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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 117





    METHYL ISOBUTYL KETONE










    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. K. Chipman,
    University of Birmingham, United Kingdom

    World Health Orgnization
    Geneva, 1990


         The International Programme on Chemical Safety (IPCS) is a
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    WHO Library Cataloguing in Publication Data

    Methyl isobutyl ketone.

        (Environmental health criteria ; 117)

        1.Ketones - adverse effects 2.Ketones - toxicity  
        I.Series

        ISBN 92 4 157117 9        (NLM Classification: QV 633)
        ISSN 0250-863X

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    CONTENTS

    ENVIRONMENTAL HEALTH CRITERIA FOR METHYL ISOBUTYL KETONE

    1. SUMMARY

    2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

         2.1. Identity
         2.2. Physical and chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. Environmental media
                     2.4.1.1  Air
                     2.4.1.2  Water
                     2.4.1.3  Tissues, body fluids, and skin washings
                     2.4.1.4  Food

    3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

         3.1. Natural occurrence
         3.2. Man-made sources
         3.3. Uses

    4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

         4.1. Transport and distribution between media
         4.2. Biotransformation
              4.2.1. Biodegradation
              4.2.2. Abiotic degradation
              4.2.3. Photochemical smog reactivity
         4.3. Bioaccumulation

    5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

         5.1. Environmental levels
              5.1.1. Air
              5.1.2. Food
              5.1.3. Water
              5.1.4. Soil
         5.2. Occupational exposure
              5.2.1. Exposure limit values

    6. KINETICS AND METABOLISM

         6.1. Experimental animals
              6.1.1. Effect on liver alcohol dehydrogenase  in vitro
         6.2. Humans

    7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

         7.1. Microorganisms
         7.2. Aquatic organisms
         7.3. Terrestrial organisms

    8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO  TEST SYSTEMS

         8.1. Single exposures
         8.2. Short-term exposure
              8.2.1. Inhalation
              8.2.2. Oral
              8.2.3. Parenteral
              8.2.4. Skin application
         8.3. Skin, eye, and respiratory irritation; sensitization
              8.3.1. Skin irritation
              8.3.2. Eye irritation
              8.3.3. Respiratory irritation
              8.3.4. Skin sensitization
         8.4. Long-term exposure
         8.5. Reproduction, embryotoxicity, and teratogenicity
         8.6. Mutagenicity and related end-points
              8.6.1. Bacterial assays
              8.6.2. Yeast assay for mitotic gene conversions
              8.6.3. L5178Y TK+/- mouse lymphoma assay
              8.6.4. Unscheduled DNA synthesis in primary rat
                     hepatocytes  in vitro 
              8.6.5. Mouse micronucleus assay
              8.6.6. Assay for structural chromosome damage
              8.6.7. Cell transformation assay
         8.7. Carcinogenicity
         8.8. Neurotoxicity
         8.9.  In vitro  toxicity assays

    9. EFFECTS ON MAN

         9.1. Acute toxicity
         9.2. Short-term exposure
         9.3. Eye and respiratory irritation
         9.4. Long-term exposure
         9.5. Placental transfer
         9.6. Neurotoxicity

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

         10.1. Evaluation of effects on the environment
         10.2. Evaluation of health risks for humans

    11. RECOMMENDATIONS

    12. FURTHER RESEARCH

    REFERENCES

    RESUME

    EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS
    SUR L'ENVIRONNEMENT

    RECOMMANDATIONS

    RECHERCHES A EFFECTUER

    RESUMEN

    EVALUACION DE LOS RIESGOS PARA LA SALUD HUMANA Y DE LOS
    EFECTOS EN EL MEDIO AMBIENTE

    RECOMENDACIONES

    OTRAS INVESTIGACIONES
    
    WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR METHYL
    ISOBUTYL KETONE (MIBK)

     Participants 

    Professor E.A. Bababunmi, Department of Tropical Paediatrics,
         Liverpool School of Tropical Medicine, Liverpool, United
         Kingdom  (Rapporteur) 

    Dr M. Cikrt, Centre of Industrial Hygiene and Occupational
         Diseases, Institute of Hygiene and Epidemiology, Prague,
         Czechoslovakia  (Vice-Chairman) 

    Dr S. Dobson, Pollution and Ecotoxicology Section, Institute of
         Terrestrial Ecology, Monks Wood Experimental Station,
         Huntingdon, United Kingdom

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

    Dr S.D. Gangolli, British Industrial Biological Research
         Association, Carshalton, Surrey, United Kingdom

    Dr C. Konantakieti, Technical Division, Food and Drug
         Administration, Ministry of Public Health, Bangkok, Thailand

    Dr O. Ladefoged, Laboratory of Pathology, Institute of Toxicology,
         National Food Agency of Denmark, Ministry of Health, Soborg,
         Denmark

    Professor A. Massoud, Department of Community Environmental and
         Occupational Medicine, Ainshams Faculty of Medicine, Cairo,
         Egypt

    Dr V. Riihimäki, Department of Industrial Hygiene and Toxicology,
         Institute of Occupational Health, Helsinki, Finland

     Secretariat 

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

    Ms B. Labarthe, International Register of Potentially Toxic
         Chemicals, United Nations Environment Programme, Geneva,
         Switzerland

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

    NOTE TO READERS OF THE CRITERIA DOCUMENTS

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

                               *    *    *

         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
    7985850)

    ENVIRONMENTAL HEALTH CRITERIA FOR METHYL ISOBUTYL KETONE

         A WHO Task Group on Environmental Health Criteria for Methyl
    Isobutyl Ketone met at Carshalton, United Kingdom, from 12 to 16
    March 1990. Dr E.M. Smith, IPCS, opened the meeting 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 health risks of exposure to
    methyl isobutyl ketone.

         The first draft of this document was prepared by Dr K.
    Chipman, University of Birmingham, United Kingdom. The second draft
    was also prepared by Dr Chipman following circulation of the first
    draft to IPCS contact points for Environmental Health Criteria
    monographs. Particularly valuable comments on the draft were made
    by the United Kingdom Department of Health, the European Chemical
    Industry Ecology and Toxicology Centre (ECETOC), and the US
    Environmental Protection Agency, National Institute of
    Environmental Health Sciences, and National Institute of
    Occupational Safety and Health.

         Dr E.M. Smith and Dr P.G. Jenkins, both members of the IPCS
    Central Unit, were responsible for the technical development and
    editing, respectively, of this monograph.

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

                                *   *   *

         Financial support for this Task Group was provided by the
    United Kingdom Department of Health as part of its contributions to
    IPCS.

         Partial financial support for the publication of this criteria
    document was kindly provided by the United States Department of
    Health and Human Services, through a contract from the National
    Institute of Environmental Health Sciences, Research Triangle Park,
    North Carolina, USA - a WHO Collaborating Centre for Environmental
    Health Effects.

    ABBREVIATIONS

    CLV              ceiling value

    GC               gas chromatography

    GRAS             generally regarded as safe

    HMP              4-hydroxy-4-methyl-2-pentanone

    ip               intraperitoneal

    MIBK             methyl isobutyl ketone

    NOEL             no-observed-effect level

    QSAR             quantitative structure activity relationship

    TLV              threshold limit value

    1.  SUMMARY

        Methyl isobutyl ketone (MIBK) is a clear liquid with a sweet
    odour and is produced commercially for wide use as a solvent. It
    can be measured by gas chromatography with flame ionization
    detection. It rapidly evaporates into the atmosphere, where it is
    rapidly phototransformed. MIBK is readily biodegradable, and this,
    together with its moderate water solubility and low octanol/water
    partition coefficient, suggests that it has a low bioaccumulation
    potential. Occupational exposure limits range from 100-410 mg/m3
    time-weighted average, TWA) and 5-300 mg/m3 (ceiling value, CLV)
    in different countries.

        MIBK is readily metabolized to water-soluble excretory products
    and is of low acute systemic toxicity in animals by the oral and
    inhalation routes of exposure. Peripheral axonopathy has not been
    reported in animal studies. There are no accurate LC50 data. A
    4-h exposure to 16 400 mg/m3 (4000 ppm) was lethal in rats.
    Liquid MIBK and vapour concentrations in the range 10-410 mg/m3
    (2.4-100 ppm) are irritant to the eyes and the upper respiratory
    tract. Concentrations up to 200 mg/m3 (50 ppm) produced no
    significant effects on humans in a simple reaction time task or a
    test of mental arithmetic. Prolonged or repeated skin contact may
    cause drying and flaking of the skin. Accidental aspiration of
    liquid MIBK can cause chemical pneumonitis.

        In a 90-day gavage study on rats, a NOEL of 50 mg/kg per day
    was found. In 90-day inhalation studies on rats and mice,
    concentrations of up to 4100 mg/m3 (1000 ppm) did not result in
    any life-threatening signs of toxicity. However, compound-related
    reversible morphological changes in the liver and kidney were
    reported. In a number of studies, MIBK concentrations as low as
    1025 mg/m3 (250 ppm) were capable of increasing liver size. With
    exposure to 4100 mg/m3 (1000 ppm) for 50 days, microsomal enzyme
    metabolism was induced in the livers of chickens. Effects at higher
    doses (up to 8180 mg/m3, 1996 ppm) were limited to increased
    liver weight with no histological damage. In 90-day studies with
    mice, rats, dogs, and monkeys, only male rats developed hyaline
    droplets in the proximal tubules of the kidney (hyaline droplet
    toxic tubular nephrosis). This effect in male rats was reversible
    and of doubtful significance for humans. Enzyme induction may be
    the basis of potentiation of haloalkane toxicity by MIBK. MIBK was
    also able to potentiate the cholestatic effect of manganese given
    with or without bilirubin.

        In baboons exposed for 7 days to 205 mg/m3 (50 ppm), effects
    on neurobehaviour were reported.

        MIBK is fetotoxic at a concentration that produces definite
    maternal toxicity (12 300 mg/m3, 3000 ppm) but is not embryotoxic
    or teratogenic at this concentration. At a concentration of 4100

    mg/m3 (1000 ppm), it was neither embryotoxic, fetotoxic, nor
    teratogenic in rats or mice.

        MIBK has been studied for genotoxicity in a number of
    short-term assays, including  in vitro  bacterial, yeast, and
    mammalian cell tests and a micronucleus assay in mice. These
    studies indicate that MIBK is not genotoxic. No reports of
    long-term or carcinogenicity studies are available.

        At 410 mg/m3 (100 ppm) MIBK can induce in humans symptoms
    such as eye irritation, headaches, nausea, dizziness, and fatigue
    consistent with a reversible depressant effect on the central
    nervous system, but there is no evidence that it produces permanent
    damage to the nervous system.

        MIBK has low toxicity for aquatic organisms and microorganisms.

        The relatively high volatility, rapid atmospheric
    hototransformation, ready biodegradability, and low mammalian and
    aquatic toxicity of MIBK indicate that adverse environmental
    effects of this substance are only likely to occur after accidental
    spills or from uncontrolled industrial effluents.

    2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

    2.1  Identity

        Common name:        Methyl isobutyl ketone (MIBK)

        Chemical structure:
                                  O   H  CH3
                                  "   '   '
                            H3C - C - C - C - CH3
                                          '   '
                                          H   H

        Chemical formula:   C6H12O

        Relative molecular  100.16
        mass:

    Common synonyms:        MIBK, MIK, 4-methyl-2-pentanone,
                            2-methyl-4-pentanone, hexanone, hexone,
                            isopropyl-acetone, 4-methyl pentan-2-one,
                            4-methyl-2-oxopentane, 2-methyl propyl
                            methyl ketone, isobutylmethyl ketone

    CAS registry number:    108-10-1

        A typical sample of MIBK has a purity of 99% (by mass); it may
    contain the following impurities: dimethyl heptane (< 0.3%), water
    (< 0.1%), methyl isobutyl carbinol (< 0.06%), mesityloxide
    (< 0.03%), acidity as acetic acid (< 0.002%), and non-volatiles
    (< 0.002%).

    2.2  Physical and chemical properties

        MIBK is a clear liquid with a sweet odour.

        Some physical and chemical properties of MIBK are given in
    Table 1. The partition coefficients of MIBK are 79 for water/air,
    90 for blood/air, and 926 for oil/air (Sato & Nakajima, 1979). MIBK
    can react violently with oxidizing agents such as peroxides,
    nitrates, and perchlorates, reducing agents, or with potassium
     tert -butoxide. When heated, MIBK may form peroxides by
    auto-oxidation and these may explode spontaneously (Sax,1979).

    Table 1.  Some physical and chemical properties of MIBK a 

                                                                   

    Physical form                      liquid

    Colour                             colourless

    Odour/taste                        sweet

    Odour threshold limit (mg/m3)      1.64 (0.4 ppm) b 
                                       1.68 (0.41 ppm) a 

    Boiling point (°C at 101 KPa)      116.2 (range, 116 to 119) c 

    Freezing point (°C)                -80.26 (range, -80 to -85) c


    Specific gravity (20°C/4°C)        0.8017

    Refractive index (nD20)            1.395 to 1.397

    Viscosity (mPa.s) (20°C)           0.58 to 0.61

    Vapour density (air = 1)           3.45

    Vapour pressure (KPa) (20°C)       1.99

    Concentration in saturated air     27
    (g/m3) (20°C) (101 KPa)

    Flashpoint (°C) (closed cup)       14

    Auto-ignition temperature (°C)     460

    Explosion limits in air            1.4 to 7.5
    (101 KPa) (% vol.)

    Solubility in water                17
    (20°C) (g/litre)

    Octanol/water partition            1.38 d 
    coefficient (log Pow)

                                                                   

    a      From: Verschueren (1983).
    b      From: Ruth (1986).
    c      For commercial products.
    d      From: Leo & Weininger (1984).

