This report contains the collective views of an international group of
    experts and does not necessarily represent the decisions or the stated
    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

    First draft prepared by Mr D J Reisman, US Environmental Protection
    Agency, Cincinnati, USA

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

              World Health Organization
              Geneva, 1998

         The International Programme on Chemical Safety (IPCS),
    established in 1980, is a joint venture of the United Nations
    Environment Programme (UNEP), the International Labour Organisation
    (ILO), and the World Health Organization (WHO).  The overall
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    assessment of the risk to human health and the environment from
    exposure to chemicals, through international peer review processes, as
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         The Inter-Organization Programme for the Sound Management of
    Chemicals (IOMC) was established in 1995 by UNEP, ILO, the Food and
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    field of chemical safety.  The purpose of the IOMC is to promote
    coordination of the policies and activities pursued by the
    Participating Organizations, jointly or separately, to achieve the
    sound management of chemicals in relation to human health and the

    WHO Library Cataloguing in Publication Data


         (Environmental health criteria; 207)

         1. Acetone 2. Environmental exposure
         I. International Programme on Chemical Safety II. Series

         ISBN 92 4 157207 8               (NLM Classification: QD 305.K2)
         ISSN 0250-863X

         The World Health Organization welcomes requests for permission to
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    proprietary products are distinguished by initial capital letters.





    1. SUMMARY
         1.1. Properties
         1.2. Uses and sources of exposure
              1.2.1. Production
              1.2.2. Uses and emissions into the environment
         1.3. Environmental transport, distribution and transformation
         1.4. Environmental levels and human exposure
         1.5. Kinetics and metabolism
         1.6. Effects on laboratory mammals and  in vitro systems
         1.7. Effects on humans
         1.8. Effects on other organisms in the laboratory and field

         2.1. Chemical identity
         2.2. Physical and chemical properties
              2.2.1. Physical properties
              2.2.2. Chemical properties
         2.3. Conversion factors
         2.4. Analytical methods
              2.4.1. Biological media
              2.4.2. Environmental media

         3.1. Natural occurrence
         3.2. Anthropogenic sources
              3.2.1. Production levels and processes
              3.2.2. Uses
              3.2.3. Releases

         4.1. Transport and distribution among media
              4.1.1. Air
              4.1.2. Water
              4.1.3. Soil
         4.2. Biotransformation
              4.2.1. Bioconcentration and biomagnification
              4.2.2. Biodegradation
                 Microbial degradation

         4.3. Bioavailability from environmental media
         4.4. Interaction with other physical, chemical or biological
         4.5. Ultimate fate following use

         5.1. Environmental levels
              5.1.1. Air
                 Indoor air
              5.1.2. Water
              5.1.3. Soil and sediment
              5.1.4. Food
              5.1.5. Other environmental levels
         5.2. General population exposure
         5.3. Occupational exposure

         6.1. Absorption
              6.1.1. Inhalation exposure
                 Human studies
                 Experimental animal studies
              6.1.2. Oral exposure
                 Human studies
                 Experimental animal studies
              6.1.3. Dermal exposure
                 Human studies
                 Experimental animal studies
              6.1.4. Absorption summary
         6.2. Distribution
              6.2.1. Inhalation exposure
                 Human studies
                 Experimental animal studies
              6.2.2. Oral exposure
              6.2.3. Injection exposure
              6.2.4. Distribution summary
         6.3. Metabolism
              6.3.1. Human studies
              6.3.2. Experimental animal studies
              6.3.3. Metabolism summary
         6.4. Elimination and excretion
              6.4.1. Human studies
               Occupational exposure studies
              6.4.2. Experimental animal studies
              6.4.3. Elimination/excretion summary
              6.4.4. Physiologically based pharmacokinetic model
         6.5. Retention and turnover

         7.1. Short-term toxicity
              7.1.1. Skin and eye irritation
         7.2. Longer-term toxicity
         7.3. Reproductive toxicity, embryotoxicity and teratogenicity
         7.4. Mutagenicity
         7.5. Carcinogenicity
         7.6. Immunotoxicity
         7.7. Special studies
         7.8. Factors modifying toxicity; toxicity of metabolites
         7.9. Mechanisms of toxicity - mode of action

