache, dizziness, gastrointestinal upset, and loss of appetite and

    weight. This paucity of incidents of reputed poisoning by MEK alone
    reflects both the low toxicity of MEK and the fact that it is most
    commonly used not on its own but as a component of solvent mixtures.

    1.7.2  MEK in solvent mixtures

         Exposure to solvent mixtures containing MEK has been associated
    with some reduction in nerve conduction velocity, memory and motor
    alterations, dermatoses and vomiting. In one longitudinal study,
    consecutive measurements of simple reaction time showed an improvement
    in performance in parallel with decreasing concentrations of MEK to
    one tenth the original values (which were up to 4000 mg/m3 for
    certain routine tasks). 

    1.8  Enhancement of the toxicity of other

         MEK potentiates the neurotoxicity of hexacarbon compounds
    ( n-hexane, methyl- n-butylketone and 2,5-hexanedione) and the liver
    and kidney toxicity of haloalkane (carbon tetrachloride and
    trichloromethane) solvents.

         The potentiation of the neurotoxic effects of hexacarbons has
    been demonstrated for all three hexacarbons in animals. The peripheral
    neuropathies observed in humans followed changes in the formulations
    of solvents to which they had been exposed, either voluntarily or
    occupationally. The mechanism by which this potentiation occurs is

         Evidence for potentiation of the liver and kidney toxicity of
    haloalkanes comes from animal studies. MEK probably activates the
    haloalkane metabolism to tissue-damaging species as a result of
    induction of the relevant oxidation enzymes. 


    2.1  Identity

                                      H   H   O   H
                                      |   |   ||  | 
    Chemical structure:           H - C - C - C - C - H
                                      |   |       |
                                      H   H       H

    Chemical formula:             C4H8O

    Synonyms:                     Butanone, 2-butanone, butane-2-one,
                                  ethyl methyl ketone, MEK, MEETCO,
                                  methyl acetone, methylpropanone 

    CAS registry number:          78-93-3

    RTECS registry number:        EL 6475000

    UN registry number:           1193

    EC registry number:           606-002-00-3

    Relative molecular mass:      72.10

    2.2  Chemical and physical properties

         Methyl ethyl ketone (MEK) is an important synthetic organic
    chemical. The physical properties of MEK are summarized in Table 1. It
    is a highly flammable, volatile, clear, colourless liquid that is
    stable under ordinary conditions. The vapour forms explosive mixtures
    with air over a range of approximately 2% to 12% (vol./vol.). The
    odour is acetone-like and variously described as sharp, fresh or
    sweet. The odour threshold appears to be around 5.9 mg/m3 (2 ppm)
    although a range between 0.74 and 147.5 mg/m3 has been reported
    (Ruth, 1986). MEK is moderately soluble in water; the solubility
    decreases with increasing temperature. It is miscible with organic
    solvents such as alcohol, ether and benzene, and forms azeotropes with
    water and many organic liquids.

         The value in Table 1 for log Po/w (logarithm of the octanol/
    water partition ratio) of 0.26 is taken from Verschuren (1983).
    Banergee & Howard (1988) quoted a slightly higher value of 0.29. Other
    partition values for MEK (at 37 °C) are: water/air = 254; blood/air =
    202; olive oil/air = 263; olive oil/water = 1.0; and olive oil/blood
    = 1.3 (Sato & Nakajima, 1979). Perbellini et al. (1984), however,
    determined partition values for saline solution/air and olive oil/air
    of 193 and 191 respectively.

        Table 1. Physical properties of MEK
    Appearance                          colourless liquid

    Relative molecular mass                   72.10          Papa & Sherman (1978)

    Specific gravity (liquid density)
     (at 20 °/4 °C)a                          0.805          Krasavage et al. (1982)

    Vapour density (air = 1.00)               2.41           Verschuren (1983)

    Vapour pressure at 20 °C (torr)           77.5           Weast (1986)

    Boiling point (°C)                        79.6           Weast (1986)

    Melting point (°C)                         -86           Weast (1986)

    Water solubility at 20 °C (g/litre)        275           Windholz (1983)

    Refractive index                         1.3788          Krasavage et al. (1982)

    Flash point (closed cup) (°C)              -6            Papa & Sherman (1978)

    Log Po/w                                  0.26           Verschuren (1983)
                                              0.29           Banergee & Howard (1988)

    Saturation concentration in
     air (g/m3 at 20 °C)                       301           Krasavage et al. (1982)

    a Specific gravity at 20 °C relative to the density of water at 4 °C
         The physical and chemical properties of MEK are determined
    largely by its carbonyl group. MEK engages in reactions typical of
    saturated aliphatic ketones. These include condensations with amines,
    aldehydes and many other organic compounds, hydrolysis (catalysed with
    acid or base), oxidation via concentrated oxidizing acids or acidic
    peroxides, and reduction with hydrogen and metal catalysts. None of
    these reactions is likely to be important in nature. On the other
    hand, MEK and other methyl ketones will react with halogens and
    hypohalides in aqueous solution to form a carboxylic acid and a
    haloform. The reaction provides a specific test for methyl ketones,
    and may produce chloroform in chlorinated water supplies contaminated
    with methyl ketones. MEK and other ketones are photochemically
    reactive when excited by wavelengths occurring in the atmosphere and
    produce free radicals which lead to the formation of photochemical
    smog (Grosjean et al., 1983).

    2.3  Conversion factors

         1 ppm = 2.95 mg/m3; 1 mg/m3 = 0.34 ppm
         (at 25 °C and 101.3 kPa)

    2.4  Sampling and analytical methods

    2.4.1  General considerations

         Analytical methods for MEK depend on the matrix. They are
    summarized in Table 2.

         Where MEK is present in a substantial concentration and is known
    to be the only or the dominant organic contaminant, simplified
    methodology is feasible. The occupational atmospheric exposure limits,
    currently in the range 295-590 mg/m3 (100-200 ppm), permit
    monitoring in the workplace with less sensitive procedures.

         The precise determination of MEK when present in the environment
    at low concentrations is a complex task because of the wide variety of
    other organic compounds that may be present and the many possibilities
    for error, interference and contamination. MEK, other ketones and
    other interfering substances are so prevalent in laboratory and
    industrial air that care must be taken in all determinations to
    minimize the possibility of contamination of samples, equipment and
    reagents. Care must be taken to avoid contamination in sampling since,
    for example, easily unnoticed sources like PVC (polyvinyl chloride)
    glue in collection equipment may leach a significant amount of MEK
    into water samples (Kent et al., 1985).

        Table 2.  Some analytical techniques for determining MEK concentrations in environmental media and biological materialsa
                   Methods                        Detection       Comments                                             Reference

    Trapping in solid sorbant tube (Tenax(R));    200 µg/m3       working range is 0.2-100 mg/m3; analysis can         Brown & Purnell
    thermal desorption: separation-detection;                     be automated                                         (1979)

    Trapping in DNPH; separation: HPLC            3-6 µg/m3       general method for aldehydes and ketones in          Riggin (1984)
    (reverse phase); detection: UV                                air; some isomeric aldehydes and ketones are
    absorption                                                    not well separated

    Trapping in solid sorbant tube               0.15 mg per      working range is 50-1500 mg/m3; acetone and          US NIOSH (1984a)
    (Ambersorb XE-347(R)); desorption:             sample         isopropanol interfere
    CS2; separation-detection: GC-FID

    Absorption of specific IR wavelengths          3 mg/m3        can measure several different pollutant              Persson et al.
    from CO2 laser; automated, computer-                          vapours simultaneously and continuously              (1984)
    controlled system

    Trapping in DNPH; colour matching             300 mg/m3       working range is 300-1200 mg/m3; other               Smith & Wood
    against standards                                             aldehydes and ketones interfere; method              (1972)
                                                                  requires no specialized equipment


    Separation from water sample by heated        0.05-1.0        water samples must be preserved from bacterial       Pellizzari et al.
    gas purge; trapping on Tenax(R); thermal      µg/litreb       action with methylene chloride, and free chlorine    (1985)
    desorption; separation-detection: GC/MS                       removed with thiosulfate; achieving lower limit
                                                                  of detection requires concentration by 
                                                                  distillation; no interference reported

    Table 2 (contd.)
                   Methods                        Detection       Comments                                             Reference

    Concentration on zeolite (ZSM-5);            2 µg/litre       developed for drinking-water analysis; no            Ogawa & Fritz
    elution with acetonitrile; derivatization                     interference reported                                (1985)
    with DNPH; separation-detection: HPLC/UV

    Direct injection of aqueous sample;          40 µg/litre      developed for industrial waste-water analysis;       Middleditch et al.
    separation-detection: GC/FID                                  no interference reported                             (1987)


    Solvent extraction with tetraethylene        0.5-5 µg/g       tetraglyme must be purified and stabilized to        Gurka et al.
    glycoldimethyl ether (tetraglyme); purge    (wet weight)      prevent peroxide formation; no interference          (1984)
    and trap; separation-detection: GC/MS                         reported

    Heated purge of sample/water slurry or        10 µg/kg        method developed for volatile organic compounds      Fisk (1986)
    of methanol extract of sample; trap;        (wet weight)      at concentrations of < 1 mg/kg; no interference
    desorption; separation-detection: GC/MS                       reported

    Biological Materials

    Mixture with dextrose and heating;           20 µg/litre      method developed for simultaneous determination      US NIOSH (1984b)
    HS analysis; GC/FID                                           of MEK, toluene and ethenol in blood; recovery
                                                                  rates 90-98%

    Incubation in sealed vial; HS               100 µg/litre      method developed for blood; uses 200-µl sample;      Ramsey & Flanagan
    analysis; separation-detection:                               applicable to urine and tissue; no interference      (1982)
    GC/FID and ECD                                                reported

    Concentration by reverse-phase                 100-150        method developed for MEK and its metabolites         Kezic & Monster
    extraction column; separation-                µg/litre        in urine; no interference reported                   (1988)
    detection: GC/FID

    Table 2 (contd.)
                   Methods                        Detection       Comments                                             Reference

    Derivatized with  o-nitrophenylhydrazine     100 µg/litre      method developed for the determination of MEK        Van Doorn et al.
    and reacted with cyclohexane;                                 in human urine                                       (1989)
    centrifuge separation; reversed-
    phase HPLC; UV (254 nm)

    Steam distillation of slurry; HS             20 µg/litre      method developed for cheese, but probably            Lin & Jeon (1985)
    analysis; separation-detection:                               widely applicable; no interference reported

    Homogenization; HS analysis;                 6 mg/litre       method developed for the identification of           Deveaux & Huvenne
    GC/FT-IR                                                      solvents of abuse in biological fluids               (1987)

    a    Abbreviations used in the table
              DNPH   2,4-dinitrophenylhydrazine
              ECD    electron-capture detector
              FID    flame ionization detector
              FT     Fourier transformed
              GC     gas chromatograph
              HPLC   high performance liquid chromatograph
              HS     headspace
              IR     infrared
              MS     mass spectrometer
              UV     ultraviolet
    b    0.05 µg/litre for drinking-water; 1.0 µg/litre for all other types of water

         The general procedure for analysis of MEK is summarized below:

    a)   collect the sample, and if necessary, chemically stabilize it;

    b)   separate MEK (and other volatile organic compounds) from the

    c)   trap and concentrate MEK (plus other organic compounds);

    d)   recover the trapped material;

    e)   separate MEK and other organic compounds;

    f)   detect and identify MEK;

    g)   determine the quantity recovered;

    h)   calculate the concentration present in the sample. 

    In actual practice the procedure may be simplified by combining or
    omitting certain steps, or it may contain an additional step, i.e. the
    preparation of 2,4-dinitrophenylhydrazine (DNPH) derivatives of MEK
    and other aldehydes and ketones. The formation of DNPH derivatives
    quantitatively captures both aldehydes and ketones, and facilitates
    their subsequent separation with either gas or liquid chromatography.
    The preparation of DNPH derivatives also forms the basis for a
    simplified, non-specific method for roughly measuring high levels of
    ketones and aldehydes without the use of sophisticated laboratory
    equipment (Smith & Wood, 1972). The use of other derivatives, such as
    imines via phenylmethylamine (Hoshika et al., 1976), azines via
    3-methyl-2-benzothiazolone (Chiavari et al., 1987), and
     O-(2,3,4,5,6-pentafluorobenzyl) oximes via
    pentafluorophenylhydrazine and pentafluorobenzyloxyamine (Kobayashi et
    al., 1980) has also been proposed.

    2.4.2 Air

         A general methodology for determining MEK in air consists of
    trapping and concentrating MEK and other volatile organic compounds in
    sampling devices containing an absorbent material, charcoal
    (carbopack) or an artificial resin (Tenax GC(R), Ambersorb XE(R),
    Amberlites XAD(R)), followed by desorption and analysis. 

         MEK decomposes when absorbed on charcoal and sample loss may
    occur after a few days (Elskamp & Schultz, 1983; Levin & Carleborg,
    1987). Ambersorb XE(R) showed good capacity, and decomposition was
    insignificant (Levin & Carleborg, 1987). Kenny & Stratton (1989)
    evaluated various mixtures to find a solvent that would provide
    optimum desorption efficiency. For samples of MEK collected on
    charcoal tubes, a mixture of carbon disulfide with 10% amyl alcohol
    was found to be an effective desorption solvent. The substitution of

    hexyl for amyl alcohol gave comparable recovery but slower GC/FID
    analysis. Both thermal desorption and solvent desorption have been
    used to release the MEK from the trapping column.

         Collectors may be passive and dependent on diffusion or a packed
    tube through which a known volume of air is drawn. Passive collectors,
    often in the form of badges, avoid the need for specialized sampling
    equipment and are convenient for monitoring individual exposure.
    However, the results of several studies suggest that passive
    (diffusive) collectors not only show significant individual and brand
    variability but also variability in their speed of uptake of different
    solvent vapours (Hickey & Bishop, 1981; Feigley & Chastain, 1982), and
    thus may require calibration against a more quantitative method. The
    trapped organic compounds are desorbed either thermally by application
    of heat or microwave radiation, or by solution in carbon disulfide,
    and are separated with gas chromatography. A wide diversity of columns
    and packings have been found satisfactory for this separation. 

         Using gas chromatography with a flame ionization detector, an
    overall precision (Sr) of 0.069 with a limit of detection of 0.004
    mg/sample was achieved (US NIOSH, 1984a).

         Methodology for analysing air samples recommended by the United
    States Environmental Protection Agency (US EPA) can detect MEK and
    most other mono-functional aldehydes and ketones at the 3-6 µg/m3
    (1-2 ppb) level (Riggin, 1984). Air is drawn through a mixture of
    isooctane and an acidified solution of 2,4-dinitrophenylhydrazine
    (DNPH), which reacts chemically with MEK. DNPH derivatives of
    aldehydes and ketones are extracted from the aqueous layer, separated
    with high performance liquid chromatography (HPLC) and detected by
    ultraviolet absorption. 

         MEK vapour can also be detected and measured directly and
    instantaneously by absorption of infrared light. The method (detection
    limit, 3 mg/m3) appears suitable for use in the workplace where only
    a limited number of solvent vapours are present (Persson et al., 1984)
    but may not reliably detect MEK in the presence of a diverse mixture
    of organic vapours, due to overlapping of infrared absorption peaks
    (Puskar et al., 1986). Ying & Levine (1989) used Fourier
    transform-infrared spectrometry (FT-IR) to determine the concentration
    of MEK in mixtures of vapours in ambient air and obtained a detection
    limit of 1 mg/m3. Surface acoustic wave devices have been tested
    experimentally for the detection of MEK and other vapours
    (Rose-Pehrsson et al., 1988) and show promise for the development of
    electronic devices that can continuously monitor and analyse vapour
    mixtures at concentrations likely to be present in the work

    2.4.3  Water

         Water samples containing high levels of MEK (e.g., industrial
    waste water) can be analysed by direct injection of the sample into a
    gas chromatograph; the detection limit is 40 µg/litre (Middleditch et
    al., 1987). Samples with low levels of MEK (e.g., drinking-water)
    require some form of concentration such as distillation (Pellizzari et
    al., 1985) or adsorption on a hydrophobic zeolite (Ogawa & Fritz,
    1985). GC/MS analysis gives a detection limit of 0.05 µg/litre
    (Pellizzari et al., 1985) whereas HPLC with UV detection has a
    detection limit of 2 µg/litre (Ogawa & Fritz, 1985).

    2.4.4  Solids

         Analysis of solid and semisolid materials such as industrial
    wastes for MEK presents special difficulties in terms of both sampling
    and analysis. The sample must be representative and of adequate size,
    since substrates such as waste tend to be very non-homogeneous and MEK
    must be completely removed from both solid and liquid components. One
    method accomplishes this by extracting the sample with an appropriate
    solvent (tetraglyme) and purging MEK and other volatile organics from
    the tetraglyme with an inert gas (Gurka et al., 1984). Another method
    (Fisk, 1986) either directly purges MEK and other organic compounds
    from a water/solid material slurry held at an elevated temperature or
    purges a methanol extract of the solid material at an elevated

    2.4.5  Biological materials

         Biological materials offer the same analytical problems as solid
    waste: MEK must be completely removed from both solid and liquid
    components of the sample. This can be accomplished by headspace
    analysis (Ramsey & Flanagan, 1982; US NIOSH, 1984b), steam
    distillation of a sample slurry followed by headspace analysis
    (Bassette & Ward, 1975; Lin & Jeon, 1985), derivation with
     o-nitrophenylhydrazine (Van Doorn et al., 1989) and, in the case of
    an entirely liquid substrate, separation and concentration by
    reverse-phase extraction (Kezic & Monster, 1988). 

         For MEK in blood the United States National Institute of
    Occupational Safety and Health method (US NIOSH, 1984b), using GC/FID,
    has a detection limit of 20 µg/litre and the Ramsey & Flanagan (1982)
    method has a detection limit of 100 µg/litre. The latter method can
    also be used for the analysis of MEK in urine with the same limit of
    detection. Other methods for analysis in urine are those of Kezic &
    Monster (1988), using GC/FID, and Van Doorn et al. (1989) using
    HPLC/UV; both methods have limits of detection of 100 µg/litre. 


    3.1  Natural occurrence

         MEK occurs naturally at low concentrations. It has been
    identified in cigarette smoke (Osborne et al., 1956; Hoshika et al.,
    1976; Higgins et al., 1983). It also has been reported in chicken
    breast muscle (Grey & Shrimpton, 1967), weed residues (Bradow &
    Connick, 1988), southern pea seeds (Fisher et al., 1979), insect
    pheromones (Cammaerts et al., 1978; Attygalle et al., 1983), juniper
    leaves (Khasanov et al., 1982); marine macroalgae (seaweeds) (Whelan
    et al., 1982) and as a product of microbial metabolism (Patel et al.,
    1982; Mohren & Juttner, 1983; Zechman et al., 1986), including
    cultures isolated from fresh water and soil (Hou et al., 1983; Patel
    et al., 1983). Berseem clover, hairy vetch and crimson clover emitted
    volatile compounds including MEK (Bradow & Connick, 1990). Six
    amaranth species emit MEK which has been shown to cause significant
    inhibition of tomato and onion seed germination (Connick et al.,
    1989). Some bacteria (e.g., thermophilic obligate methane-oxidizing
    bacteria) can oxidise 2-butanol to produce MEK (Imai et al., 1986).
    Studies have shown that MEK is a normal component of flavour and odour
    in a wide range of foods, especially cheese and other fermented
    products (Zakhari et al., 1977), often as a result of bacterial
    activity (Lin & Jeon, 1985). Seven types of fish contain MEK, although
    reported levels were low relative to other compounds (Sakakibara et
    al., 1990). MEK has been detected in coyote urine (Schultz et al.,
    1988), in the urine of non-occupationally exposed humans (Tsao &
    Pfeiffer, 1957; Mabuchi, 1969), in human blood (Mabuchi, 1969) and in
    exhaled air (Conkle et al., 1975). The MEK in exhaled air may have
    been derived from food, but the observations of Poli et al. (1985) and
    other researchers (see section 6) strongly suggest that MEK and
    similar carbonyl compounds are minor products of normal mammalian

    3.2  Production levels, processes and uses

    3.2.1  World production

         Although MEK is an important industrial chemical, world
    production figures are not available. Annual production in the USA,
    reported by the US International Trade Commission, ranged from 212 to
    305 thousand tonnes over the period 1980-1987 and averaged 258
    thousand tonnes (USITC, 1981-1988). Current (1987) annual capacity and
    production values for western Europe are 308 and 215 thousand tonnes,
    respectively (Chemical Business Newsbase, 1988). Japanese annual
    capacity and production figures in 1986 were 180 and 139 thousand
    tonnes, respectively (Chemical Business Newsbase, 1987). Argentinean
    annual capacity was 15 thousand tonnes in 1985 (Chemical Business
    Newsbase, 1986). A production plant opened in Brazil in 1991 but
    information on capacity and production is not available (personal
    communication from E. de S. Nascimento).

    3.2.2  Production processes

         MEK is produced mainly by dehydrogenation of  sec-butyl alcohol
    (Liepins et al., 1977; SRI International, 1985, 1988). In the USA, one
    process uses  sec-butyl alcohol vapour at 400 to 550 °C oxidized with
    a zinc oxide catalyst. Reaction gases are condensed and the condensate
    fractionated in a distillation column. The yield of MEK is 85 to 90%
    (Lowenheim & Moran, 1975). Any uncondensed reaction gases are scrubbed
    with water or a non-aqueous solvent and the waste stream from the
    scrubber, which contains MEK and reaction by-products, is either
    recycled or discarded (Liepins et al., 1977). In Europe,  sec-butyl
    alcohol is dehydrogenated over Rainey nickel or copper chromite
    catalyst at 150 °C (Papa & Sherman, 1978)

         MEK is also produced by the oxidation of  n-butane, either as
    the main product or as a by-product in the manufacture of acetic acid
    (Liepins et al., 1977; Papa & Sherman, 1978). Liquid butane reacts
    with compressed air in the presence of a transition metal acetate
    catalyst, normally cobalt acetate, and the reaction product phase is
    separated. The hydrocarbon-rich phase is recycled to the reactor and
    the aqueous phase with MEK is withdrawn and purified. MEK and other
    organic compounds with low boiling points are separated from acetic
    acid by distillation. Reaction conditions determine whether MEK or
    acetic acid is the principal product (Lowenheim & Moran, 1975). Butane
    oxidation accounted for about 13% of the 1987 MEK production capacity
    in the USA (SRI International, 1988) but for none of the 1984
    production capacity in western Europe (SRI International, 1985). Other
    methods exist for the commercial manufacture of MEK (Papa & Sherman,
    1978), but there is no evidence that any of these alternatives are of
    current importance.

    3.2.3  Other sources

         In addition to manufacture by the chemical industry, MEK and
    other carbonyls are incidentally produced as components of exhaust
    from jet (Miyamoto, 1986) and internal combustion engines (Seizinger
    & Dimitriades, 1972; Creech et al., 1982; Hampton et al., 1982) and
    from industrial activities such as retort distillation of oil shale
    (Hawthorne et al., 1985) and gasification of coal (Pellizzari et al.,
    1979). MEK comprises about 0.05% of the hydrocarbon exhaust gases of
    motor vehicles, and in 1987 the vehicle emission of MEK in the USA was
    estimated to be 1909 tonnes (Somers, 1989). Thus its anthropogenic
    production by vehicles plus an additional amount by stationary engines
    was no more than 0.1% of the industrial production in the USA.
    Grosjean et al. (1983) concluded, however, that during smog episodes
    in the Los Angeles basin much of the ambient level of MEK was produced

    3.2.4  Uses

         The major uses of MEK reflect its excellent characteristics as a
    solvent (Table 3). Its high solvency for gums, resins and many
    synthetic polymers permits formulations with high solid content and
    low viscosity. It is also inert to metal, evaporates rapidly, and is
    relatively low in toxicity compared with solvents like benzene which
    MEK replaced (Zakhari et al., 1977; Basu et al., 1981). 

    Table 3. Major uses of MEK in the USAa

             End use                                 %

         Solvent - protective coatings              65

         Solvent - adhesives                        15

         Solvent - magnetic tape production          8

         Lubricating oil dewaxing                    5

         Chemical intermediate                       4

         Miscellaneous                               3

    a From: Manville Chemical Products Corp. (1988) 

         The largest single use of MEK is as a solvent for vinyl plastic
    used in coatings and moulded articles. Other important uses are as a
    solvent for lacquers and for cellulose nitrate, cellulose acetate,
    acrylics, and adhesive coatings. Its properties as a selective solvent
    make it ideal for dewaxing lubricating oils. MEK is also used for
    degreasing metals, in the manufacture of magnetic tapes, inks and
    smokeless powder, and as a chemical intermediate in the production of
    methyl ethyl ketoxime, MEK peroxide, methyl isopropyl ketone and many
    other compounds.

         In addition to industrial uses, MEK is an ingredient in a variety
    of consumer products such as lacquers, varnishes, spray paints, paint
    removers, sealers and glues (Zakhari et al., 1977). In both consumer
    products and industrial applications, MEK is frequently only one of
    several components in a mixture of organic solvents. 

         MEK is also used as an extraction solvent in the processing of
    foodstuffs and food ingredients, e.g., in fractionation of fats and
    oils, decaffeination of tea and coffee, and extraction of flavourings.

    3.3  Release into the environment

         Releases of MEK are mainly into the atmosphere (Reilly, 1988).
    These can result from: spillage; venting of gases and fugitive
    emissions during manufacture, transfer and use; solvent evaporation
    from coated surfaces; loss from landfills and waste dumps; and engine
    exhaust (Basu et al., 1981; LaRegina & Bozzelli, 1986). Relatively
    little MEK is lost during manufacture when the process is enclosed.
    The average annual release from four manufacturing plants in the USA
    was estimated to be 82 tonnes per site, equal to a total of 328 tonnes
    or about 0.1% of their annual production (Reilly, 1988).

         The bulk of MEK eventually evaporates to the atmosphere, since
    the major use of MEK is as a solvent for coatings and adhesives. In
    industry, some of the MEK evaporated from surface coatings or lost
    during cooking and thinning of resin is removed from the ventilation
    exhaust by absorption on charcoal filters or by incineration of the
    exhaust stream. The latter method can reduce emission by up to 97%
    (Gadomski et al., 1974), and removal is accomplished in a single step
    without generating a residue for subsequent disposal (DiGiacomo,

         The waste stream from MEK production contains acetic acid and a
    variety of alcohols, aldehydes, ketones and other organic compounds.
    It is likely that butane and other organic compounds are discharged
    into the atmosphere from the reaction section, but no specific
    information is available (Liepins et al., 1977). 

         MEK is released from other industrial operations involving its
    use, and from activities such as retort distillation of oil shale and
    gasification of coal (Pellizzari et al., 1979; Hawthorne et al.,

         It has been detected in drinking-water (Ogawa & Fritz, 1985), in
    well water (Jacot, 1983), in ground water (Botta et al., 1984) and in
    leachate from a hazardous waste site (Jacot, 1983). MEK occurs in
    water often as a result of natural processes (section 3.1).
    Atmospheric input and direct anthropogenic pollution contribute
    significantly to elevated levels (Grosjean & Wright, 1983). 