    2.3  Conversion factors

        1 ppm = 4.1 mg/m3
        1 mg/m3 = 0.244 ppm

    2.4  Analytical methods

    2.4.1  Environmental media

        Gas chromatography (GC) is suitable for analysing trace
    quantities of MIBK (Analytical Quality Control, 1972; Webb et al.,
    1973) and the use of fused capillary columns is advantageous. The
    use of bonded-phase capillary columns may overcome the need for
    solid or liquid phase extraction of samples. Flame ionization
    detection (FID) is very sensitive (Webb et al., 1973), while mass
    spectroscopy is particularly useful for identifying MIBK in complex
    media.

    2.4.1.1  Air

        Measurement of MIBK in air involves sampling (10-12 litres at
    a rate of 0.2 litre/min) on charcoal, silica gel, or some
    chromatographic column packings, followed by desorption with carbon
    disulfide and further analysis by gas chromatography with flame
    ionization detection (Tomczyk & Rogaczewska, 1979; NIOSH, 1984;
    Moshlakova & Indina, 1986). The method has been validated over the
    range of 208-836 mg/m3(52-209 ppm) and the probable useful
    concentration range is 40-1230 mg/m3 (10-300 ppm) (NIOSH, 1984).
    No interferences were reported. Using this technique, Bamberger et
    al. (1978) reported an average desorption efficiency of
    approximately 81% following the exposure of a dosimeter for 5 h to
    103 or 410 or 820 mg MIBK/m3 (25 or 100 or 200 ppm). Storage in
    a covered dosimeter for 2 weeks reduced the recovery to 69%. Levin
    & Carleborg (1987) investigated a range of adsorbents for work-room
    air sampling of MIBK. The retention capacity was as follows (for 5
    mg generated at 85% relative humidity at 0.2 litres/min in 5 litres
    air): XAD-2, 21%; XAD-4, 65%; XAD-7, 39%; activated charcoal, 97%;
    Ambersorb XE-348, 98%. Although recovery was reduced to 61%
    following storage of samples on charcoal, recoveries were not
    reduced under these conditions for Ambersorb XE-348.

        MIBK can also be sampled efficiently by the use of
    Tenax-GC(R), a polymer of 2,6-diphenyl- p -phenylene oxide. Its
    main advantages are its high temperature stability and low affinity
    for water vapour. For MIBK, collection efficiency is 99% using 135
    g Tenax-GC(R)/17 litres of air. This method is more sensitive
    than the charcoal/solvent desorption technique and produces samples
    that remain stable for 6 months (Brown & Purnell, 1979).

    2.4.1.2  Water

        Techniques such as head-space sampling when there is no
    interference (Corwin, 1969), liquid-liquid extraction (Keith, 1974;
    Austern et al., 1975), distillation, or stripping with an inert gas
    stream (Webb et al., 1973; Ellison & Wallbank, 1974) have been
    used, because water is not a suitable solvent for gas
    chromatographic analysis. The use of synthetic resin gas
    chromatographic columns gives low detection limits (µg/ml range)
    and high recovery; for example, they have been used in the analysis
    of traces of MIBK in drinking-water (Burnham et al., 1972). Ellison
    & Wallbank (1974) removed MIBK from waste water and waste sludges
    by steam distillation and partitioning into cyclohexanone before
    gas chromatographic analysis.

    2.4.1.3  Tissues, body fluids, and skin washings

        The presence of MIBK and other 2-pentanones in 24-h urine
    samples of unexposed human beings has been demonstrated using gas
    chromatography and mass spectrometry (Zlatkis & Liebich, 1971).
    Bellanca et al. (1982) used both gas chromatography and mass
    spectroscopy in the electron ionization mode and, for more
    sensitive detection, employed select ion monitoring coupled with
    capillary gas chromatography. These methods were used to detect
    MIBK liberated into head-space gas from samples of brain, liver,
    lung, vitreous fluid, kidney, and blood. MIBK and its metabolites
    have been detected by gas chromatography in the serum of
    guinea-pigs administered MIBK (DiVincenzo et al., 1976), and
    Moshlakova & Indina (1986) have detected MIBK (0.006 to 0.06
    mg/cm2) in skin washings of workers using gas chromatography and
    flame ionization detection.

    2.4.1.4  Food

        Residual MIBK in food packaging films can be analysed by gas
    chromatography (Raccio & Widomski, 1981; Fernandes, 1985). For milk
    analyses, gas chromatography can be combined with mass spectroscopy
    (Weller & Wolf, 1989).

    3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

    3.1  Natural occurrence

        MIBK occurs naturally in food, is a permitted flavouring agent
    with GRAS status in the USA, and is used in food contact packaging
    materials. It is found in a wide range of foods, e.g., fruits,
    baked potatoes, cheese, milk, some meats, and some alcoholic
    beverages. The following values have been reported: papaya, 8
    µg/kg; beer, 10 to 120 µg/kg; coffee, 6.5 mg/kg (TNO 1983a,b; 1986;
    1987).

    3.2  Man-made sources

        MIBK is produced commercially by acetone condensation, followed
    by catalytic hydrogenation in a one-step catalytic process. The
    annual production in the USA in 1975 was estimated to be 80 500
    tonnes (Lande et al., 1976), and the annual global production in
    1975 was estimated to be 250 000 tonnes (OECD, 1977). Consumption
    in the European Economic Community (EEC) in 1981 was estimated to
    be 45 000 tonnes (ECDIN, 1990).

    3.3  Uses

        MIBK is used as one of the component ketones in lacquers, such
    as cellulose and polyurethane lacquers (Sabroe & Olsen, 1979), and
    as a minor component of paint solvents, including car and
    industrial spray paints (Hänninen et al., 1976; Elofsson et al.,
    1980). It also has uses as an extraction solvent, e.g., in
    pharmaceutical products and in the manufacture of methyl amyl
    alcohol and as a denaturant for ethyl alcohol (Zakhari et al.,
    1977).

    4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    4.1  Transport and distribution between media

        There are no experimental data on the transport, mobility, and
    concentration of MIBK in the environment.

        MIBK is moderately soluble in water and volatilizes only slowly
    from soil and surface waters. A theoretical half-life of 33 days,
    in a body of water with a depth of 1 m, can be calculated according
    to the Fugacity Model of MacKay & Wolkoff (1973). Based on its
    moderate water solubility and low soil adsorption coefficient, MIBK
    is a potential contaminant of ground water (see section 5.1.3).

    4.2  Biotransformation

    4.2.1  Biodegradation

        Using the standard dilution method with sludge from a
    waste-treatment plant, Bridié et al. (1979b) found a biological
    oxygen demand after 5 days at 20°C (BOD5) for MIBK of 76% of the
    theoretical oxygen demand (ThOD). MITI (1978) confirmed that MIBK
    was readily biodegradable in fresh water and sea water. Price et
    al. (1974) studied the biodegradability of MIBK and found that the
    nonacclimated extent of bio-oxidation was 56, 66, 69, and 69% at 5,
    10, 15, and 20 days, respectively, in fresh water. The respective
    values in synthetic salt water were 15, 46, 50, and 53%. The
    measured chemical oxygen demand (COD) was 2.4 mg/mg.

        Data are not available on the biodegradation of MIBK in soil.

    4.2.2  Abiotic degradation

        MIBK is degraded in the atmosphere by OH radicals. Cox et al.
    (1980) and Atkinson et al. (1982) found kOH reactivity constants
    of 12.4 x 10-12 and 14.5 x 10-12 cm3/mol per sec,
    respectively, which corresponded to half-lives of 0.57 and 0.55
    days. MIBK is also photodegraded. The major phototransformation
    product is acetone, which has a kOH of 0.5 x 10-12 cm3/mol
    per sec, corresponding to a half-life of 16 days (Cox et al.,
    1980).

    4.2.3  Photochemical smog reactivity

        There is some experimental evidence indicating the
    participation of ketones in the photochemical smog cycle as
    free-radical chain initiators. However, their contribution to
    overall smog generation has not been established, but is thought to
    be minor (Lande et al., 1976).

    4.3  Bioaccumulation

        There are no data on the ability of MIBK to accumulate in
    biological material. However, its moderate water solubility and low
    octanol/water partition coefficient (log Pow) suggest that it has
    low bioaccumulation potential (OECD, 1984). MIBK is not expected to
    be persistent. It will probably volatilize fairly readily except in
    wet environments and may be oxidized in the atmosphere. Due to its
    low log Pow, it is unlikely that it will be appreciably absorbed.

    5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    5.1  Environmental levels

    5.1.1  Air

        MIBK release into the atmosphere may occur during its
    production through fugitive emissions and incomplete removal of
    vapours from reaction gases before they are vented or disposed of
    in a scrubber. In the Federal Republic of Germany, MIBK belongs to
    class III, air emissions of which must not exceed (as the sum of
    all compounds in any class) 150 mg/m3 (37 ppm) at a mass flow of
    3 kg/h or more. The maximum recommended ambient concentrations are
    0.2 mg/m3 (0.05 ppm) in Czechoslovakia and must not exceed 0.1
    mg/m3 (0.025 ppm) in the USSR (IRPTC, 1990). MIBK has been
    detected in automotive exhaust emissions (Hampton et al., 1982).

    5.1.2  Food

        MIBK is allowed as a component of food packaging and is allowed
    to come in contact with food materials in the USA and the EEC. The
    EEC limit for thesumof all permitted solvents is 60 mg/m2 on the
    side with food contact. The intake via food flavourings based on a
    1970 survey of usage in the USA was estimated to be 3.35 mg/person
    per day (NTIS, 1985). The levels in particular foods were: baked
    goods, 10.9 mg/kg; frozen dairy products 11.5 mg/kg; meat products,
    2.6 mg/kg; soft candy, 12.3 mg/kg; gelatins, puddings, 10.9 mg/kg;
    beverages, 10.2 mg/kg.

        MIBK has also been detected in human breast milk (Pellizzari
    et al., 1982).

    5.1.3  Water

        MIBK may be released during the discharge of spent scrubbing
    water from industrial production processes. Traces of MIBK have
    been found in tap water in the USA (CEC, 1976) and in the United
    Kingdom (Fawell & Hunt, 1981). MIBK is included in the Code of
    Federal Regulations (CFR, 1987), which lays down methods for the
    analysis of organic chemicals in ground water at hazardous waste
    sites. MIBK has frequently been detected in leachates from waste
    sites (Francis et al., 1980; Sawhney & Kozloski, 1984; Garman et
    al., 1987; Brown & Donnelly, 1988).

    5.1.4  Soil

        MIBK can contaminate soil as a result of accidental spillage
    or disposal of solid wastes or sludges (Basu et al., 1968), but
    there are no data on levels in soil.

    5.2  Occupational exposure

        Closed production systems should ensure that occupational
    exposures are below recommended occupational exposure limits.
    However, emissions that occur when MIBK is used as a solvent, e.g.,
    in paints and lacquers, are less easily controlled. Hänninen et al.
    (1976) reported a mean time-weighted average (TWA) concentration of
    7 mg/m3 (range, 4-160 mg/m3) (1.7 ppm; range, 1-39 ppm) in the
    breathing zone of spray painters in car repair shops. Residual MIBK
    contained in plastic products can outgas under reduced pressure
    conditions and may appear as a contaminant in the environment of
    spacecraft (MacEwen et al., 1971). It has been detected at levels
    of < 0.005 to 0.02 mg/m3 in the atmosphere of spacecraft
    (Rippstein & Coleman, 1984). MIBK has also been found as a volatile
    degradation product of polypropylene at temperatures of 220 or 280
    °C (Frostling et al., 1984). According to a study by Kristensson &
    Beving (1987), exposure measurements for workers painting indoors
    for periods of 6-8 h indicated that the concentrations of probe
    solvents (including MIBK) were usually well below prescribed
    threshold limit values.

    5.2.1  Exposure limit values

        Exposure limit values for various countries are given in Table
    2. The USSR requires special skin and eye protection for workers
    exposed to MIBK.


    Table 2.  Some national occupational air exposure limits used in various
              countries a 

                                                                                 

    Country/       Exposure limit description b               Value     Effective
    organization                                             (mg/m3)   date
                                                                                 

    Australia      Recommended threshold limit value (TLV)
                   - Time-weighted average (TWA)              205      1985(r)
                   - Short-term exposure limit (STEL)         300

    Belgium        Recommended threshold limit value (TLV)
                   - Time-weighted average (TWA)              205      1988(r)
                   - Short-term exposure limit (STEL)         300

    Finland        Occupational exposure limit (MPC)
                   - Time-weighted average (TWA)              210      1987
                   - Short-term exposure limit (STEL)         315
                   - Ceiling value (CLV)                      300

                                                                                 

    Table 2 (contd).

                                                                                 

    Country/       Exposure limit description b               Value     Effective
    organization                                             (mg/m3)   date
                                                                                 

    Germany,       Recommended threshold limit value (MAK)
    Federal        - Time-weighted average (TWA)              400      1988(r)
    Republic of    - Short-term exposure limit (STEL)        2000

    Japan          Administrative concentration
                   - Time-weghted average (TWA)               205      1990(n)

    Netherlands    Recommended threshold limit value (MXL)
                   - Time-weighted average (TWA)              240      1989(r)

    Poland         Permissible exposure limit (MPC)
                   - Time-weighted average (TWA)              200      1982(r)

    Romania        Permissible exposure limit (MPC)
                   - Time-weighted average (TWA)              200      1984(r)
                                                                     
    Switzerland    Permissible exposure limit (MAK)
                   - Time-weighted average (TWA)              205      1987(r)

    Sweden         Permissible exposure limit (HLV)
                   - Time-weighted average (TWA)              100      1990(n)
                   - Short-term exposure limit (STEL)         200

    United         Occupational exposure standard (OES)
    Kingdom        - Time-weighted average (TWA)              205      1990(n)
                   - Short-term exposure limit (STEL)         300

    USA (ACGIH)    Recommended threshold limit value (TLV)
                   - Time-weighted average (TWA)              205      1987(r)
                   - Short-term exposure limit (STEL)         300
        (OSHA)     Permissible exposure limit (PEL)
                   - Time-weighted average (TWA)              205      1990(n)
                   - Short-term exposure limit (STEL)         300

    USSR           Temporary exposure limit (TSEL)
                   - Ceiling value (CLV)                        5      1989

    Yugoslavia     Permissible exposure limit (MAC)
                   - Time-weighted average (TWA)              410      1971(r)
                                                                                 

    Table 2 (contd).

    a    From IRPTC, 1990
    b    TWA = a maximum mean exposure limit based generally over the period of a working day.
         STEL = a maximum concerntration of exposure for a specified time duration (generally 10-30 min.)
    (n) = directly notified by countries
    Where no effective date appears in the IRPTC legal file, the year of the reference from which the data
    are taken is shown, indicated by (r).
    