         8.1. Effects on humans
              8.1.1. Non-occupational exposure
              8.1.2. Occupational exposure
         8.2. Subpopulations at special risk

         9.1. Aquatic organisms
              9.1.1. Acute toxic effects on aquatic fauna
              9.1.2. Chronic effects on aquatic fauna
              9.1.3. Effects on aquatic plants

         9.2. Effects on bacteria and protozoa
         9.3. Terrestrial organisms
              9.3.1. Effects on fauna
              9.3.2. Effects on flora

         10.1. Evaluation of human health effects
         10.2. Evaluation of effects on the environment







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

                                 *     *     *

         A detailed data profile and a legal file can be obtained from the
    International Register of Potentially Toxic Chemicals, Case postale
    356, 1219 Châtelaine, Geneva, Switzerland (telephone no. + 41 
    22 - 9799111, fax no. + 41 22 - 7973460, E-mail irptc@unep.ch).

                                 *     *     *

         This publication was made possible by grant number
    5 U01 ES02617-15 from the National Institute of Environmental Health
    Sciences, National Institutes of Health, USA, and by financial support
    from the European Commission.

    Environmental Health Criteria



         In 1973 the WHO Environmental Health Criteria Programme was
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         The first Environmental Health Criteria (EHC) monograph, on
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         Since its inauguration the EHC Programme has widened its scope,
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         The original impetus for the Programme came from World Health
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    *    Effects on laboratory mammals and  in vitro test systems
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    Selection of chemicals

         Since the inception of the EHC Programme, the IPCS has organized
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    FIGURE 1

         All Participating Institutions are informed, through the EHC
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    available on request.  The Chairpersons of Task Groups are briefed
    before each meeting on their role and responsibility in ensuring that
    these rules are followed.



    Dr D. Anderson, British Industrial Biological Research Association
    (BIBRA) Toxicology International, Carshalton, Surrey, United Kingdom

    Dr Sin-Eng Chia, Department of Community, Occupational and Family
    Medicine, National University of Singapore, Faculty of Medicine,

    Mr J. Fawell, National Centre for Environmental Toxicology, Medmenham,
    United Kingdom

    Dr L. Fishbein, Fairfax, Virginia, USA ( Chairman)

    Dr H. Hansen, Division of Toxicology, Agency for Toxic
    Substances and Disease Registry, Atlanta, Georgia, USA

    Mr H. Malcolm, Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, Huntingdon, United Kingdom ( Co-Rapporteur)

    Dr M.V. Park, Edinburgh Centre for Toxicology, Edinburgh, United

    Mr D.J. Reisman, National Center for Environmental Assessment, US
    Environmental Protection Agency, Cincinnati, Ohio, USA
    ( Co-Rapporteur)

    Dr A. Wibbertman, Fraunhofer Institute for Toxicology and Aerosol
    Research, Hanover, Germany ( Vice-Chairman)


    Dr D. Morgott, Toxicological Sciences Laboratory, Health, Safety and
    Environment, Eastman Kodak Company, Rochester, New York, USA
    (representing the American Industrial Health Council)

    Dr D. Owen, Shell Chemicals Europe Limited, London, United Kingdom
    (representing the European Centre for Ecotoxicology and Toxicology of

    Dr P. Montuschi, Department of Pharmacology, Catholic University of
    the Sacred Heart, Rome, Italy (representing the International Union of


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


         A WHO Task Group on Environmental Health Criteria for Acetone met
    at the British Industrial Biological Research Association (BIBRA)
    Toxicology International, Carshalton, Surrey, United Kingdom, from 1
    to 5 December 1997. Dr S. Jaggers opened the meeting and welcomed the
    participants on behalf of the host institute. Dr E. Smith, IPCS,
    welcomed the participants on behalf of the Director, IPCS, and the
    three IPCS cooperating organizations (UNEP/ILO/WHO). The Task Group
    reviewed and revised the draft criteria monograph and made an
    evaluation of the risks for human health and the environment from
    exposure to acetone.