    4.1  Transport in the environment

         MEK appears to be highly mobile in the natural environment (Lande
    et al., 1976). It is water soluble (Windholz, 1983) and evaporates
    rapidly in air. The generally low values for MEK in outdoor air
    probably stem mainly from its rapid removal by photodecompo-sition.
    Scavenging by aqueous droplets and dry deposition, which also
    represent potential routes of loss from the atmosphere, are balanced
    to an unknown extent by evaporation of MEK from water and soil. There
    is no specific information on partitioning of MEK in the environment.
    Although Basu et al. (1981) estimated from its physical properties
    that MEK will "exhibit low sediment-water and soil-water partitioning
    and be susceptible to substantial leaching from soils to which it is
    not extensively chemically bound", there is no information on chemical
    binding of MEK to sediment particles. As mentioned above, MEK has,
    however, been detected in ground water and the leachate from hazardous
    waste sites (section 3.3). 

    4.2  Bioaccumulation and biodegradation

         On the basis of its octanol/water partition and water solubility,
    bioconcentration factors (BCF) of approximately 1 and 0.5,
    respectively, have been calculated for MEK (US EPA, 1985b). In view of
    its high water solubility, ecosystem modelling (Metcalf et al., 1973;
    Chiou et al., 1977) indicates that it is unlikely that MEK will
    accumulate in food webs. It is absorbed and metabolized by organisms
    present in the environment, e.g., in waste water (Dore et al., 1975;
    Bridie et al., 1979a) and in soil (Perry, 1968). It is rapidly
    metabolized by mammals (Di Vincenzo et al., 1976, 1978; Dietz et al.,
    1981; Miyasaka et al., 1982) and by many microbes (Gerhold & Malaney,
    1966; Dojlido, 1977; Urano & Kato, 1986). MEK is nearly completely
    degradable at concentrations up to 800 mg/litre on the basis of
    biochemical oxygen demand (BOD), and the rate of degradation decreases
    with increasing concentration of MEK. Using activated sludge there was
    complete degradation of MEK in 8 days at a concentration of 200
    mg/litre (200 ppm) and in 9 days at a concentration of 400 mg/litre
    (400 ppm) (Dojlido, 1979). At a concentration of 20 mg/litre in river
    water containing preadapted microbes, MEK was completely degraded in
    2.5 days (Dojlido, 1977). Delfino & Miles (1985) reported a slower
    rate of decomposition in aerobic ground water; 1 mg/litre was fully
    degraded in 14 days. However, a bacterial species  (Alcaligenes
     faecalis) found in sewage sludge metabolized MEK slowly if at all
    (Marion & Malaney, 1963). The data on mammals and microbes suggest
    that MEK is rapidly absorbed and metabolized by most living organisms
    (Basu et al., 1981).

         MEK in air is rapidly decomposed by photochemical processes,
    mainly through oxidation by hydroxyl free radicals as well as some
    decomposition by direct photolysis (Levy, 1973; Laity et al., 1973;

    Dilling et al., 1976; Grosjean, 1982; Seinfeld, 1989). Basu et al.
    (1981) estimated a half-life of 5.4 h for photochemical decomposition
    in urban atmospheres. They further concluded that the lower
    concentration of photochemically produced oxidants in rural air will
    lead to a substantially lower rate of photochemical decomposition in
    these areas. The concentration of MEK and other carbonyls is higher in
    urban air (Grosjean & Wright, 1983; Snider & Dawson, 1985). Greater
    anthropogenic emissions and photochemical synthesis of carbonyls from
    free radicals (Grosjean et al., 1983) may overwhelm the more rapid
    photochemical decomposition in urban atmospheres. Scavenging by
    aqueous droplets and dry deposition may also be important processes in
    the removal of atmospheric MEK (Grosjean & Wright, 1983). 

         MEK (and other saturated aliphatic carbonyls) is not chemically
    reactive under conditions found in most natural waters and in general
    will not degrade rapidly from physical causes once deposited in water
    (US EPA, 1985b). The exception is water containing free halogens (such
    as chlorine) or hypohalides. MEK reacts with these to form a haloform
    and propionic acid (Basu et al., 1981). This can be a cause for
    concern in chlorinated waste water and water supplies, since the
    chloroform thus produced is more toxic than the original MEK (US EPA,


    5.1  Environmental levels

    5.1.1  Air

         Although MEK is widely present in the natural environment,
    concentrations are always low even under conditions of pollution
    (Table 4). In minimally polluted outdoor air, the level is less than
    3 µg/m3 (1 ppb), but 131 µg/m3 (44.5 ppb) has been measured under
    conditions of heavy air pollution in the Los Angeles basin.
    Volatilization of MEK from building materials and consumer products
    can pollute indoor air to levels above adjacent outside air. In a
    study of 15 Italian urban homes, De Bortoli et al. (1985, 1986)
    reported 8 µg/m3 as a mean indoor air value and 38 µg/m3 as a
    maximum value. Maximum and average values for MEK in outdoor air
    adjacent to these homes were 12 and 3.8 µg/m3 respectively. Shah &
    Singh (1988) reported four observations of MEK in indoor air in the
    USA; the median and mean values were 21 and 27 µg/m3 (7.1 and 9.2
    ppb), respectively. In a confined and tightly sealed space, however,
    MEK concentrations can be much higher. Liebich et al. (1975) measured
    1.9 to 4.4 mg/m3 (665 to 1505 ppb) in Space Lab IV.

         Human activities, other than the deliberate manufacture and use
    of MEK, may in some circumstances contribute significantly to
    environmental levels. MEK is a minor component, < 2.95 mg/m3 (1.0
    ppm), of gasoline engine exhaust and also has been detected in the
    exhaust from diesel engines and jet aircraft. The US Environmental
    Protection Agency estimated that 1909 tonnes of MEK was emitted in
    motor vehicle exhaust in the USA in 1987 ("Mobile source estimates for
    methyl ethyl ketone"; personal communication by J.H. Somers, 1989). In
    addition, Grosjean et al. (1983) concluded that synthesis of MEK and
    other carbonyls from hydrocarbons in vehicle exhaust by photochemical
    reactions in the atmosphere may greatly exceed their direct production
    by motor vehicles. Thus, away from industrial areas where MEK is
    manufactured or used, it is likely that motor vehicles are an
    important and possibly major source of atmospheric pollution by MEK.
    Smoking cigarettes and other tobacco products contributes slightly to
    individual exposure. Although the concentration of MEK in cigarette
    smoke (Table 4) may exceed recommended levels of permissible
    occupational exposure (Table 5) by several a Assuming a respiratory
    volume of 20 m3 per day times, the total amount of MEK generated by
    smoking a single cigarette is about 1/74th of the acceptable human
    daily chronic intake in the USA (15.43 mg/day) (US EPA, 1986). MEK
    also has been detected in the gases from structural (building) fires
    (Lowry et al., 1981).

    5.1.2 Water

         MEK concentrations in exposed natural waters are less than 0.1
    mg/litre (0.1 ppm) and are usually below the level of detection. Ewing
    et al. (l977) analysed 204 samples from rivers with industrialized
    basins; only one sample contained MEK (0.023 mg/litre). Jungclaus et
    al. (1978) measured significant levels of MEK in waste water from a
    chemical plant but could not detect it in either water or sediment of
    the brackish Delaware River receiving this waste. Despite its rapid
    disappearance from water, trace amounts of MEK have been detected
    widely in drinking-water (US EPA, 1985b). A potential source is
    solvent leached from the cemented joints of plastic pipe (Wang &
    Bricker, 1979; Boettner et al., 1981). A single unexpectedly high
    value of 0.47 mg/litre (0.47 ppm) in mist from the landward edge of
    the Los Angeles basin probably resulted from scavenging of heavily
    polluted air (Grosjean & Wright, 1983). Data on MEK in sediment (US
    EPA, 1985b) were based on four samples and are difficult to interpret.
    Sawhney & Kozloski (1984) studied organic pollution of leachates from
    municipal landfill sites in Connecticut, USA. MEK concentrations
    ranging between 4.8 and 8.2 mg/litre were measured over a two-year
    period at one site. This high value may have resulted not only from a
    substantial input but also from reduced microbial activity and no
    evaporative loss to the air. 

         Environmental concentrations in a number of media are shown in
    Table 4.

        Table 4. Concentrations of MEK in the environment
    Source                            Concentration        Reference
    Air (rural)

    South-western USA                  1.77 µg/m3          Snider & Dawson (1985)
                                        (0.6 ppb)

    Air (urban)

    South-western USA, Tucson           7.1 µg/m3          Snider & Dawson (1985)
                                        (2.4 ppb)

    USA, Los Angeles basin            0-131.3 µg/m3        Grosjean et al. (1983)
                                      (0-44.5 ppb)

    Sweden, traffic areas             7.7-94 µg/m3         Jonsson et al. (1985)
                                      (2.6-32 ppb)

    Italy                           < 2.1-12.1 µg/m3       De Bortoli et al. (1985)
                                     (< 0.7-4.1 ppb)

    Japan (air pollution)              12.7 µg/m3          Anonymous (1978)
                                        (4.3 ppb)

    Air (indoor)

    Italy (homes)                   < 2.1-38.1 µg/m3       De Bortoli et al. (1985)
                                    (< 0.7-12.9 ppb)

    USA (homes)                   detected in 3 out of     Jarke et al. (1981)
                                       87 samples

    Space Lab IV                     1.96-4.44 mg/m3       Liebich et al. (1975)
                                    (0.665-1.505 ppm)


    Sea water (Gulf Stream)         < 0.022 mg/litre       Corwin (1969) 

    Sea water (Mediterranean)       < 0.008 mg/litre       Corwin (1969) 

    Mist (California, USA)           < 0.47 mg/litre       Grosjean & Wright (1983) 

    Drinking-water (USA)            < 0.0016 mg/litre      Ogawa & Fritz (1985) 

    Ground water (hazardous         4.8-8.2 mg/litre       Sawhney & Kozloski (1984)
     waste landfill sites, USA)

    Table 4 (contd.)
    Source                            Concentration        Reference
    Rivers (industrialized           0.023 mg/litrea       Ewing et al. (1977)
     areas, USA)

    Waste water (oil well, USA)       1.5 mg/litre         Sauer (1981) 

    Waste water (Chemical plant,      8-20 mg/litre        Jungclaus et al. (1978)

    Waste water (plant, Poland)      > 100 mg/litre        Dojlido (1977) 


    USA                              0.050-23 mg/kg        US EPA (1985b) 

    Anthropogenic sources

    Automobile exhaust              < 0.3-2.95 mg/m3       Seizinger & Dimitriades
                                      (0.1-1.0 ppm)        (1972)

    Cigarette smoke                80-207 µg/cigarette     Higgins et al. (1983) 

    a MEK was detected in only one of 204 samples.
    Table 5. Levels of estimated daily MEK intake from different
    sources/routes of exposure

         Type/route of exposure               Daily intake
         Foodstuffs                              1590 µg

         Drinking-water (2 litres)               3.2 µg 

         Ambient aira
           outdoor, rural                         36 µg
           outdoor, urban                       < 2620 µg
           indoor                               < 760 µg

         Tobacco smoking (20 cigarettes)        < 1620 µg 
    a Assuming a respiratory volume of 20 m3 per day

    5.1.3  Foodstuffs

         MEK is produced in small amounts by animals, higher plants, algae
    and microbes, and is a widespread, although generally minor, component
    of taste and odour in foods (Zakhari et al., 1977). It has been
    identified in some foodstuffs and beverages. Using the DNPH method
    with column or paper chromatography, it has been identified (but not
    quantified) in white bread (Ng et al., 1960), tomatoes (Schormüller &
    Grosch, 1964), cooked turkey meat (but not in raw meat and with more
    MEK in roasted than in boiled meat, the level increasing with roasting
    time) (Hrdlicka & Kuca, 1965), and in egg white (Sato et al., 1968).
    Using gas chromatography, traces of MEK were found in fresh chicken
    meat (pectoral muscle) with a marked increase in samples kept for 4
    days at room temperature. It was not found in caecal gas from living
    chickens but was detected in the gas 18 and 24 h after death (Grey &
    Shrimpton, 1967). MEK has also been detected in cottonseed oil
    (Dornseifer et al., 1965), honey (Cremer & Riedmann, 1964), coffee
    (Gianturco et. al., 1966), roast barley (Shimizu et al., 1969), and in
    the mushroom  Agaricus bisporus (Staüble & Rast, 1971). By means of
    GC/MS, Wong et al. (1967) detected MEK in codfish and Kahn et al.
    (1968) reported its presence in a low-boiling distillation fraction of
    Canadian whisky. 

         In a study of compounds related to milk flavour, Wong & Patton
    (1962) determined MEK concentrations using the DNPH method with column
    separation and paper chromatography. The concentrations in two samples
    of untreated milk were 0.77 and 0.79 mg/litre and in two samples of
    cream were 0.154 and 0.177 mg/litre. Gordon & Morgan (1972) examined
    the influence of volatile compounds in milk on "feed" flavour and
    reported MEK concentrations of 0.25-0.35 mg/litre in moderately "feed"
    flavoured milk and 0.50-1.0 mg/litre in strongly flavoured milk, with
    a highest concentration detection of 1.4 mg/litre. They concluded that

    MEK is one of the compounds responsible for producing the unpleasant
    "feed" flavour in milk. Using the DNPH method and paper
    chromatography, Harvey & Walker (1960) detected MEK in New Zealand
    cheddar cheese one day after manufacture. The concentration increased
    during ripening, reaching 0.9 mg/kg at 40 weeks, and was related to
    the development of typical Cheddar cheese flavour. In another study of
    the chemical nature of USA Cheddar cheese flavour, Day et al. (1960)
    analysed the volatile flavour fraction of cheeses over 1 year old
    using DNPH and column partition chromatography, and reported
    approximate MEK concentrations of 12.5 mg/kg. Keen et al. (1974)
    postulated that the formation of MEK in New Zealand Cheddar cheese,
    for which levels as high as 19 mg/kg had been reported, occurred in
    steps carried out by different microbial species including
     Streptococcus cremaris, Pediococcus cerevisiae, Lactobacillus
     plantarum and  Lactobacillus brevis. They considered that MEK was
    an important flavour constituent in the cheese. 

         In another investigation of monocarbonyl compounds as flavour
    components, Mookherjee et al. (1965) measured MEK in fresh and stale
    (8 weeks old) potato chips with the DNPH method and liquid-liquid
    chromatography. In fresh potato chips the concentration of MEK was 1.8
    µmoles/kg, and this increased to 2.2 µmoles/kg in stale chips.

         Amylomaize starches are heat treated in the production of films
    and fibres to concentrate the amylose. Bryce & Greenwood (1963) used
    gas chromatography to measure pyrolysis products (including MEK) of
    potato starch, potato amylose and amylopectin, maltose, isomaltose and
    glucose. MEK was not detected in untreated starch nor in starch
    pyrolysed  in vacuo for 20 min at 200 and 220 °C. With increasing
    temperatures the concentration of MEK increased; at 230, 250, 300, 350
    and 400 °C the MEK concentrations were 10, 15, 50, 65 and 70 moles x
    107/g starch, respectively. 

         Small quantities (up to 2 ng/1.5 g bean) were found in soybeans
     (Clycine max) and winged beans  (Psophocarpus tetragonolobus) by
    means of dynamic headspace GC/MS (Del Rosario et al., 1984). 

         However, the reported concentrations of MEK in foods are low and
    food consumption is not considered a significant source of population

    5.2  General population exposure

         Stofberg & Grundschober (1984) calculated the consumption ratio
    between the quantity of a flavouring material consumed as an
    ingredient of basic and traditional foods and the quantity of that
    same flavouring material consumed as a component of added flavourings
    by a certain population. If the consumption ratio is more than 1, this
    substance is consumed predominantly as an ingredient of traditional
    foods. For MEK, this ratio may be up to 411. The annual consumption in
    the USA of MEK via apple juice is 85 kg, white bread 70 132 kg, butter

    34 kg, carrot 154 kg, Cheddar cheese 30 139 kg, Swiss cheese 198 kg,
    fish 81 kg, potato chips 31 kg, tomato 31 878 kg, and yoghurt 1104 kg.
    Assuming a population of 230 millions, the estimated average daily
    intake in the USA amounts to 1.59 mg/kg foodstuff. Some information on
    the MEK contents of various foodstuffs is given in Table 6. The
    European Economic Community regulates the level of MEK in certain
    foodstuffs; these are given in Table 7. 

         In addition to the MEK that is naturally present, foods may also
    contain MEK absorbed from plastic packaging materials. This can be
    derived from solvent left in the plastic during manufacture
    (Kontominas & Voudouris, 1982) or represent one of the many organic
    compounds produced during extrusion (Fernandes et al., 1986). It can
    also be produced by irradiation of polyethylene film during the
    sterilization of packaged foods with an electron beam (Azuma et al.,
    1983). Although the presence of MEK and associated organic compounds
    from packaging materials may affect the flavour of foods, it probably
    does not represent a significant source of population exposure.

        Table 6. MEK concentrations of certain foodstuffs
    Source                                 Concentration     Reference
    Bean seeds (raw)                         0.5 mg/kg       Del Rosario et al. (1984)
    Bean seeds (heated at                  0.7-2.0 mg/kg     Del Rosario et al. (1984)
     190 °C)

    Pea seeds                            0.074-0.39 mg/kg    Fisher et al. (1979) 

    Milk ("feed"-flavoured)              0.25-14 mg/litre    Gordon & Morgan (1972)

    Bread                                   3.06 mg/kg       Sosulski & Mahmoud (1979) 

    Cheddar cheese                          12.5 mg/kg       Day et al. (1960)
                                             19 mg/kg        Bills et al. (1966) 

    Table 7. Food uses of MEK permitted in the European Economic Community
    Conditions of use                       Maximum residue limits in the extracted
                                            foodstuff, food or food-contact material
    In manufactured or regenerated          0.6 mg/dm2 on the side in contact with
    cellulose film that comes into          foodstuffs
    contact with fooda

    Fractionation of fats/oilsb             5 mg/kg in the fat/oil 

    Decaffeination of, or removal of        20 mg/kg in the coffee or tea
    irritants and bitterings from,          (as granules, powder, leaves,
    coffee and teab                         etc.)

    Preparation of flavourings              1 mg/kg in the foodstuff
    from natural flavouring materialsb

    a Council Directive 83/229/EEC

    b Council Directive 88/344/EEC
         Higgins et al. (1983) analysed the gas phase organic compounds in
    cigarette smoke. In cigarettes with high tar content (7-45 mg per
    cigarette), the MEK level was 63-131 µg/cigarette, whereas in ultralow
    tar delivery cigarettes (advertised value < 0.01-0.2 mg per
    cigarette), it was 0.93-4 µg MEK/cigarette.

         Levels of estimated daily MEK intake from different sources/
    routes of exposure are given in Table 5.

    5.3  Occupational exposure

         Information on measured levels of occupational exposure is
    summarized in Table 8. Some national occupational exposure limits for
    MEK in workplace air are shown in Table 9. In a study of an electronic
    parts plant in the USA, Lee & Parkinson (1982) reported that workers
    were exposed to mixtures of solvent vapours containing MEK. Inoue et
    al. (1983), in a nationwide survey of Japanese factories, found that
    MEK was widely used as a component of solvent mixtures. A study by
    Falla (1987) of 19 British plants manufacturing or applying surface
    coatings reported that none had MEK concentrations in excess of 295
    mg/m3 (100 ppm). The highest TWA value, 723 mg/m3 (245 ppm),
    reported by Lee & Murphy (1982) represented a worker who entered the
    highly polluted vinyl dip room (502-1785 mg/m3; 170-605 ppm) only
    occasionally, but without always donning his respirator hood. A
    co-worker stationed in the vinyl dip room who wore his respirator hood
    constantly had TWA exposures of 307-617 mg/m3 (104-209 ppm). De Rosa
    et al. (1985) examined 504 work stations in 81 Italian plants (shoe

    factories, painting operations and printing plants) and found that the
    TLV for MEK (590 mg/m3, 200 ppm) was rarely exceeded.

    5.4  Peri-occupational exposure

         Many small industries in the Netherlands are located in inner
    city areas. The influence of such industries on the quality of indoor
    air in adjacent houses was studied by Verhoeff et al. (1987), who
    monitored the indoor air of a car-body repair shop, an offset printing
    office and surrounding houses for organic solvents, including MEK.
    Monitoring was carried out for one week, and the individual exposure
    of workers and residents was investigated by biological monitoring of
    the exhaled breath with additional personal air sampling of the
    workers. Concentrations in both the factories were lower than 29.5
    mg/m3, i.e. 5% of the Dutch MAC values (590 mg/m3). In the
    personal air samples of the employees, MEK was at or below the
    detection level. In the house located directly over the car-body
    repair shop, the average concentrations of MEK were about 50% those in
    the shop, while two floors above, MEK was detected only once. 

        Table 8.  Occupational exposure to MEK via air
    Activity                      Country   Sampling                 Concentration              Reference
                                            details                  mg/m3 (ppm)
    Printing and printing         Japan     personnel (62)           0-265 (0-90)               Miyasaka et al. (1982)
    machine manufacturing

    Shoe factory                  Italy     not given                0-300 (0-102)              Brugnone et al. (1983)

    Shoe factories, painting      Italy     personnel (1 h)          0-1110 (0-376)a            De Rosa et al. (1985)
    operations, printing plants             (504)

    Miscellaneous factories       Italy     personnel (4 h) (65)     10-953 (3.4-323)           Ghittori et al. (1987)

    Sheet metal shop              Sweden    area (continuous)        approx. 3-44               Persson et al. (1984)
                                                                     (approx. 1-15)

    Organic chemical waste        USA       area (9)                 < 0.06 (< 0.02)            Decker et al. (1983)
    incinerator                                                      (vicinity)
                                            personnel (7)            < 0.06-189 (< 0.02-64)
                                                                     (exposed workers)

    Radio components              USA       personnel (range         0-38 (0-13)                Lee & Parkinson (1982)
    manufacturing                           of jobs)

    Solvent recycling plant       USA                                < LDQ-166 (< LDQ-38)b      Kupferschmid & Perkins (1986)

    Plastic items factory         USA       no details               0.07-0.16                  Ahrenholz & Egilman (1983)

    Surface coatings              United    area (59)                < 295 (100)                Falla (1987)
    factories                     Kingdom


    Table 8 (contd)
    Activity                      Country   Sampling                 Concentration              Reference
                                            details                  mg/m3 (ppm)
    Lubricating oil               USA       personnel (38)           0.09-80 (> 0.029-27)       Emmel et al. (1983)

    Miscellaneous factories       USA       personnel (179)          0-0.59 (0-0.2)             Whitehead et al. (1984)
    with spray application                                           (non-exposed
    of glue and paint                                                workers)
                                                                     1.18-6.2 (0.4-2.1)
                                                                     (exposed workers)

    Aircraft maintenance          USA       personnel (9)            0-65 (0-22)c               Thoburn & Gunter (1982)

    Athletic equipment            USA       personnel (12)           307-723                    Lee & Murphy (1982)
    factory                                                          (104-245 TWA)d
                                                                     (vinyl dip room)
                                                                     0.89-534 (0.3-181)
                                                                     TWA (elsewhere)

    a    MEK was found in 85/504 samples
    b    LDQ = lowest detectable quantity
    c    MEK was detected in only one of nine samples 
    d    8-h time-weighted average
        Table 9. Some national occupational exposure limits for MEK in air
    Country         Exposure limit          Category of limitb            Reference
                     mg/m3 (ppm)
    Argentina            590 (200)          TWA                           IRPTC (1987, 1991)
                         885 (300)          STEL

    Brazil               460 (155)          for 48 h/week                 IRPTC (1987, 1991) 

    Germany              590 (200)          TWA                           IRPTC (1987, 1991)
                        1180 (400)          30 min. STEL
                                            (average value, 
                                            4 x per shift)

    Hungary               200 (68)          TWA (8 h)                     IRPTC (1987, 1991)
                       1000 (2950)          STEL (30 min)

    Italy                590 (200)          TWA                           Notified by country 

    Japan                590 (200)          TWA                           IRPTC (1987, 1991) 

    Netherlands          590 (200)          TWA                           a

    Sweden                150 (50)          TWA                           IRPTC (1987, 1991)
                         300 (100)          STEL (15 min)

    United Kingdom       590 (200)          TWA (8 h), OES                Notified by country
                         885 (300)          STEL (10 min), OES

    USA (NIOSH/OSHA)     590 (200)          TWA (10 h)                    US NIOSH (1990)
                         885 (300)          STEL (15 min)
                       8850 (3000)          IDLH

    USA (ACGIH)          590 (200)          TLV (TWA)                     ACGIH (1991)
                         885 (300)          STEL
                        2 mg/litre          BEI
                     urine; end of

    Yugoslavia           295 (100)                                        Notified by county

    TWA and TLV are, with one exception, in the range of 295-590 mg/m3 (100-200 ppm). The
    latter is stated to be the highest concentration which can be tolerated by humans without
    discomfort (ACGIH, 1986). In addition a short-term exposure limit of 885-1180 mg/m3
    (300-400 ppm) has been established by some nations. 

    a    Dutch Expert Committee for Occupational Standards (1991)
    b    Abbreviations: BEI = biological exposure index (ACGIH); IDLH = concentration
         immediately dangerous to life or health (US NIOSH); OES = occupational exposure
         standard (UK); STEL = short-term exposure limit; TLV = threshold limit value
         (ACGIH); TWA = time weighted average

    6.1  Absorption

    6.1.1  Percutaneous absorption

         Percutaneous absorption of MEK appears to be rapid (Munies &
    Wurster (1965) and Wurster & Munies (1965) reported that MEK was
    present in the exhaled air of human subjects within 2.5-3.0 min after
    it was applied to normal skin of the forearm, and the concentration of
    MEK in exhaled air reached a plateau in 2-3 h. The rate of absorption
    was controlled mainly by the moisture content of the skin. With dry
    skin, absorption was slow, and it took 4-5 h for the concentration of
    MEK in expired air to attain a plateau. With moist skin, absorption
    was very rapid initially. MEK was detected in expired air in
    measurable concentrations within 30 seconds after an application of
    MEK to the forearm, and a maximum concentration in expired air,
    averaging four times the plateau level for normal and dry skin, was
    achieved in 10-15 min. The concentration of MEK in expired air, and
    thus its absorption, subsequently declined to a plateau level somewhat
    above that for normal and dry skin because the MEK partially
    desiccated the moist skin with which it was in contact. Munies &
    Wurster (1965) concluded that the rapid percutaneous absorption of MEK
    reflected its olive oil-water partition coefficient, which is close to
    unity. Their data have been used to calculate minimum rates of
    percutaneous penetration of 0.46 µgÊcm-2Êmin-1 for dry or normal
    skin and 0.59 µgÊcm-2Êmin-1 for moist skin (JRB Associates, Inc.,
    1980). These rates are minimal because they are based solely on
    exhalation from the lungs and ignore all other excretion processes for

         As the elimination of MEK via inhalation constitutes only 5 to
    10% of the total loss (Cushny, 1910), these rates should be multiplied
    by factors of 10-20. This gives a percutaneous absorption of 5-10
    µgÊcm-2Êmin-1, which is identical to the value measured for methyl
    isobutyl ketone by DiVincenzo et al. (1978). 