    6.  KINETICS AND METABOLISM

    6.1  Experimental animals

        Following the intraperitoneal (ip) injection of 450 mg MIBK/kg
    body weight to guinea-pigs, two metabolites were found in the serum
    (DiVincenzo et al., 1976). The major metabolite,
    4-hydroxy-4-methyl-2-pentanone (HMP), was formed by oxidation of
    MIBK, while a minor metabolite, 4-methyl-2-pentanol, was formed by
    reduction of MIBK (Fig. 1). The serum half-life and total clearance
    time for parent MIBK were calculated as 66 min and 6 h,
    respectively, whereas 4-hydroxy-4-methyl-2-pentanone (HMP) was
    cleared in 16 h. The hydroxylation products of MIBK, such as
    4-methyl-2-pentanol, are expected either to be conjugated with
    sulfate or glucuronic acid and excreted in the urine or to enter
    intermediary metabolism to be converted to carbon dioxide.

    FIGURE 1

        HMP and 4-methyl-2-pentanone have also been identified in rats
    (Pilon, 1987). MIBK increased aniline hydroxylase activity and
    cytochrome P-450 concentration in chicken liver microsomes after
    inhalation (4100 mg/m3, 1000 ppm, for 50 days) (Abou-Donia et
    al., 1985b). The induction by MIBK was apparently of similar
    capacity to that of methyl  n -butyl ketone (Abou-Donia et al.,
    1985a). It is likely that MIBK can induce its own oxidative
    metabolism as well as that of other substances. The study of

    Malyscheva (1988) (section 8.2.4) suggested that MIBK is absorbed
    through the skin as well as via the oral and inhalation routes
    (section 8.1). A comparison of intraperitoneal and oral LD50
    values (Zakhari et al., 1977) suggests an oral absorption of 30% or
    more. Malyscheva (1988) showed dermal absorption followed by
    extensive distribution (toxic signs in many organs). Likewise,
    inhalation studies producing liver and kidney changes are
    suggestive of extensive distribution (MacEwen et al., 1971; Vernot
    et al., 1971).

        The structure of MIBK precludes the metabolic production of
    2,5-hexane-dione, the neurotoxic agent formed from both hexane and
    methyl  n -butyl ketone.

    6.1.1  Effect on liver alcohol dehydrogenase in vitro

        MIBK in  N,N -dimethylacetamide has been shown to reduce the
    activity of mouse liver alcohol dehydrogenase  in vitro 
    (Cunningham et al., 1989).

    6.2  Humans

        MIBK and other substituted 2-pentanones have been reported in
    urine samples from unexposed humans (Zlatkis & Liebich, 1971). MIBK
    was detected in various tissues and body fluids (section 2.4.1.3)
    of two individuals who suffered fatal exposure to a mixture of
    organic solvents. The concentration range of MIBK in the tissues
    and body fluids of the two decedents was 1.4-2.5 and 0.2-0.8 mg/kg,
    respectively. The tissue distribution differed markedly between the
    two individuals (Bellanca et al., 1982). The inhalation study
    carried out by Dick et al. (1990) with human volunteers suggested
    that exposures to 410 mg MIBK/m3 (100 ppm) for 4 h causes steady
    state blood levels to be attained. Blood and breath samples
    collected 90 min after exposure indicated essentially complete
    clearance of the absorbed MIBK. Hjelm et al. (1990) exposed human
    volunteers for 2 h during light physical excercise to MIBK (10,
    100, and 200 mg/m3; 2.4, 24.4, and 48.8 ppm). The concentration
    of MIBK in blood rose rapidly after the onset of exposure, during
    which no plateau level was reached. No tendency towards saturation
    kinetics was observed over the dose range, the apparent blood
    clearance being 1.6 litres/h per kg throughout. Only 0.04% of the
    total MIBK dose was eliminated unchanged via the kidneys within 3
    h after exposure.

    7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

        Toxicity data reported in this chapter should be interpreted
    with caution, since the tests were conducted under static
    conditions using nominal rather than measured concentrations.
    Actual concentrations experienced by the test organisms cannot be
    determined for these tests.

    7.1  Microorganisms

        MIBK has low toxicity for microorganisms as indicated by the
    threshold concentrations required for inhibition of growth (Table
    3).

    Table 3.  Toxicity of MIBK for microorganisms

                                                                                      

    Species                 Threshold           Duration of   Reference
                            concentration for      study
                            growth inhibition
                            (mg/litre)
                                                                                      

    Protozoa

      Saprozoic                  > 800             48 h       Bringmann & Kühn (1981)
      flagellate
       (Chilomonas
       paramaecium)

      Bacteriovorous               450             72 h       Bringmann & Kühn (1981)
      flagellate
       (Entosiphon
       sulcatum)

      Bacteriovorous               950             20 h       Bringmann & Kühn (1981)
      ciliate ( Uronema
       parduczi)

    Bacterium

       Pseudomonas putida          275             16 h       Bringmann & Kühn (1977b)
                                                                                      
    
    Table 4.  Acute toxicity of MIBK for aquatic organisms

                                                                                     

    Species                       LC50       Duration            Reference
                                  (mg/litre) of study
                                                                                     

    Freshwater fish

      Golden orfe                 672-744      48 h         Juhnke & Lüdemann (1978)
       (Leuciscus idus
        melanotus)

      Goldfish                      460        24 h         Bridié et al. (1979b)
       (Carassius auratus)
      Fathead minnow        approx. 525        96 h         Call et al. (1985)
       (Pimephales promelas)

    Invertebrates

       Freshwater

      Water flea                   4280        24 h         Bringmann & Kühn (1977a)
       (Daphnia magna)             1550        24 h         Bringmann & Kühn (1982)

       Marine

      Brine shrimp                 1230        24 h         Price et al. (1974)
       (Artemia salina)

    Freshwater algae

      Green algae                   725 a       8 days       Bringmann & Kühn (1977b)
       (Scenedesmus
        quadricauda)

      Bluegreen algae               136 a       8 days       Bringmann & Kühn (1978)
       (Microcystis
        aeruginosa)
                                                                                      

    a  Threshold concentration for reduction of total biomass

    7.2  Aquatic organisms

        MIBK appears to have low toxicity for aquatic organisms (Table
    4). The maximum zero lethality concentration (LC0) is in the
    range of 480-720 mg/litre (Juhnke & Lüdemann, 1978). Using a QSAR
    model, Lipnick et al. (1987) showed that the 24-h LC50 of 460
    mg/litre reported by Bridié et al. (1979a) in goldfish  (Carassius
    auratus)  fitted a narcotic mechanism of action.

        Aquatic invertebrates are less sensitive than fish to the
    toxicity of MIBK, 24-h LC50 values of 4280 mg/litre (Bringmann &
    Kuhn, 1977a) and 1550 mg/litre (Bringmann & Kuhn, 1982) having been
    reported for the water flea  Daphnia magna  and 1230 mg/litre for
    the brine shrimp  Artemia salina  (Price et al., 1974). The
    LC100 and LC0 values for  Daphnia magna  were 5000 and 2280
    mg/litre, respectively (Bringmann & Kuhn, 1977a).

        The toxicity of MIBK was also measured in the green alga
     Scenedesmus quadricauda , in which the 8-day threshold for
    toxicity was 725 mg/litre (Bringmann & Kuhn, 1977b), and in the
    relatively more sensitive cyanobacterium (blue-green alga)
     Microcystis aeruginosa , in which the toxicity threshold was 136
    mg/litre (Bringmann & Kuhn, 1978).

    7.3  Terrestrial organisms

        Experimental data are not available.

    8.  EFFECTS ON EXPERIMENTAL ANIMALS AND IN VITRO TEST SYSTEMS

    8.1  Single exposures

        MIBK is of low acute toxicity by the oral and inhalation routes
    of exposure (Table 5).

        The maximum time for which rats could be exposed to a saturated
    atmosphere of MIBK without dying was 15 min (Smyth et al., 1951).
    In one study, six rats survived a 4-h exposure to 8200 mg MIBK/m3
    (2000 ppm), but, following a 4-h exposure to 16 400 mg/m3 (4000
    ppm), all six animals died within 14 days.

        In studies by Specht (1938) and Specht et al. (1940), female
    guinea-pigs were exposed to MIBK concentrations of 4100, 69 000,
    and 115 000 mg/m3 (1000, 16 800, and 28 000 ppm, respectively)
    for up to 24 h. In view of the method used for generating the
    atmosphere (allowing measured amounts of MIBK to evaporate freely
    to one cubic meter volume of air at 25-26 °C), the two higher
    levels must be greatly exaggerated because the saturation
    concentration in air for MIBK at 25 °C is 40 000 mg/m3. At 4100
    mg/m3 there was minimal eye or nasal irritation. However, there
    was a decreased respiratory rate during the first 6 h of exposure,
    which was attributed to a narcotic effect. The higher levels
    produced obvious signs of eye and nose irritation, followed by
    salivation, lacrimation, ataxia, progressive narcosis, and death.
    The highest level killed 50% of the animals within 45 min. Autopsy
    and histopathological investigations in some animals showed fatty
    livers and congestion of the brain, lungs, and spleen, but no
    damage to the heart and kidneys was observed.

        A single ip injection of 500 mg MIBK/kg body weight in
    guinea-pigs did not induce changes in the serum ornithine-carbamyl
    transferase level, and there were no histopathological changes in
    the liver. However, an injection of 1000 mg/kg body weight killed
    one out of four animals, and a slight increase in the serum
    ornithine-carbamyl transferase level was seen in the survivors 24
    h after dosing. Histopathologically, there was possible lipid
    accumulation in liver cells but no evidence of liver damage
    (Divincenzo & Krasavage, 1974). It should be noted that an ip
    injection of 560 mg/kg produced minimal effects in rats (Vezina et
    al., 1985), suggesting that mice are more sensitive than rats (the
    ip LD50 is 590 mg/kg in mice, see Table 5).


        Table 5.  LD50 and LC50 values for MIBK in rats and mice

                                                                                                                     

    Route of                 Species  Duration         LD50 or LC50         Reference
    exposure                          of exposure
                                                                                                                     

    Oral (LD50)              rat                   4570 mg/kg body weight  Smyth et al. (1951)

                             rat                   4600 mg/kg body weight  Batyrova (1973)

                             rat                   2080 mg/kg body weight  RTECS (1987)

                             mouse                 2850 mg/kg body weight  Batyrova (1973)

                             mouse                 1900 mg/kg body weight  Zakhari et al. (1977)

    Intraperitoneal (LD50)   mouse                 590 mg/kg body weight   Zakhari et al. (1977)

    Inhalation (LC50)        rat        4 h        8.2-16.4 g/m3           Smyth et al. (1951); Smyth (1956)

                             mouse      2 h        20.5 g/m3               Batyrova (1973)

                             mouse      45 mins    74.2 g/m3               Zakhari et al. (1977)
                                                   (18 105 ppm)

                                                                                                                     
    
        In male Sprague-Dawley rats, a single oral dose of MIBK
    enhanced the hepatotoxicity of a single ip dose of chloroform given
    24 h later. The no-observed-effect and minimal-effect levels of
    MIBK were 375 and 560 mg/kg body weight, respectively (Vezina et
    al., 1985). The ketone potentiation of haloalkane-induced
    hepatonecrosis has been attributed to enhanced bioactivation of the
    haloalkane, which is mediated by the increased cytochrome P-450
    activity induced by the ketone (Branchflower et al., 1983). The
    extent of potentiation of carbon tetrachloride liver toxicity (as
    shown by an increase in plasma alanine transaminase activity and
    bilirubin concentration) was found to depend on the concentration
    of both MIBK and carbon tetrachloride in male rats. The minimum
    effective MIBK dose decreased 10-fold when the carbon tetrachloride
    dose was increased from 0.01 ml/kg to 0.1 ml/kg. These findings
    suggest that liver injury is determined by the product of MIBK and
    carbon tetrachloride doses (Pilon et al., 1988). Attention should
    be paid to this when working in environments containing mixtures of
    solvents.

    8.2  Short-term exposure

    8.2.1  Inhalation

        In rats exposed to 410 mg/m3 (100 ppm) for 2 weeks, there was
    an increase in kidney weight. An increase in both liver and kidney
    weights was observed after exposure to 820 mg/m3 (200 ppm) for 2
    weeks or 410 mg/m3 (100 ppm) for 90 days. Histopathological
    investigations showed hyaline droplets in the proximal tubules of
    the kidney and this finding was named hyaline droplet toxic tubular
    nephrosis (MacEwen et al., 1971; Vernot et al., 1971). In rats,
    dogs, and monkeys exposed continuously for 90 days to MIBK at 410
    mg/m3 (100 ppm) under reduced oxygen tension and reduced
    atmospheric pressure (65% oxygen at 34.7 k Pa), liver and kidney
    weights were increased in rats after 90 days. Hyaline droplets were
    observed in rat kidney epithelium after 15 days, but this effect
    was reversible after a 3- to 4-week recovery period. No
    histopathological changes were reported in monkeys or dogs and no
    sex differences were reported for any parameter (MacEwen et al.,
    1971).