         Mr D.J. Reisman, US Environmental Protection Agency, Cincinnati,
    USA, prepared the first draft of this monograph. The second draft,
    incorporating comments received following the circulation of the first
    draft to the IPCS Contact Points for Environmental Health Criteria
    monographs, was also prepared by Mr. Reisman.

         Dr E.M. Smith and Dr P.G. Jenkins, both of the IPCS Central Unit,
    were responsible for the overall scientific content and technical
    editing, respectively.

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

                                    *  *  *

         The US Environmental Protection Agency funded the preparation of
    this Environmental Health Criteria monograph, financial support for
    the Task Group meeting was provided by the United Kingdom Department
    of Health, and the meeting was organized by the British Industrial
    Biological Research Association (BIBRA).


    BOD            biochemical oxygen demand
    CAS            Chemical Abstracts Services
    DOT/UN/NA/IMCO Department of Transportation/United Nations/North
                   America/International Maritime Dangerous Goods Code
    EINECS         European Inventory of Existing Chemical Substances
    EPA            Environmental Protection Agency
    FID            flame ionization detector
    GC             gas chromatography
    HPLC           high performance liquid chromatography
    HRGC           high resolution gas chromatography
    HSDB           Hazardous Substances Data Bank
    IC             ion chromatography
    LOEL           lowest-observed-effect level
    MS             mass spectrometry
    NCI            National Cancer Institute
    NIOSH          National Institute for Occupational Safety and Health
    NOEL           no-observed-effect level
    OHM/TADS       Oil and Hazardous Materials/Technical Assistance Data
    ppbv           parts per billion (by volume)
    RBC            red blood cell
    RCRA           Resource Conservation and Recovery Act
    RGD            reduction gas detector
    RTECS          Registry of Toxic Effects of Chemical Substances
    TWA            time-weighted average
    UV             ultraviolet
    v/v            volume per volume
    WBC            white blood cell

    1. SUMMARY

    1.1 Properties

         Acetone (relative molecular mass = 58.08) is a clear colourless
    flammable liquid (flash point -17°C closed cup, -9°C open cup;
    flammability limits in air at 25°C = 2.15-13% v/v). The explosive
    limits in air are 2.6-12.8% v/v. It has a high evaporation rate
    (vapour pressure 181.72 mmHg at 20°C) and a low viscosity (0.303 cP at
    25°C). It is miscible with water and organic solvents.

    1.2 Uses and sources of exposure

    1.2.1 Production

         Acetone is manufactured mainly by the cumene peroxidation or
    isopropyl alcohol dehydrogenation processes. The cumene peroxidation
    process produces trace quantities of benzene as a by-product.

    1.2.2 Uses and emissions into the environment

         Acetone is used mainly as a solvent and intermediate in chemical
    production. Major uses are in the production of methyl methacrylate,
    methacrylic acid and higher methacrylates, bisphenol A, methyl
    isobutyl ketone, drug and pharmaceutical applications, and as a
    solvent for coatings and for cellulose acetate. There are also food
    uses as an extraction solvent for fats and oils, and as a
    precipitation agent in sugar and starch purification.

         Atmospheric emissions occur from consumer products including nail
    polish removers, particle board, carpet backing, some paint removers,
    and liquid/paste waxes or polishes. Certain detergents/cleansers,
    adhesives, and automobile carburetor and choke cleaners also contain

         Acetone is released into surface water in wastewater effluents
    from a wide range of manufacturing processes and industries, such as
    paper, plastic, pharmaceuticals, specialty cleaning and polishing
    products, paint and allied products, gum and wood chemicals, cyclic
    intermediates, industrial organic chemicals, gypsum products, paper
    board products, and energy-related industries, such as
    coal-gasification and oil shale processing.

         Sources of acetone release into soil include disposal of
    agricultural and food waste, animal waste, atmospheric wet deposition,
    household septic tank effluents and chemical waste disposal sites.