    6.1.2  Inhalation absorption

         The absorption of MEK via the lungs was examined by Perbellini et
    al. (1984) in a study of workers exposed in industrial workplaces. The
    MEK concentration in alveolar and expired air correlated significantly
    with the environmental concentration, and averaged 30% of the latter.
    In more recent studies (Liira et al., 1988a, 1988b), values for
    pulmonary absorption ranging from 41.1% to 55.8% were obtained. Liira
    et al. (1988b) suggested that differences in their values may have
    reflected variations in breathing technique during the collection of
    samples rather than actual changes in uptake. Deeper inhalation
    increased the alveolar volume relative to the dead space (the
    non-alveolar volume of the respiratory system), and thus increased the
    apparent absorption (personal communication by J. Liira, 1989). When

    the alveolar retention of MEK (about 70%) measured by Perbellini et
    al. (1984/1985) is transformed to overall pulmonary retention, their
    observations and those of Liira et al. (1988a,b) are in agreement,
    showing that about 50% of inhaled MEK is taken up. 

         Results of studies by Liira et al. (1988a,b, 1990a,b) indicated
    a rapid transfer of MEK vapour into the blood stream. Perbellini et
    al. (1984, 1985), reported that the concentrations of MEK in the blood
    and urine were significantly correlated with the environmental
    concentration, indicating rapid transfer to the blood and thence to
    other tissues. In human volunteer subjects, exercise during exposure
    markedly increased the MEK level in blood in comparison with sedentary
    behaviour (Liira et al., 1988b), indicating that the blood MEK level
    also depended on the rate of uptake. Ghittori et al. (1987) and
    Miyasaka et al. (1982) also found significant correlations between
    environmental levels of MEK and amounts excreted in the urine of
    exposed workers. The concentration of MEK in urine rose from
    essentially zero to 70% of its maximum value during the first 2 h of
    an 8-h shift (Miyasaka et al., 1982).

         Ong et al. (1991) studied biological monitoring of occupational
    exposure to MEK in 67 healthy male workers employed in plastic bag or
    video-tape production. Their ages ranged between 18 and 52 years with
    an average working experience of 8.6 years. For the majority of the
    workers, atmospheric MEK concentrations were in the range 30-885
    mg/m3 (10-300 ppm). MEK concentrations in urine, blood and exhaled
    air were measured once weekly at the end of a shift. About 10% of
    absorbed MEK was eliminated in the exhaled air. Following exposure to
    590 mg/m3 (200 ppm), the urinary concentration was 5.1 µmol/litre or
    4.11 mg/g creatinine. The correlation coefficients (tau) between
    atmospheric MEK concentration and end-of-shift urine, blood and
    exhaled air were 0.89, 0.85 and 0.79, respectively. The authors also
    reported good correlation between blood and urinary MEK (tau = 0.86)
    and between blood and exhaled air concentrations (tau = 0.8) but poor
    correlation between exhaled air and urinary MEK concentrations.

    6.1.3  Ingestion absorption

         In male rats given a large MEK dose (1505 or 1690 mg/kg) in
    water, blood concentrations reached maxima of 0.95 and 0.94 mg/ml 4 h
    after ingestion and subsequently declined sharply, indicating
    protracted absorption of this dose from the gastro-intestinal tract
    (Traiger & Bruckner, 1976; Dietz & Traiger, 1979; Dietz et al., 1981).

    6.1.4  Intraperitoneal absorption

         The results of DiVincenzo et al. (1976) and Zakhari et al.
    (1977), who used intraperitoneal injections of MEK in research on
    metabolism and toxicity, suggest that absorption from the peritoneal
    cavity is rapid.

    6.2  Distribution

         The distribution of MEK in human tissues was examined by
    Perbellini et al. (1984) in two solvent-exposed workers who died
    suddenly of heart attacks at the workplace. The results of this study
    (Table 10) indicate that the solubility of MEK is similar for all
    tissues. Brugnone (1985) calculated the uptake and distribution of MEK
    from the lungs. With a blood/air partition coefficient of 202, MEK can
    reach equilibrium concentration in a compartment in about 3 min.
    Distribution volumes were 6.0 for vessel-rich tissues, 39.6 for muscle
    and 12.8 for fat. Biological half-lives for the same tissues were 0.8,
    21.8 and 23.3 min, respectively. The results of  in vitro 
    measurements at 37 °C of human tissue-gas partition coefficients,
    obtained by exposing samples of blood and tissue to a known
    concentration of MEK (Fiserova-Bergerova & Diaz, 1986), differed from
    the observations of Perbellini et al. (1984). The partition
    coefficients ranged from 96 to 162, but did not exceed 111, with the
    exceptions of whole blood (125), blood plasma (133) and fat (162).
    Other blood-gas partition coefficients measurements for MEK are 202
    (Sato & Nakajima, 1979) and 215 (Pezzagno et al., 1983). Traiger &
    Bruckner (1976) and DiVincenzo & Krasavage (1974) provided evidence
    that MEK can enter the liver of rats and guinea-pigs, and Dowty et al.
    (1976) reported that it can cross the placenta and enter the human

    6.3  Metabolic transformation

         MEK has been reported to be a metabolic end product of natural
    gas (methane 88%, ethane 5%, propane 5%, isobutane 2% with traces of
     tert-butyl mercaptan and methyl acrylate) inhaled for 2 h by ICR
    mice (Tsukamoto et al., 1985a). In an  in vivo  study of the
    metabolism of propane,  n-butane and  iso-butane inhaled for 1 h by
    ICR mice, it was found that  n-butane gave rise to  sec-butanol and
    MEK (Tsukamoto et al., 1985b).  In vitro  studies showed that mouse
    liver microsomal preparations metabolized  n-butane to  sec-butanol,
    the precursor of MEK (Tsukamoto et al., 1985b). Inhalation by male
    Sprague-Dawley rats of  sec-butanol at concentrations of 5900 mg/m3
    (2000 ppm) for 3 days or 1475 mg/m3 (500 ppm) for 5 days caused
    marked enzyme induction of cytochrome P-450 in liver and kidney but
    other butanol isomers did not have this effect (Aarstad et al., 1985,
    1986). The authors concluded that the mechanism of induction was via
    the  sec-butanol metabolite MEK.

    Table 10. Solubility (partition coefficient) of MEK in human tissuesa
         Tissues             Tissue/air             Tissue/blood
         Blood                  183                    1.00

         Kidney                 197                    1.08

         Liver                  180                    0.98

         Brain                  168                    0.92

         Fat                    161                    0.88

         Muscle                 212                    1.16

         Heart                  254                    1.39

         Lung                   147                    0.80

    a From: Perbellini et al. (1984)

    6.3.1  Animal studies

         Traiger & Bruckner (1976) showed that the toxic effects of MEK
    and 2-butanol were essentially identical in rats, and that 2-butanol
    was rapidly oxidized to MEK. DiVincenzo et al. (1976) identified the
    metabolites of MEK in guinea-pigs as 2-butanol, 3-hydroxy-2-butanone
    and 2,3-butanediol. They hypothesized that the metabolism followed
    both oxidative and reductive pathways, with the latter leading to the
    production of 2-butanol. The former, employing microsomal omega-1
    oxidization, oxidized MEK to 3-hydroxy-2-butanone, which was
    subsequently reduced to 2,3 butanediol. Further research utilizing
    rats (Dietz & Traiger, 1979; Dietz et al., 1981) clarified the
    pathways of rat MEK metabolism and permitted a calculation of rate
    constants for the elimination of MEK and its metabolites from the
    blood as well as for the metabolic transformations (Fig. 1). The body
    was divided into two compartments: (a) the liver, where metabolic
    transformations took place; and (b) the blood, which was the site of
    sampling. Experimental data and equations derived from this data
    indicated that the major metabolic pathway is butanol -> MEK ->
    3-hydroxy-2-butanone -> 2,3-butanediol, with small or non-existent
    reverse flows. Dietz et al. (1981) estimated that an oral dose of
    2-butanol or MEK resulted, on a molar basis, in the same blood
    level-time curve for 2,3-butanediol as 28-30% of this amount given as
    an intravenous dose of 2,3-butanediol. Their data indicated that
    transformations of 2-butanol to MEK and of 3-hydroxy-2-butanone to
    2,3-butanediol are rapid and that transformation of MEK to
    3-hydroxy-2-butanone is much slower. It is likely that 2-butanol, like
    ethanol (Mezey, 1976), inhibits oxidative pathways of drug metabolism

    and thus inhibits the hydroxylation step leading to
    3-hydroxy-2-butanone. This possibility is supported by the observation
    of Dietz et al. (1981) that 2-butanol, at concentrations similar to
    those achieved in the blood of rats in the above experiment,
    significantly inhibited  N-dealkylation of aminopyrine by rat liver
    microsomes  in vitro . 

         In rats exposed by inhalation to 1760 mg MEK/m3 (600 ppm),
    there were only marginal effects on microsomal cytochrome P-450
    activities (Liira et al., 1991). However, a daily dose of 1.4 ml MEK
    per kg for 3 days increased the amounts of ethanol- and
    phenobarbital-inducible cytochromes P-450 (P-450 IIEI and P-450 IIB)
    (Raunio et al., 1990). In a study on male Sprague-Dawley rats,
    pretreatment with MEK elevated total microsomal cytochrome P-450 and
    NADPH-dependent cytochrome-c-reductase, the rates of oxidation of
     N-nitrosodimethylamine, benzphetamine and pentoxyresorufin, and also
    the levels of immunoreactive protein for both P-450 isozymes (Brady et
    al., 1989). In a study of hepatotoxicity in rats, Brondeau et al.
    (1989) found that MEK increased liver cytochrome P-450 content
    (33-86%) and glutathione-S-transferase (GST) activity (42-64%) but had
    no effect on serum glutamate dehydrogenase (GLDH) activity. Robertson
    et al. (1989) studied the effects on hepatic cytochrome P-450
    activities of repeated daily doses of 1.87 ml/kg given by gavage to
    male Fischer-344 rats. The activity of 7-ethoxy
    coumarin- O-deethylase was increased by up to 500% after 1 to 7 days
    of MEK treatment, but there was practically no change in
    benzphetamine- N-demethylase activity. In another study in male
    Sprague-Dawley rats, administration of MEK by gavage caused an
    increase in hepatic acetanilide hydroxylase and a marginal increase in
    aminopyrine- N-demethylase activities (Traiger et al., 1989).

    6.3.2  Human studies

         MEK has been identified as a minor but normal constituent of
    urine (Tsao & Pfeiffer, 1957), serum and urine of diabetics (Mabuchi,
    1969), and expired air (Conkle et al., 1975). Its production in the
    body has been attributed to isoleucine catabolism (Tsao & Pfeiffer,
    1957; Przyrembel et al., 1979). Although Smith (1981) mentioned MEK as
    a product of autoxidation of cholesterol, no evidence was offered that
    this process occurred  in vivo . The studies of Perbellini et al.
    (1984) and Liira et al. (1988a,b) indicate that the same metabolites
    are produced and excreted in humans as in experimental animals. Liira
    (personal communication by J. Liira, 1989) further indicated that in
    an inhalation exposure to 590 mg MEK/m3 (200 ppm) the calculated
    areas under the curves of blood solvent concentration versus time
    (AUC) for MEK and 2,3-butanediol were equal, which suggests that MEK
    is almost completely transformed to 2,3-butanediol. The bulk of MEK
    absorbed thus enters the general metabolism and is transformed to
    simple compounds like carbon dioxide and water.

    FIGURE 1

    6.4  Elimination and excretion

         MEK and its metabolites are excreted by the lungs and kidneys.
    Liira et al. (1988a) reported that only 3% of the calculated absorbed
    dose during a 4-h exposure to 590 mg MEK/m3 (200 ppm) was secreted
    unchanged in the exhaled air of volunteers after the exposure. The
    fractional elimination of unchanged substance however depends on the
    efficiency of metabolic clearance. Since metabolic saturation for MEK
    in humans begins at relatively low levels (about 100 ppm) of exposure
    (Liira et al., 1990a), proportionally greater amounts of MEK would be
    expected to be excreted via the lungs (and kidneys) at high exposure

         Relatively little of the absorbed MEK is excreted unchanged via
    the kidneys; a study of occupationally exposed workers revealed that
    it is less than 0.1% of the alveolar uptake (Miyasaka et al., 1982).
    In a similar study of workers occupationally exposed to a mixture of
    solvents, the excretion of MEK and a major recognizable metabolite,
    3-hydroxy-2-butanone, was 0.1% of alveolar uptake (Perbellini et al.,
    1984). The concentrations of both MEK and 3-hydroxy-2-butanone in
    urine were significantly correlated with the environmental level of
    MEK. Other metabolites of MEK, 2-butanol or 2,3-butanediol, which
    DiVincenzo et al. (1976) identified in the serum of guinea-pigs, were
    not detected in the urine of the exposed workers. Liira et al.

    (1988a), however, reported that human excretion of 2,3-butanediol was
    individually variable but averaged 2% of the absorbed MEK. The urinary
    excretion of 2-butanol, a minor metabolite of MEK, was examined by
    Kamil et al. (1953), who found that clearance of 2-butanol
    administered by gavage in rabbits was about 14% of the administered
    dose and in the form of a glucuronide. 

         Since MEK and 2,3-butanediol disappear from blood and urine and
    there is no evidence for accumulation elsewhere in the body, the above
    data suggest that the bulk of MEK absorbed by mammals enters the
    general metabolism and is eliminated from the body as simple compounds
    like carbon dioxide and water whose source is not readily
    identifiable. The specific pathways by which MEK is metabolized have
    not been identified. There also is no information on loss of MEK in

    6.5  Turnover

         Both animal and human data indicate a rapid turnover of MEK. In
    guinea-pigs receiving an intraperitoneal dose of 450 mg MEK per kg,
    the half-life of MEK in blood serum was 4´ h and the clearance time
    for MEK in serum was 12 h. For the metabolites 2-butanol,
    3-hydroxy-2-butanone and 2,3-butanediol, the clearance time in serum
    was 11 h (DiVincenzo et al., 1976). In rats given a 2.2-ml/kg oral
    dose of 2-butanol, the butanol was largely cleared from the blood in
    15 h and the 2-MEK derived from the butanol was cleared in 24 h
    (Traiger & Bruckner, 1976). In a study by Dietz & Traiger (1979) on
    rats given an oral dose of 2-butanone of 2.1 mg/kg, there was a
    half-life of 3.6 h for MEK in blood if the rate of loss was assumed to
    be constant between the two times of measurement (4 h and 18 h) after
    dosing. Data from a study of Dietz et al. (1981) on rats receiving
    oral doses of 2-butanol or MEK also indicate a half-life of about 4 h
    for MEK. These authors reported that the clearance rate for
    3-hydroxy-2-butanone and 2,3-butanediol was independent of dose for
    the two doses used (0.4 and 0.8 g/kg) and that the half-lives for
    these metabolites of MEK were 47 min and 3.45 h, respectively. Liira
    et al. (1988a) reported a steady increase in blood concentrations
    during 4-h exposures of human volunteer subjects to 590 mg/m3 (200
    ppm) and observed a rapid elimination of MEK, with half-lives of 30
    min during the first post-exposure hour and 81 min thereafter. An
    inhalation study with two volunteer subjects exposed to MEK for 4 h at
    concentrations of 74, 590 and 1180 mg/m3 (25, 200 and 400 ppm)
    indicated that the kinetics of MEK were dose dependent at higher
    exposure concentrations, i.e. much higher levels of MEK in blood were
    reached relative to inhaled concentrations, and the post-exposure
    elimination of MEK in blood was slower (zero-order kinetics).
    Simulated exposure to MEK for 8 h suggests that saturation kinetics
    are reached at about 295 mg/m3 (100 ppm) at rest and 148 mg/m3 (50
    ppm) during light exercise (Liira et al., 1990a).

    6.6  Metabolic interactions

         Ingestion of ethanol (0.8 g/kg) combined with an inhalation
    exposure to MEK (590 mg/m3, 200 ppm) inhibited the oxidative
    metabolism of MEK and led to a marked increase in the blood
    concentration of MEK (Liira et al., 1990b). There was a concurrent,
    even more pronounced elevation of the blood 2-butanol concentration;
    the most likely explanation is competitive inhibition by ethanol of
    the oxidation of 2-butanol back to MEK. Ethanol also appeared to
    interact with the further biotransformation of 2,3-butanediol as the
    urinary excretion of the metabolite was increased. Co-exposure with
    xylene, however, had no effect on the human metabolism or rate of
    elimination of MEK (Liira et al., 1988b).

    6.7  Mechanisms of action

         There is very limited information on the mechanisms of toxic
    action of MEK. Relatively high inhaled concentrations 1475-29 500
    mg/m3 (500-10 000 ppm) caused pulmonary vasoconstriction and
    hypertension in cats and dogs (Zakhari et al., 1977). From the
    toxicological point of view, interactions leading to the potentiation
    of effects, particularly neurotoxicity, by other intrinsically toxic
    substances constitute the main hazard of MEK. The mechanisms
    underlying these interactions are incompletely known (see section 10).


    7.1  Acute exposure

    7.1.1  Lethal doses

         Data on the acute toxicity of MEK to experimental animals are
    summarized in Table 11. Oral toxicity is low with LD50 values
    ranging from 2 to 6 g/kg for adult mice and rats. Intraperitoneal
    LD50 values are lower (approximately 1.5 g/kg for 24 h and 0.6 g/kg
    for 14 days). A larger dermal LD50 value for rabbits, i.e. > 8 g/kg
    (contact time: 24 h; observation time: 14 days), may reflect slower
    and less complete absorption via the skin, although it may also
    reflect species differences in sensitivity to MEK. The lethal dose of
    MEK given to rats in the only study using dosing by pulmonary
    aspiration (Panson & Winek, 1980) was 0.8 g/kg. This is well below the
    intraperitoneal 24-h LD50 for adult rats but similar to the 14-day
    value (Lundberg et al., 1986). It cannot be excluded that the high and
    rapid lethality of this aspirated dose to adult rats (5/6 deaths in 
    < 24 h, with 4/6 reported as dying "instantly") may reflect serious
    damage to the lungs. 

         Studies examining the effects of acute inhalation of MEK are not
    entirely comparable since they used not only different species but
    also different concentrations of MEK, exposure times, and periods over
    which survival was measured. For mice the LC50 (45-min exposure) was
    about 200 000 mg/m3. The lowest concentration lethal to all rats
    exposed by inhalation for 8 h was 47 200 mg/m3 and the lowest
    concentration producing lethality in a 4-h exposure was 5900 mg/m3
    (2000 ppm). Guinea-pigs survived exposure to 29 500 mg/m3 for 4 to
    4.7 h and showed no abnormal signs at 9735 mg/m3. A concentration of
    97 350 mg/m3 was lethal to all exposed guinea-pigs in 3.3 to 4.2 h,
    whereas a slightly lower concentration, 73 750 mg/m3, although
    ultimately lethal to all animals, permitted some guinea-pigs to
    survive a 5.4-h exposure (Patty et al., 1935; Specht et al., 1940). 

    7.1.2  Non-lethal doses

         Non-lethal acute doses of MEK produced a number of measurable
    changes in experimental animals (Table 11). An oral dose of 1.5 g/kg
    to rats resulted in a 63% increase in liver triglycerides after 16 to
    23 h, but did not alter liver histology or increase either of two
    enzymes, serum glutamic-pyruvic transaminase (alanine transferase
    (ALT)) and hepatic glucose-6-phosphatase (Traiger & Bruckner, 1976).
    These results suggest that this dose caused metabolic disturbances to
    the liver of rats. Much smaller acute intraperitoneal doses (0.049 to
    0.194 g/kg) to rats appeared not to damage the liver. A single oral
    dose (15 mmol/kg) of MEK did not affect the hepatobiliary function of
    rats over an observation period of 10 to 96 h (Hewitt et al., 1986).
    A graded series of single doses of MEK to guinea-pigs revealed high
    sensitivity to small changes in dosage. The low dose (0.75 g/kg)

    appeared to produce no liver damage, whereas 1.5 g/kg produced slight
    liver damage and 2.0 g/kg produced major liver damage. These results
    also suggest that guinea-pigs and rats may be equally sensitive to MEK
    in terms of liver damage even though guinea-pigs survive acute
    exposure to higher concentrations of MEK vapour than do rats
    (DiVincenzo & Krasavage, 1974). 

         Consistent increases in the frequency of food-reinforced lever
    pressing by rats were detected at MEK exposures as low as 74 mg/m3
    (25 ppm) for 2 h (Garcia et al., 1978). Vestibulo-ocular effects were
    detected during continuous intravenous administration of MEK for 1 h
    via the caudal vein at a dosage as low as 0.005 g/kg per min (Tham et
    al., 1984). This dosage is roughly equivalent to inhalation of 2700
    mg/m3 (900 ppm). Glowa & Dews (1987) reported that exposure of mice
    to 885 mg/m3 (300 ppm) for 30 min did not significantly alter
    schedule-controlled responses, whereas concentration-related
    suppression of response occurred at consecutive increasing
    concentrations (for 30 min) ranging from 2950 to 29 500 mg/m3 (1000
    to 10 000 ppm) (see section 7.3.1).

         It can be concluded from observations of their behaviour that
    respiratory irritation occurred in guinea-pigs exposed to 29 500
    mg/m3 or more within 2 min (Patty et al., 1935; Specht et al.,
    1940). In survivors, post-exposure recovery from this effect was
    rapid. Rats exposed for 8 h/day to 29 500 mg/m3 showed severe
    irritation of the upper respiratory tract after a "few days"
    (Altenkirch et al., 1979).

    7.1.3  Skin and eye irritation

         In skin irritation studies, a small dose (8 mg) applied to
    clipped skin and covered by an impervious plastic film for 24 h (which
    was followed by a 14-day observation period) produced only minor
    irritation in male New Zealand albino rabbits (Smyth et al., 1962). A
    dose of 400 mg applied to the clipped dorsal skin of restrained albino
    rabbits in a gauze patch produced mild to moderate irritation in some
    cases (Weil & Scala, 1971). Data from this latter study, however, were
    highly variable and may reflect the fact that its purpose was
    intercomparison of laboratories rather than the effects of MEK on test
    animals. Neat MEK (0.1 ml) applied to the clipped skin of the flanks
    of guinea-pigs and rabbits daily for 10 days and left uncovered caused
    erythema and oedema after 24-72 h. These effects were more marked in
    rabbits (Wahlberg, 1984a). 

        Table 11.  Acute toxicity of MEK for mammalsa
    Species          Number and sex     Exposure concentration      Exposure        Study      Effects                          Reference
    (strain)                            and range                   duration        duration
    Oral studies

    Rat (Sprague-    both sexes, 6-12   not stated                  one dose                   LD50 (7 days) < 0.8 g/kg b.w.    Kimura et al.
    Dawley) new      animals/group                                                             2.5 (2.0-3.1) g/kg b.w.          (1971)
    born 14 day      6 male/group                                                              2.9 (2.3-3.5) g/kg b.w.
    young adult                                                                                2.7 (2.1-3.5) g/kg b.w.
    older adult

    Rat (Carworth-   5 female/group     not stated                  one dose        14 days    LD50 (14 days)                   Smyth et al.
    Wistar)                                                                                    5.52 (4.50-6.80) g/kgb           (1962)

    Rat (Sprague-    5 male/group       1.505 g/kg b.w.             one dose        24 h       after 16-23 h, no effect on      Traiger &
    Dawley)                                                                                    liver histology, serum glutamic  Bruckner (1976)
                                                                                               pyruvic transaminase, or 
                                                                                               hepatic glucose-6-phosphatase; 
                                                                                               63% increase in liver 

    Rat (Fischer-    32 male/group      0.072-1.082 g/kg b.w.       one dose        24 h       no evidence of liver             Brown & Hewitt
    344)                                                                                       dysfunction; slight damage at    (1984)
                                                                                               highest dose to kidney proximal 

    Mouse (CF1)      10 male/group in   2.0-5.1 g/kg b.w.           one dose        24 h       LD50 (24 h)                      Zakhari et al.
                     each of 6 groups                                                          3.14 ± 0.67 g/kg b.w.            (1977)

    Inhalation studies

    Mouse (Swiss     10 male/group      four levels over the        4 h                        decreased duration of            De Ceaurriz et
    OF1)                                range 4726-7192 mg/m3                                  immobility in escape -           al. (1983)
                                        (1602-2438 ppm)                                        directed swimming test

    Table 11 (contd)
    Species          Number and sex     Exposure concentration      Exposure        Study      Effects                          Reference
    (strain)                            and range                   duration        duration
    Mouse (CD1)      12 males per       five concentrations over    continuous      2´ h       increasing dose-related          Glowa & Dews
                     concentration      the range 885-29 500        (30 min per                behavioural effects starting     (1987)
                                        mg/m3 (300-10 000 ppm)      concentration)             at 2950 mg/m3 (1000 ppm)

    Mouse (CF1)      6 groups of        147 500-294 000 mg/m3       45 min                     LC50 (45 min) 205 000 ± 32 500   Zakhari et al.