        Four groups of six male and six female F-344 rats and six male
    and six female B6C3F1 mice were exposed to 0, 44, 2050, or 8180
    mg MIBK/m3 (0, 10.1, 501, or 1996 ppm, respectively) for 6 h/day
    (for 5 days with 2 days off followed by 4 more consecutive days of
    exposure) (Dodd et al., 1982; Phillips et al., 1987). Lacrimation
    was observed in the highest dose group, but no ophthalmological
    lesions or alterations in body weight gain were found. Liver
    weight, expressed as a percentage of body weight, was increased in
    male and female rats and in female mice exposed to 8180 mg/m3. A
    statistically significant increase in liver weight was also
    observed in male rats exposed to 2050 mg/m3. Male and female rats
    and female mice showed a significant increase in both absolute and

    relative kidney weights when exposed to 8180 mg/m3. However, male
    mice at this exposure level exhibited a significant decrease in
    relative kidney weight. Of the animals exposed to 2050 mg/m3,
    only male rats exhibited an increase in kidney weight, but this was
    not statistically significantly different from the control value.
    Hyaline droplet formation was seen in the kidneys of male rats
    exposed to 2050 and 8180 mg/m3. Epithelial regeneration of the
    proximal convoluted tubules was also seen at 8180 mg/m3. There
    were no histopathological abnormalities in rats and mice exposed to
    414 mg/m3, and this concentration was considered a clear
    no-observed-adverse-effect level (Dodd et al., 1982). In a
    subsequent study, four groups of 14 male and 14 female F-344 rats
    and 14 male and 14 female B6C3F1 mice were exposed to 0, 205,
    1025, or 4100 mg MIBK/m3 (0, 50, 250, or 1000 ppm, respectively)
    for 6 h/day (5 days/week for 90 days). No growth retardation or
    clinical effects were observed in either rats or mice. Clinical
    observations were made in addition to measurements of body and
    organ weights (heart, kidneys, liver, lungs, and testes).
    Haematology, ophthalmology, gross pathology, and histology were
    also investigated and, in rats, water consumption and urine and
    serum chemistry analyses were made. Male rats and mice exposed to
    4100 mg/m3 (1000 ppm) showed a slight increase in liver weight
    (approximately 11%) and in liver weight per body weight ratio, and
    liver weight was also slightly increased in male mice exposed to
    1025 mg/m3 (250 ppm). However, neither gross nor microscopic
    hepatic lesions were observed, and urinalysis and serum chemistry
    values were normal. In male rats exposed to 1025-4100 mg/m3
    (250-1000 ppm), there was an increase in the number of hyaline
    droplets within the proximal tubular cells of the kidney. No other
    gross or microscopic renal changes were observed (Dodd & Eisler,
    1983; Phillips et al., 1987). It was considered that the hyaline
    droplet effects produced by MIBK may be specific to the male rat
    due to the presence of alpha-2-µglobulin (Phillips et al., 1987).

        In studies by Brondeau et al. (1989), groups of five hens were
    continuously exposed for 50 days by inhalation to either 4100 mg
    MIBK/m3 (1000 ppm) or 3520 mg  n -hexane/m3 (1000 ppm) or for
    30 days to a mixture of 4100 mg MIBK/m3 and 3520 mg  n
    -hexane/m3. Inhalation of  n -hexane alone had no effect on
    hepatic microsomal enzymes, but inhalation of MIBK or the MIBK/ n
    -hexane mixture increased significantly the aniline hydroxylase
    activity and cytochrome P-450 content of the liver (Abou-Donia et
    al., 1985b). Inhalation of 2440 to 12 400 mg MIBK/m3 (595 to 3020
    ppm) in rats produced enhancement of the liver cytochrome P-450
    content and glutathione- S -transferase activity and also enhanced
    the ability of 1,2-dichlorobenzene to increase serum glutamate
    dehydrogenase activity.

        Experiments in open-chest cats demonstrated that significant
    pulmonary hypertension and vasoconstriction, with reduced pulmonary
    arterial flow, occurred as a result of MIBK inhalation for 5 min at
    all concentrations tested (410 to 41 000 mg/m3 (100 to 10 000

    ppm)). Systemic arterial pressure and vascular resistance were not
    significantly affected (Zakhari et al., 1977). Broncho-constriction
    was also produced by MIBK inhalation for 5 min, the effect being
    statistically significant at concentrations at or above 2050
    mg/m3 (500 ppm) or 4100 mg/m3 (1000 ppm) for pulmonary
    resistance or transpulmonary pressure, respectively. Adult mongrel
    dogs with open-chest surgery showed pulmonary hypertension at an
    inhalation concentration of 20.5 mg MIBK/m3 (5 ppm) for 5 min. At
    41 mg/m3 (10 ppm), myocardial contractility occurred (Zakhari et
    al., 1977).

    8.2.2  Oral

        Three daily doses of 375 or 1500 mg MIBK/kg body weight given
    by gavage to rats reduced the bile flow produced by an intravenous
    injection of taurocholate (20 mg per kg body weight) (Plaa &
    Ayotte, 1985). The effect of MIBK on the cholestatic activity of
    manganese, with or without bilirubin, has also been investigated in
    male Sprague-Dawley rats. MIBK was administered by gavage in corn
    oil at doses ranging from 188 to 1502 mg/kg body weight once a day
    for 1, 3, or 7 days (Vezina et al., 1985; Vezina and Plaa, 1987).
    MIBK was not cholestatic but, at doses of 375 mg/kg or more, was
    found to potentiate the cholestasis induced by a
    manganese-bilirubin combination when this was given 18 h after the
    1-day treatment with MIBK. When given for 3 or 7 days, MIBK
    produced a dose-related enhancement of the cholestasis induced by
    a manganese-bilirubin combination. A 3-day treatment with MIBK (750
    mg/kg) was also shown to potentiate the cholestasis induced by
    manganese alone. Two known metabolites of MIBK (HMP and
    4-methyl-2-pentanol) were also able to potentiate the cholestatic
    effect of the manganese-bilirubin combination or of manganese alone
    in male Sprague-Dawley rats. When the metabolite was given by
    gavage 18 h prior to the administration of the manganese-bilirubin
    combination, cholestasis was potentiated by 375 mg/kg or 1502 mg/kg
    (expressed as equivalents of MIBK) of 4-methyl-2-pentanol or HMP,
    respectively. Lower doses did not decrease bile flow rate.
    4-Methyl-2-pentanol was also more effective than HMP as a
    potentiator following daily treatment for 3 days prior to
    manganese-bilirubin administration. However, with manganese alone,
    HMP was more effective. It was suggested that the potentiation of
    cholestasis may be associated with metabolic induction or might
    reflect a separate mechanism of action involving a membrane
    interaction (Vezina & Plaa, 1988).

        The toxic effects of MIBK in Sprague-Dawley rats (groups of 30
    animals of each sex) were examined following 13 weeks of oral
    gavage administration at levels of 0, 59, 250, or 1000 mg/kg daily.
    Body weight, food consumption, organ weight, morbidity, clinical
    chemistry, haematology, and histopathology evaluations were
    performed. All surviving animals were killed after 90 days (13
    weeks) and 10 animals of each sex per group were examined.
    Nephrotoxicity was seen as a general nephropathy for both male and

    female rats administered 1000 mg/kg per day. Although increased
    liver and kidney weights were observed for males and females at
    1000 mg/kg per day, there were no corresponding histopathological
    lesions present in the liver. The effects seen at 1000 mg/kg per
    day were present to a significantly lesser extent in the females
    and males fed 250 mg/kg per day. No effects were observed at 50
    mg/kg per day, identifying a no-observed-effect level
    (Microbiological Associates, 1986).

    8.2.3  Parenteral

        In studies by Krasavage et al. (1982), rats (strain and number
    not specified) were given intraperitoneal injections of MIBK or a
    mixture of methyl ethyl ketone (MEK) and MIBK (9:1 by volume), 5
    times/week, for 35 weeks. The dose levels for the first 2 weeks
    were 10, 30, and 100 mg per kg body weight, and these were then
    doubled for the remainder of the treatment period. Body weight gain
    suppression was seen after 3-4 weeks of treatment. The only other
    effect noted was transient narcosis during the first 4 weeks at the
    highest dose. Pulmonary vascular effects were observed following an
    intraperitoneal administration of MIBK to cats (threshold dose 8
    mg/kg), but bronchoconstriction was not seen following an
    intraperitoneal administration of 4-32 mg/kg (Zakhari et al.,
    1977).

    8.2.4  Skin application

        In rats exposed dermally to 300-600 mg MIBK/kg per day for 4
    months, dose- and time-dependent morphological changes were
    observed in the skin, brain, liver, adrenals, spleen, and testis.
    Body temperature decreased and oxygen consumption increased
    (Malyscheva, 1988).

    8.3  Skin, eye, and respiratory irritation; sensitization

    8.3.1  Skin irritation

        A single 10-h occluded application of MIBK to the shaved skin
    of rabbits produced erythema, which occurred immediately after the
    application and persisted for up to 24 h. Daily applications of 10
    ml on 10 cm2 skin for 7 days caused drying and flaking of the
    surface (Krasavage et al., 1982).

    8.3.2  Eye irritation

        Undiluted MIBK (0.1 ml) produced some irritation within 10 min
    when instilled in the rabbit eye. Inflammation and conjunctival
    swelling occurred within 8 h; the inflammation, swelling, and
    exudate present at 24 h had disappeared by 60 h (Krasavage et al.,
    1982).

    8.3.3  Respiratory irritation

        De Ceaurriz et al. (1981) measured the reflex decrease in
    respiratory rate in male Swiss OF1 mice as an index of sensory
    irritation. MIBK caused a concentration-dependent decrease in
    respiratory rate during a 5-min exposure, and a 50% decrease in
    respiratory rate (RD50) was seen at 13 100 mg/m3 (3195 ppm).
    Specht et al. (1940) attributed the decreased respiratory rate to
    a narcotic effect. It should be recognized that the reduction may
    not be due to sensory irritation.

    8.3.4  Skin sensitization

        There are no reports of skin sensitization studies.

    8.4  Long-term exposure

        No long-term toxicity studies have been reported.

    8.5  Reproduction, embryotoxicity, and teratogenicity

        In studies by Tyl (1984) and Tyl et al. (1987), groups of 35
    pregnant Fischer-344 rats and 30 pregnant CD-1 mice were exposed to
    1230, 4100, or 12 300 mg MIBK/m3 (300, 1000, or 3000 ppm) on days
    6-15 (inclusive) of gestation. The animals were sacrificed on days
    21 (rats) or 18 (mice) and fetuses examined for external, visceral,
    and skeletal alterations. In rats, exposure to 12 300 mg/m3
    resulted in maternal toxicity with decreased body weight gain,
    increased relative kidney weight, decreased food consumption, and
    fetotoxicity (reduced fetal body weight per litter and delays in
    skeletal ossification). Clinical signs in dams included loss of
    coordination, negative toe pinch, paresis, muscular weakness,
    piloerection, lacrimation, and perioral encrustation. No increase
    in fetal malformation was observed in any group. At 1230 and 4100
    mg/m3, there was no maternal, embryo, or fetal toxicity, or
    malformations. However, reduced fetal body weight and delay in some
    ossification parameters were observed at the lowest dose but not at
    the intermediate dose level. These effects were attributed to the
    larger litter size (average 10.8) in this group compared to that in
    controls (9.5).

        In mice, exposure to 12 300 mg/m3 produced maternal toxicity
    with increased mortality (3/25), increased absolute and relative
    liver weights, and fetotoxicity (increased incidence of dead
    fetuses, reduced fetal body weight per litter, and delayed or
    reduced ossification). Clinical signs in dams included irregular
    gait, paresis, hypoactivity, ataxia, negative toe pinch, and
    lacrimation. There was no treatment-related increase in
    embryotoxicity or fetal malformations at any exposure concentration
    tested. No significant treatment-related maternal, embryo, or fetal
    toxicity (including malformations) was observed at 1230 or 4100
    mg/m3.

    Table 6.  Mutagenicity and related end-points

                                                                                       

          System                    Dose                    Response     Reference

                                                                                       
    Bacterial Assays

    Salmonella typhimurium a         0.04-4 µg/plate         negative     Chemical
    strains TA98, TA100,                                                 Manufacturers
    TA1537, TA1538                                                       Association
                                                                         (1984);
                                                                         O'Donoghue et
                                                                         al. (1988)

    Salmonella typhimurium a 
    strains TA1535, TA1537          Up to 8000 µg/ml        negative     Brooks et al.
    TA1538, TA98, TA100                                                  (1988)

     Eschericia coli 
    strains WP2 and                 Up to 8000 µg/ml        negative     Brooks et al.
    WP2  uvr  A                                                           (1988)

    Yeast Assays

     Saccharomyces cerevisiae JDI   Up to 5 mg/ml          negative     Brooks et al.
    mitotic gene conversion                                              (1988)
    assay ± rat liver S9

    Mammalian cell assays in vitro :

    L51784 TK +/- mouse             0.001-100 µl/ml         negative     Chemical
    lymphoma mutation assay         (preliminary assay)                  Manufacturers
    (± rat liver S9)                0.4-6 µl/ml             negative     Association
                                                                         (1984);
                                                                         O'Donoghue et
                                                                         al. (1988)
    Primary rat hepatocytes;        0.01-100 µl/ml          negative     Chemical
    unscheduled DNA synthesis                                            Manufacturers
    (DNA repair)                                                         Association
                                                                         (1984);
                                                                         O'Donoghue et
                                                                         al. (1988)

    Cultured rat liver cells        Up to 1000 µl/ml        negative     Brooks et al.
    chromosomal damage assay        (half the dose for                   (1988)
    RL4 cells                       50% inhibition of
                                    cell growth)

                                                                                       

    Table 6 (contd).
                                                                                       

          System                    Dose                    Response     Reference
                                                                                       

    Balb/3T3; cell transformation   2-5 µl/ml (-S9)         inconclusive Chemical
    assay ± rat liver S9            1-7 µl/ml (+S9)                      Manufacturers
                                                                         Association
                                                                         (1984);
                                                                         O'Donoghue et
                                                                         al. (1988)

    Mammalian in vivo assay

    Mouse (male and female)         0.73 ml/kg ip           negative     Chemical
    micronucleus assay              (maximum tolerated                   Manufacturers
    (polychromatic                  dose level)                          Association
    erythrocytes)                                                        (1984);
                                                                         O'Donoghue et
                                                                         al. (1988).