    1.3 Environmental transport, distribution and transformation

         Acetone released to the atmosphere is degraded by a combination
    of photolysis and reaction with hydroxyl radicals. The average
    half-life for acetone degradation in the atmosphere is approximately
    30 days. Acetone can be physically removed from air by wet deposition.
    The dominant degradation process for acetone in soil and water is
    biodegradation, and acetone is readily biodegradable. Volatilization
    of acetone from the aquatic environment can be a significant transport
    process. Acetone is a volatile compound that will evaporate from dry
    surfaces. Since acetone is miscible in water, it can leach readily in
    most types of soil. Concurrent biodegradation may diminish the general
    significance of leaching if biodegradation occurs fast enough.

    1.4  Environmental levels and human exposure

         Exposure to acetone results from both natural and anthropogenic
    sources. Acetone also occurs as a metabolic component in blood, urine
    and human breath. It occurs as a biodegradation product of sewage,
    solid wastes and alcohols, and as an oxidation product of humic
    substances. Acetone has been detected in a variety of plants and foods
    including onions, grapes, cauliflower, tomatoes, morning glory, wild
    mustard, milk, beans, peas, cheese and chicken breast. Natural
    emissions from a variety of tree species contain acetone vapour. Human
    sources of emissions to the aquatic environment include waste-water
    discharges from many industries and leaching from industrial and
    municipal landfills. A major source of human emission to air is
    evaporation of acetone solvent from coating products such as paints,
    cleaners, varnishes and inks. Acetone is an emission product from the
    combustion of wood, refuse and plastics. It is also emitted in exhaust
    from automobile, diesel and turbine engines. Concentrations of acetone
    monitored in the atmosphere range from 0.5 to 125.4 µg/m3 (0.2-52.9

    1.5  Kinetics and metabolism

         Acetone is one of three ketone bodies that occur naturally
    throughout the body. It can be formed endogenously in the mammalian
    body from fatty acid oxidation. Fasting, diabetes mellitus and
    strenuous exercise increase endogenous generation of acetone. Under
    normal conditions, the production of ketone bodies occurs almost
    entirely within the liver and to a smaller extent in the lung and
    kidney. The process is continuous, and the three products are excreted
    into the blood and transported to all tissues and organs of the body
    where they can be used as a source of energy. Two of these ketone
    bodies, acetoacetate and ß-hydroxybutyrate, are organic acids that can
    cause metabolic acidosis when produced in large amounts, as in
    diabetes mellitus. Acetone, in contrast, is non-ionic and is derived
    endogenously from the spontaneous and enzymatic breakdown of
    acetoacetate. Endogenous acetone is eliminated from the body either by

    excretion in urine and exhaled air or by enzymatic metabolism. Under
    normal circumstances, metabolism is the predominant route of
    elimination and handles 70-80% of the total body burden.

         Acetone is rapidly absorbed via the respiratory and
    gastrointestinal tracts of humans and laboratory animals, as indicated
    by the detection of acetone in blood within 30 min of inhalation
    exposure and 20 min of oral administration. Studies of rats indicate
    that orally administered acetone is extensively absorbed, whereas
    during inhalation exposures humans absorb approximately 50% of the
    amount of inhaled acetone. However, lower and higher respiratory
    absorption values have been reported. The nasal cavities of humans and
    laboratory animals appear to have a limited ability to absorb and
    excrete acetone vapour, compared with the remainder of the respiratory

         Acetone is uniformly distributed among non-adipose tissues and
    does not accumulate in adipose tissues. In mice, maximum acetone
    concentrations in adipose tissues were reported to be about one-third
    of those in non-adipose tissues following inhalation exposure. Acetone
    is rapidly cleared from the body by metabolism and excretion.
    Half-times for acetone in human alveolar air and venous and arterial
    blood are -4, 6 and 4 h, respectively. Exhalation is the major route of
    elimination for acetone and its terminal metabolite (CO2) and the
    fraction of administered acetone that is exhaled as unchanged acetone
    is dose-related. Urinary excretion of acetone and its metabolites
    occurs, but this route of elimination is minor compared with
    exhalation of acetone and respiratory CO2.