                     10 males           (50 000-100 000 ppm)                                   mg/m3 (69 500 ± 11 000 ppm)      (1977)

    Mouse (white)    both sexes, 6      303 850 mg/m3               until death                average survival 43 min          La Belle &
                     animals/group      (103 000 ppm)                                                                           Brieger (1955)

    Rat (Sprague-    6 animals, sex     74-2360 mg/m3               2-6 h           2-6 h      behavioural change (increased    Garcia et al.
    Dawley)          unspecified        (25-800 ppm)                                           frequency of lever pressing)     (1978)
                                                                                               which persisted for < 2 to
                                                                                               > 11 days

    Rat (albino)     8 males/group      23 158-59 590 mg/m3         4 h             14 days    LC50 (4 h) 34 500 mg/m3          La Belle &
                                        (7850-20 200 ppm)                                      (11 700 ppm)                     Brieger (1955)

    Rat (Wistar)     5 males/group      23 600 mg/m3                8 h             14 days    lethal to 3/6 within 14 days     Smyth et al.
                                        (8000 ppm)                                                                              (1962)

    Rat (Wistar)     data not           47 200 mg/m3                8 h             14 days    lethal to 6/6 within 14 days     Smyth et al.
                     supplied           (16 000 ppm)                                                                            (1962)

    Guinea-pig       6 unspecified      approx. 9735 mg/m3          90-810 min      4-8 days   no abnormal signs                Patty et al.
                     sex/group;         (3300 ppm)                                                                              (1935)
                     3 groups

    Guinea-pig       6 unspecified      approx. 29 500 mg/m3        90-810 min      4-8 days   90 min: no injury; 280 min:      Patty et al.
                     sex/group;         (10 000 ppm)                                           unconsciousness and slight       (1935)
                     3 groups                                                                  injury, no deaths; 810 min:
                                                                                               unconsciousness and moderate
                                                                                               injury, no deaths

    Table 11 (contd)
    Species          Number and sex     Exposure concentration      Exposure        Study      Effects                          Reference
    (strain)                            and range                   duration        duration
    Guinea-pig       10 females         73 750 mg/m3                325 min         < 2 days   all animals died during or       Specht et al.
                                        (25 000 ppm)                                           post exposure                    (1940)

    Guinea-pig       6 unspecified      approx. 97 350 mg/m3        30-250 min      4-8 days   30 min: slight injury; 90 min:   Patty et al.
                     sex/group;         (33 000 ppm)                                           unconsciousness and moderate     (1935)
                     3 groups                                                                  injury, no deaths; lethal to
                                                                                               all animals in 200-250 min

    Guinea-pig       6 unspecified      approx. 303 850 mg/m3       10-55 min       4-8 days   10 min: slight injury; 30 min:   Patty et al.
                     sex/group;         (103 000 ppm)                                          unconsciousness and moderate     (1935)
                     3 groups                                                                  injury, no deaths, lethal to
                                                                                               all animals in 45-55 min

    Intravenous study

    Rat (Sprague-    18 females         several infusion rates      60 min          60 min     threshold limit for vestibulo-   Tham et al.
    Dawley)                             including 5 mg/kg b.w.                                 ocular disturbance (depression   (1984)
                                        per min                                                of nystagmus following 
                                                                                               accelerated rotation) 5 mg/kg
                                                                                               b.w. per min; MEK concentration
                                                                                               in blood, 101 mg/litre

    Pulmonary aspiration study

    Rat (Sprague-    3 males and        800 mg/kg b.w.              one dose      survivors    lethal 5/6 in < 24 h; 4/6 died   Panson & Winek
    Dawley)          3 females                                                    sacrificed   instantly; produced pulmonary    (1980)
                                                                                  at approx.   haemorrhage
                                                                                  24 h

    Intraperitoneal studies

    Mouse (CF1)      10 male/groups;    0.5-2.0 g/kg b.w.           one dose        24 h       LD50 (24 h)                      Zakhari et al.
                     5 groups                                                                  1.66 ± 0.74 g/kg b.w.            (1977)

    Table 11 (contd)
    Species          Number and sex     Exposure concentration      Exposure        Study      Effects                          Reference
    (strain)                            and range                   duration        duration
    Rat (Sprague-    6 female/group;    not stated                  one dose        24 h       LD50 (24 h) 1.554                Lundberg et
    Dawley)          number of groups                                                          (1.229-1.966) g/kg b.w.          al. (1986)

    Rat (Sprague-    6 female/group;    not stated                  one dose        14 days    LD50 (14 day) 0.607              Lundberg et
    Dawley)          number of groups                                                          (0.486-0.748) g/kg b.w.          al. (1986)

    Rat (Sprague-    6 female/group;    0.049-0.194 g/kg b.w.       one dose        18 h       no significant elevation of      Lundberg et
    Dawley)          3 groups                                                                  serum sorbital dehydrogenase     al. (1986)

    Guinea-pig       4 male/group       0.75-2.0 g/kg               one dose        24 h       0.75 g/kg b.w.: no elevation     DiVincenzo &
                                                                                               in serum OCTc level, no          Krasavage
                                                                                               obvious lipid deposition in      (1974)
                                                                                               hepatocytes, no deaths; 
                                                                                               1.5 g/kg b.w.: elevated serum 
                                                                                               OCT level, lipid deposition in
                                                                                               hepatocytes, no deaths; 
                                                                                               2.0 g/kg b.w.: elevation
                                                                                               in serum OCT level, lipid 
                                                                                               deposition in hepatocytes, 
                                                                                               lethal to 1/4 animals

    Dermal studies

    Rabbit (Albino,  4 males            amounts not stated;         24 h            14 days    LD50 (14 days) > 8 g/kg          Smyth et al.
    New Zealand)                        kept in contact with                                                                    (1962)
                                        clipped flank skin
                                        under plastic film

    Rabbit (Albino,  5 males            8 mg on clipped             one dose        24 h       minor irritation                 Smyth et al.
    New Zealand)                        uncovered skin                                                                          (1962)

    Table 11 (contd)
    Species          Number and sex     Exposure concentration      Exposure        Study      Effects                          Reference
    (strain)                            and range                   duration        duration
    Rat (Albino)     8 males            0.4 mg on 2.5 cm2           24 h            72 h       variable results: no irritation  Weil & Scala
                                        lightly covered pad                                    to moderate irritation 1 day     (1971)
                                        on clipped back skin                                   and 3 days after applicationd

    Rabbit (Albino)  6 animals intact   0.5 ml to clipped           24 h            72 h       slight erythema subsiding by     Hazleton
                     skin, 6 animals    abdominal skin with                                    72 h                             (1963a)
                     abraded skin,      semi-occlusive
                     sex unspecified    cover

    Ocular studies

    Rabbit (Albino)  6 of unspecified   0.1 ml to one eye of        30 sec          14 days    severe irritation, including     Hazleton
                     sex                each rabbit                                            corneal damage and scleral       (1963b)
                                                                                               haemorrhage in 2/6 rabbits

    Rabbit (Albino)  5 male per         not stated                  3 min                      solution of 130 g/litre water    Larson et al.
                     concentration                                                             produced significant oedema in   (1955)
                                                                                               eyelid in 1 h

    Rabbit (Albino,  not specified      4 mg/eyee                   1 min           18-24 h    severe chemical burn             Smyth et al.
    New Zealand)                                                                                                                (1962)

    Rabbit (Albino)  6 males            8 mg to one eye of          20 sec          7 days     variable results; no irritation  Weil & Scala
                                        each rabbit                                            to moderate irritation 1 day, 3  (1971)
                                                                                               days and 7 days after

    Rabbit (Albino,  6 of unspecified   8 mg to one eye of          described       7-10 days  slight swelling, redness and     MB Research
    New Zealand)     sex                each rabbit                 as brief                   discharge from eye for 4 to      Lab. Inc.
                                                                                               10 days                          (1979)

    Table 11 (contd)

    a    Values from the literature were recalculated as necessary to yield dosages in terms of ppm, g or g/kg
    b    95% confidence limits
    c    OCT = ornithine carbamyl transferase
    d    Purpose of study was intercomparison of testing laboratories that evaluated MEK and other substances by purportedly identical methods
    e    Not clear whether one eye or both eyes were dosed

         The results of studies on eye irritation in rabbits are
    inconsistent. Smyth et al. (1962) reported that 0.005 ml (4 mg)
    created a severe chemical burn in the rabbit eye, whereas a study by
    MB Research Lab. Inc. (1979) reported less severe irritant effects
    from the larger dose of 0.1 ml (80 mg). Data from a study by Weil &
    Scala (1971) were also inconsistent but indicated that a dose of 0.1
    ml (80 mg) produced minimal to moderate eye irritation. Undiluted MEK
    was used in all three studies but Smyth et al. (1962) used the grading
    system for eye injury described in Carpenter & Smyth (1946), whereas
    MB Research Lab., Inc. (1979) and Weil & Scala (1971) used the Draize
    scoring system (Draize et al., 1944). In all studies irritation
    disappeared or was markedly reduced by 7 days after treatment. Opaque
    corneas were apparent following exposure of guinea-pigs to 295 000 mg
    MEK/m3 (100 000 ppm) for 30 min; recovery from this effect was
    complete in 4-8 days (Patty et al., 1935).

    7.2  Repeated exposures

         Data on repeated exposure of mammals to MEK are summarized in
    Table 12. None of the concentrations tested, not even the highest (17
    700 mg/m3 (6000 ppm) 8 h/day for up to 7 weeks) was clearly lethal
    or even significantly harmful. The death of experimental animals
    (rats) at this highest dose was not associated with neurological signs
    and appeared to result exclusively from bronchopneumonia (Altenkirch
    et al., 1978, 1979). These authors did not comment on possible
    connections between bronchopneumonia and exposure to 17 700 mg/m3.
    Female rats exposed to 14 750 mg/m3 (5000 ppm) 6 h/day, 5 days per
    week, for 90 days showed only slightly increased liver weight,
    slightly decreased brain and spleen weights, and slightly altered
    blood chemistry in comparison with controls. Male rats receiving this
    exposure showed only a slightly increased liver weight. At lower
    concentrations of MEK (3688 and 7375 mg/m3 (1250 and 2500 ppm))
    there was only slightly increased liver weight for female rats and no
    significant differences for males in comparison with controls
    (Cavender et al., 1983). In another subchronic inhalation study
    (Toxigenics, 1981), male and female rats were exposed to MEK
    concentrations of 3700, 7430 and 14 870 mg/m3 (1254, 2518 and 5041
    ppm) 6 h/day, 5 days/week, for 90 days. No significant effects on food
    consumption, eyes or nervous system were observed. In addition, no
    MEK-induced morphological changes in the central or peripheral nervous
    system were detected. Lower levels of exposure resulted in few
    measurable effects. Inhalation of 2242 and 2360 mg/m3 (760 and 800
    ppm) 6 h/day, 5 days/week, for 4 weeks by rats caused some enlargement
    of the liver and slightly modified the  in vitro  metabolism of liver
    microsomes (Nilsen & Toftgard, 1980; Toftgard et al., 1981). Ten
    intraperitoneal injections of 0.034 g/kg over 2 weeks produced no
    effect on the kidney (Bernard et al., 1989). However, exposure of rats
    to 590 mg/m3 (200 ppm) 12 h/day for 24 weeks transiently decreased
    nerve conduction velocity after 4 weeks (Takeuchi et al., 1983).
    Geller et al. (1978) reported that exposure of baboons to 295 mg/m3
    (100 ppm) for 7 days increased the response time in a delayed "match

    to sample" task. However, this effect was transient and disappeared
    during the course of repeated exposure. Following intermittent
    exposure of rats to 3319 g/m3 for up to 5 months there was no
    morphological evidence of peripheral neurotoxicity (Saida et al.,
    1976). It is possible that the transient nature of the neurological
    and behavioural changes induced by MEK exposure may be due to
    behavioural and/or physiological adaptations. The latter may reflect
    more rapid metabolism of MEK with prolonged exposure.

         Short-term dermal exposure to small amounts of MEK resulted, at
    most, in mild local irritation. Two topical applications of an
    unstated amount to the ears of various strains of mice (Swiss, Balb/c,
    CBA, C5681/6, DBA/2, B6D2F1) produced no significant swelling or other
    signs (Descotes, 1988). In rabbits and guinea-pigs, a dose of 0.08 g
    applied to the skin, without covering, once a day for 10 days to the
    same site resulted in a slight to moderate increase in skinfold
    thickness, whereas a much smaller dose (8 mg) applied to the same site
    in rabbits 3 times a day for 3 days resulted in barely detectable
    irritation (Wahlberg, 1984a). Open application of MEK to the shaved
    flanks of guinea-pigs for 3 days produced slight erythema, epidermal
    thickening and dermal cell infiltration (Anderson et al., 1986). In
    the cat, injection of 150 mg MEK (99.98% pure) per kg, twice a day, 5
    days/week, for up to 8.5 months, into subcutaneous tissue produced
    abscesses, skin ulceration and generalized weakness but no evidence of
    damage to the nervous system (Spencer & Schaumburg, 1976). In the one
    long-term dermal study of MEK (Horton et al., 1965), 8 mg dissolved in
    water was applied by dropper or brush to clipped skin of mice twice a
    week for a year. Few details were given of the results because this
    was the control for a study on carcinogenesis of the skin in which a
    MEK/water solution was the solvent for compounds under test. Horton et
    al. (1965) stated that the control mice did not develop skin tumours,
    and they did not mention any adverse effects from this prolonged
    application of MEK.

        Table 12.  Repeated exposure of mammals to MEKa
    Route          Species (strain),   Exposure and range              Results                                                 Reference
                   number and sex
    Inhalation     rat (Wistar),       590 ± 118b mg/m3 (200 ± 40b     transient differences in nerve conduction claimed       Takeuchi et al.
                   8 males             ppm) 12 h/day for 24 weeks      after 4 weeks, but no significant differences           (1983)

    Inhalation     rat (Albino),       693 ± 77b mg/m3 (235 ± 26b      no significant gross or microscopic                     La Belle &
                   25, sex             ppm) 7 h/day, 5 days/week       pathological changesc                                   Brieger (1955)
                   unspecified         for 12 weeks

    Inhalation     rat (Wistar),       885 mg/m3 (range 867-894)       no significant change in leucocyte or serum             Li et al. (1986)
                   7 females           (300 ppm (range 294-303))       alkaline phosphatase activity
                                       8 h/day for 7 days

    Inhalation     rat (Sprague-       3322 and 7723 mg/m3 (1026       at 7723 mg/m3 minor effects on dams, decreased          Schwetz et al.
                   Dawley),            and 2618 ppm) 7 h/day           food consumption and weight gain, and increased         (1974)
                   pregnant, 25 per    for 10 days (gestation          water consumption; no effects on dams at 1180 mg/m3
                   concentration       days 6-15)

    Inhalation     rat (Sprague-       2242 and 2360 mg/m3 (760 and    significant enlargement of liver; no effect on          Nilsen &
                   Dawley), 4          800 ppm), 6 h/day, 5 days       total liver microsomal concentration of cytochrome      Toftgard (1980);
                   male/concentration  per week for 4 weeks            P-450;  in vitro liver microsomal metabolism of         Toftgard et al.
                                                                       biphenyl unaffected, but slight effects on the          (1981)
                                                                       metabolism of benzo[a]pyrene, 4-androstene-3,17-
                                                                       dione, and 5alpha-androstane-3alpha,17ß-diol

    Inhalation     rat (Fischer-       3688, 7375, 14 750 mg/m3        females at 14 750 mg/m3 increased in liver weight,      Cavender et al.
                   344), 15 males,     (1250, 2500, 5000 ppm)          smaller braind and spleene weight, slightly altered     (1983)
                   15 females/         6 h/day, 5 days/week for        blood chemistryf; females at 3688, 7375 mg/m3 
                   concentration       90 days                         nonsignificant increase in liver weight; males at 
                                                                       14 750 mg/m3 increased in liver weight. No pathological
                                                                       lesions, including peripheral nerves, attributed to 
                                                                       MEK exposure.  No effect on reproductive tissues 
                                                                       (testis, epididymis, seminal vesicle, vagina, cervix, 
                                                                       uterus, oviduct, ovary)

    Table 12 (contd)
    Route          Species (strain),   Exposure and range              Results                                                 Reference
                   number and sex

    Inhalation     rat (Fischer-       3699, 7430, 14 870 mg/m3        elevated group mean body weights at 3699 and 7430       Toxigenics
                   344), 15 males,     (1254, 2518, 5041 ppm)          mg/m3; highest concentration: decreased group mean      (1981)
                   15 females/         6 h/day, 5 days/week for        body weight, increased liver weight, liver/body
                   concentration       90 days                         weight ratio and liver/brain weight ratio, increased
                                                                       mean corpuscular haemoglobin; highest concentration
                                                                       (males): increased kidney/body weight ratio, decreased
                                                                       spleen and brain weights; highest concentration
                                                                       (females): decreased brain/body weight ratio, increased
                                                                       kidney/brain weight ratio; no significant effects at
                                                                       any concentration on food consumption, eyes, nervous
                                                                       system, and no morphological changes in central or
                                                                       peripheral nervous systems

    Inhalation     rat (Sprague-       3319 mg/m3 (1125 ppm) 24 h      no morphological effects on peripheral nerves           Saida et al.
                   Dawley), 36 of      per day for 16 days to 5                                                                (1976)
                   unspecified sex     months

    Inhalation     rat (Wistar),       29 500 mg/m3 (10 000 ppm) for   severe irritation of upper respiratory tract; slight    Altenkirch et
                   5 males             a "few days"; 17 700 mg/m3      loss of weight; death during seventh week from          al. (1978,
                                       (6000 ppm) ± 15% for 8 h/day,   bronchopneumonia; no neurological signs                 1979)
                                       7 days/week for 15 weeks

    Inhalation     guinea-pig,         693 ± 77b mg/m3 (235 ± 26b      no significant effects                                  La Belle &
                   15 of unspecified   ppm) 7 h/day, 5 days/week for                                                           Brieger (1955)
                   sex                 12 weeks

    Inhalation     baboon,             295 mg/m3 (100 ppm) for 7 days  no impairment of discrimination in a behavioural        Geller et al.
                   4 males                                             test, slight increase in response time early in         (1978)
                                                                       experiment, but not at end of experiment

    Table 12 (contd)
    Route          Species (strain),   Exposure and range              Results                                                 Reference
                   number and sex

    Intra-         rat (Sprague-       0.034 g/kg, 5 days/week for     no effect on kidney function                            Bernard et al.
    peritoneal     Dawley),            2 weeks                                                                                 (1989)
                   female, number

    Subcutaneous   cat, 6 of           0.15 g/kg twice/day, 5 days     abscesses, skin ulceration and generalized weakness     Spencer &
                   unspecified sex     per week for up to 8.5 months   in some animals; no damage to nervous                   Schaumburg
                                                                       system structure or function                            (1976)

    Dermal         mouse (Swiss),      unstated amount applied twice   no significant swelling of treated ear                  Descotes (1988)
                   12 of unspecified   to one ear                      

    Dermal         mouse               8 mg (50 mg of 17% solution)    no papilloma evident after 1 year                       Horton et al.
                   (C3H/He)            applied to clipped skin twice                                                           (1965)
                   10-25 males         per week for 1 year

    Dermal         guinea-pig, 3       80 mg rubbed into skin at       slight to moderate increase in skinfold thickness       Wahlberg (1984a)
                   and rabbit, 4,      same site once daily for        at end of 10 days
                   of unspecified      10 days

    Dermal         guinea-pig          80 mg applied to 1.0 cm2 on     no reaction until day 2; at end of experiment,          Anderson et al.
                   10 females          shaved flank 3 times daily      slight redness and increase in dermal inflammatory      (1986)
                                       for 3 days                      cell count

    a    Values from the literature recalculated as ppm, mg or g/kg
    b    Standard deviation of the mean
    c    Depressed growth (average weight 70% of controls at end of experiment) may be due to causes other than MEK exposure; animals showed signs
         of "vitamin deficiency" (no details given) and infection in latter part of experiment.
    d    Significantly different at the < 0.01 level from 0, 3688 and 7375 mg/m3 (0, 1250, and 2500 ppm) female group values
    e    Significantly different at the < 0.05 level from 0, 3688 and 7375 mg/m3 (0, 1250, and 2500 ppm) female group values
    f    Females in the 14 750 mg/m3 (5000 ppm) group had a small but significant elevation in serum potassium, alkaline phosphatase and glucose
         levels, and a significant reduction in serum glutamic-pyruvic transaminase level.

    7.3  Neurotoxicity

    7.3.1  Behavioural testing

         Neurotoxicity studies have been carried out on MEK, usually as
    part of studies on the neurotoxicity of methyl isobutyl ketone (MIBK)
    and MIBK/MEK mixtures.

         An increase in response rate (lever pressing) was reported in a
    group of six adult Sprague-Dawley rats (sex unspecified) exposed to
    MEK at various concentrations between 74 and 2360 mg/m3 (25 and 800
    ppm) for 2 h at approximately weekly intervals. An increase in
    response rate also occurred in a group of four rats exposed to 74
    mg/m3 (25 ppm) for 6 h at 2-day intervals (Garcia et al., 1978).

         Geller et al. (1978) examined behavioural effects (match to
    sample (MTS) test) in baboons exposed to MEK by inhalation. Four young
    male baboons (2 years old) were exposed continuously to MEK at a
    concentration of 295 mg/m3 (100 ppm) for 7 days. There were no
    effects on performance of the test in terms of the ability to
    discriminate visual stimuli but reaction time increased. However, in
    two of the baboons, response times returned to pre-exposure control
    values by day 7.

         Tham et al. (1984) examined the vestibulo-oculomotor reflex (VOR)
    during intravenous infusion of MEK into the caudal veins of 18 female
    Sprague-Dawley rats. The threshold for depression of the VOR was an
    infusion rate of 70 µmol/kg (0.005 g/kg per min) for 1 h (total dose
    30 mg) and the associated arterial blood level was 1.4 mmol/litre.
    General depression of the central nervous system followed depression
    of the VOR. 

         Glowa & Dews (1987) exposed continuously by inhalation a group of
    12 adult male white mice (Charles River CD1) to concentrations of MEK
    that were increased at 30 min intervals until the mice failed to
    respond to a visual stimulus. The concentrations, in ascending order
    for each 30 min, were 885, 2950, 8850, 16 520 and 29 500 mg/m3 (300,
    1000, 3000, 5600 and 10 000 ppm) with a total exposure time of 2´ h.
    Mice responded to a visual stimulus and the response rate was used as
    an indicator. There was no effect at a concentration of 885 mg/m3,
    a slight decrease in response rate at 2950 mg/m3 and a 75% decrease
    at 8850 mg/m3. Most mice ceased to respond at 16 520 mg/m3 and all
    failed to respond at 29 500 mg/m3. The response rate returned to the
    control value 30 min after exposure ended. The EC50 (concentration
    decreasing response rate by 50%) was calculated to be 8528 (SD = 2033)
    mg/m3 (2891 (SD = 689) ppm). An EC10 was calculated and
    dose-response estimates were derived. The concentrations of MEK
    producing a 10% decrease in response rate in 0.1%, 1% and 19% of a
    population were 50, 195 and 885 mg/m3 (17, 66 and 300 ppm),

         Couri et al. (1977) exposed continuously by inhalation young male
    Wistar rats to 2210 mg MEK/m3 (750 ppm) for either 7 or 28 days. In
    those exposed for 7 days there was a significant reduction in
    hexobarbital sleep times. In the group exposed for 28 days the
    reduction in sleep times was less marked.

    7.3.2  Histopathology

         In chickens, cats, rats and mice exposed by inhalation to 3975
    mg/m3 (1500 ppm) for periods of up to 12 weeks, there was no
    evidence of neuropathy and no histopathological changes were reported
    (Couri et al., 1974).

         Saida et al. (1976) exposed groups of 36 Sprague-Dawley rats (sex
    unspecified) continuously to MEK at a concentration of 3319 mg/m3
    (1125 ppm) for periods of 16, 25, 35 and 55 days. Additional studies
    were carried out with up to 5 months of exposure. There were no
    abnormal clinical observations in any group. At the end of the
    exposure period, rats were sacrificed and the sciatic nerve and foot
    muscle excised. Spinal cord and dorsal root ganglion specimens were
    taken from the same rats. Quantitative histology
    (neurofilaments/µm2; frequency of inpouching of myelin sheath,
    denuded axons/mm2) showed no abnormality in rats exposed for up to
    5 months. 

         Cavender et al. (1983) reported no neurological abnormalities in
    Fischer-344 rats in a 90-day inhalation study on MEK alone. Groups of
    15 male and 15 female rats were exposed 6 h/day, 5 days/week, for 90
    days to MEK concentrations of 3688, 7375 and 14 750 mg/m3 (1150,
    2500 and 5000 ppm). All rats were observed twice daily for clinical
    signs. At the end of the exposure period, the eyes of each animal were
    examined by ophthalmoscopy, and neurological function (posture, gait,
    tone and symmetry of facial muscles, and pupillary, palpebral,
    extensor-thrust and cross-extensor thrust reflexes) was evaluated. No
    abnormalities were found. Necropsy, including histopathology of the
    sciatic and tibial nerves, was carried out on all rats, with special
    neuropathological studies on the medulla, sciatic and tibial nerves in
    5 male and 5 female rats from each group. There were no changes
    attributable to MEK.

    7.4  Developmental toxicity

         Schwetz et al. (1974) exposed 44 pregnant rats from days 6-15 of
    gestation (sperm = day 0) to two concentrations of MEK vapour, i.e.
    nominally 2950 mg/m3 in 23 rats and 8850 mg/m3 in 21 rats (1000
    and 3000 ppm), for 7 h/day; 43 rats were air-exposed as controls. The
    average values for measured concentrations in this study were 3322 and
    7723 mg/m3 (1126 and 2618 ppm), respectively. There was no evidence
    of maternal toxicity. Fetal weight and crown-rump length were
    significantly decreased at 3322 mg/m3, but not at 7723 mg/m3. At
    3322 mg/m3 there was also a significant increase, compared to the

    controls, in the number of litters with fetuses showing skeletal
    anomalies, and at 7723 mg/m3 a significantly increased incidence of
    litters with sternebral and soft tissue anomalies was reported. Four
    grossly malformed fetuses were found (two with brachygnathia and two
    acaudate with imperforate anus), all in different litters in the 7723
    mg/m3 group. These malformations had not been observed previously in
    more than 400 control litters of this strain. Fetal body dimensions,
    however, were not significantly different from controls. When the data
    were analysed on a per litter basis, there was evidence of a
    teratogenic effect.

         However, the incidence of major malformations in these studies
    was sufficiently low that evidence for teratogenic effects was
    considered questionable, and the studies were repeated (John et al.,
    1980; Deacon et al., 1981). The methodology was identical except for
    the inclusion of an additional level of exposure, nominally 1180
    mg/m3 (400 ppm). Average measured MEK concentrations during the
    experiment were 1215, 2956 and 8865 mg/m3 (412, 1002 and 3005 ppm).
    The only evidence for maternal effects was decreased weight gain and
    increased water consumption (no figures given) by dams exposed to 8865
    mg/m3. None of the dosages had significant effects on the incidence
    of pregnancy, incidence of resorption, average number of implantations
    and live fetuses per dam, fetal weight and length, or incidence of
    external or soft tissue abnormalities. There were statistically
    significant differences in the incidences of some skeletal anomalies
    occurring in the 8875 mg/m3 group compared to the controls. There
    were increased incidences of lumbar ribs and delayed ossification of
    the cervical centra, but a decreased incidence of delayed ossification
    of the skull. Since these skeletal abnormalities occurred at low
    incidences among the population from which the experimental animals
    were drawn, the results of this study were interpreted as indicating
    a low level of fetotoxicity and no evidence for embryotoxic or
    teratogenic effects for MEK at exposure levels up to 8865 mg/m3.