                                                                                       

    a   Preincubation mutation assay incorporating Arochlor-induced rat liver S9


    8.6  Mutagenicity and related end-points

        A summary of the reported data on MIBK mutagenicity is given
    in Table 6.

    8.6.1  Bacterial assays

        A pre-incubation assay with Salmonella typhimurium (strains
    TA98, TA100, TA1537, TAl538) was conducted at dose levels of 0.04
    to 4 µg/plate both in the presence and absence of a metabolic
    activation system prepared from Aroclor-induced rat liver
    homogenate (S9 fraction). Precautions were taken to prevent the 
    escape of MIBK vapour and assure prolonged exposure of the bacteria 
    to the test substance. MIBK did not cause an increase in reverse gene 
    mutation (Chemical Manufacturers Association 1984; O'Donoghue et 
    al., 1988).

        Both MIBK and the oxidative metabolite 4-hydroxy-4-methyl-2-
    pentanone (HMP) (see section 6.1) were tested for mutagenicity in
    Salmonella typhimurium strains TA98, TA100, TA1535, TA1537, and
    TA1538, and in  Eschericia coli  strains WP2 and WP2  uvr  A
    (Brooks et al., 1988). Aroclor-induced rat liver S9 fraction was
    included. No induction of reverse gene mutation was observed up to

    a maximum concentration of 8000 µg MIBK/ml (pre-incubation assay in
    a sealed container) or 4000 µg HMP/plate (plate incorporation
    assay).

    8.6.2  Yeast assay for mitotic gene conversions

        MIBK and the metabolite HMP were assayed for mitotic gene
    conversion using log-phase cultures of the yeast  Saccharomyces
    cerevisiae  JD1 (Brooks et al., 1988). Compounds were tested up to
    a concentration of 5 mg/ml in the presence and absence of rat liver
    S9 fraction in a sealed container for 18 h. Neither compound
    induced mitotic gene conversion.

    8.6.3  L5178Y TK+/- mouse lymphoma assay

        A preliminary assay was carried out in the presence and absence
    of a metabolic activation system at doses of 0.001-100 µl/ml. The
    non-activated cultures showed 3 to 157% total relative growth,
    while the cultures containing the rat liver S9 fraction had a
    relative growth of 23-95% compared with untreated control cultures.
    No increase in mutation frequencies was observed in cultures
    containing the metabolic activation system, but in the
    non-activated cultures, a 2-fold increase above controls was seen
    at two non-consecutive doses. An increase in mutation frequency of
    approximately 5 times the concurrent control occurred at one test
    concentration, but this concentration also caused 97% cell death.
    In the absence of a dose-related effect, this result was considered
    equivocal. A repeat assay was performed using duplicate cultures
    and a narrower range of doses (0.4-6 µl/ml). The total relative
    growth ranged from 1 to 80% in non-metabolically activated cells
    and from 28 to 63% in cultures that contained the S9 fraction. None
    of the activated cultures revealed increased mutation frequencies.
    A borderline positive result was found at 6 µl/ml, but different
    mutation frequencies occurred in the duplicate cultures and 96-99%
    of the cells were killed (Chemical Manufacturers Association, 1984;
    O'Donoghue et al., 1988).

    8.6.4  Unscheduled DNA synthesis in primary rat hepatocytes in vitro

        When MIBK was tested at five dose levels ranging from 0.01
    µl/ml to 100 µl/ml in a single assay, there was an increase of less
    than 5 fold in labelled nuclear grains in cells treated with MIBK
    compared with cells of the solvent control plates (Chemical
    Manufacturers Association, 1984; O'Donoghue et al., 1988). Since
    the value did not exceed that of the negative control by two
    standard deviations of the control value, it was considered that,
    under the conditions tested, MIBK did not cause a significant
    increase in the nuclear grain count.

    8.6.5  Mouse micronucleus assay

        Male and female mice were administered MIBK by ip injection at
    the maximum tolerated dose level of 0.73 ml/kg body weight, and
    bone marrow polychromatic erythrocytes were estimated 12, 24, and
    48 h later. There were no significant differences between the
    treated and control animals in the ratio of polychromatic to
    normochromatic erythrocytes. The number of micronucleated
    polychromatic erythrocytes per 1000 cells was not significantly
    increased in the MIBK-treated animals (Chemical Manufacturers
    Association, 1984; O'Donoghue et al., 1988).

    8.6.6  Assay for structural chromosome damage

        MIBK (purity > 98.5%) and the metabolite HMP were tested (24-h
    exposure) in cultured rat liver cells (RL4) for the ability to
    induce chromosomal damage. Metabolic activation with S9 mix was not
    used because RL4 cells are metabolically competent. The
    concentrations of MIBK employed were 0.125, 0.25, and 0.5 times the
    concentration required for 50% inhibition of cell growth. Maximum
    concentrations tested were thus 1000 µg MIBK/ml and 4000µg HMP/ml
    (this HMP level was equivalent to the concentration required for
    >60% growth inhibition). Incubations with MIBK were sealed to
    prevent loss by evaporation. MIBK did not produce chromosomal
    damage, but HMP gave a small increase (which was not dose related)
    in chromatid damage within the concentration range 2000-4000 µg/ml.
    It should be noted that HMP did not induce reverse gene mutation in
    bacteria or mitotic gene conversion in yeast (Brooks et al., 1988).

    8.6.7  Cell transformation assay

        In studies reported by the Chemical Manufacturers Association
    (1984) and O'Donoghue et al. (1988), MIBK was tested in the
    Balb/3T3 (clone A31-1) morphological transformation assay. Doses of
    2.4, 3.6, and 4.8 µl MIBK/ml were added to the culture medium in
    the absence of a metabolic activation system, and 1, 2, and 4 µl
    MIBK/ml were added in the presence of such a system (Aroclorinduced
    rat liver S9 fraction). MIBK produced a positive response in the
    non-activated cultures only (4.8 µl MIBK per ml gave 3 type III
    foci in 15 dishes). A confirmatory study was conducted with doses
    of 2, 3, 4, and 5 µl/ml and 4, 5, 6, and 7 µl/ml, respectively, in
    the presence and absence of S9 fraction. No significant increase in
    the number of transformed foci was found in this study, either in
    the presence or absence of the metabolic activation system. Thus,
    the effect of MIBK on cell transformation was not reproducible in
    the two assays and the ambiguity of the results makes them
    unreliable.

    8.7  Carcinogenicity

        No carcinogenicity studies have been reported.

    8.8  Neurotoxicity

        In a study by Krasavage et al. (1982), rats were given ip
    injections of MIBK, or a mixture of methyl ethyl ketone and MIBK
    (9:1 by volume), 5 times/week, for 35 weeks. The dose levels of 10,
    30, and 100 mg/kg body weight were doubled after 2 weeks of
    treatment. Transient anaesthesia was noted during the first 4 weeks
    in the highest dose group, but there was no evidence of peripheral
    neuropathy. In dogs administered 300 mg MIBK/kg body weight per day
    subcutaneously (sc) for 11 months, electromyographic examination
    showed no evidence of neurotoxicity.

        Cats treated subcutaneously with 150 mg MIBK/kg body weight per
    day or a mixture of methyl ethyl ketone/MIBK (9:1) twice daily, 5
    times/week, for up to 8.5 months showed no evidence of nervous
    system damage (Spencer & Schaumburg, 1976). In beagle dogs
    receiving similar treatment, there were no neurotoxic changes
    (Krasavage et al., 1982).

        Groups of male rats were exposed to 5330 mg/m3 (1300 ppm)
    methyl  n -butyl ketone for 4 months or 6150 mg/m3 (1500 ppm)
    MIBK for 5 months (Spencer et al., 1975). Methyl  n -butyl ketone
    produced a toxic distal axonopathy. MIBK produced minimal distal
    axonal changes, but 3% methyl  n -butyl ketone was present as a
    contaminant in the MIBK, and the design of the cages used may have
    caused compression neuropathy (Spencer et al., 1975; Spencer &
    Schaumburg, 1976). Animals exposed to MIBK showed slight signs of
    narcosis, but body weight gain was normal, and, at 5 months, there
    were no clinical signs of neurological dysfunction. Rats exposed
    for 3 h to 102 mg MIBK/m3 (25 ppm) showed a 58% increase in
    pressor lever response, which had not returned to control levels 7
    days after the end of exposure (Geller et al., 1978). The maximum
    motor-fibre conduction velocity in the tail nerve decreased
    markedly when male rats were treated with methyl  n -butyl ketone
    (401 mg/kg, 5 times/week for 55 weeks) but not when they were
    treated with MIBK (601 mg/kg, 5 times/week for 55 weeks). However,
    treatment with MIBK (201 mg/kg) facilitated the neurotoxic effect
    of methyl  n -butyl ketone (401 mg/kg) possibly due to the
    demonstrated ability of MIBK to increase the metabolic activity of
    10 000 g liver supernatants towards both MIBK and methyl  n -butyl
    ketone (Nagano et al., 1988).

        Discriminatory behaviour and memory in baboons was not affected
    by exposures of 82-164 mg/m3 (20-40 ppm) (Geller et al., 1978).
    Geller et al. (1979) reported an effect on accuracy of performance
    of tasks in a ``delayed match-to-sample discrimination-test'' in
    baboons exposed for 7 days to 205 mg/m3 (50 ppm) MIBK, but there
    was no change in response when MIBK was combined with methyl ethyl
    ketone at 295 mg/m3 (100 ppm).

        De Ceaurriz et al. (1984) exposed male Swiss OF1 mice to an
    atmosphere containing MIBK and measured the total duration of
    immobility during a 3-min ``behavioural despair'' swimming test. At
    concentrations of 2714, 3104, 3309, and 3657 mg/m3 (662, 757,
    807, and 892 ppm), a dose-dependent decrease of mobility was
    observed (25, 38, 46, and 70% respectively). The authors noted that
    the mean active level of MIBK was lower for this neurobehavioural
    effect (3292 mg/m3 (893 ppm) for 50% inhibition of immobility)
    than for an effect on sensory irritation (13 100 mg/m3 (3195 ppm)
    for 50% inhibition of respiratory rate) (De Ceaurriz et al., 1981,
    section 8.3.3).

        In inhalation studies on hens (five per group) into the effect
    of MIBK on  n -hexane-induced neurotoxicity, a continuous exposure
    period of 90 days was followed by a 30-day observation period
    (Abou-Donia et al., 1985b). One group of hens was exposed to 3520
    mgnw-hexane/m3 (1000 ppm) and another group to 4100 mg MIBK/m3
    (1000 ppm). Four additional groups were exposed simultaneously to
    3520 mg  n -hexane/m3 (1000 ppm) and 410, 1025, 2050, or 4100 mg
    MIBK/m3 (100, 250, 500, or 1000 ppm, respectively). A control
    group was exposed to ambient air in an exposure chamber. Hens
    continuously exposed to 4100 mg MIBK/m3 developed weakness of the
    legs with subsequent recovery. Inhalation of 3520 mg  n
    -hexane/m3 produced mild ataxia. Exposure to 3520 mg  n
    -hexane/m3 together with 1025, 2050, or 4100 mg MIBK/m3
    resulted in signs of neurotoxicity including paralysis, the
    severity of which depended on the MIBK concentration. Hens
    continuously exposed to the 3520/410 mg/m3  n -hexane/MIBK
    mixture exhibited severe ataxia throughout the observation period.
    Histopathological examination of hens exposed to the  n
    -hexane/MIBK mixture showed large swollen axons and degeneration
    of the axon and myelin of the spinal cord and peripheral nerves.
    There were no histopathological abnormalities in the central
    nervous system of hens exposed only to MIBK. This demonstrates that
    MIBK potentiates the neurotoxic action of  n -hexane. In a
    subsequent study, in which hens were exposed for 50 days to MIBK at
    4100 mg/m3 (1000 ppm) or to  n -hexane, it was suggested that
    the potentiation by MIBK of  n -hexane neurotoxicity is related to
    the induction by MIBK of liver microsomal cytochrome P-450,
    resulting in increased metabolism of  n -hexane to its neurotoxic
    metabolites (sections 6.1, 8.2.1). The findings also suggest that
    the neurotoxicity of technical methyl butyl-ketone (methyl  n
    -butyl ketone/MIBK (7/3)) was correctly attributed to the methyl
     n -butyl ketone component (Abdo et al., 1982). Simultaneous
    treatment of hens with 41, 205, or 410 mg/m3 (10, 50, or 100 ppm)
    technical methyl butyl ketone, 5 days/week for 90 days, with a
    dermal application of technical grade  0 -ethyl- 0 -4-nitrophenyl
    phenylphosphonothionate (EPN, 1.0 mg/kg, 85%) greatly enhanced the
    neurotoxic effects. It was proposed that MIBK partially contributed
    to this potentiation by inducing cytochrome P-450 and thus
    enhancing the formation of neurotoxic products from methyl- n
    -butyl ketone and EPN (Abou-Donia et al., 1985a).

        The effect of MIBK on the duration of ethanol-induced loss of
    righting reflex and on ethanol elimination has been studied in
    mice. MIBK was dissolved in corn oil and injected ip 30 min before
    ethanol (4 g/kg ip). At a dose of 501 mg/kg, MIBK significantly
    prolonged the duration of ethanol-induced loss of righting reflex.
    The concentrations of ethanol in blood and brain on return of the
    righting reflex were similar in MIBK-treated and control animals
    (Cunningham et al., 1989).