         In a further study (Mast et al., 1989; Schwetz et al., 1991),
    groups of 10 virgin female Swiss CD1 mice and 33 plug-positive (day 0)
    females were exposed by inhalation on gestation days 6-15 to mean
    concentrations of 1174 ± 27, 2980 ± 83 and 8909 ± 233 mg/m3 (398 ±
    9, 1010 ± 28 and 3020 ± 79 ppm). There was no evidence of maternal
    toxicity, although there was a slight, treatment-related increase in
    liver/body weight ratios that was significant at the highest dose
    level. Mild fetal toxicity was evident at this maternal dose level as
    a reduction in mean fetal body weight, statistically significant for
    males. There was no increase in the incidence of intrauterine death,
    but there was an increased dose-related incidence of misaligned
    sternebrae, statistically significant at the highest dose level. There
    were no significant increases in the incidence of malformations,
    although there were several malformations in one litter (cleft palate,
    fused ribs, missing vertebrae, syndactyly) in treated groups but not
    in the control group nor in contemporary control data. On the basis of
    this study it was concluded that the no-observed-adverse-effect level

    (NOAEL) was 2978 mg/m3 (1010 ppm) and the
    lowest-observed-adverse-effect level (LOAEL) was 8096 mg/m3 (3020

    7.5  Mutagenicity and related end-points

         Short-term genotoxicity tests  in vitro  and  in vivo  are
    summarized in Table 13. Although MEK has given negative results in
    most conventional assays, Zimmermann et al. (1985) found that MEK and
    certain other polar aprotic solvents were strong inducers of
    aneuploidy in the yeast. The induction of aneuploidy by MEK was
    markedly potentiated by coexposure to ethyl acetate (Mayer & Goin,
    1988) or with nocodazol (methyl [5- (2-thienyl-carbonyl)-1
    H-benzimidazol-2-yl]-carbamate) (Mayer & Goin, 1987).

         O'Donoghue et al. (1988) conducted mutagenicity studies on MEK.
    The test systems comprised the Salmonella/microsome (Ames) assay, the
    L5178/TK+/- mouse lymphoma (M/L) assay, the BALB/3T3 cell
    transformation (CT) assay, unscheduled DNA synthesis (UDS) and the
    micronucleus test. MEK was not found to be genotoxic in these assays.

         Other studies of MEK utilizing cultures of mammalian cells as
    test systems also yielded little or no evidence of mutagenicity and
    related effects. Perocco et al. (1983) tested MEK and other important
    industrial chemicals at concentrations of 10-2 to 10-4 mol/litre
    (0.72 to 0.0072 g MEK/litre) with an  in vitro  system utilizing
    cultures of human lymphocytes to determine toxicity and ability to
    inhibit DNA synthesis. Cultures were grown both with and without S9
    mix derived from phenobarbital-induced rat liver. MEK at the
    concentrations tested showed no evidence of cytotoxic or genotoxic
    action. Chen et al. (1984) examined the effects of MEK on metabolic
    cooperation between 6-thioguanine-resistant and
    6-thioguanine-sensitive Chinese hamster lung fibroblast V79 cells and
    obtained equivocal results. Holmberg & Malmfors (1974) also found some
    evidence of MEK cytotoxicity to ascites tumour cells cultured with the
    solvent for up to 5 h. Although there was no significant increase in
    irreversibly injured cells at MEK concentrations of 0.05 and 0.1
    g/litre, there was a moderate increase in damaged cells at 0.1
    g/litre. An ultrastructural study (Veronesi, 1984) utilizing a medium
    containing relatively high concentrations of MEK (0.3 g/litre)
    produced axoplasmic granularities in a few cultures. The relationship
    of this effect to possible MEK-induced neurotoxicity  in vivo  is not

    7.6  Carcinogenicity

         No long-term carcinogenicity studies have been reported. 

        Table 13.  Short-term genotoxicity tests on MEK
    Method                   Concentration       Experimental conditions; comments            Results   References
    In vitro studies

    Bacterial assays         3 µmol/plate         Salmonella typhimurium TA98, TA100, TA1535,   -         Florin et al. (1980)
                                                 TA1537 with and without S-9

                             10 mg/plate          S. typhimurium TA98, TA100, TA1535,           -         Nestmann et al. (1980)
                                                 TA1537 with and without S-9

                             approx.              S. typhimurium TA104: maximum non-toxic       -         Marnett et al. (1985)
                             1 mg/plate          dose > 3 µmol

                             0.05-32 µl/plate     S. typhimurium TA98, TA100, TA1535,           -         O'Donoghue et al. (1988)
                                                 TA1537, TA1538 with and without S-9

                             4 mg/plate           Escherichia coli WP2 and WP2 uvrA             -         Brooks et al. (1988)

    Mitotic gene             5 mg/ml              Saccharomyces cerevisiae (JD1)                -         Brooks et al. (1988)
     conversion assay

    Induction of mitotic     3.54%                S. cerevisiae (D61.M)                         +         Zimmermann et al. (1985)

                             0.50-1.96%           S. cerevisiae (D61.M)                         +         Mayer & Goin (1987)

    Chromosome assay         1 mg/ml             rat liver RL4 cells                           -         Brooks et al. (1988)

    Cell transformation      9-18 µl/ml          BALB/3T3                                      -         O'Donoghue et al. (1988)

    UDS test                 0.1-5.0 µl/ml       primary rat (Sprague-Dawley) hepatocyte       -         O'Donoghue et al. (1988)

    Table 13 (contd)
    Method                   Concentration       Experimental conditions; comments            Results   References

    In vivo studies

    Micronucleus test        1.9 ml/kg           CD1 mice (male and female),                  -         O'Donoghue et al. (1988)
                             intraperitoneal     time: 12, 24, 48 h

                             411 mg/kg           Chinese hamster, time: 12, 24, 48, 72 h      -         Basler (1986)


    8.1  General population exposure

         The only record of non-occupational acute toxicity from MEK was
    a case of accidental self-poisoning (Kopelman & Kalfayan, 1983). A
    47-year old woman inadvertently ingested an unknown amount of MEK and
    was found unconscious, hyperventilating, and suffering from severe
    metabolic acidosis. Her plasma concentration of MEK was 950 mg/litre.
    She responded promptly to an infusion of sodium hydrogen carbonate and
    was discharged from the hospital after a week. The metabolic effects
    of MEK ingestion by humans are not well characterized and it is
    uncertain that the acidosis was produced by MEK.

    8.2  Effects of short-term exposure

         There are limited data on behavioural and other effects on humans
    of short-term exposure to MEK. Nakaaki (1974) found that exposure to
    266-797 mg/m3 (90-270 ppm) for up to 4 h per day caused his subjects
    to underestimate times of 5 to 30 seconds. Dick et al. (1984, 1988,
    1989), on the other hand, found that a 4-h exposure of human subjects
    to 590 mg/m3 (200 ppm) had no significant effect in a variety of
    behavioural tests. These included psychomotor, visual vigilance, dual
    task, sensorimotor and psychological tests. Solvent mixtures of 295 mg
    MEK/m3 (100 ppm) and 186 mg toluene/m3 (50 ppm), and of 295 mg
    MEK/m3 (100 ppm) and 298 mg acetone/m3 (125 ppm) similarly had no
    significant effect on the results of these behavioural tests. 

    8.3  Skin irritation and sensitization

         MEK (0.1 ml) rubbed into volar forearm skin daily for 18 days and
    left uncovered did not produce persistent erythema or swelling
    (Wahlberg, 1984a). A 5-min contact with 1.5 ml of analytical grade MEK
    confined to a 20-mm circle on the forearm produced a temporary
    whitening of the skin, but no visible erythema, alteration in
    cutaneous blood flow or other indication of irritation to the skin
    (Wahlberg, 1984b).

         A male painter developed dermatitis 18 months after commencing
    spray painting using an epoxy-polyamide paint (Varigos & Nurse, 1986).
    A patch test with "a small amount" of MEK applied to areas of skin 
    3 cm in diameter on each forearm caused these areas of skin to turn
    bright red within 10 min. The spots were itchy, but there was no
    induration or oedema. The reaction reached its maximum after 15 min
    and then gradually faded. The test was repeated after 2 days, and gave
    the same results. Application of the same grade of MEK to normal
    forearm skin of five male volunteers produced no reaction. 

    8.4  Occupational exposure

    8.4.1  MEK alone

         There is no record that MEK toxicity has ever caused death or a
    large scale industrial accident, and only one acute occupational
    poisoning has been ascribed to MEK. An 18-year-old seaman with good
    vision and no previous eye problems was exposed to MEK vapour of
    unknown concentration while stripping paint, and promptly noted
    headache, mild vertigo and blurred vision (Berg, 1971). The diagnosis
    was retrobulbar neuritis. He was given vitamin B complex and steroid
    therapy, and his vision returned to normal in 36 h. However, blood
    analysis exhibited a positive methanol content (no value reported)
    according to the criteria given by Kaye (1961). Thus a potentiation of
    the effects due to combined exposure to MEK and methanol cannot be

         Data for occupational poisoning ascribed to chronic exposure to
    MEK in the absence of other solvents are equally limited. Long-term
    exposure of 51 Italian workers to MEK produced indications of
    neurotoxicity with slightly, but not significantly, reduced nerve
    conduction velocities and various other symptoms such as headache,
    loss of appetite and weight, gastrointestinal upset, dizziness,
    dermatitis and muscular hypotrophy, but no clinically recognizable
    neuropathy (Freddi et al., 1982). There has been a brief report of
    chronic exposure of American workers, in a factory producing coated
    fabric, to 885-1770 mg MEK/m3 (300-600 ppm) in the apparent absence
    of other solvents (Smith & Mayers, 1944). Workers complained of
    dermatoses and numbness of fingers and arms.

    8.4.2  MEK in solvent mixtures

         It was reported that MEK was commonly present as part of solvent
    mixtures containing hexane, and that the TLV for hexane (148 mg/m3,
    50 ppm) was exceeded in 89 of the work stations (mainly in shoe
    factories) (De Rosa et al., 1985). MEK potentiates the toxicity of
    hexane and these authors concluded that in these shoe factories the
    risk of neurotoxicity was extremely high. Observations by Tangredi et
    al. (1981), Brugnone et al. (1981) and Cresci et al. (1985) supported
    the widespread nature of this health problem in Italian industry,
    especially shoe factories. Arques Espi & Quintanilla Almagro (1981)
    also found that mixtures of solvent vapours including MEK and hexane
    posed an excessive risk in 95 of 114 work stations examined in a study
    of Spanish shoe factories. In a nationwide survey of Japanese
    factories, Inoue et al. (1983) found that MEK is widely used as a
    component of solvent mixtures. In a study of electronic parts plants
    in the USA (Lee & Parkinson, 1982), workers were found to be exposed
    to mixtures of solvent vapours containing MEK and as many as nine
    other components, although not hexane or other solvents whose toxic
    action MEK is known to potentiate. Observations on Finnish car
    painters (Husman, 1980; Husman & Karli, 1980) suggested that long-term

    exposure to complex solvent mixtures whose components individually and
    jointly are far below the legal concentration limits may produce
    significant adverse effects. Noma et al. (1988) similarly suggested
    that complex mixtures of volatile organic compounds, rather than a
    high concentration of any single compound, may be responsible for
    unhealthy air in buildings.

         Descriptions of the effects of occupational exposures to mixtures
    of solvent vapours not necessarily potentiated by MEK are summarized
    in Table 14. There are only two cases of acute occupationally related
    toxicity from such mixtures, and only a limited number of adequately
    documented cases of adverse effects from chronic occupational exposure
    which did not involve potentiation of hexacarbon toxicity. The only
    acute cases involved two young women waterproofing seams of raincoats
    with resins dissolved in acetone or MEK (Smith & Mayers, 1944).
    Post-exposure measurements revealed workplace concentrations of
    785-1178 mg/m3 (330-495 ppm) for acetone and 1174-1655 mg/m3
    (398-561 ppm) for MEK. The total solvent concentration was estimated
    to be 1000 ppm. Both women fainted at work and subsequently displayed
    a number of temporary neurological and other symptoms.

         However, the majority of these studies are difficult to interpret
    because they lack either a quantitative description of the solvent
    vapours in the work environment, or the description is based on
    post-exposure analyses that may not be typical of working conditions
    during most of the exposure. In these studies it is also impossible to
    make any certain assessment of the role(s) played by individual
    components. Mixed solvent exposures have been associated with
    alteration in nerve conduction velocity (Viader et al., 1975; Dyro,
    1978; Triebig et al., 1983), memory and motor alterations (Binaschi et
    al., 1976), and dermatoses and vomiting (Lee & Murphy, 1982). Fagius
    & Grönqvist (1978) reported neurological effects in 3 out of 42
    workers exposed in a steelworks to organic solvents. However, the
    actual role of MEK in these effects is not clear.

        Table 14.  Effects of occupational exposure to mixtures of solvent fumes containing MEK
    Concentrations of MEK and other              No. of workers  Exposure    Effects                         Defects in study       Reference
    components                                      exposed      duration

    MEK 1174-1655 mg/m3 (389-561 ppm),                2          few hours   eyes watering, gastric          measurements of work   Smith &
    acetone 785-1178 mg/m3 (330-495 ppm)                                     distress, fainting,             environment limited    Mayers
                                                                             convulsions, twitching,         to post exposure       (1944)
                                                                             headache, spinal pressure


    MEK 561-885 mg/m3 (190-300 ppm),                  13         1 year or   fatigue, frequent headache,     measurements of work   Lee &
    toluene 139-177 mg/m3 (37-60 ppm),                           more        dizziness, incoordination,      environment limited    Murphy
    MIBK 37-41 mg/m3 (9-14 ppm)                                              skin rashes, vomiting           to post exposure       (1982)

    MEK 30 mg/m3 (10 ppm), toluene                    2          2 and 6.5   paraesthesis in extremities,    measurements of work   Dyro
    94-488 mg/m3 (25-130 ppm)                                    years       reduced motor nerve conduction  environment limited    (1978)
                                                                             velocity, weakness in           to post exposure
                                                                             individuals exposed for long
                                                                             periods, improvement following
                                                                             cessation of exposure

    MEK 62-51 mg/m3 (21-180 ppm), acetone             1          1 year      altered consciousness and       measurements of work   Dyro
    86-595 mg/m3 (36-250 ppm)                                                EEG, reduced motor nerve        environment limited    (1978)
                                                                             conduction velocity             to post exposure

    MEK 142 mg/m3 (48 ppm), isobutanol                8          not stated  headache, dizziness, fatigue,   measurements of work   Binaschi
    67 mg/m3 (23 ppm), MIBK 16 mg/m3 (4 ppm),                                depression, significant         environment limited    et al.
    toluene 180 mg/m3 (48 ppm), butyl acetate                                reduction in short-term         to post exposure;      (1976)
    43 mg/m3 (9 ppm), xylene 347 mg/m3                                       memory and hand steadiness      period of exposure
    (80 ppm)                                                                                                 not indicated

    Table 14 (contd)
    Concentrations of MEK and other              No. of workers  Exposure    Effects                         Defects in study       Reference
    components                                      exposed      duration
    MEK 115 (avg), 2655 (max) mg/m3,  n-butanol         9         8-35        significant changes in         measurements of work   Denkhaus
    67 (avg), 1200 (max) mg/m3, isobutanol                       years       several sub-populations of      environment limited    et al.
    172 (avg), 3000 (max) mg/m3; 2-butoxy-                                   peripheral blood lymphocytes:   to post exposure       (1986)
    ethanol 25 (avg), 350 (max) mg/m3,                                       decrease in certain type of
    2-ethoxyethanol 5 (avg), 53 (max) mg/m3,                                 T-cells and helper cells,
    2-methoxyethanol 6 (avg), 150 (max) mg/m3,                               increase in natural killer
    toluene 86 (avg), 750 (max) mg/m3,                                       cells and B-lymphocytes
     m-xylene 19 (avg), 220 (max) mg/m3,
    MBK 2 (avg), 27 (max) mg/m3

    MEK 9-124 mg/m3 (3-42 ppm),                       5          > 10 years  no significant differences      measurements of work   Lundberg
    xylene 0-6111 mg/m3 (0-1408 ppm),                                        in serum activities of liver    environment limited    &
    toluene 0-1260 mg/m3 (0-336 ppm),                                        enzymes between exposed         to post exposure       Hakansson
    isobutanol 0-1045 mg/m3 (0-345 ppm),                                     workers and controls                                   (1985)
     n-butanol 0-1548 mg/m3 (0-511 ppm),
    ethanol 0-1094 mg/m3 (0-582 ppm),
    ethyl acetate 0-2095 mg/m3 (0-582 ppm),
     n-butyl acetate 0-1691 mg/m3 (0-356 ppm),
    methyl acetate 3-181 mg/m3 (1-60 ppm),
    white spirit 2-30 mg/m3 (1-17 ppm),
    methylene chloride 10-2460 mg/m3 (3-707 ppm),
    isopropanol 5-260 mg/m3 (2-106 ppm),
    exposure to 2-8 solvents plus MEK

    MEK < 9-401 mg/m3 (< 3-136 ppm),                  66         average     significant reduction in        measurements of work   Triebig
    xylene < 4-82 mg/m3 (< 1-19 ppm),                            5 years     sensory conduction in           environment limited    et al.
    toluene 11-551 mg/m3 (3-147 ppm),                                        comparison with controls, no    to post exposure       (1983)
    ethyl acetate < 11-302 mg/m3 (< 3-84 ppm)                                suggestion of neuropathy,
    trichloroethane 11-601 mg/m3 (2-110 ppm)                                 change in conduction velocity
                                                                             correlated with exposure

    Table 14 (contd)
    Concentrations of MEK and other              No. of workers  Exposure    Effects                         Defects in study       Reference
    components                                      exposed      duration

    MEK 15-620 mg/m3 (5-210 ppm), acetone             17         not stated  no health problems associated   measurements of work   Cohen &
    < 119-495 mg/m3 (< 50-208 ppm), xylene                                   with exposure to MEK            environment limited    Maier
    < 22 mg/m3 (< 5 ppm), toluene < 19-34                                                                    to post exposure       (1974)
    mg/m3 (< 5-9 ppm), petroleum naphtha
    (concentration unknown)

    MEK mainly < 443, max. 5115 mg/m3                 42         0.5-8       1 likely and 2 suspected        measurements of work   Fagius &
    (mainly < 150, max. 1734 ppm), trichloroethylene             years       cases of polyneuropathy,        environment limited    Gronqvist
    mainly < 161 mg/m3 (< 30 ppm);                                           slight loss of sensitivity      to post exposure       (1978)
    at low levels butanol, butyl acetate, butyl                              to vibration correlated
    diglycol, cyclohexanol, diacetal, ethyl                                  with level of solvent ex-
    glycol acetate, ethanol, isoforone,                                      posure during preceding
    methylene chloride, MIBK, toluene,                                       6 months
    xylene, "solvesso 100 and 150"a

    MEK 0-74 mg/m3 (avg, 3 mg/m3) (0-25               1006b      average     overall death rate below        none                   Wen et al.
    (avg. 1) ppm), toluene 4 mg/m3 (1 ppm);                      21.6 years  expected level, excess of                              (1985)
    at very low levels benzene, "hexane",                                    deaths from cancer associ-
    MIBK, xylene                                                             ated with lubricating oil,
                                                                             not MEK

    a    hydrocarbon solvent mixtures
    b    workers from lube oil and dewaxing plant

         In a study on a group of 9 parquet-flooring workers (age, 25-58
    years; exposure time, 8-35 years), Denkhaus et al. (1986) noted
    significant changes in several subpopulations of peripheral blood
    lymphocytes, which could constitute an early indication of a
    haematological or immunological effect. Benzene was not detected in
    the ambient air and no investigation was made to determine which
    components of the solvent mixtures produced the observed changes in
    lymphocyte populations. Anshelm Olson et al. (1981) studied the simple
    reaction time (SRT) performance in a group of 42 workers (age, 18 to
    52 years; employment, 0.5 to 8.1 years) from a plastic coating line of
    a steel factory (the same group had previously been studied by Fagius
    & Grönqvist, 1978). The study was longitudinal and covered a period of
    27 months during which SRT was measured three times. Originally, the
    workers had been exposed to significant concentrations of MEK (up to
    4000-5000 mg/m3 in certain regular tasks) and to much lower levels
    of other solvents. Five months after the completion of major
    improvements in the work environment which reduced the levels of MEK
    to about 20 mg/m3 (maximum of about 400 mg/m3), a second SRT
    measurement was made and a third measurement was performed 15 months
    later. The workers' performance on the SRT test improved over the
    three measurements. Moreover, on the first occasion SRT was correlated
    to the degree of exposure. The authors concluded that the workers'
    central nervous functioning had been adversely affected by solvent

         Mutti et al. (1982a) carried out a study of exposure to organic
    solvents in an Italian shoe factory. The exposed group consisted of 95
    workers (24 males, 71 females) with an age range of 16-62 years (mean,
    30.9 ± 11.7 years), and the exposure duration ranged from 1 to 25
    years (mean, 9.1 ± 8 years). The approximate mean air concentrations
    in the breathing zone, over a 2-year period, for a number of solvents
    were: MEK, 115 mg/m3 (39 ppm);  n-hexane, 317 mg/m3 (90 ppm);
    cyclohexane, 315 mg/m3 (92 ppm); and ethyl acetate, 205 mg/m3 
    (57 ppm). The exposed workers complained of sleepiness, dizziness,
    weakness, paraesthesia and hypo-aesthesia. Other neurological
    symptoms, such as headache, muscular cramps, neurasthenic syndrome and
    sleep disturbances, were found more often in exposed workers, but the
    differences in incidence between the exposed and reference group were
    not statistically significant.

         Among exposed workers the mean motor nerve conduction velocity
    was significantly reduced in the median and peroneal nerves but not in
    the ulnar nerve. The amplitude of the motor action potential (MAP) was
    significantly reduced in all nerves and its duration was increased in
    the ulnar nerve. There were no significant effects on the distal
    latency. The number of abnormal action potentials observed in the
    median and peroneal nerves of exposed workers was significantly
    increased. There was a correlation between the reduction in motor
    conduction velocity and exposure.

         In a follow-up study, electrophysiological measurements including
    somatosensory evoked potentials (SEPS) were recorded from a group of
    15 female shoe factory workers aged 19-53 years (mean age, 26.6 ± 11.4
    years) with a solvent exposure duration of 2-8 years (mean, 4.5 ± 2.3
    years) (Mutti et al., 1982b). The mean air concentrations for various
    solvents in the breathing zone of the workers were: MEK, 177 mg/m3
    (60 ppm);  n-hexane, 690 mg/m3 (196 ppm); cyclohexane, 585 mg/m3
    (170 ppm); and ethyl acetate, 360 mg/m3 (100 ppm).

         Electrophysiological measurements in peripheral nerves showed
    significant reductions in maximal motor and distal sensory nerve
    conduction velocities in the median and ulnar nerves and reduced
    maximal motor nerve conduction velocity in the peroneal nerve. The
    latency of the sensory peak action potential was significantly
    increased in the median and ulnar nerves. The amplitude of all
    peripheral nerve action potentials was slightly reduced but this was
    not statistically significant. There were also changes in the SEPs
    with significant increase in the latency of some early component
    peaks. The amplitude of some of the early peaks was significantly
    reduced. The neurotoxicity was attributed primarily to  n-hexane.

    8.5  Carcinogenicity

         In a historical prospective mortality study of 446 male workers
    in two MEK dewaxing plants, with an average follow up of 13.9 years,
    the observed deaths (46) were below the expected (55.51). There was a
    slight deficiency of deaths from neoplasms (13 observed; 14.26
    expected) but there was a significant increase of deaths from tumours
    of the buccal cavity and pharynx (2 observed; 0.13 expected). However,
    there were significantly fewer deaths from lung cancer (1 observed;
    6.02 expected). In view of the small numbers, it was concluded that
    there was no clear evidence of cancer hazard in these workers
    (Alderson & Rattan, 1980).


    9.1  Microorganisms

         The effects of MEK on microorganisms have been studied in several
    species important to freshwater aquatic systems. As shown in Table 15,
    growth inhibition generally occurs at levels ranging from 120 mg/litre
    for the cyanobacterium (blue-green alga)  Microcystis aeruginosa to
    4300 mg/litre for the green alga  Scenedesmus quadricauda.

         A number of bacterial species have also been tested, the effect
    levels ranging from 10 to 5050 mg/litre. Kulshrestha & Marth (1974a-f)
    conducted a series of studies to determine if MEK and other volatile
    compounds associated with the flavour of raw or mildly heated milk are
    able to inhibit the growth of certain pathogenic bacteria and other
    bacteria important in the manufacture of fermented dairy products.
    Nutrient broth laced with the organisms and MEK at levels of 1, 10,
    100 and 1000 mg/litre was plated after 5, 8, 11 and 14 h of incubation
    in an air-tight vessel. Results are shown in Table 15. MEK was
    considered bacteriostatic to  Escherichia coli, Salmonella
     typhimurium, Staphylococcus aureus, Leuconostoc citrovorum and
     Streptococcus thermophilus at levels as low as 10-100 mg/litre.
    However, Walton et al. (1989) reported that MEK at concentrations up
    to 1 g/kg dry weight of soil had little effect on the respiration of
    microorganisms in moist soil. Volskay & Grady (1988) found that MEK at
    1 g/litre depressed respiration of sewage sludge organisms by only
    11%. Ingram (1977) noticed changes in the fatty acid and phospholipid
    composition of the cell membranes of  E. coli when cultured with a
    sublethal (0.218 mol/litre) concentration of MEK. 

         Tests in fungi demonstrated that MEK has a very slight
    stimulating effect on the germination of uredospores in two species of
    rust (French, 1961; French et al., 1977). Growth of a mixture of other
    fungal species was inhibited by about 50% by 6.4 mg MEK/g seed when
    the fungi were cultured on moist wheat seed (Nandi & Fries, 1976).

         Growth of a mixture of other fungal species on moist wheat seed
    at 30 °C was inhibited by 50% following exposure for 5 days to
    approximately 6.4 mg MEK/g seed (Nandi & Fries, 1976). Germination of
    the wheat seeds was also reduced but there was no statistical
    evaluation of these data.

        Table 15.  Effects of methyl ethyl ketone on microorganisms
    Organism            Species, strain                 Concentration   Effect                               Reference

    (Blue-green alga     Microcystis aeruginosa                120       inhibition of cell multiplication    Bringmann & Kuhn (1978)

    Bacteria             Pseudomonas putida                   1150       inhibition of cell multiplication    Bringmann & Kuhn (1977a)

                         Photobacterium phosphoreum           5050       50% reduction in light output        Curtis et al. (1982)

                         Escherichia coli, ML30                10        slight but not consistently          Kulshrestha & Marth (1974a)
                                                                         significant inhibition of growth

                         Escherichia coli, ML30                100       significant inhibition after 5 h     Kulshrestha & Marth (1974a)

                         Escherichia coli, ML30               1000       10% reduction in growth              Kulshrestha & Marth (1974a)

                         Escherichia coli, B15                72.1       65% growth inhibition after 1 h;     Egyud (1967)
                                                                         30% after 2 h

                         Salmonella typhimurium              1 & 10      slight but not consistently          Kulshrestha & Marth (1974b)
                                                                         significant inhibition of growth

                         Salmonella typhimurium                100       some inhibition of growth            Kulshrestha & Marth (1974b)

                         Salmonella typhimurium               1000       significant inhibition of growth     Kulshrestha & Marth (1974b)

                         Staphylococcus aureus, 100             1        no significant inhibition of growth  Kulshrestha & Marth (1974c)

                         Staphylococcus aureus, 100            10        some inhibition of growth            Kulshrestha & Marth (1974c)

                         Staphylococcus aureus, 100        100 & 1000    significant inhibition of growth     Kulshrestha & Marth (1974c)

    Table 15 (contd)
    Organism            Species, strain                 Concentration   Effect                               Reference
                         Streptococcus lactis                   1        no significant inhibition of growth  Kulshrestha & Marth (1974d)

                         Streptococcus lactis                  10        significant inhibition at early      Kulshrestha & Marth (1974d)
                                                                         stages of incubation

                         Streptococcus lactis              100 & 1000    significant inhibition of growth     Kulshrestha & Marth (1974d)

                         Leuconostoc citrovorum                 1        no significant inhibition of growth  Kulshrestha & Marth (1974e)

                         Leuconostoc citrovorum                10        some inhibition of growth            Kulshrestha & Marth (1974e)

                         Leuconostoc citrovorum            100 & 1000    significant inhibition of growth     Kulshrestha & Marth (1974e)

                         Streptococcus thermophilus,            1        no significant inhibition of growth  Kulshrestha & Marth (1974f)

                         Streptococcus thermophilus,           10        growth inhibition at later stages of Kulshrestha & Marth (1974f)
                        ST4                                              incubation

                         Streptococcus thermophilus,        100 & 1000   significant inhibition of growth     Kulshrestha & Marth (1974f)


    Fungi                Puccinia graminis, var. tritica,   not given    slight stimulation to germination    French (1961)
                        spores (wheat stem rust)

                         Uromyces phaseoli, (Reben),          1000       very slight stimulation to           French et al. (1977)
                        Wint., spores (bean rust)                        germination

                         Puccinia helianthi, Schw. chr.,       50        very slight stimulation to           French (1984)
                        spores (sunflower rust)                          germination

    Table 15 (contd)
    Organism            Species, strain                 Concentration   Effect                               Reference
                         Uromyces vignae, Barcl.,              500       no effect on germination             French (1984)
                        spores (cowpea rust)

                        various fungi found on wheat         6.4a       slight inhibition of fungal growth   Nandi & Fries (1976)
                        seeds:  Septoria nerdorum, Fusarium
                         nivale, Aspergillus glaucus,
                         Aspergillus candidus, Penicillium
                        sp.,  Alternaria, sp. 

    Green algae          Chlorella sp.                         806       no effect on chlorophyll content     Dojlido (1979)
                                                                         after 7 days exposure

                         Scenedesmus quadricauda              4300       slightly inhibited cell              Bringmann & Kuhn (1978)

    Protozoa             Entosiphon sulcatum                   190       slightly inhibited cell              Bringmann (1978)

    a  mg/g seed.

    9.2  Aquatic organisms

         MEK has been tested on numerous species of freshwater and marine
    vertebrates and invertebrates in short-term tests. The results
    indicate that MEK is generally of low toxicity to aquatic animals,
    with median lethal (LD50) levels ranging from 1382 to 8890 mg/litre
    (Table 16). Almost all of the acute tests were conducted under static
    conditions, in open vessels, with nominal measurements of MEK
    concentration, all of which may underestimate the true toxicity level
    of MEK. No chronic studies at low concentrations have been conducted.

         Curtis et al. (1982) related the effect of MEK on the
    bioluminescence of a bacterium to the 96-h LC50 in fathead minnows
    in an attempt to find an inexpensive yet accurate substitute for
    lethality tests. The relationship for ketones (r2 = 0.81, n = 7) is
    described by the equation:

                  log LC50 = 0.74 (log EC50 + 0.79)

    where the EC50 (5 min) is the concentration causing a 50% reduction
    in light output.

         This relationship predicts a 96-h LC50 for fathead minnows of
    3388 mg/litre, which agrees well with the measured value (Veith et
    al., 1983) of 3200 mg/litre. Similarly, LeBlanc (1984) found a highly
    significant correlation (P < 0.01) between the LC50 values
    reported for warm-water and cold-water fish, saltwater and freshwater
    fish, marine and freshwater invertebrates, and marine and freshwater
    algae. There was a remarkable similarity among acute toxicity values
    across three trophic levels. Data in Tables 15 and 16 lend further
    support to this conclusion. 

    9.3  Terrestrial organisms

    9.3.1  Animals

         The effect of MEK on the alarm behaviour of social insects has
    been studied. It was considered inactive in producing alarm behaviour
    in the ant  Iridomyrmex preinosus (Blum et al., 1966), the harvester
    ant  Pogonomyrmex badius (Blum et al., 1971) and the honeybee  Apis
     Mellifera (Boch & Shearer, 1971). Alarm behaviour was measured by
    the number of insects that were attracted to the chemical and was
    indexed relative to the activity of natural pheromones, including

        Table 16.  Effects of methyl ethyl ketone on aquatic organisms
    Species                     Concentration   Effects and comments            pH        Temperature      Hardness       Reference
                                 (mg/litre)                                                   (°C)

     Artemia salina                   1950       24-h LC50, bottles not       not given     not given       not given      Price et al. (1974)
     (brine shrimp)                             sealed and may have lost
                                                MEK during experiment

     Daphnia magna (water flea)       < 180      no discernible effect          7.21        21.0-23.0      38 mg/litre     Union Carbide Corp.
                                                                                                             CaCO3        (1980a)

     Daphnia magna (water flea)       < 520      24-h LC50                     8 ± 0.2      not given     173 ± 13 mg/l    Le Blanc (1980)
                                    < 520       48-h LC50
                                    < 70        no discernible effect

     Daphnia magna (water flea)       1382       48-h LC50                      7.21        21.0-23.0      38 mg/litre     Union Carbide Corp.
                                 (918-3349)a                                                                 CaCO3        (1980a)

     Daphnia magna (water flea)       2500       24-h LC0                      7.6-7.7        20-22       16 ° (German)    Bringmann & Kuhn (1977b)

     Daphnia magna (water flea)       8890       24-h LC50                     7.6-7.7        20-22       16 ° (German)    Bringmann & Kuhn (1977b)

     Daphnia magna (water flea)      10 000      24-h LC100                    7.6-7.7        20-22       16 ° (German)    Bringmann & Kuhn (1977b)


     Leucissus idus melanotus         4400b      LC0, period not mentioned    not given     not given       not given      Juhnke & Luedemann
     (golden orfe)                   4800b                                                                                 (1978)

     Leucissus idus melanotus         4600b      LC50                         not given     not given       not given      Juhnke & Luedemann
     (golden orfe)                   4880b                                                                                 (1978)


    Table 16 (contd)
    Species                     Concentration   Effects and comments            pH        Temperature      Hardness       Reference
                                 (mg/litre)                                                   (°C)

     Leucissus idus melanotus        4800b       LC100                        not given     not given       not given      Juhnke & Luedemann
     (golden orfe)                  5040b                                                                                 (1978)

     Lebistes reticulatus            2000        disturbed behaviour          not given      20 ± 1       27.5 mg/litre    Dojlido (1979)
     (guppy)                                                                                                 CaCl2

     Lebistes reticulatus            5700        24-h LC50, open              not given      20 ± 1       27.5 mg/litre    Dojlido (1979)
     (guppy)                                    containers may have lost                                     CaCl2
                                                MEK during test

     Pimephales promelas             3200        96-h LC50                       7.5         25 ± 1       42.2 mg/litre    Veith et al. (1983)
     (fathead minnow)                                                                                        CaCO3

     Lepomis macrochirus            < 1000       no discernible effect          7.93           21         240 mg/litre     Union Carbide Corp.
     (bluegill sunfish)                                                                                      CaCO3        (1980b)

     Lepomis macrochirus             4467        96-h LC50                      7.93           21         240 mg/litre     Union Carbide Corp.
     (bluegill sunfish)                                                                                      CaCO3        (1980b)

     Gambusia affinis                5600        96-h LC50                     7.8-8.3        room          not given      Wallen et al. (1957)
     (mosquito fish)                                                                     temperaturec

     Cyprinodon variegatus            400        no discernible effect        not given       25-31         not given      Heitmuller et al.
     (sheepshead minnow)                                                                                                  (1981)

     Carassius auratus              > 5000       24-h LC50                       7.0         20 ± 1       100 mg/litre     Bridie et al. (1979b)

    a    95% confidence limits
    b    Values are from different laboratories
    c    No specific value given

         MEK was found to be moderately effective as a fumigant against
    the Caribbean fruit fly,  Anastrepha suspensa (Davis et al., 1977).
    Treatments of 790 mg/m3 (286 ppm) for 2 h or 316 mg/m3 (107 ppm)
    for 7 h destroyed 100% of the larvae in naturally infected guavas,
    whereas exposure to 221 mg/m3 (75 ppm) for 3 h destroyed 92% of the
    larvae. Kwan & Gatehouse (1978) applied between 0.31 and 0.37 mg MEK
    topically to the dorsal thorax of tsetse flies  (Glossina morsitans
     morsitans) weighing 17-19 mg. One day after treatment, the MEK had
    a significant effect on the activity of males but not females. The
    mortality in MEK-treated insects was marginally but consistently
    higher than in the untreated controls. No apparent inhibitory or other
    effect of MEK was noted with respect to feeding or mating. Vale et al.
    (1988) found MEK to be a very effective attractant for tsetse flies
    and used it in a successful control effort in which the flies were
    attracted to insecticide-coated netting. Uspenskii & Repkina (1974)
    reported that an unspecified dose of MEK caused an increase in the
    physiological age of the tick  Ixodes perculcatus, an effect that
    increased the insect's sensitivity to DDT. 

    9.3.2  Plants

         MEK has an effect on the germination of seeds of several plant
    species. Nandi & Fries (1976) observed that the germination of wheat
    seeds was inhibited when the seeds were treated with 6.4 mg MEK/g
    seed. At this level, 10% of the experimental seeds germinated versus
    60% of the control seeds. Germination of lettuce was inhibited 50% by
    MEK at 12.5 (± 4) mmol/litre (equivalent to 900 ± 288 mg/litre)
    dissolved in agar (Reynolds, 1977). Schulz et al. (1981) reported,
    however, that a mixture of acetone and MEK had no inhibitory effect on
    the growth of rye grass at concentrations up to 1 g/litre.


         The principal toxic effects noted with MEK exposure stem from its
    ability to potentiate the known toxicities of other solvents (Table
    17). Two such interactions are described in detail below. 

    10.1  Hexacarbon neuropathy

    10.1.1  Introduction

         MEK interacts with hexacarbon compounds and potentiates their
    neurotoxicity (WHO, 1991). Potentially MEK co-exposure could affect
    the metabolism of the hexacarbon compounds or the toxic process by
    which the hexacarbons induce the neuropathy. The critical metabolic
    pathway for hexacarbon induced neuropathy is outlined in Fig. 2, and
    the scheme by which the peripheral nerve axonal degradation is thought
    to occur is given in Fig. 3. The metabolic pathway involves hepatic
    microsomal oxidation to 2,5-hexanedione, the proximate neurotoxicant,
    which is thought to induce cross-linking of neurofilaments, blockage
    of transport at the node of Ranvier, and swelling from accumulated
    neurofilaments proximal to the nodes and axonal degeneration distal to
    the nodes.

    10.1.2  Animal studies

         The phenomenon of potentiation of hexacarbon neurotoxicity by MEK
    has been firmly established by  in vivo  studies mainly on rats
    (Table 17) and also has been demonstrated in tissue culture (Veronesi
    et al., 1984). In every study in which the dose of  n-hexane, methyl
    butyl ketone (MBK), or 2,5-hexanedione (2,5-HD) was large enough and
    sustained for a sufficient period, clinical signs of neural
    degeneration were produced. These signs were made more severe by
    co-exposure to MEK. In addition, the period prior to the onset of
    symptoms was frequently shortened by co-exposure to MEK. Minimum
    sustained continuous exposure concentrations that induced neuropathy
    in these experiments were 295/1408 and 590/1056 mg/m3 (100/400 and
    200/300 ppm) MEK/ n-hexane mixtures. An intermittent exposure (8
    h/day) of rats to 2950/31 680 mg/m3 (1000/9000 ppm) MEK/ n-hexane
    mixture produced severe neuropathy, whereas similar exposure to a
    lower concentration, i.e. 590/1760 mg/m3 (200/500 ppm)
    MEK/ n-hexane mixture yielded no evidence of hexacarbon
    neurotoxicity. Intermittent exposure (8 h/day, 5 days/week) to
    5900/820 mg/m3 (2000/200 ppm) MEK/MBK mixture produced some neural
    degeneration and mild clinical signs. Oral dosing of rats once a day,
    5 days/week, with a mixture of MEK/2,5-HD (0.159/0.253 g/kg) produced
    marked clinical signs (Ralston et al., 1985). Even with doses of MBK
    too low to produce significant neuropathy, studies generally indicated
    that co-exposure with MEK induced changes compatible with enhanced
    toxicity, such as reduced velocity of nerve conduction, elevated
    hepatic microsomal enzyme activity, or reduced clearance of 2,5-HD
    from the blood or the body. The only study reporting no evidence of
    potentiation (Spencer & Schaumburg, 1976) compared MBK at 0.150 g/kg

    with one tenth this concentration of MBK, 0.015 g/kg, in combination
    with MEK. Since there were no control data on the effects of 0.015
    g/kg of MBK alone and the dose of MEK was very low, it is difficult to
    interpret the meaning of this study. Concentrations of MEK in
    inhalation studies did not exceed 3319 mg/m3 (1125 ppm), and
    continuous exposure to this concentration was demonstrated by Saida et
    al. (1976) not to produce neuropathological effects. Thus it is
    considered unlikely that MEK itself produces neuropathy.

         The property of potentiation of hexacarbon neurotoxicity is not
    unique to MEK, but is shared at least by methyl  n-propyl ketone,
    methyl  n-amyl ketone and methyl  n-hexyl ketone, none of which
    appear intrinsically neurotoxic (Misumi & Nagano, 1985). 

         The mechanism by which MEK potentiates hexacarbon neurotoxicity
    is not well understood, although potential metabolic interactions have
    been examined. In rats, simultaneous inhalation of  n-hexane and MEK
    resulted in lower levels of 2,5-HD  in vivo  in urine (Iwata et al.,
    1984; Shibata et al., 1990a) and initially lower but later somewhat
    elevated levels of MBK and 2,5-HD  in vivo  in serum (Shibata et al.,
    1990b). Both Iwata et al. (1984) and Shibata et al. (1990b) concluded
    that potentiation of  n-hexane neurotoxicity by MEK could not be
    explained solely by increased 2,5-HD formation. Pretreatment of rats
    with MEK (1.87 ml/kg, 4 daily doses) prior to inhalation of  n-hexane
    resulted in higher levels of 2,5-HD in several tissues, including
    blood (Robertson et al. (1989). Abdel Rahman et al. (1976) reported
    that an 8-h simultaneous exposure of rats to MEK and MBK did not
    result in measurable levels of MBK or of 2,5-HD in blood, whereas a
    6-day continuous co-exposure resulted in substantially raised levels
    of MBK and 2,5-HD. Continuous co-exposure for 23 days, however,
    resulted in further elevation of MBK in blood, but no measurable level
    of 2,5-HD. Simultaneous administration of 2,5-HD and MEK, either as a
    single dose or as six repeated daily doses in rats, resulted in a
    greater total area under the curve for 2,5-HD in blood compared with
    administration of 2,5-HD alone (Ralston et al., 1985).

         In guinea-pigs, increased levels of 2-hexanol and 2,5-HD were
    found following intraperitoneal administration of a MEK/MBK mixture
    compared with intraperitoneal administration of MBK alone (Couri et
    al., 1978).

         MEK administration has also been shown to induce a number of  in
     vivo and  in vitro  parameters of hepatic oxidative metabolism
    (Couri et al., 1977; Wagner et al., 1983; Misume & Nagano, 1985;
    Raunio et al., 1990).

        Table 17.  Interaction of MEK with other solvents and their metabolitesa
    Route of administration,      Dose and/or             Exposure                  Effects/results                              Reference
    species (strain),            concentration
    number and sex

    Inhalation, rat,         820 mg/m3 (200 ppm) MBK;     8 h/day,        muscular weakness lasted longer after exposure to     Duckett et al.
    9 sex unspecified        5900/820 mg/m3               5 days/week,    MEK/MBK than after MBK alone                          (1974)
    MBK, 8 sex unspecified   (2000/200 ppm) MEK/MBK       6 weeks

    Inhalation, rat          1760 mg/m3 (500 ppm)         8 h/day,        no significant enhancement of neuropathological       Iwata et al.
    (Wistar), 6 males        hexane; 1475/1760 mg/m3      7 days/week,    damage evident in peripheral nerve                    (1984)
    per groupb               (500/500 ppm) MEK/hexane     33 weeks        electrophysiological function; 2,5-hexanedione 
                                                                          and other hexane metabolites in urine reduced 
                                                                          with co-exposure

    Inhalation, rat          923 mg/m3 (225 ppm) MBK;     24 h/day,       MEK enhanced MBK-induced peripheral neurotoxicity     Saida et al.
    (Sprague-Dawley),        3319/923 mg/m3 (1125/225     16-66 days                                                            (1976)
    12/group, sex            ppm) MEK/MBK

    Inhalation, rat          923 mg/m3 (225 ppm) MBK;     24 h/day,       hexobarbital sleeping time significantly reduced in   Couri et al.
    (Wistar), 5 males        2213/923 mg/m3 (750/225      7 or 28 days    group exposed continuously for 7 days to MEK/MBK      (1977)
    per group                ppm) MEK/MBK                                 (and in 2213 mg MEK/m3 (750 ppm) controls), but not 
                                                                          in MBK group; interpreted as evidence for elevated
                                                                          microsomal enzyme activity in MEK/MBK and MEK

    Table 17 (contd)
    Route of administration,      Dose and/or             Exposure                  Effects/results                              Reference
    species (strain),            concentration
    number and sex
    Inhalation, rat          1760, 2464 mg/m3 (500, 700   approx.         experiments yielded similar results: potentiation of  Altenkirch et
    (Wistar), 5 males        ppm) hexane; 295/1408,       24 h/day,        n-hexane neurotoxicity in MEK/hexane groups as         al. (1982a)
    per group                590/1056, 590/1760 mg/m3     7 days/week,    shown by shortened period before onset of clinical
                             (100/400, 200/300, 200/500   9 weeks         signs (weakness and paresis); hypersalination
                             ppm) MEK/hexane                              in MEK/hexane groups only; neural degeneration
                                                                          in all solvent-treated groups (no mention of
                                                                          differences among these groups)

    Inhalation, rat          1760, 2464 mg/m3 (500, 700   8 h/day, every  co-exposure to MEK/hexane resulted in earlier and     Schnoy et al.
    (Wistar), 5 groups       ppm) hexane; 295/1408,       day for 1-89    more pronounced degeneration of pulmonary             (1982);
    of 2-5 malesc            590/1056, 590/1760 mg/m3     days            nerves than exposure to hexane alone; there were no   Schmidt et al.
                             (100/400, 200/300, 200/500                   consistent differences in degeneration of alveolar    (1984)
                             ppm) MEK/hexane                              epithelium between the hexane and MEK/hexane

    Inhalation, rat          1640, 923 mg/m3 (400, 225    24 h/day,       2,5-HD detected in blood after 6 days but not after   Abdel-Rahman
    (Wistar), unspecified    ppm) MBK; 2213/923 mg/m3     6 or 23 days    23 days, and there were elevated MBK blood levels     et al. (1976)
    number/group, male       (750/225 ppm) MEK/MBK                        in group exposed to MEK/MBK; severe neuropathy in
                                                                          group exposed to MEK/MBK for 23 days

    Inhalation, rat          2464 mg/m3 (700 ppm)         8 h/day,        no evidence of potentiation of hexane neurotoxicity:  Altenkirch et
    (Wistar), 5 males        hexane; 590/1760 mg/m3       7 days/week,    no abnormal clinical signs or elevated                al. (1982a)
    per group                (200/500 ppm) MEK/hexane     40 weeks        neuropathology in solvent-treated groups

    Inhalation, rat          3520 mg/m3 (1000 ppm)        8 hd            2,5-hexanedione in urine markedly less after co-      Iwata et al.
    (Wistar), 5 males        hexane; 2950/3520 mg/m3                      exposure with MEK than after exposure to hexane       (1983)
    per group                (1000/1000 ppm) MEK/hexane                   alone

    Table 17 (contd)
    Route of administration,      Dose and/or             Exposure                  Effects/results                              Reference
    species (strain),            concentration
    number and sex
    Inhalation, rat          Experiment 1: 35 200 mg/m3   8 h/day,        experiments yielded similar results; acceleration     Altenkirch et
    (Wistar), 5 males        (10 000 ppm) hexane; 3245/   7 days/week,    of  n-hexane neurotoxicity in MEK/hexane group as       al. (1978,
    per group                31 330 mg/m3 (1100/8900      15-19 weeks     shown by more severe clinical signs (gait             1979)
                             ppm) MEK/hexane                              disturbances, weakness and paresis), greater 
                                                                          degeneration of peripheral nerves and shortened 
    5 males/group            Experiment 2: 35 200 mg/m3                   period before onset of signs and neural degeneration; 
                             (10 000 ppm) hexane; 2950/                   hyper-salivation in MEK/hexane groups
                             31 680 mg/m3 (1000/9000
                             ppm) MEK/hexane

    12 males/group           Experiment 3: 35 200 mg/m3
                             (10 000 ppm) hexane; 2950/
                             31 680 mg/m3 (1000/9000
                             ppm) MEK/hexane

    Inhalation, rat          35 200 mg/m3 (10 000 ppm)    4 h or 8 h,     MEK did not enhance degeneration of intrapulmonary    Schnoy et al.
    (Wistar), 7 groups       hexane; 2950/31 680 mg/m3    8 h/day for     nerves; enhanced degeneration of alveolar epithelium  (1982);
    of 2-3 males             (1000/9000 ppm)              2-14 days       in the MEK/hexane group after 14 days exposure in     Schmidt et al.
                             MEK/hexanee                                  comparison with the hexane group                      (1984)

    Inhalation, rat          352 mg/m3 (100 ppm) hexane;  12 h/day,       marked impairment of nerve conduction velocities in   Takeuchi et
    (Wistar), 8 males        590/352 mg/m3 (200/100       7 days/week,    MEK/hexane group; no evidence of significant          al. (1983)
    per group                ppm) MEK/hexane              24 weeks        potentiation of morphological effects of  n-hexane

    Inhalation, mouse        615 mg/m3 (150 ppm) MBK;     24 h/day,       hexobarbital sleeping time significantly lower in     Couri et al.
    (Swiss), 5/group         2950/615 mg/m3 (1000/150     7 days          MEK/MBK group than in MBK group (or in MEK 2950       (1978)
    sex unspecified          ppm) MEK/MBK                                 mg/m3 (1000 ppm) controls); interpreted as evidence
                                                                          for elevated microsomal enzyme activity in
                                                                          MEK/MBK group

    Table 17 (contd)
    Route of administration,      Dose and/or             Exposure                  Effects/results                              Reference
    species (strain),            concentration
    number and sex
    Subcutaneous injection,  288 mg/kg b.w. MBK;          1/day, 5 days   significantly enhanced neurotoxicity (slower motor    Misumi &
    rat (Donryu),            288/288 mg/kg b.w.           per week, 20    fibre conduction velocity and increased motor distal  Nagano (1985)
    8 males/group            MEK/MBK                      weeks           latency of tail nerve) and more pronounced weakness
                                                                          in rats receiving MEK/MBK than MBK alone

    Subcutaneous injection,  150 mg/kg b.w. MBK;          5 days/week     peripheral neuropathological changes and paresis      Spencer &
    cat, 9 (sex              135/15 mg/kg b.w.            for up to 8.5   with MBK; possible nerve degeneration in animals      Schaumburg
    unspecified) MBK,        MEK/MBK                      months          treated with MEK/MBK                                  (1976)
    4 (sex unspecified)

    Other ketones

    Subcutaneous injection,  150 mg/kg b.w. MIBK;         2/day, 5 days   no evidence of enhanced MIBK-induced                  Spencer &
    cat, 4, sex              135/15 mg/kg b.w.            per week, up    neuropathology                                        Schaumburg
    unspecified, MIBK,       MEK/MIBK                     to 8.5 months                                                         (1976)
    6, sex unspecified,

    Inhalation, rat          3220 mg/m3 (700 ppm) EBK;    16-20 h/day,    exposure to MEK/EBK at 2065 and 4130 mg MEK/m3        O'Donoghue et
    (Charles River), 15      207/3220, 2065/3200,         4 days          produced a 2.5-fold increase in serum 2,5-Hpdn over   al. (1984)
    males/group for          4130/3200 mg/m3 (70/700,                     that produced by EBK alone; no 2,5-HD detected in
    EBK and controls;        700/700, 1400/700 ppm)                       serum
    5 males/group            MEK/EBK
    for MEK/EBK

    Oral, rat (Charles       0.25 to 4 g/kg b.w. EBK;     1/day, 5 days   2 and 4 g EBK/kg b.w. fatal with or without MEK;      O'Donoghue et
    River), 4 males in       1.5, 0.75/0.25-4 g/kg b.w.   per week, 14    greater neurological damage and dysfunction, and      al. (1984)
    control group            MEK/EBK                      weeks           around 1.5-fold increase in 2,5-Hpdn and 2,5-HD
                                                                          with 1.5/1.0 g/kg b.w. MEK/EBK than with 1.0 g
                                                                          EBK/kg b.w.; no neurotoxicity evident in doses
                                                                          of EBK below 1.0 g/kg b.w.