    8.9  In vitro toxicity assays

        In contrast to methyl  n -butyl ketone and  n -hexane, MIBK
    caused little or no cytopathological or growth-inhibiting effects
    in cultured mouse neuroblastoma cells (Selkoe et al., 1978). MIBK
    in  N,N -dimethylacetamide reduced the activity of mouse liver
    alcohol dehydrogenase  in vitro  (Cunningham et al., 1989). MIBK
    was found to inhibit the sulfhydryl-dependent creatine kinase and
    adenylate kinase enzymes  in vitro  but not to the same extent as
    did the neurotoxic agent, methyl- n -butyl ketone (Lapin et al.,
    1982).

    9.  EFFECTS ON MAN

    9.1  Acute toxicity

        In a study on the sensory threshold, Silverman et al. (1946)
    exposed 12 volunteers of both sexes to various concentrations of
    MIBK for a 15-min period. This period permitted an accurate
    observation of olfactory fatigue and increasing or decreasing
    irritation of mucous membranes. The sensory response limit was 410
    mg/m3 (100 ppm). The majority of the subjects found the odour
    objectionable at 820 mg/m3 (200 ppm), and the vapour irritated
    the eyes. The low odour threshold (1.64 mg/m3) (Ruth, 1986) and
    the irritant effects can provide warning of high concentrations.
    Because of its low viscosity, MIBK may, when swallowed, also be
    aspirated into the lungs causing a chemical pneumonitis (Panson &
    Winek, 1980).

    9.2  Short-term exposure

        Workers exposed to 410 mg MIBK/m3 (100 ppm) complained either
    of headache and nausea or of respiratory irritation (Elkins, 1959).
    Tolerance was said to be acquired during the working week but was
    lost over the weekend. Reduction of the exposure to 82 mg/m3 (20
    ppm) largely eliminated the complaints. In the study of Hjelm et
    al. (1990) (see section 6.3) on human volunteers, CNS symptoms
    (headache and/or vertigo and/or nausea) were reported at 2-h
    exposure levels of 10-200 mg MIBK/m3 (2.4-48.8 ppm). There were
    no significant effects from exposure on the performance of a
    reaction time task or a test of mental arithmetic.

    9.3  Eye and respiratory irritation

        Exposure to a concentration of 820 mg MIBK/m3 (200 ppm) for
    a 15-min period caused eye irritation in 12 human volunteers
    (Silverman et al., 1946). Undiluted MIBK splashed in the eyes may
    cause painful irritation (Shell, 1957). A group of workers exposed
    to 410 mg MIBK/m3 (100 ppm) complained of respiratory tract
    irritation, but there were no complaints at 82 mg/m3 (20 ppm)
    (Elkins, 1959). In the study of Hjelm et al. (1990) (see section
    6.3) on human volunteers, irritation particularly of the nose and
    throat was reported at 2-h exposure levels of 10, 100, and 200
    mg/m3 (2.4, 24.4, and 48.8 ppm).

    9.4  Long-term exposure

        In workers exposed to up to 2050 mg MIBK/m3 (500 ppm) for
    20-30 min per day and to 328 mg/m3 (80 ppm) for much of the
    remainder of the working day, over half of the 19 workers
    complained of weakness, loss of appetite, headache, eye irritation,
    stomach ache, nausea, vomiting, and sore throat. A few of the
    workers experienced insomnia, somnolence, heartburn, intestinal
    pain, and some unsteadiness. Four workers had slightly enlarged

    livers and six had a nonspecific colitis. Clinical chemistry
    examination revealed no abnormalities in any of the workers. Five
    years later, work practices had greatly improved, the highest MIBK
    concentration was 410-430 mg/m3 (100-105 ppm), and the general
    concentration was 205 mg/m3 (50 ppm). A few workers still
    complained of gastrointestinal and central nervous system effects,
    and slight liver enlargement had persisted in two workers, but
    other symptoms had disappeared (Armeli et al., 1968).

    9.5  Placental transfer

        MIBK was detected in maternal and umbilical cord blood samples
    from 11 patients (Dowty et al., 1976).

    9.6  Neurotoxicity

        A few isolated cases of peripheral neuropathy have been
    reported after exposure to spray paint or lacquer thinner that
    apparently contained MIBK and other hydrocarbon solvents, including
    neurotoxic agents (Oh & Kim, 1976; Aubuchon et al., 1979).

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

    10.1  Evaluation of effects on the environment

        MIBK is not likely to persist in the environment. It will
    slowly volatilize from soil and water and is readily biodegraded in
    fresh and salt water. In the atmosphere, MIBK is estimated to be
    degraded by OHÊ radicals with a half-life of approximately 14 h.
    MIBK is not expected to bioaccumulate and has a low toxicity for
    microorganisms, fish, algae, and aquatic invertebrates. Only in
    cases of accidental spillage or inappropriate disposal of wastes
    into the environment are levels of MIBK likely to cause toxicity to
    organisms in the environment.

    10.2  Evaluation of health risks for humans

        The general population is exposed to low levels of MIBK. Only
    small quantities have been detected in food, drinking-water, and
    other beverages (baked goods, 10.9 mg/kg; frozen dairy products,
    11.5 mg/kg; gelatins, puddings, 10.9 mg/kg; beverages, 10.2 mg/kg).
    For general population exposure, maximum ambient air concentrations
    in the range of 0.1 to 0.2 mg/m3 have been defined by two
    countries.

        Occupational exposure occurs particularly in the production and
    use of lacquers, paints, and extraction solvents. The major route
    of entry is by inhalation. The low odour threshold (1.64 mg/m3)
    and the irritant effects can provide warning of high
    concentrations. Exposure to levels of 10-410 mg/m3 (2.4-100 ppm)
    produced perceptible irritation of either the eyes, nose, or
    throat, and 820 mg/m3 (200 ppm) produced discomfort. Symptoms
    such as headache, nausea, and vertigo also occurred at a level of
    10-410 mg/m3 (2.4-100 ppm). There were no significant effects
    from a 2-h exposure of up to 200 mg/m3 (50 ppm) on a simple
    reaction time task or test of mental arithmetic.

        In the single report concerning long-term occupational
    exposure, where workers were exposed to 2050 mg MIBK/m3 (500 ppm)
    for 20-30 min per day and to 328 mg/m3 (80 ppm) for much of the
    remainder of the working day, more than half of the 19 workers
    complained of weakness, loss of appetite, headache, eye irritation,
    stomach ache, nausea, vomitting, and sore throat. A few workers
    experienced insomnia, somnolence, and some unsteadiness. Four had
    slightly enlarged livers and six had nonspecific colitis. Five
    years later, work practices had greatly improved and the highest
    concentrations were reduced to about one fifth of the previous
    level. A few workers still complained of irritation of the eyes and
    upper respiratory tract as well as gastrointestinal and central
    nervous system symptoms. Prolonged skin contact with MIBK caused
    irritation and flaking of the skin.

        In animal studies, acute systemic MIBK toxicity is low by the
    oral and inhalation routes. In a 90-day study, Sprague-Dawley rats
    were given MIBK by gavage at doses of 50, 250, or 1000 mg/kg body
    weight per day. Lethargy was noted in the highest-dose group and
    males showed reduced body weight gain. In this group there was
    generalized nephropathy, with an increase in relative kidney weight
    and hepatomegaly. Relative kidney weight was also increased in the
    animals fed 250 mg/kg per day, and slight hepatomegaly was reported
    in male rats only. There were no histopathological lesions in the
    liver or other tissues at any dose level. It was concluded that the
    NOEL was 50 mg/kg per day. In 90-day inhalation studies on rats and
    mice, concentrations of up to 4100 mg/m3 (1000 ppm) did not
    result in any life-threatening signs of toxicity. However,
    compound-related reversible morphological changes in the liver and
    kidney were reported. Levels of 4100 mg/m3 produced evidence of
    central nervous system depression. MIBK was capable of increasing
    liver weight (at > 1025 mg/m3 (250 ppm)) and inducing hepatic
    microsomal metabolism. This may be the explanation for the
    exacerbation of haloalkane toxicity and the potentiation of the
    neurotoxicity of  n -hexane. In 90-day studies with mice, rats,
    dogs, and monkeys, only male rats developed hyaline droplets in the
    proximal tubules of the kidney (hyaline droplet toxic tubular
    nephrosis). This effect in male rats was reversible and of doubtful
    significance for humans. MIBK reduces the activity of mouse liver
    alcohol dehydrogenase  in vitro . It has also been found to
    potentiate the cholestatic effects of manganese given with or
    without bilirubin.

        In rats and mice exposed to MIBK by inhalation at
    concentrations of 1230, 4100, or 12 300 mg/m3 (300, 1000, or 3000
    ppm) on days 6 to 15 of gestation and sacrificed on day 21 (rats)
    or day 18 (mice), marked maternal toxicity was observed at the
    highest concentration in both species. This concentration produced
    fetotoxicity (reduced fetal body weight and delayed ossification)
    but was not embryotoxic or teratogenic. At 4100 and 1230 mg/m3
    there was no maternal toxicity and no evidence of embryotoxicity,
    fetotoxicity, or teratogenicity.

        MIBK did not induce gene mutation in bacterial test systems
    (Salmonella typhimurium and  Escherichia coli ) either with or
    without metabolic activation. Negative results were also obtained
    in tests (both with and without metabolic activation) for mitotic
    gene conversion in yeast ( Saccharomyces cerevisiae ) and in gene
    mutation tests using cultured mammalian cells (mouse lymphoma).  In
    vitro  assays for unscheduled DNA synthesis in primary rat
    hepatocytes and for structural chromosome damage in cultured rat
    liver cells (RL4) were negative. An  in vivo  micronucleus test in
    mice was negative. These data indicate that MIBK is not genotoxic.

    11.  RECOMMENDATIONS

        At the levels of MIBK to which the general human population is
    exposed, there is unlikely to be any hazard. In the occupational
    health context, where the major route of exposure is by inhalation,
    atmospheric levels should be kept below the recommended
    occupational exposure limits by suitably designed work processes
    and engineering controls, including ventilation. Skin and eye
    contamination should be avoided. Suitable protective clothing and
    respiratory protection should be readily available for use in
    enclosed spaces, in emergencies, and for certain maintenance
    operations. MIBK is inflammable and should be handled accordingly.

        MIBK has low toxicity for microorganisms and fish, and its
    half-life in the environment is short. Consequently, there is no
    risk to the environment provided there are adequate controls to
    minimize emissions. Large-scale release could have local adverse
    effects on the environment.

    12.  FURTHER RESEARCH

    1.  MIBK affects a number of enzyme systems. Therefore, it can
    significantly influence the biotransformation of xenobiotics that
    are metabolized by these enzymes. Since humans are usually exposed
    to more than one compound, studies on the combined effects of
    mixtures containing MIBK should be undertaken.

    2.  There is very little information available on the dose-response
    relationships for the effects of MIBK on the human central nervous
    system (e.g., reaction time, behavioural effects), on the upper
    airways and mucous membranes, or on kidney function. More
    information on toxico-kinetics is needed for MIBK alone and in
    mixture with other solvents. The skin penetration of MIBK should be
    assessed.

    3.  Epidemiological studies should be undertaken to elucidate the
    effects on the nervous system of long-term exposure to moderate
    concentrations of MIBK alone or in mixture with other solvents.

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    VEZINA, M. & PLAA, G.L. (1988) Methyl isobutyl ketone metabolites
    and potentiation of the cholestasis induced in rats by a
    manganese-bilirubin combination or manganese alone. Toxicol. appl.
    Pharmacol. 92: 419-427.

    VEZINA, M., AYOTTE, P., & PLAA, G.L. (1985) Potentiation of
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    WEBB, R.G., GARRISON, A.W., KEITH, L.H., & MCGUIRE, J.H. (1973)
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    WELLER, J.P. & WOLF, M. (1989) Mass spectroscopy and headspace gas
    chromatography. Beitr. gerichtl. Med., 47: 525-532.

    ZAKHARI, S., LEVY, P., LIEBOWITZ, M., & AVIADO, D.M. (1977) Acute
    oral, intraperitoneal, and inhalation toxicity of methyl isobutyl
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    10-14, pp. 93-133.

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    in human urine. Clin. Chem., 17: 592-594.

    RESUME

        La méthylisobutylcétone est un liquide limpide d'odeur
    douceâtre produite en vue d'une vaste utilisation commerciale comme
    solvant. On peut la doser par chromatographie en phase gazeuse avec
    détection par ionisation de flamme. Elle s'évapore rapidement dans
    l'atmosphère où elle subit une photoconversion à brève échéance. La
    méthylisobutylcétone est facilement biodégradable et, compte tenu
    de sa solubilité moyenne dans l'eau et de son faible coefficient de
    partage entre l'octanol et l'eau, elle devrait présenter un faible
    potentiel de bioaccumulation. Les limites d'exposition
    professionnelle sont de 100-400 mg/m3 (moyenne pondérée par
    rapport au temps: TWA) et de 5-300 mg/m3 (valeur plafond: CLV)
    selon les pays.

        La méthylisobutylcétone est rapidement métabolisée en produits
    d'excrétion solubles dans l'eau et sa toxicité aiguë générale est
    faible chez l'animal après exposition par voie orale ou
    respiratoire. L'expérimentation animale n'a pas révélé
    d'axonopathie périphérique. On ne dispose pas de données précises
    sur la CL50. Une exposition de 4 heures à une concentration de 16
    400 mg/m3 (4000 ppm) a été mortelle pour des rats. La
    méthylisobutylcétone liquide ou sous forme de vapeurs à la
    concentration de 10 à 410 mg/m3 (2,4 à 100 ppm) est irritante
    pour les yeux et les voies respiratoires supérieures. Des
    concentrations allant jusqu'à 200 mg/m3 (50 ppm) n'ont produit
    aucun effet sensible sur l'homme lors d'épreuves portant sur le
    temps de réaction et le calcul mental. Un contact prolongé ou
    répété avec la peau peut produire un dessèchement et des crevasses.
    L'aspiration accidentelle de méthylisobutylcétone liquide peut
    provoquer une pneumonie chimique.

        Lors d'une étude de 90 jours effectuée en gavant des rats, on
    a obtenu une dose sans effet observable de 50 mg/kg par jour. Des
    études d'inhalation de 90 jours portant sur des rats et des souris
    à des concentrations allant jusqu'à 4100 mg/m3 (1000 ppm) n'ont
    pas révélé de signes de toxicité engageant le pronostic vital.
    Toute fois des altérations morphologiques réversibles liées à
    l'administration de ce composé ont été observées au niveau du foie
    et des reins. Dans un certain nombre d'études, on a observé une
    hypertrophie du foie dès la dose de 1025 mg/m3 (250 ppm). Exposés
    à 4100 mg/m3 (1000 ppm) pendant 50 jours, des poulets ont
    présenté une induction des enzymes microsomiques. A doses plus
    élevées (jusqu'à 8180 mg/m3, 1996 ppm) les effets se limitaient
    à un accroissement du poids du foie sans lésion histologique. Lors
    d'études de 90 jours effectuées sur des souris, des rats, des
    chiens et des singes, seuls les rats mâles ont présenté des
    altérations histologiques: présence de gouttelettes hyalines dans
    les tubules proximaux des reins (néphrose tubulaire toxique à
    inclusions hyalines). Cet effet s'est révélé réversible et sa
    portée en toxicologie humaine demeure incertaine. Il est possible
    que la potentialisation de la toxicité des alcanes halogénés par la

    méthylisobutylcétone repose sur une induction enzymatique. La
    méthylisobutylcétone potentialise également l'effet cholestatique
    du manganèse administré avec ou sans bilirubine.

        Des babouins exposés pendant sept jours à une dose de 205
    mg/m3 (50 ppm) ont présenté des troubles neuro-comportementaux.

        La méthylisobutylcétone est foetotoxique à une concentration
    manifestement toxique pour la mère (12 300 mg par m3, 3000 ppm)
    mais elle n'est pas embryotoxique ni tératogène à cette
    concentration. A la concentration de 4100 mg/m3 (1000 ppm), on
    n'a pas observé d'embryotoxicité, de foetotoxicité ni de
    tératogénicité chez les rats et les souris.

        On a recherché la génotoxicité éventuelle de la
    méthylisobutylcétone en pratiquant un certain nombre d'épreuves à
    court terme, consistant notamment en tests sur des cellules
    mammaliennes, des bactéries et des levures ainsi que dans la
    recherche de micro-noyaux chez la souris. Les résultats indiquent
    que la méthyliso-butylcétone n'est pas génotoxique. En ce qui
    concerne la génotoxicité à long terme ou la cancérogénicité, on ne
    dispose d'aucune donnée.

        A la concentration de 410 mg/m3 (100 ppm), la
    méthylisobutylcétone peut produire des symptômes chez l'homme
    consistant en irritation occulaire, migraines, nausées, vertiges et
    fatigue et qui correspondent à un effet dépresseur réversible sur
    le système nerveux central. Toutefois, rien n'indique l'existence
    de lésions permanentes.

        La toxicité pour les organismes et micro-organismes aquatiques
    est faible.

        Compte tenu de la volatilité relativement forte de la
    méthylisobutylcétone, de sa photoconversion rapide dans
    l'atmosphère, de sa biodégradabilité et de sa faible toxicité pour
    les mammifères et la faune aquatique, il est vraisemblable que
    cette substance ne peut exercer d'effets néfastes sur
    l'environnement qu'à la suite de déversements accidentels ou de la
    décharge incontrôlée d'effluents industriels.

    EVALUATION DES RISQUES POUR LA SANTE HUMAINE ET DES EFFETS SUR
    L'ENVIRONNEMENT

    1.  Evaluation des effets sur l'environnement

        La méthylisobutylcétone ne devrait pas persister dans
    l'environnement. Elle se volatilise lentement à partir du sol et de
    l'eau et subit une biodégradation rapide dans l'eau douce et l'eau
    salée. Dans l'atmosphère, on pense qu'elle est décomposée par les
    radicaux libres OH avec une demi-vie d'environ 14 heures. Elle ne
    s'accumule probablement pas et présente une faible toxicité pour
    les micro-organismes, les poissons, les algues et les invertébrés
    aquatiques. Ce n'est qu'en cas de déversement accidentel ou de
    rejet incontrôlé de déchets que cette substance est susceptible
    d'atteindre des concentrations toxiques pour les êtres vivants.

    2.  Evaluation des risques pour la santé humaine

        La population générale n'est exposée qu'à de faibles
    concentrations de méthylisobutylcétone. On en a décelé de faibles
    quantités dans les denrées alimentaires et dans l'eau de
    consommation ou autres boissons (produits panifiés, 10,9 mg/kg;
    produits laitiers, 11,5 mg/kg; gélatines, puddings, 10,9 mg/kg;
    boissons diverses, 10,2 mg/kg). En ce qui concerne la population
    générale, deux pays ont fixé des concentrations maximales dans
    l'air ambiant qui se situent dans les limites de 0,1 à 0,2 mg/m3.

        L'exposition professionnelle se produit notamment lors de la
    production et de l'utilisation de vernis, de peintures et de
    solvants d'extraction. La principale voie de pénétration est
    l'inhalation. Le faible seuil olfactif (1,64 mg/m3) et les effets
    irritants de cette substance peuvent avertir de la présence de
    fortes concentrations. L'exposition à ces concentrations de 10 à
    410 mg/m3 (2,4 à 100 ppm) a produit une irritation perceptible au
    niveau des yeux, du nez et de la gorge; à 820 mg/m3 (200 ppm), on
    éprouve une sensation de malaise. Entre 10 et 410 mg par m3 (2,4
    à 100 ppm), on a également observé des céphalées, des nausées et
    des vertiges. Une exposition de deux heures à des concentrations
    allant jusqu'à 200 mg/m3 (50 ppm) n'a pas produit d'effets
    sensibles à en juger par un simple test de temps de réaction et de
    calcul mental.

        On ne dispose que d'un seul rapport faisant état d'une
    exposition professionnelle de longue durée à une dose de 2050
    mg/m3 (500 ppm), 20 à 30 minutes par jour et à 328 mg/m3 (80
    ppm) pour la majeure partie du reste de la journée. Plus de la
    moitié des 19 ouvriers exposés se sont plaints de faiblesse, de
    perte d'appétit, de maux de tête, d'irritation oculaire, de maux
    d'estomac, de nausées, de vomissements et de maux de gorge.
    Quelques ouvriers ont éprouvé de l'insomnie, de la somnolence et
    une perte d'équilibre. Chez quatre d'entre eux on a constaté une
    légère hypertrophie du foie et chez six autres une colite non

    spécifique. Cinq années plus tard, les méthodes de travail
    s'étaient considérablement améliorées et les concentrations
    maximales réduites au cinquième des teneurs précédentes. Quelques
    ouvriers se sont encore plaints d'irritation au niveau des yeux et
    des voies respiratoires supérieures ainsi que de symptômes
    digestifs et neurologiques. La contact prolongé avec la peau a
    provoqué une irritation cutanée et des crevasses.

        Il ressort de l'expérimentation animale que la toxicité
    générale aiguë de la méthylisobutylcétone est faible, par voie
    orale ou par inhalation. Lors d'une étude de 90 jours, des rats
    Sprague-Dawley ont reçu par gavage de la méthylisobutylcétone à des
    doses quotidiennes de 50, de 250 et 1000 mg/kg de poids corporel.
    On a noté une léthargie chez des animaux du groupe soumis à la dose
    la plus élevée et, chez les mâles, une réduction du gain de poids.
    Les animaux de ce groupe présentaient une néphropathie généralisée,
    avec augmentation du poids relatif des reins et une hypertrophie du
    foie. Cette augmentation du poids relatif des reins était également
    notable chez les animaux soumis à la dose de 250 mg/kg, mais à
    cette dose, on ne constatait qu'une légère hypertrophie du foie
    chez les mâles. Quelle que soit la dose, on n'a pas constaté de
    lésion histopathologique au niveau du foie ou des autres tissus. La
    dose sans effet observable a été évaluée à 60 mg/kg et par jour.
    Lors d'une étude de même durée au cours de laquelle on a fait
    inhaler à des rats et des souris des concentrations allant jusqu'à
    4100 mg/m3 (1000 ppm) on n'a pas relevé de signes de toxicité
    engageant le pronostic vital. Toute fois des altérations
    morphologiques réversibles liées à l'administration de cette
    substance ont été observées au niveau du foie et des reins. A la
    concentration de 4100 mg par m3, on observait des signes de
    dépression du système nerveux central. La méthylisobutylcétone a
    provoqué une augmentation du poids du foie (à une dose supérieure
    à 1025 mg/m3, soit 250 ppm) et provoqué l'induction des enzymes
    microsomiques du foie. C'est ce dernier mécanisme qui serait à la
    base de l'exacerbation de la toxicité des alcanes halogénés et de
    la potentialisation de la neurotoxicité dunw-hexane. Lors d'études
    de 90 jours sur des souris, des rats, des chiens et des singes, on
    a observé, chez les rats seulement, l'apparition d'inclusions
    hyalines dans les tubules proximaux des reins (néphrose tubulaire
    à inclusions hyalines d'origine toxique). Cet effet observé chez
    les rats mâles était réversible et il est douteux qu'il ait une
    signification quelconque en toxicologie humaine. La
    méthylisobutylcétone réduit l'activité de l'alcool-déshydrogénase
    hépatique chez la souris  in vitro . On a également constaté
    qu'elle potentialisait les effets cholestatiques du manganèse en
    présence ou en l'absence de bilirubine.

        Des rats et des souris exposés par inhalation à des
    concentrations de 1230, 4100 ou 12 300 mg/m3 (300, 1000 ou 3000
    ppm) du sixième au quinzième jours de la gestation puis sacrifiés
    le vingt-et-unième jour (rats) ou le dixhuitième jour (souris), ont
    présenté des signes marqués d'intoxication à la concentration la

    plus forte. Cette concentration était foetotoxique (réduction du
    poids foetal et ossification retardée) mais n'était ni
    embryotoxique ni tératogène. Aux concentrations de 4100 et 1230
    mg/m3, on n'a constaté aucune toxicité pour les mères ni signe
    d'embryotoxicité, de foetotoxicité ou de tératogénicité.

        La méthylisobutylcétone n'a pas produit de mutation génique
    dans des systèmes d'épreuve bactériens (Salmonella typhimurium et
     Escherichia coli ), qu'il y ait ou non activation métabolique. On
    a également obtenu des résultats négatifs dans différentes épreuves
    (avec ou sans activation métabolique) à la recherche de conversions
    géniques mitotiques dans des levures ( Saccharomyces cerevisiae )
    ou lors d'épreuves de mutation génique sur des cellules
    mammaliennes en culture (lymphome murin). La recherche  in vitro 
    d'une synthèse anarchique de l'ADN dans des hépatocytes primaires
    de rat et de lésions chromosomiques structurales dans des cellules
    de foie de rat en culture (RL4) s'est révélée négative. Chez la
    souris, la recherche  in vivo  de micro-noyaux s'est également
    révélée négative. Toutes ces données montrent que la
    méthyl-isobutylcétone n'est pas génotoxique.

    RECOMMANDATIONS

        Les concentrations de méthylisobutylcétone auxquelles la
    population, dans son ensemble, est susceptible d'être exposée, ne
    présentent vraisemblablement aucun danger. La principale voie
    d'exposition professionnelle est la voie respiratoire, aussi les
    concentrations atmosphériques devront être maintenues en dessous
    des limites recommandées d'exposition professionnelle, grâce à un
    aménagement convenable des procédés de production et à des moyens
    mécaniques tels que la ventilation. Il convient d'éviter toute
    contamination de la peau et des yeux. Des vêtements protecteurs
    appropriés ainsi que des masques respiratoires doivent être placés
    dans les ateliers confinés; ils seront utilisés en cas d'urgence ou
    pour effectuer certaines opérations d'entretien. La
    méthylisobutylcétone est inflammable et doit donc être manipulée
    avec les précautions d'usage.

        La méthylisobutylcétone présente une faible toxicité pour les
    micro-organismes et pour les poissons et sa demivie dans
    l'environnement est courte. Il s'ensuit qu'elle ne présente aucun
    risque pour l'environnement, dans la mesure où des mesures
    appropriées sont prises pour réduire les émissions au minimum. La
    décharge de quantités importantes dans l'environnement pourrait
    avoir localement des effets indésirables.

    RECHERCHES A EFFECTUER

    1.  La méthylisobutylcétone affecte un certain nombre de systèmes
        enzymatiques. Elle peut donc avoir une influence sensible sur
        la biotransformation des produits xénobiotiques métabolisés
        par ces enzymes. Etant donné que l'homme est généralement
        exposé à plusieurs composés différents, il faudrait
        entre-prendre des études sur les effets combinés de mélanges
        contenant de la méthylisobutylcétone.

    2.  On ne dispose que de très peu d'informations sur la relation
        dose-réponse relative aux effets toxiques de la
        méthylisobutylcétone sur le système nerveux central (par
        exemple temps de réaction, effets comportementaux), sur les
        voies respiratoires supérieures, sur les muqueuses et sur la
        fonction rénale. Il faudrait obtenir davantage de
        renseignements sur la toxico-cinétique de cette cétone, soit
        seule soit associée à d'autres solvants. Il faudra également
        étudier la pénétration percutanée de la méthylisobutylcétone.

    3.  Il faudrait entreprendre des études épidémiologiques pour
        élucider les effets exercés à long terme sur le système
        nerveux central par des concentrations moyennes de
        méthylisobutylcétone soit seule soit associée à d'autres
        solvants.