    Table 17 (contd)
    Route of administration,      Dose and/or             Exposure                  Effects/results                              Reference
    species (strain),            concentration
    number and sex
    Oral, rat (Fischer-      253 mg/kg b.w. 2,5-HD;       1/day, 5 days   marked neurological dysfunction consistently          Ralston et al.
    344), 5 males/group      159/253 mg/kg b.w.           per week, ca.   appeared weeks earlier in rats receiving              (1985)
                             MEK/2,5-HDf                  13 weeks        MEK/2,5-HD

    Oral, rat (Fischer-      253 mg/kg  b.w. 2,5-HD;      1/day, 1        MEK did not alter gastric absorption of 2,5-HD;       Ralston et al.
    344), 5 males/group      159/253 mg/kg b.w.           or 7 days       clearance of 2,5-HD from blood slower from rats       (1985)
                             MEK/2,5-HD                                   receiving MEK/2,5-HD

    Oral, rat (Fischer-      253 mg/kg b.w. 2,5-HD;       1/day, 5 days   most of radiolabelled 2,5-HD bound to protein;        Ralston et al.
    344), 5 males/group      159/253 mg/kg b.w.           per week, 1,    greater binding to protein with MEK/2,5-HD            (1985)
                             MEK/2,5-HD                   2 or 3 weeks    after 1 week, but reverse true after 2 and 3 weeks

    Halogenated alkanes

    Oral, intraperitoneal,   1.505 g/kg b.w. MEK;         1 oral dose     potentiation of CCl4 hepatotoxicity by MEK as         Traiger &
    rat (Sprague-            0.16 g/kg b.w. CCl4          MEK followed    shown by greater fatty vacuolation and necrosis       Bruckner
    Dawley), 3-5 males/                                   16 h later      of liver, increased hepatic triglyceride and          (1976)
    experimental group,                                   with 1 ip       GPT, and decreased hepatic glucose-6-phosphatase
    5-20 males/control                                    dose CCl4

    Oral, intraperitoneal,   1.691 g/kg b.w. MEK;         1 oral dose     potentiation of CCl4 hepatotoxicity by MEK as         Dietz & Traiger
    rat (Sprague-            0.16 g/kg b.w. CCl4          MEK followed    shown by increased hepatic triglyceride and           (1979)
    Dawley), males at                                     16 h later      GPT
    least 5/group                                         with 1 ip
                                                          dose CCl4

    Oral, intraperitoneal,   1.082 g/kg b.w. MEK;         1 oral dose     potentiation of CHCl3 hepatotoxicity by both          Hewitt et al.
    rat (Sprague-            0.797, 1.196 g/kg b.w.       MEK followed    doses of MEK as shown by increased GPT and OCT        (1983)
    Dawley), 5 or 6          CHCl3                        18 h later with
    males/groupg                                          1 ip dose CHCl3

    Table 17 (contd)
    Route of administration,      Dose and/or             Exposure                  Effects/results                              Reference
    species (strain),            concentration
    number and sex
    Oral, intraperitoneal,   0.072 to 1.082 g/kg b.w.     1 oral dose     potentiation of CHCl3 renal and hepatic toxicity      Brown & Hewitt
    neal, rat (Fischer-      MEK; 0.797 g/kg b.w.         MEK followed    by MEK at all dosages as shown by histological and    (1984)
    344), 6 males per        CHCl3                        18 h later with several biochemical criteria; potentiation greatest
    experimental                                          1 ip dose       at 0.361 to 0.721 g/kg b.w. MEK, and slightly
    group, 32 males                                       CHCl3           reduced at 1.082 g/kg b.w.h
    in control group

    Oral, rat (Sprague-      1.082 g/kg b.w. MEK;         1 dose MEK      MEK followed by CHCl3 did not induce cholestasis,     Hewitt et al.
    Dawley), 6 males         0.797 to 1.594 g/kg b.w.     followed 10     but MEK given 10 to 24 h prior to CHCl3 potentiated   (1986)
    per group                CHCl3                        to 96 h later   its ability to increase plasma bilirubin
                                                          with 1 dose

    Oral, rat (Sprague-      1.082 g/kg b.w. MEK;         1 dose MEK      MEK followed by CHCl3 10 to 48 h later potentiated    Hewitt et al.
    Dawley), 6 males         0.797 g/kg b.w. CHCl3        followed 10     hepatotoxicity as indicated by elevated ALT and       (1987)
                                                          to 96 h later   OCT levels
                                                          by 1 dose

    a    Values from the literature have been recalculated as ppm or g/kg body weight.
    b    Iwata et al. (1984) states that 24 rats were divided into four groups, but does not specify that groups were of equal numbers.
    c    Animals were apparently co-exposed with those described in Altenkirch et al. (1982a).
    d    Description of exposure not entirely clear but a subsequent paper (Iwata et al., 1984) refers to this as a single exposure.
    e    Animals co-exposed with those described in Altenkirch et al. (1978).
    f    MEK and 2,5-HD doses were 0.317 and 0.506 g/kg, respectively, for first 8 days of experiment.
    g    5 males at the lower dose and 6 at the higher; 11 males in the control group
    h    Measurements were made 24 h after the oral dose of CHC13 or CCl4.
    Abbreviations: GPT = plasma glutamic-pyruvic transaminase; OCT = plasma ornithine carbamyl transferase; ALT = plasma alanine aminotransferase;
    b.w. = body weight; ip = intraperitoneal; 2,5-HD = 2,5-hexanedione; 2,5-Hpdn = 2,5-heptanedione; CCl4 = carbon tetrachloride; CHCl3 = chloroform

    FIGURE 2

    FIGURE 3

    10.1.3  Human studies  Solvent abuse

         Solvent abuse, the deliberate inhalation of solvent vapours for
    their euphoric effects, has been reported in many countries and has
    involved the use of lacquer thinners, glues and other readily
    available commercial items. Prockop et al. (1974) suggested that there
    were several hundred habitual "huffers", i.e. solvent abusers, in
    Tampa, Florida, USA, and Altenkirch et al. (1978) reported about 2000
    in Berlin, Germany, in 1974. Outbreaks of polyneuropathy among Berlin
    huffers, which involved  n-hexane toxicity potentiated by MEK,
    provided a major stimulus for research on the health effects of MEK
    and its interactions with hexacarbon solvents.

         Chronic huffers in Berlin inhaled fumes from about a half litre
    of liquid per day, either poured into a plastic bag or over rags
    (Altenkirch et al., 1977, 1982b). Inhalation sessions extended for as
    long as 10 or 12 h, and exposure periods of 5 to 7 years were not
    unusual. Prior to the end of 1975 no major damage to health resulting
    from chronic solvent abuse had been observed. At that time there
    appeared abruptly a number of cases of polyneuropathy among chronic
    huffers. All these were young males, mainly between 16 and 21 years of
    age. The initial symptom was paraesthesia of the toes accompanied in
    some cases by weakness of the legs. The paraesthesia ascended rapidly
    from distal to proximal and in 2 to 3 weeks affected the entire legs.
    This was followed rapidly by paraesthesia of the arms which also
    ascended from distal to proximal. Extensor muscles were always
    affected first and most severely. There also was severe muscle atrophy
    and a "glove and stocking" type sensory impairment of the hands and
    feet. In all cases there also was excessive sweating of the hands and
    feet, and in some cases discoloration and reduced skin temperature of
    these areas. In addition there was loss of weight and damage to the
    teeth. Head, neck and trunk muscles remained undisturbed, although in
    severe cases there was paresis of the phrenic nerve and reduced
    pulmonary function. The degree of impairment ranged from moderate
    crippling, which permitted walking with assistance, to complete
    tetraplegia. Symptoms continued to develop for 6 to 10 weeks after
    cessation of solvent abuse. Remission was slow, took up to a year,
    developed from proximal to distal, and was incomplete in those most
    severely affected. Neurophysiological and histological findings were
    similar to those reported in experimental animals (section 7). Motor
    and sensory nerve conduction velocities were reduced in proportion to
    the degree of paresis. There were lesions of the axons, paranodal axon
    swellings, clumping of the nerve filaments and demyelination. The
    outbreak of neuropathy came a few months after a change in the
    formulation of a solvent from one composed of  n-hexane, benzene
    fraction, ethyl acetate and toluene to a similar mixture with less
    (16%)  n-hexane and the addition of 11% MEK. This was interpreted as
    evidence that even long exposure to the substantial amount of

     n-hexane (31%) in the original formulation did not result in
    neuropathy, and that neuropathy developed only after the toxicity of
     n-hexane was potentiated by simultaneous exposure to MEK. 

         The seven cases of polyneuropathy reported from Tampa, Florida,
    USA, apparently resulted from a small amount of  n-hexane (0.5%)
    potentiated by other components in the solvent mixture (Prockop et
    al., 1974; Spencer et al., 1980). Two similar cases of polyneuropathy
    were reported from Japan (Goto et al., 1974), these were produced by
    chronic sniffing of a glue that contained 25%  n-hexane and 20% MEK.
    What is puzzling in view of the absence of neuropathy in Berlin prior
    to the addition of MEK to a solvent mixture containing  n-hexane is
    that Goto et al. (1974) also reported two cases of neuropathy
    resulting from chronic sniffing of glue solvent containing only
     n-hexane and toluene. However, Oh & Kim (1976) reported a case of
    polyneuropathy produced by chronic abuse of mixtures containing MEK,
    methyl isobutyl ketone (MIBK) and many other solvents, but apparently
    not  n-hexane or MBK. There was, however, no analysis of the solvent
    mixtures. There was no experimental evidence to suggest that any of
    the solvents known to be present in the mixtures alone, or MEK and
    MIBK together, could produce this type of neuropathy. An alternative
    explanation is that the MIBK contained MBK as an impurity.  Occupational exposure

         Although there have been many cases of occupationally related
    poisoning by exposure to neurotoxic hexacarbon solvents (Spencer et
    al., 1980), poisonings in which neurotoxicity has been associated with
    concurrent MEK exposure are limited. In occupational health studies
    concentrating on  n-hexane neurotoxicity, the study populations were
    exposed to several other solvents, including MEK (WHO, 1991). One of
    the most thoroughly investigated cases occurred in 1973 in a fabric
    factory in Ohio, USA (Allen et al., 1974). In 1973, an employee at the
    factory was found to have a severe sensorimotor neuropathy. Other
    co-workers at the plant were also found to have similar symptoms,
    which initiated a search for a causative agent in the workplace. Of
    the 1157 workers examined, 86 manifested signs and symptoms indicative
    of peripheral neuropathy, including parathesiae in arms and legs and
    weakness in the hands and legs. Subsequent investigation found that in
    the year prior to the confirmation of the first case, MBK had been
    substituted for MIBK as a co-solvent with MEK. Exposure occurred by
    skin contact and by inhalation. Measured concentrations of MEK in
    certain areas of greatest exposure were 251-2251 mg/m3 (85-763 ppm),
    while concentration for MBK ranged from 9 to 640 mg/m3 (2.3-156
    ppm). The introduction of MBK into the factory was associated with the
    observed neurotoxicity. Spencer et al. (1980) pointed out that several
    animal studies showed that concurrent exposure to MEK accelerated
    MBK-induced neurotoxicity.

    10.2  Haloalkane solvents

    10.2.1  Studies in animals

         Carbon tetrachloride (CCl4), chloroform (CHCl3) and related
    haloalkane solvents are liver and kidney poisons as well as central
    nervous depressants (Gosselin et al., 1984). It has long been known
    that the hepatotoxic action of CCl4 is potentiated by ethanol, and
    more recently that the hepatic and/or renal toxicity of CCl4,
    CHCl3, trichloroethylene, 1,1,2-trichloroethane and related
    compounds is potentiated by  n-hexane, ethanol, isopropanol, acetone,
    MEK, MBK, 2,5-HD, and other ketones or chemicals that are metabolized
    to ketones (Hewitt et al., 1980). Even an increase of naturally
    occurring ketones in the body via diabetes can precipitate
    potentiation. Decreasing the transformation of isopropanol to acetone
    by the administration of an inhibitor of alcohol dehydrogenase,
    pyrazole, has reduced potentiation of haloalkane toxicity. Although
    the phenomenon is referred to as haloalkane toxicity, experimental
    work in general appears largely or entirely limited to chlorinated
    compounds, and specific studies on MEK are limited to interactions
    with CCl4 and CHCl3.

         The effects of MEK and CCl4 or CHCl3 on rats are summarized
    in Table 17. At the doses used, MEK and the haloalkanes separately
    produced mild liver and kidney injury at most. When exposure to MEK
    was followed within 10 to 48 h by a haloalkane, there was severe
    injury to the liver, with marked and abrupt replacement of normal
    hepatic cells by necrotic and fatty, vacuolated tissue, an increase in
    hepatic triglyceride, and, presumably, a corresponding decrease in
    normal liver function. Hepatic enzymes were released into the blood by
    breakdown of liver tissue, resulting in elevated levels of plasma
    glutamic-pyruvic transaminase, plasma ornithine carbamyltransferase,
    and plasma alanine aminotransferase. There was also an increase in
    plasma bilirubin, although this was not accompanied by a decrease in
    bile secretion as was the case with some other ketones (Hewitt et al.,
    1986). A dose of MEK as small as 0.072 g/kg potentiated the effects of
    CHCl3 given 18 h later, and 1.505 g/kg MEK potentiated the effects
    of CCl4. Lower doses were not studied. 

         The mechanism of potentiation is not fully understood but
    increased bioactivation of haloalkanes is believed to play a central
    part in the potentiation effect. CCl4 is metabolized  in vivo  with
    homolytic cleavage of the carbon-chlorine bond to produce highly
    reactive free radicals that exert their toxic effects a) by binding
    covalently to proteins and other elements, and b) via lipid
    peroxidation (Anders, 1988). It is likely that the toxic effects of
    CHCl3 also are produced in part by this mechanism (Hewitt et al.,
    1980, 1987). The toxicity of CCl4 is enhanced by pretreatment with
    various agents such as phenobarbital, ethanol, isopropanol, 2-butanol
    and the ketone metabolites of the last two compounds (acetone and MEK)
    (Cornish & Adefuin, 1967; Traiger & Plaa, 1972; Traiger & Bruckner,
    1976; Gosselin et al., 1984). Recent studies have shown that the

    ethanol-inducible cytochrome P-450 isozyme (P-450IIE1) plays an
    important role in haloalkane metabolism (Johansson &
    Ingelman-Sundberg, 1985). It is a high affinity enzyme and operates at
    a low concentration range for various substrates (Nakajima et al.,
    1990). CCl4 hepatotoxicity in rats has been found to be potentiated
    by induction of the P-50IIE1 isozyme with ethanol and the injury was
    most marked in the perivenous liver cells where the expression of
    induction was the highest (Lindros et al., 1990). In addition to
    ethanol, P-450IIE1 is known to be induced by acetone and MEK (Ko et
    al., 1987; Raunio, et al., 1990; Albano et al., 1991). However, while
    a relatively large oral dose of MEK (1.4 ml for 3 days) to rats
    increased the amount of ethanol- and phenobarbital-inducible
    cytochromes P-450 (P-450IIE1 and P-450IIB, respectively) (Raunio et
    al., 1990), inhalation exposure of rats to 1770 mg MEK/m3 (600 ppm),
    10 h/day for 7 days, caused only marginal effects on microsomal
    cytochrome P-450 activities in the liver (Liira et al., 1991).

    10.2.2  Potentiation of haloalkane toxicity in humans

         There are no reports of MEK potentiation of haloalkane renal and
    hepatic toxicity in humans.


    11.1  Human health risks

    11.1.1  Non-occupational exposure

         Low level non-occupational exposure to MEK is widespread from a
    variety of natural and anthropogenic sources, since MEK is a normal,
    though minor, mammalian metabolite. External sources include food,
    water and air. In the USA, the average daily per capita intake of MEK
    from food is estimated to be 1.6 mg. In addition to MEK present
    naturally, foods may contain MEK that has been added in food
    processing or absorbed from plastic packaging materials. MEK is rarely
    detected in exposed natural waters where it may originate from
    microbial activity and atmospheric and anthropogenic inputs, but is
    frequently detected at low concentrations in drinking-water where it
    presumably is leached from cemented joints of plastic pipes. Leaching
    from landfill hazardous waste dumps is another potential source of
    groundwater, and hence drinking-water, contamination. Measured
    concentrations in food and water are so low, however, that it is
    unlikely that either of these represent a significant source of

         In minimally polluted outdoor air, the MEK concentration is less
    than 3 µg/m3 (1.0 ppb) but has been measured at 134 µg/m3 (44.5 ppb)
    under conditions of dense smog. Away from industrial areas where
    MEK is manufactured or used, major sources may be vehicle exhaust and
    photochemical reactions in the atmosphere. In smog episodes,
    photochemical production of MEK may greatly exceed direct
    anthropogenic emission. Volatilization of MEK from building materials
    and consumer products can pollute indoor air to levels far above
    outdoor air, and a concentration as high as 48 µg/m3 (12.9 ppb) was
    measured in an Italian home. MEK also is present in tobacco smoke
    (e.g., 80-207 µg/cigarette). 

         For the general population, daily MEK intake is estimated to
    range between 1.6 and 4.2 mg, depending on the location site (rural or
    urban), with an additional 1.6 mg in the case of smokers. There is no
    evidence of any adverse effects on the general population from
    exposure to MEK. Data from experimental animal studies show that toxic
    effects occur at dose levels that are 3 orders of magnitude higher
    than the estimated daily intake. Non-occupational poisoning from MEK
    alone is limited to a single case, which resulted in no lasting

         MEK is, however, known to potentiate the toxicity of two classes
    of organic solvents, unbranched aliphatic hexacarbons and haloalkanes,
    and chronic exposure to consumer products containing MEK and
     n-hexane have produced outbreaks of polyneuropathy among individuals
    deliberately inhaling fumes from these mixtures for their euphoric
    effects. Co-exposure to MEK and either hexacarbons or haloalkanes via

    the abuse of consumer products remains a potential public health
    hazard. Injuries from such poisoning can be severe, permanently
    disabling and even fatal.

    11.1.2  Occupational exposure

         MEK is an important industrial chemical which is used mainly as
    a component of solvent mixtures for application of a wide variety of
    coatings and adhesives. Moderate occupational exposure via air is
    widespread because losses to the environment result mainly from
    solvent evaporation from coated surfaces, and MEK is not viewed as an
    especially dangerous substance. Most national limits for occupational
    exposure are set at 590 mg/m3 (200 ppm), with a higher short-term
    exposure level of 885 mg/m3 (300 ppm), and these limits appear
    acceptable. On site measurements, however, indicate that workers may
    be chronically exposed to still higher MEK concentrations in small
    factories such as shoe factories, printing plants and painting
    operations, due to inadequate ventilation. Lesser amounts of MEK are
    lost to the air with concurrent worker exposure during manufacture,
    shipping, repackaging and preparation of coatings and adhesives.
    Industrial exposure from contact with liquid MEK does not appear an
    important problem.

         Chronic co-exposure to MEK and either unbranched aliphatic
    hexacarbon or haloalkane solvents represents a significant potential
    occupational hazard. Serious toxic effects could occur. Although there
    are no records of industrial accidents involving MEK potentiation of
    haloalkane toxicity, MEK potentiation of hexacarbon neurotoxicity may
    have caused at least one major industrial accident in which an
    outbreak of polyneuropathy followed introduction of MEK into a solvent
    mixture. Thus MEK, in the mixed solvent atmosphere of many industrial
    activities, can present a toxic hazard.

    11.1.3  Relevant animal studies

         Acute MEK toxicity has been shown in animal studies to be low by
    the oral and inhalation route. The lowest oral dose modifying body
    structure (damage of kidney tubules) was 1 g/kg body weight in rats.
    Ten intraperitoneal injections of 34 mg/kg body weight over a 2-week
    period produced transient injection site irritations but no effect on
    the kidney. In a 90-day inhalation study, female rats exposed to 14.75
    g/m3 for 6 h/day, 5 days per week, showed only slightly increased
    liver weight, slightly decreased brain and spleen weight, and slightly
    altered blood chemistry in comparison with controls; male rats showed
    only a slightly increased liver weight. A transient decrease in nerve
    conduction velocity was found following exposure to 590 mg/m3 (12
    h/day for 24 weeks). The transient nature of neurological and
    behavioural changes induced by MEK may be due to adaptation or more
    rapid metabolism of MEK. Short-term dermal exposure to small amounts
    of MEK results in mild local irritation, at most. Results of studies
    of eye irritation are inconsistent, possibly due to different scoring 

    techniques; 4 mg created severe chemical burns in the eye in one study
    whereas in other studies less severe signs were reported following a
    dose of 80 mg. 

         An inhalation study provided evidence for low level fetotoxicity
    in the absence of maternal toxicity at 8825 mg/m3. Thus MEK may be
    a low grade teratogen in rats. There is a lack of data on other
    aspects of reproduction in animals, and no relevant data have been
    reported for humans. 

         MEK has given negative results in most conventional mutagenicity
    assays. There is evidence of aneuploidy in yeast but this may not be
    relevant to humans or other mammals. 

    11.2  Effects on the environment

         MEK occurs naturally at low concentrations in air, water and
    soil. It is highly mobile in the natural environment and is not
    accumulated in any individual compartment. MEK is rapidly synthesized
    and destroyed by photochemical processes in the atmosphere. There is
    no specific information on either partitioning of MEK in any
    environmental compartment or on chemical binding to sediment

         MEK is synthesized biologically and is rapidly metabolized by
    bacteria (even at high concentrations), mammals and probably many
    other organisms. Levels produced by fungi can cause inhibition of
    plant germination. Observations on microorganisms, higher plants,
    invertebrates, fish and mammals suggest a low level of toxicity.
    Environmental levels of MEK appear to be too low to cause any damage
    except in the immediate vicinity of highly polluted sites. Effects on
    the aquatic environment are likely to appear at levels between 1 and
    10 mg/litre. The potentiation of solvent toxicity by MEK appears
    environmentally irrelevant, although substantial information is
    lacking. Overall, MEK does not represent a significant threat to the


    12.1  Human health protection

         MEK on its own appears a relatively safe organic solvent, but its
    use in combination with other solvents, in particular haloalkanes or
    unbranched aliphatic hexacarbons, should be avoided. Industries should
    be strongly encouraged to take all necessary precautions to ensure
    that workers are not exposed to both MEK and solvents whose toxicity
    is potentiated by MEK. 

    12.2  Environmental protection

         MEK is unlikely to present a hazard to the environment except in
    cases of major spills or discharges.


    a)   Further research should be undertaken to clarify the precise
         mechanisms by which MEK potentiates the toxicity of haloalkanes
         and hexacarbons.

    b)   Epidemiological studies are needed to determine exposure-response
         relationships regarding MEK-induced potentiation of hexacarbon
         and haloalkane toxicity.

    c)   Radiolabelled balance studies should be conducted to determine
         accurately the routes and rates of excretion of MEK and its
         metabolites. The results of such studies would be particularly
         useful for improving methods of biological monitoring.

    d)   Comprehensive studies of reproductive and developmental toxicity
         should be undertaken in representative rodent and non-rodent

    e)   The binding capacity of soils and sediments for MEK should be


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    Conversion factors for various solvents (ppm --> mg/m3)

    acetone                        2.38

    2-butanol                      3.03

     n-butanol                      3.03

    2-butoxyethanol                4.83

    butyl acetate                  4.75

    cyclohexane                    3.44

    DBP                           11.38

    DCB                            6.01

    ethanol                        1.88

    2-ethoxyethanol                3.68

    ethyl acetate                  3.6

    ethyl butyl ketone             4.6

     n-hexane                       3.52

    isobutanol                     3.03

    isopropanol                    2.45

    2-methoxyethanol               3.11

    methyl acetate                 3.6

    methyl butyl ketone            4.1

    methyl ethyl ketone            2.95

    methyl isobutyl ketone         4.1

    methylene chloride             3.48

    toluene                        3.75

    trichloroethane                5.46

    trichloroethylene              5.38

    white spirit                   1.75

    xylene                         4.34

    From: Clayton & Clayton (1981) and Weast (1986)


    1.  Propriétés et méthodes d'analyse

         La méthyléthylcétone est un liquide limpide, incolore, volatil et
    très inflammable dont l'odeur rappelle celle de l'acétone. Elle est
    stable dans les conditions ordinaires, mais peut donner naissance à
    des peroxydes explosifs en cas de stockage prolongé. Elle peut aussi
    former des mélanges explosifs avec l'air. Elle est très soluble dans
    l'eau, miscible à de nombreux solvants organiques et forme des
    azéotropes avec l'eau et beaucoup de liquides organiques. Dans
    l'atmosphère, elle produit des radicaux libres qui peuvent favoriser
    la formation d'un smog photochimique. 

         On dispose de plusieurs méthodes analytiques pour mesurer les
    concentrations de méthyléthylcétone dans l'air, l'eau, les
    échantillons biologiques, les effluents et d'autres milieux. Dans les
    méthodes les plus sensibles, la méthyléthylcétone est piégée et
    concentrée soit sur un sorbant solide, soit sous forme de dérivé de la
    2,4-dinitrophénylhydrazine (DNPH). La méthyléthylcétone absorbée et
    les autres composés organiques volatils sont désorbés, séparés par
    chromatographie gazeuse et dosés à l'aide d'un spectromètre de masse
    ou d'un détecteur à ionisation de flammes. Le produit de dérivation de
    la méthyléthylcétone est séparé des substances apparentées par
    chromatographie liquide à haute performance et mesuré par
    spectrophotométrie ultraviolette. Dans des milieux tels que les
    déchets solides ou les substances biologiques, la méthyléthylcétone
    doit d'abord être séparée du substrat, par exemple par extraction à
    l'aide d'un solvant ou par distillation à la vapeur. Les
    concentrations élevées de méthyléthylcétone dans l'air peuvent être
    mesurées de façon continue par absorption infrarouge. Les limites de
    détection sont de 3 µg/m3 dans l'air, 0,05 µg/litre dans l'eau de
    boisson, 1,0 µg/litre dans les autres types d'eau, 20 µg/litre dans le
    sang et 100 µg/litre dans l'urine.

    2.  Sources d'exposition et usages

    2.1  Production et autres sources

         Selon des statistiques récentes, la production annuelle (en
    milliers de tonnes) est la suivante: Etats-Unis d'Amérique, 212 à 305;
    Europe de l'Ouest, 215; Japon, 139. D'autres sources de contamination
    de l'environnement par la méthyléthylcétone sont les gaz d'échappement
    des réacteurs et des moteurs à combustion interne ainsi que certaines
    activités industrielles comme la gazéification du charbon. Elle est
    également présente en quantités notables dans la fumée de tabac. Aux
    Etats-Unis d'Amérique, la quantité de méthyléthylcétone émise par les
    moteurs représente plus de 1% de la quantité fabriquée volontairement.
    En cas de smog, la production photochimique de méthyléthylcétone et
    d'autres carbonyles à partir de radicaux libres peut être bien
    supérieure aux émissions résultant des activités humaines. La

    méthyléthylcétone peut aussi avoir une origine biologique et elle a
    été identifiée parmi les produits du métabolisme microbien. Elle a
    également été détectée dans divers produits naturels, notamment des
    végétaux supérieurs, des phéromones d'insectes, des tissus animaux,
    ainsi que chez l'homme dans le sang, l'urine et l'air expiré. Elle
    constitue probablement un produit mineur du métabolisme normal des

    2.2  Usages et pertes dans l'environnement

         La méthyléthylcétone est un excellent solvant, ce qui explique
    que sa principale application soit la fabrication de revêtements
    protecteurs et d'adhésifs. Elle est également utilisée comme
    intermédiaire chimique, comme solvant dans la fabrication des rubans
    magnétiques, pour l'élimination des cires dans les huiles de graissage
    et dans l'industrie alimentaire. Elle entre également dans la
    composition de nombreux produits d'usage courant comme les vernis et
    les colles. Dans la plupart de ces applications, la méthyléthylcétone
    est mélangée à d'autres solvants organiques. La libération dans
    l'environnement résulte principalement de l'évaporation des solvants
    à partir des surfaces enduites et concerne essentiellement
    l'atmosphère. La libération de méthyléthylcétone dans l'eau est la
    conséquence de sa présence dans les effluents provenant de sa
    fabrication et de diverses opérations industrielles. Elle a été
    détectée dans des eaux naturelles dans lesquelles sa présence pourrait
    s'expliquer par une activité microbienne, l'absorption à partir de
    l'atmosphère ou une pollution anthropogène.

    3.  Transport et distribution dans l'environnement

         La méthyléthylcétone est extrêmement mobile dans l'environnement
    naturel où elle se renouvelle rapidement. Elle est très soluble dans
    l'eau et s'évapore facilement. Dans l'atmosphère, elle subit une
    décomposition photochimique rapide, mais elle est également
    synthétisée par des processus photochimiques. Elle réagit avec les
    halogènes libres ou les hypochlorites et leurs homologues halogénés
    présents dans l'eau pour former un dérivé halogéné plus toxique que la
    molécule initiale. La méthyléthyl-cétone est transportée par l'air et
    par l'eau, mais elle ne s'accumule dans aucun compartiment et elle ne
    persiste pas longtemps là où il existe une activité microbienne. Elle
    est rapidement métabolisée par les microbes et les mammifères. Le
    phénomène de bioaccumulation n'a jamais été mis en évidence. La
    méthyléthylcétone existe naturellement dans certaines espèces de
    trèfle et elle est produite par des champignons à des concentrations
    qui peuvent affecter la germination de certaines plantes.

    4.  Concentration dans l'environnement et exposition humaine

         La population générale est fréquemment exposée à de faibles doses
    de méthyléthylcétone. Lorsque la pollution atmosphérique est très
    faible, la concentration est inférieure à 3 µg/m3 (< 1 ppb), mais

    on a mesuré jusqu'à 131 µg/m3 (44,5 ppb) en atmosphère très polluée.
    En dehors des zones industrielles de fabrication ou d'utilisation de
    la méthyléthylcétone, les gaz d'échappement des véhicules automobiles
    et les réactions photochimiques dans l'atmosphère peuvent être les
    principales sources de contamination. Les cigarettes et les autres
    formes de tabac à fumer contribuent à l'exposition individuelle (20
    cigarettes en contiennent jusqu'à 1,6 mg). La volatilisation de la
    méthyléthylcétone présente dans les matériaux de construction et les
    produits de consommation peut entraîner une pollution de l'air des
    locaux bien supérieure à celle de l'air extérieur. Les concentrations
    dans les eaux naturelles dépassent rarement 100 µg/litre (100 ppb) et
    sont généralement inférieures au seuil de détection. Toutefois, on a
    souvent trouvé des traces de méthyléthylcétone dans l'eau de boisson
    (environ 2 µg/litre). Il est probable que les solvants entrant dans la
    composition des joints des tuyauteries de plastique sont à l'origine
    de cette pollution. Bien que la méthyléthylcétone soit un constituant
    normal de nombreux aliments, les concentrations sont faibles et
    l'alimentation ne peut être considérée comme une source importante
    d'exposition. Aux Etats-Unis d'Amérique, la quantité moyenne ingérée
    quotidiennement avec les aliments, principalement le pain blanc, les
    tomates et le fromage Cheddar, est estimée à 1,6 mg par personne. La
    méthyléthylcétone peut être présente naturellement dans les aliments,
    mais elle peut aussi se former lors de l'affinage du fromage, de
    l'entreposage de la viande de volaille, de la cuisson ou de la
    transformation des aliments, ou être absorbée à partir des emballages
    en matière plastique. 

         L'exposition industrielle à des concentrations modérées de
    méthyléthylcétone est fréquente. Toutefois, dans certaines régions, le
    personnel travaillant dans de petites entreprises (fabriques de
    chaussures, imprimeries, ateliers de peinture) peut être exposé à des
    concentrations beaucoup plus élevées en raison d'une ventilation
    insuffisante. Ces travailleurs sont généralement exposés à un mélange
    de solvants, notamment au  n-hexane. 

    5.  Cinétique et métabolisme

         La méthyléthylcétone est rapidement absorbée par contact cutané,
    inhalation, ingestion et injection intrapéritonéale. Elle passe très
    vite dans le sang, et de là dans les autres tissus. Il semble que sa
    solubilité soit à peu près la même dans tous les tissus. L'élimination
    de la méthyléthylcétone et de ses métabolites est pratiquement totale
    chez les mammifères au bout de 24 heures. Elle est métabolisée dans le
    foie où la plus grande partie est oxydée en 3-hydroxy-2-butanone avant
    d'être réduite en 2,3-butanediol. Une petite partie peut être réduite
    en 2-butanol, mais celui-ci est rapidement oxydé pour redonner la
    molécule initiale. Chez les mammifères, la majeure partie de la
    méthyléthylcétone ingérée entre dans le cycle métabolique général
    et/ou est éliminée sous forme de molécules simples comme le dioxyde de
    carbone et l'eau. L'excrétion de la méthyléthylcétone et de ses

    métabolites caractéristiques se fait principalement par les poumons,
    bien que de petites quantités soient éliminées par les reins. 

         La méthyléthylcétone augmente l'activité enzymatique du
    cytochrome P-450 microsomal. Il est possible que ce renforcement de
    l'activité enzymatique, et par conséquent du potentiel de
    transformation métabolique de l'organisme, explique pourquoi la
    méthyléthylcétone potentialise la toxicité des solvants du groupe des
    alcanes halogénés et des hydrocarbures aliphatiques à six atomes de

    6.  Effets sur les animaux d'expérience

         La méthyléthylcétone présente une toxicité faible à modérée pour
    les mammifères, qu'il s'agisse de toxicité aiguë, à court terme ou
    chronique. Chez la souris et le rat, la LD50 est de 2 à 6 g/kg de
    poids corporel, la mort survenant 1 à 14 jours après l'ingestion d'une
    dose unique. La dose moyenne entraînant la mort après une exposition
    unique aux vapeurs de méthyléthylcétone est d'environ 29 400 mg/m3
    (10 000 ppm), bien que des cobayes aient survécu à une exposition de
    4 heures à cette concentration. Dans des essais d'intoxication aiguë
    par voie orale, la dose la plus faible ayant entraîné une modification
    de structure des organes a été de 1 g/kg de poids corporel chez le
    rat. Cette dose a provoqué des lésions des tubules du rein.
    L'inhalation par des rats d'air contenant 74 mg/m3 (25 ppm) pendant
    6 heures a provoqué des changements de comportement mesurables qui ont
    persisté pendant plusieurs jours. Une exposition répétée à 14 750
    mg/m3 (5000 ppm) (6 h/jour, 5 jours/semaine) n'a provoqué la mort
    d'aucun animal. On n'a observé qu'un effet mineur sur la croissance et
    la structure et il n'y a eu aucune modification neuropathologique. Des
    poulets, des chats ou des souris exposés à 3975 mg/m3 (1500 ppm)
    pendant des périodes allant jusqu'à 12 semaines n'ont présenté aucun
    signe de changement neuropathologique. Des effets transitoires sur le
    comportement ou la neurophysiologie ont été détectés chez des rats et
    des babouins à la suite d'expositions répétées à des concentrations ne
    dépassant pas 295 à 590 mg/m3 (100 à 200 ppm). 

         Une faible foetotoxicité a été observée à 8825 mg/m3 (3000
    ppm), mais elle ne s'accompagnait d'aucune toxicité maternelle; aucun
    effet embryotoxique ou tératogène n'a été constaté à des
    concentrations inférieures à cette valeur. Après avoir exposé de façon
    répétée des rattes en gestation à une concentration de 8825 mg/m3,
    on a observé dans leur progéniture une augmentation légère mais
    significative de certains types d'anomalie du squelette rarement
    observés chez les animaux non exposés.

         Plusieurs épreuves classiques de mutagénicité ont été pratiquées,
    mais la seule qui ait donné un résultat positif a été une étude
    d'hétéroploïdie sur la levure  Saccharomyces cerevisiae. 

         La méthyléthylcétone ne présente pas de toxicité aiguë pour les
    poissons ou les invertébrés aquatiques, la CL50 se situant entre
    1382 et 8890 mg/litre.

         Elle a un effet inhibiteur sur la germination de plusieurs
    plantes, même à des concentrations que l'on peut rencontrer dans la
    nature. La croissance des algues aquatiques est également inhibée.

         Des concentrations relativement élevées de méthyléthylcétone,
    comparées aux concentrations naturelles, ont été utilisées dans des
    expériences de fumigation. Cette substance s'est révélée un fumigant
    modérément efficace contre la mouche des fruits des Caraïbes. D'autre
    part, elle a un effet attractif très net sur la mouche tsé-tsé. Des
    concentrations allant jusqu'à 20 mg/litre retardent le processus de
    biodégradation mais ne l'arrêtent pas complètement. Jusqu'à 100
    mg/litre, la méthyléthylcétone est bactériostatique pour différentes
    bactéries. A des concentrations plus élevées (1000 mg/litre et
    au-delà) elle inhibe la croissance des bactéries et des protozoaires.

    7.  Effets sur l'homme

    7.1  Méthyléthylcétone seule

         Aucun effet notable n'a été observé lors de tests psychologiques
    et de comportement après exposition à 590 mg/m3 (200 ppm). Une
    exposition de courte durée à la méthyléthylcétone seule ne semble pas
    présenter de risques importants, que ce soit pour les professionnels
    ou pour le public en général. L'exposition, dans des conditions
    expérimentales, à une concentration de 794 mg/m3 (270 ppm), à raison
    de 4 heures par jour, a eu un effet à peu près nul sur le comportement
    et un contact de 5 minutes avec la substance liquide n'a provoqué
    qu'une décoloration temporaire de la peau. On n'a signalé qu'un seul
    cas d'intoxication aiguë par la méthyléthylcétone en dehors de tout
    contexte professionnel. Il s'agit d'un cas d'ingestion accidentelle
    qui ne semble pas avoir laissé de séquelles. On n'a jamais signalé de
    cas d'exposition professionnelle ayant entraîné la mort. Il existe
    deux rapports faisant état d'intoxication professionnelle chronique et
    un rapport d'intoxication professionnelle aiguë, mais ce dernier est
    sujet à caution. Dans un des cas d'intoxication chronique,
    l'exposition à 880-1770 mg/m3 (300-600 ppm) a provoqué des
    dermatoses, un engourdissement des doigts et des bras et divers
    symptômes, parmi lesquels des céphalées, des étourdissements, des
    troubles gastro-intestinaux et une perte d'appétit et de poids. Le
    faible nombre d'intoxications attribuées à la méthyléthylcétone seule
    tient à la fois à la faible toxicité de cette substance et au fait
    qu'elle est rarement utilisée seule, mais plutôt en mélange avec
    d'autres solvants.

    7.2  Méthyléthylcétone dans les mélanges de solvants

         L'exposition à des mélanges de solvants contenant de la
    méthyléthylcétone a été associée à une réduction de la vitesse de
    conduction nerveuse, à des troubles de la mémoire, à des troubles
    moteurs, à des dermatoses et à des vomissements. Dans une étude
    longitudinale, des mesures consécutives du temps de réaction simple
    ont montré une amélioration des performances parallèlement à une
    diminution de la concentration de méthyléthylcétone jusqu'à un dixième
    de la valeur initiale (qui pouvait atteindre 4000 mg/m3 pour
    certaines tâches de routine). 

    8.  Renforcement de la toxicité des autres solvants

         La méthyléthylcétone potentialise la neurotoxicité des solvants
    à six atomes de carbone ( n-hexane, méthyl- n-butylcétone et
    2,5-hexanedione) ainsi que la toxicité hépatique et rénale des
    solvants de la famille des alcanes halogénés (tétrachlorure de carbone
    et trichlorométhane).

         La potentialisation des effets neurotoxiques des composés à six
    atomes de carbone a été démontrée chez l'animal pour les trois
    substances citées ci-dessus. Les neuropathies périphériques observées
    chez l'homme se sont produites à la suite de changements dans la
    formulation des solvants auxquels les sujets avaient été exposés, soit
    volontairement, soit en raison de leur activité professionnelle. Le
    mécanisme de cette potentialisation n'a pas été élucidé.

         La potentialisation de la toxicité hépatique et rénale des
    alcanes halogénés a été mise en évidence dans des études chez
    l'animal. La méthyléthylcétone active probablement la métabolisation
    des haloalcanes en substances toxiques pour les tissus en induisant la
    production des enzymes oxydantes responsables de cette transformation.


    1.  Propiedades y métodos analíticos

         La metiletilcetona (MEC) es un líquido transparente, incoloro,
    volátil, muy inflamable, de olor parecido a la acetona. Es estable en
    condiciones normales pero puede formar peróxidos si se almacena
    durante mucho tiempo; esos peróxidos pueden ser explosivos. La MEC
    también puede formar mezclas explosivas con el aire. Es muy soluble en
    agua, miscible con muchos disolventes orgánicos, y forma mezclas
    azeotrópicas con el agua y con numerosos líquidos orgánicos. En la
    atmósfera, la MEC produce radicales libres que pueden llevar a la
    formación de nieblas fotoquímicas.

         Existen varios métodos analíticos para medir los niveles
    ambientales de MEC en el aire, el agua, las muestras biológicas, los
    desechos y otros materiales. Con los métodos más sensibles, la MEC se
    separa y se concentra ya sea en un sorbente sólido o como derivado de
    la 2,4-dinitrofenilhidrazina (DNFH). La MEC y otros compuestos
    orgánicos volátiles absorbidos son desorbidos, separados mediante
    cromatografía de gases y medidos con un espectrómetro de masas o un
    detector de ionización de llama. La MEC derivada se separa de los
    compuestos afines mediante cromatografía de líquidos de alto
    rendimiento y se mide mediante absorción ultravioleta. En medios como
    desechos sólidos y material biológico, la MEC debe separarse en primer
    lugar del sustrato con métodos como la extracción por solventes o la
    destilación de vapores. Las concentraciones elevadas de MEC en el aire
    pueden controlarse de modo continuo mediante absorción infrarroja. Los
    límites de detección son 3 µg/m3 en el aire, 0,05 µg/litro en el
    agua potable, 1,0 µg/litro en otros tipos de agua, 20 µg/litro en
    sangre total y 100 µg/litro en orina. 

    2.  Fuentes de exposición y usos

    2.1  Producción y otras fuentes

         Las cifras más recientes de fabricación industrial anual (en
    miles de toneladas) son: EEUU, 212 a 305; Europa occidental, 215;
    Japón, 139. Además de su fabricación, las fuentes de MEC en el medio
    ambiente son los gases de escape de motores de reactores y de
    combustión interna, y las actividades industriales como la
    gasificación del carbón. Se encuentra en cantidades importantes en el
    humo de tabaco. En los Estados Unidos, la producción de MEC en motores
    no supera el 1% de su fabricación deliberada. En los episodios de
    nieblas, la producción fotoquímica de MEC y otros carbonilos a partir
    de radicales libres puede ser mucho mayor que la emisión antropogénica
    directa. La MEC se produce biológicamente y se ha identificado como
    producto del metabolismo microbiano. Se ha detectado asimismo en gran
    diversidad de productos naturales, entre ellos los vegetales
    superiores, las feromonas de insectos, en tejidos animales y en el
    hombre, en sangre, orina y aire exhalado. Probablemente es un producto
    secundario del metabolismo normal en el mamífero. 

    2.2  Usos y pérdidas al medio ambiente

         El uso principal de la MEC, la aplicación de revestimientos
    protectores y adhesivos, refleja sus excelentes características como
    disolvente. También se utiliza como intermediario químico, como
    disolvente en la producción de cintas magnéticas y para eliminar la
    cera del aceite lubricante, así como en la manipulación de alimentos.
    Además de las aplicaciones industriales, figura como ingrediente común
    en productos de consumo como barnices y pegamentos. En la mayoría de
    las aplicaciones, la MEC es componente de una mezcla de disolventes
    orgánicos. Las pérdidas al medio ambiente son principalmente al aire
    y se deben sobre todo a la evaporación de disolventes a partir de las
    superficies revestidas. Se libera al agua como componentes de los
    desechos de su fabricación y a partir de diversas operaciones
    industriales. Se ha detectado en aguas naturales, procedente
    probablemente de la actividad microbiana y del aporte atmosférico, así
    como de la contaminación antropogénica.

    3.  Transporte y distribución en el medio ambiente

         La MEC es sumamente móvil en el medio ambiente natural y está
    sometida a una transformación rápida. Es muy soluble en el agua y se
    evapora fácilmente a la atmósfera. En el aire, la MEC sufre una rápida
    descomposición fotoquímica y es también sintetizada por procesos
    fotoquímicos. En agua que contiene halógenos libres o hipohalitos,
    reacciona para formar un haloformo más tóxico que el compuesto
    original. La MEC se distribuye tanto por el aire como por el agua,
    pero no se acumula en ningún compartimento aislado, ni persiste mucho
    tiempo donde existe actividad microbiana. Se metaboliza rápidamente en
    los microbios y los mamíferos. No hay pruebas de bioacumulación. La
    MEC aparece naturalmente en algunas especies de trébol y es producida
    por hongos en concentraciones que afectan a la germinación de algunas

    4.  Niveles ambientales y exposición humana

         La exposición de la población general a bajos niveles de MEC es
    muy extensa. En aire poco contaminado, la concentración es inferior a
    3 µg/m3 (< 1 ppmm), pero en condiciones de fuerte contaminación
    atmosférica se ha medido un nivel de 131 µg/m3 (44,5 ppmm). Lejos de
    las zonas industriales donde se fabrica o se usa la MEC, las
    principales fuentes pueden ser los escapes de vehículos y las
    reacciones fotoquímicas en la atmósfera. Los cigarrillos y otros
    productos del tabaco que se someten a combustión contribuyen a la
    exposición individual (20 cigarrillos contienen hasta 1,6 mg). La
    volatilización de la MEC de materiales de construcción y productos de
    consumo pueden contaminar el aire de interiores hasta niveles muy
    superiores a los del aire libre adyacente. Las concentraciones de MEC
    en aguas naturales expuestas rara vez se encuentran por encima de los
    100 µg/litro (100 ppmm) y suelen encontrarse por debajo del nivel de
    detección. No obstante, se han detectado cantidades muy reducidas de
    MEC en el agua potable (aproximadamente 2 µg/litro) que probablemente

    proceden de disolventes lixiviados a partir del material de las juntas
    de las tuberías de plástico. Aunque la MEC es un componente normal de
    muchos alimentos, las concentraciones son bajas y el consumo de
    alimentos no puede considerarse una fuente significativa de exposición
    para la población. La ingesta media diaria por habitante de los
    Estados Unidos con los alimentos se calcula en 1,6 mg, en su mayor
    parte a partir del pan blanco, los tomates y el queso tipo Cheddar.
    Además de la MEC presente en el medio natural, puede producirse en la
    maduración de los quesos, el envejecimiento de la carne de ave, la
    cocción o la manipulación de alimentos, o por absorción a partir de
    los envases de plástico.

         La exposición industrial a niveles moderados de MEC está muy
    extendida. No obstante, en algunas regiones los trabajadores de
    fábricas pequeñas (por ejemplo, fábricas de calzado, imprentas y
    fábricas de pinturas) están expuestos a concentraciones mucho más
    elevadas por una ventilación insuficiente. En esas fábricas, la
    exposición se da por lo general a una mezcla de disolventes entre los
    que figura el  n-hexano.

    5.  Cinética y metabolismo

         La absorción de MEC es rápida por contacto cutáneo, inhalación,
    ingestión e inyección intraperitoneal. Pasa rápidamente a la sangre y
    de ella a otros tejidos. La solubilidad de la MEC parece similar en
    todos los tejidos. La eliminación de la MEC y sus metabolitos en
    mamíferos se completa en su mayor parte en 24 horas. Se metaboliza en
    el hígado, donde se oxida a 3-hidroxi-2-butanona y a continuación se
    reduce a 2,3-butanodiol. Una pequeña porción puede reducirse a
    2-butanol, pero éste se oxida rápidamente para dar de nuevo MEC. La
    mayor parte de la MEC que ingresa al organismo de mamíferos pasa al
    metabolismo general y/o se elimina en forma de compuestos simples,
    como dióxido de carbono y agua. La excreción de MEC y sus metabolitos
    reconocibles se hace principalmente por los pulmones, aunque pequeñas
    cantidades se eliminan por el riñón. 

         La MEC aumenta la actividad enzimática del citocromo P-450 en los
    microsomas. Este aumento de la actividad enzimática y con ello del
    potencial del organismo para la transformación metabólica puede ser el
    mecanismo por el que la MEC potencia la toxicidad de los disolventes
    a base de haloalcanos y hexacarbonos alifáticos. 

    6.  Efectos en los animales de experimentación

         La MEC tiene toxicidad aguda, a corto plazo y crónica de baja a
    moderada en los mamíferos. Los valores de la DL50 en ratones y ratas
    adultos son 2-6 g/kg de peso corporal; la muerte sobreviene en los
    días 1 a 14 después de una sola dosis por vía oral. Las
    concentraciones medias de vapor que producen letalidad en las ratas
    tras una sola exposición giran en torno a los 29 400 mg/m3 (10 000
    ppm), aunque los cobayos sobrevivieron a una exposición de 4 horas a
    esta concentración. La dosis oral aguda más baja en modificar la

    estructura corporal fue de 1 g/kg de peso corporal, que produjo
    lesiones en los túbulos renales de la rata. La inhalación de 74
    mg/m3 (25 ppm) durante 6 horas produjo en la rata cambios de
    comportamiento medibles que persistieron durante varios días. La
    exposición repetida de ratas a 14 750 mg/m3 (5000 ppm) (6 h/día, 5
    días/semana) no produjo letalidad, tuvo sólo ligeros efectos en el
    crecimiento y la estructura, y no se observaron cambios
    neuropatológicos. No hubo pruebas de que la MEC produjera cambios
    neuropatológicos en pollos, gatos o ratones expuestos a 3975 mg/m3
    (1500 ppm) durante periodos de hasta 12 semanas. Tras la exposición
    repetida de ratas y babuinos a concentraciones tan bajas como 295-590
    mg/m3 (100 a 200 ppm) se observaron efectos transitorios en el
    comportamiento o la neurofisiología.

         Se ha observado un nivel bajo de fetotoxicidad sin toxicidad
    materna a 8825 mg/m3 (3000 ppm), pero no hay pruebas de efectos
    embriotóxicos o teratogénicos a niveles más bajos de exposición. La
    exposición repetida de ratas preñadas a 8825 mg/m3 indujo en sus
    crías un aumento pequeño pero significativo de ciertos tipos de
    anomalías esqueléticas cuya incidencia entre la población no expuesta
    es baja.

         Aunque se examinó en varios sistemas de ensayo de mutagenicidad
    convencionales, la única prueba de mutagenicidad se observó en un
    estudio sobre aneuploidia en la levadura  Saccharomyces cerevisiae.

         La MEC no presenta toxicidad aguda para los peces ni los
    invertebrados acuáticos; los valores de la CL50 varían desde 1382
    hasta 8890 mg/litro.

         La MEC inhibe la germinación de varias especies vegetales,
    incluso con niveles que se dan en la naturaleza. Inhibe el crecimiento
    de algas acuáticas.

         En comparación con los niveles de base naturales, se han
    utilizado concentraciones relativamente elevadas de MEC para fumigar
    en condiciones experimentales. Es moderadamente eficaz como fumigante
    contra la mosca caribeña de la fruta y atrae con gran eficacia a la
    mosca tse-tse. Con niveles de MEC de hasta 20 mg/litro se retrasa la
    biodegradación pero no se detiene el proceso por completo. Con niveles
    de hasta 100 mg/litro, la MEC es bacteriostatica para algunas
    bacterias. Con concentraciones más altas (1000 mg/litro o más) se
    inhibe el crecimiento de bacterias y protozoarias.

    7.  Efectos en el ser humano

    7.1  MEC por sí sola

         La exposición a 590 mg/m3 (200 ppm) no tuvo efectos de
    importancia en varios ensayos comportamentales y psicológicos. La
    exposición a corto plazo a MEC por sí sola no parece constituir un
    riesgo de importancia, ni ocupacional ni para el público en general.

    La exposición experimental a una concentración de 794 mg/m3 (270
    ppm) durante 4 h/día tuvo escaso o ningún efecto en el comportamiento,
    y un contacto de 5 minutos con MEC líquida no produjo más que un
    blanqueamiento temporal de la piel. Sólo hay un informe no ocupacional
    de toxicidad aguda a la MEC. Se debió a una ingestión accidental y no
    pareció producir lesiones duraderas. No hay pruebas de que la
    exposición ocupacional a la MEC haya originado ningún caso de muerte.
    Se han notificado dos casos de envenenamiento ocupacional crónico y
    uno dudoso de envenenamiento ocupacional agudo. En uno de los casos
    crónicos, la exposición a 880-1770 mg/m3 (300-600 ppm) dió lugar a
    dermatosis, endormecimiento de los dedos y los brazos, y diversos
    síntomas como dolor de cabeza, mareos, trastornos gastrointes-tinales
    y pérdida de apetito y de peso. Esta escasez de incidentes de
    envenamiento por MEC por sí sola refleja tanto su baja toxicidad como
    el hecho de que se usa más comunmente no por sí sola sino como
    componente de mezclas de disolventes. 

    7.2  La MEC en mezclas de disolventes

         La exposición a mezclas de disolventes con MEC se ha asociado a
    cierta reducción en la velocidad de conducción nerviosa, la memoria y
    alteraciones motoras, dermatosis y vómitos. En un estudio
    longitudinal, las medidas consecutivas de tiempo de reacción simple
    demostraron que mejoraba el rendimiento en paralelo al ir disminuyer
    de las con concentraciones de MEC hasta un décimo de los valores
    originales (que fueron de hasta 4000 mg/m3 para ciertas tareas

    8.  Potenciación de la toxicidad de otros disolventes

         La MEC potencia la neurotoxicidad de compuestos hexacarbonados
    ( n-hexano, metil- n-butilcetona y 2,5-hexanodiona) y la toxicidad
    hepatica y renal de los disolventes a base de haloalcanos
    (tetracloruro de carbono y triclorometano).

         La potenciación de los efectos neurotóxicos de los hexacarbonos
    se ha demostrado con los tres hexacarbonos en el animal. Las
    neuropatías periféricas observadas en humanos siguieron a cambios en
    la formulacion de disolventes a los que habían estado expuestos, ya
    sea voluntariamente o en el trabajo. El mecanismo por el que se
    produce esta potenciación no está claro.

         Las pruebas de la potenciación de la toxicidad hepática y renal
    de los haloalcanos proceden de estudios animales. La MEC activa
    probablemente el metabolismo de los haloalcanos de las especies que
    dañan los tejidos como resultado de la inducción de las enzimas
    oxidativas pertinentes.

    See Also:
       Toxicological Abbreviations
       Methyl ethyl ketone (ICSC)