    RESUMEN

        La metil isobutil acetona (MIBA) es un líquido transparente de
    buen olor que se produce a escala comercial y tiene un uso muy
    extendido como disolvente. Puede medirse mediante cromatografía de
    gases con detección de ionización de llama. Se evapora rápidamente
    a la atmósfera, donde se fototransforma en poco tiempo. La MIBA es
    fácilmente biodegradable, lo que, junto con su moderada solubilidad
    en el agua y su reducido coeficiente de partición octanol/agua,
    sugiere que tiene un bajo potencial de bioacumulación. Los límites
    de exposición profesional varían entre 100-410 mg/m3 (promedio
    ponderado en el tiempo) y 5-300 mg/m3 (valor máximo) en distintos
    países.

        La MIBA se metaboliza fácilmente para dar productos de
    excreción hidrosolubles y su toxicidad sistémica aguda en animales
    es baja por las vías de exposición oral y de inhalación. No se ha
    observado axonopatía periférica en estudios realizados en animales.
    No se dispone de datos exactos sobre la CL50. La exposición a 16
    400 mg/m3 (4000 ppm) durante 4 horas resultó letal para la rata.
    Las concentraciones de MIBA líquida y en vapor comprendidas entre
    10 y 410 mg/m3 (2,4-100 ppm) son irritantes para los ojos y las
    vías respiratorias superiores. Con concentraciones de hasta 200
    mg/m3 (50 ppm) no se observaron en el hombre efectos
    significativos en una prueba sencilla de tiempo de reacción ni en
    una prueba de aritmética mental. El contacto cutáneo prolongado o
    repetido puede desecar y descamar la piel. La aspiración accidental
    de MIBA líquida puede provocar pneumonitis química.

        En un estudio de ceba de ratas durante 90 días, se determinó
    un nivel sin efecto observado de 50 mg/kg. En estudios de
    inhalación durante 90 días en ratas y ratones, concentraciones de
    hasta 4100 mg/m3 (1000 ppm) no produjeron ningún signo de
    toxicidad con peligro para la vida. No obstante, se notificaron
    cambios morfológicos reversibles relacionados con el compuesto en
    el hígado y el riñón. En varios estudios se observó que
    concentraciones de MIBA tan bajas como 1025 mg/m3 (250 ppm) eran
    capaces de aumentar el tamaño del hígado. Mediante la exposición a
    4100 mg/m3 (1000 ppm) durante 50 días, se indujo actividad
    metabólica en las enzimas microsómicas del hígado del pollo. A
    dosis más elevadas (hasta 8180 mg/m3, 1996 ppm) los efectos se
    limitaron a un aumento del peso del hígado sin lesiones
    histológicas. En estudios durante 90 días con ratones, ratas,
    perros y monos, sólo las ratas macho presentaron corpúsculos
    hialinos en los túbulos proximales del riñón (nefrosis tubulotóxica
    de corpúsculos hialinos). Este efecto en la rata macho resultó ser
    reversible y de dudosa importancia para el hombre. La inducción
    enzimática puede ser la base de la potenciación de la toxicidad de
    los haloalcanos por la MIBA. Se observó también que la MIBA era
    capaz de potenciar el efecto colestático del manganeso administrado
    con o sin bilirrubina.

        En papiones expuestos durante 7 días a 205 mg/m3 (50 ppm),
    se observaron efectos en el neurocomportamiento.

        La MIBA resulta fetotóxica a una concentración que produce sin
    lugar a dudas toxicidad materna (12 300 mg/m3, 3000 ppm) pero no
    es embriotóxica ni teratogénica en esa concentración. En una
    concentración de 4100 mg/m3 (1000 ppm), no resultó ni
    embriotóxica, ni fetotóxica ni teratogénica en la rata ni en el
    ratón.

        Se ha estudiado la genotoxicidad de la MIBA en varios ensayos
    a corto plazo, inclusive pruebas in vitro con bacterias, levaduras
    y células de mamíferos y un ensayo de micronúcleos en el ratón.
    Esos estudios indican que la MIBA no es genotóxica. No se dispone
    de informes sobre estudios a largo plazo ni estudios de
    carcinogenicidad.

        Aunque con una concentración de 410 mg/m3 (100 ppm) la MIBA
    puede inducir en el hombre síntomas como irritación ocular, dolores
    de cabeza, náuseas, mareos y fatiga, que corresponden a un efecto
    reversible de depresión del sistema nervioso central, no existen
    pruebas de que produzca lesiones permanentes en el sistema
    nervioso.

        La toxicidad de la MIBA para organismos y micro-organismos
    acuáticos es baja.

        La volatilidad relativamente alta de la MIBA, su rápida
    fototransformación en la atmósfera, su fácil biodegradación y su
    baja toxicidad para mamíferos y organismos acuáticos indican que
    los efectos medioambientales adversos de esta sustancia
    probablemente sólo se producirán como consecuencia de vertidos
    accidentales o de efluentes industriales no controlados.

    EVALUACION DE LOS RIESGOS PARA LA SALUD HUMANA Y DE LOS
    EFECTOS EN EL MEDIO AMBIENTE

    1.  Evaluación de los efectos en el medio ambiente

        La MIBA tiene pocas probabilidades de persistir en el medio
    ambiente. Se volatiliza poco a poco desde el suelo y el agua y se
    biodegrada fácilmente en agua dulce y salada. En la atmósfera, se
    ha calculado que la MIBA es degradada por los radicales OHÊ una
    semivida de aproximadamente 14 horas. En principio, la MIBA no se
    bioacumula y tiene una toxicidad baja para micro-organismos, peces,
    algas e invertebrados acuáticos. Sólo en los casos de vertido
    accidental o de evacuación inadecuada de desechos en el medio
    ambiente es probable que los niveles de MIBA provoquen toxicidad en
    los organismos del entorno.

    2.  Evaluación de los riesgos para la salud humana

        La población general está expuesta a niveles reducidos de MIBA.
    Se han detectado sólo pequeñas cantidades en los alimentos, el agua
    potable y otras bebidas (alimentos horneados, 10,9 mg/kg; productos
    lácteos congelados, 11,5 mg/kg; gelatinas y budines, 10,9 mg/kg;
    bebidas, 10,2 mg/kg). En cuanto a la exposición de la población
    general, dos países han definido concentraciones máximas en el aire
    entre 0,1 y 0,2 mg/m3.

        La exposición profesional tiene lugar especialmente en la
    producción y utilización de lacas, pinturas y disolventes de
    extracción. La principal vía de entrada es por inhalación. El bajo
    umbral olfativo (1,64 mg/m3) y los efectos irritantes pueden
    servir como indicadores de las concentraciones elevadas. La
    exposición a niveles de 10-410 mg/m3 (2,4-100 ppm) produjo
    irritación perceptible de los ojos, la nariz, o la garganta y 820
    mg/m3 (200 ppm) produjeron molestias. Con un nivel de 10-410
    mg/m3 (2,4-100 ppm) también se produjeron síntomas como dolor de
    cabeza, náuseas y vértigos. No se observaron efectos significativos
    debidos a una exposición durante 2 horas a hasta 200 mg/m3 (50
    ppm) al realizar una prueba sencilla de tiempo de reacción ni una
    prueba de aritmética mental.

        En el único informe sobre un estudio de la exposición
    profesional a largo plazo, en el que se expuso a trabajadores a
    2050 mg MIBA/m3 (500 ppm) durante 20-30 minutos al día y a 328
    mg/m3 (80 ppm) durante la mayor parte del resto de la jornada
    laboral, más de la mitad de los 19 trabajadores se quejaron de
    debilidad, pérdida del apetito, dolores de cabeza, irritación
    ocular, dolor de estómago, náuseas, vómitos y dolor de garganta.
    Algunos trabajadores sufrieron insomio, somnolencia y cierta
    inestabilidad. En cuatro se observó un ligero agrandamiento del
    hígado y en seis se observó colitis no específica. Al cabo de 5
    años, las prácticas laborales habían mejorado en gran medida y las
    concentraciones más elevadas se redujeron a aproximadamente la

    quinta parte del nivel anterior. Algunos trabajadores siguieron
    quejándose de irritación en los ojos y de las vías respiratorias
    superiores así como de síntomas gastrointestinales y del sistema
    nervioso central. El contacto cutáneo prolongado con la MIBA
    provocó irritación y descamación de la piel.

        En estudios en animales, la toxicidad sistémica aguda de la
    MIBA es baja por las vías oral y respiratoria. En un estudio de 90
    días de duración, se cebó con MIBA a ratas Sprague-Dawley en dosis
    diarias de 50, 250 ó 1000 mg/kg de peso corporal. Se observó
    letargo en el grupo que recibió la dosis más alta y en los machos
    se observó una reducción del ritmo de aumento del peso corporal. En
    este grupo se observó nefropatía generalizada, con aumento del peso
    relativo del riñón y hepatomegalia. El peso relativo del riñón
    también aumentó en los animales alimentados con 250 mg/kg al día,
    y se observó ligera hepatomegalia sólo en los machos. No
    aparecieron lesiones histopatológicas en el hígado ni en otros
    tejidos con ninguna de las dosis administradas. Se concluyó que el
    nivel de efecto no observado era de 50 mg/kg al día. En estudios de
    inhalación durante 90 días realizados en ratas y ratones, las
    concentraciones de hasta 4100 mg/m3 (1000 ppm) no originaron
    ningún signo de toxicidad que pusiera en peligro la vida. No
    obstante, se comunicó la observación de cambios morfológicos
    reversibles relacionados con el compuesto en el hígado y el riñón.
    Con niveles de 4100 mg/m3 se observaron signos de depresión del
    sistema nervioso central. La MIBA fue capaz de aumentar el peso del
    hígado (concentración > 1025 mg/m3 (250 ppm)) y de inducir el
    metabolismo microsómico hepático. Esto puede explicar la
    exacerbación de la toxicidad de los haloalcanos y la potenciación
    de la neurotoxicidad del n‹hexano. En estudios de 90 días con
    ratones, ratas, perros y monos, sólo las ratas macho desarrollaron
    corpúsculos hialinos en los túbulos proximales del riñón (nefrosis
    tubulotóxica de corpúsculos hialinos). Este efecto en ratas macho
    resultó ser reversible y de dudosa importancia para el hombre. In
    vitro, la MIBA reduce la actividad de la deshidrogenasa alcohólica
    en el hígado del ratón. También se ha observado que potencia los
    efectos colestáticos del manganeso administrado con o sin
    bilirrubina.

        En ratas y ratones expuestos a la inhalación de MIBA en
    concentraciones de 1230, 4100 ó 12 300 mg/m3 (300, 1000 ó 3000
    ppm) en los días 6 a 15 de la gestación y sacrificados el día 21
    (ratas) o el día 18 (ratones), se observó una notable toxicidad
    materna a la concentración más elevada en ambas especies. Esta
    concentración produjo fetotoxicidad (peso del cuerpo fetal reducido
    y retraso en la osificación) pero no resultó embriotóxico ni
    teratogénico. A 4100 y 1230 mg/m3 no se observó ni toxicidad
    materna ni síntomas de embriotoxicidad, fetotoxicidad o
    teratogenicidad.

        La MIBA no indujo mutación genética en sistemas de ensayo
    bacterianos (Salmonella typhimurium y Escherichia coli), con o sin

    activación metabólica. También se obtuvieron resultados negativos
    en los ensayos (tanto con y sin activación metabólica) para la
    conversión mitótica de genes en levaduras (Saccharomyces
    cerevisiae) y en pruebas de mutación génica con cultivos de células
    de mamíferos (linfoma de ratón). Los ensayos in vitro sobre
    síntesis no controlada de ADN en hepatocitos primarios de rata y
    sobre lesiones cromosómicas estructurales en cultivos de células
    hepáticas de rata (RL4) resultaron negativos. En el ratón, un
    ensayo de micronúcleo in vivo resultó negativo. Estos datos indican
    que la MIBA no es genotóxica.

    RECOMENDACIONES

        En los niveles de MIBA a que está expuesta la población humana
    general, es poco probable que se plantee riesgo alguno. En el medio
    laboral, donde la principal vía de exposición es por inhalación,
    los niveles atmosféricos deben mantenerse por debajo de los límites
    de exposición profesional recomendados mediante procesos de trabajo
    y controles de ingeniería, inclusive la ventilación, de diseño
    adecuado. Debe evitarse la contaminación de la piel y de los ojos.
    Debe facilitarse el uso de prendas protectoras adecuadas y de
    protección respiratoria en los espacios cerrados, en casos de
    emergencia y para ciertas operaciones de mantenimiento. La MIBA es
    inflamable y debe manipularse teniendo esta característica en
    cuenta.

        La MIBA tiene baja toxicidad para los microorganismos y los
    peces, y su semivida en el medio ambiente es corta. Por
    consiguiente, no presenta riesgos para el medio ambiente siempre
    que se apliquen las medidas de control adecuadas para reducir al
    mínimo las emisiones. El vertido en gran escala podría ejercer
    efectos adversos en el medio ambiente a escala local.

    OTRAS INVESTIGACIONES

    1.  LA MIBA afecta a varios sistemas enzimáticos. Por lo tanto,
        puede influir de modo significativo en la bio-transformación
        de sustancias biológicas externas que son metabolizadas por
        estas enzimas. Como las personas suelen estar expuestas a más
        de un compuesto, deben llevarse a cabo estudios sobre los
        efectos combinados de muestras que contengan MIBA.

    2.  Se dispone de muy poca información sobre las relaciones
        dosis‹respuesta en cuanto a los efectos de la MIBA en el
        sistema nervioso central humano (por ejemplo, tiempo de
        reacción, efectos conductuales) en las vías respiratorias
        superiores y las mucosas, o en la función renal. Se necesita
        más información sobre la toxicocinética de la MIBA por sí sola
        y mezclada con otros disolventes. Debe evaluarse la
        penetración cutánea de la MIBA.

    3.  Deben emprenderse estudios epidemiológicos para dilucidar los
        efectos que tiene en el sistema nervioso la exposición a largo
        plazo a concentraciones moderadas de MIBA, por sí sola o
        mezclada con otros disolventes.



    See Also:
       Toxicological Abbreviations
       Methyl isobutyl ketone (HSG 58, 1991)
       Methyl isobutyl ketone (ICSC)