         Exogenously supplied acetone enters into many metabolic reactions
    in tissues throughout the body, but the liver appears to be the site
    of most extensive metabolism. Carbon from orally administered acetone
    has been detected in cholesterol, ammo acids, fatty acids and glycogen
    in rat tissues, urea in urine and unchanged acetone and CO2 in
    exhaled breath. Metabolically, acetone is degraded to acetate and
    formate; this accounts for the entry of carbon from acetone into
    cholesterol, fatty acids, urea and amino acids, and formation of
    3-carbon gluconeogenic compounds.

         Gluconeogenesis from acetone has been proposed to proceed by two
    pathways. The first pathway proceeds through the initial catalytic
    action of acetone monooxygenase and acetol monooxygenase, which
    convert acetone to acetol and acetol to methylglyoxal, respectively.
    Both of these enzymatic activities are induced by acetone and have
    been identified as an isozyme of ethanol-inducible, hepatic eytochrome
    P-450IIE1. The second gluconeogenic pathway involves the formation of
    1,2-propanediol from acetone catalysed by acetone monooxygenase and a
    non-characterized enzyme capable of converting acetol to

    1.6  Effects on laboratory mammals and in vitro systems

         Oral LD50 values in adult rats are in the range of 5800-7138
    mg/kg. The 4-h inhalation LC50 value is 76 000 mg/m3 (32 000 ppm).

         Acute exposure to acetone has been found to alter performance in
    neurobehavioural tests in laboratory animals at concentrations greater
    than 7765 mg/m3 (>3270 ppm).

         Experimental animal data characterizing the effects of long-term
    oral or inhalation exposure to acetone are not available, due probably
    to its low toxicity and its endogenous characteristics.

         Prolonged acetone inhalation exposure of rats to 45 100 mg/m3
    (19 000 ppm), 3 h/day, 5 days/week for 8 weeks, produced a reversible
    decrease in absolute brain weight. No consistent changes were noted in
    weights of other organs or the whole body, in blood chemical indices,
    in liver triglyceride levels or in the histology of the heart, lung,
    kidney, brain or liver.

         In a 90-day gavage study of rats, increased blood parameters
    (increased haemoglobin, haematocrit) were observed at dose levels
    >500 mg/kg per day, and a NOAEL of 500 mg/kg per day was identified.
    In a 13-week drinking-water study, toxic effects were noted in male
    rats exposed to concentrations >20 g/litre (approx. 1700 mg/kg body
    weight per day), namely increased relative organ weights, altered
    haematological indices and mild nephropathy. In female rats
    administered the highest concentration, 50 g/litre (approx. 3400 mg/kg
    body weight per day), the effects were increased organ relative
    weights and altered haematological indices. In addition, a 13-week
    exposure to 50 g/litre caused altered relative testis weight and
    altered sperm motility and morphology in male rats. Female mice given
    50 g/litre (approx. 11 298 mg/kg body weight per day) in
    drinking-water had altered liver and spleen weights and a marginally
    increased incidence of centrilobular hepatocellular hypertrophy. No
    toxic effects were observed in male mice administered 20 g/litre (4858
    mg/kg body weight per day), the highest acetone level administered to
    male mice. Thirteen-week exposures to concentrations < 10 g/litre
    (900 mg/kg body weight per day) in drinking-water were associated with
    no toxic effects in male rats; concentrations < 20 g/litre were
    NOELs for female rats (1600 mg/kg body weight per day) and mice (male
    4858 mg/kg body weight per day; female 5945 mg/kg body weight per day)
    of both sexes.

         In a preliminary 14-day drinking-water study of rats and mice,
    dose-related centrilobular hepatocellular hypertrophy was noted in
    male mice exposed to concentrations of 20-100 g/litre.

         Pretreatraent of rodents with acetone enhances the hepatotoxic
    effects of a number of compounds, notably halogenated alkanes, It is
    hypothesized that the potentiation of the hepatotoxicity is mediated
    by acetone-induced elevations of enzymatic activities (hepatic
    mixed-function oxidases) that are responsible for the generation of
    toxic intermediates from administered halogenated alkanes.

         Acetone has tested negatively for genetic toxicity in numerous
    non-mammalian systems, as well as in  in vitro and  in vivo
    mammalian systems. Positive results are restricted to a single test
    for aneuploidy in a yeast species exposed to high concentrations of
    acetone (6.82%) in its growth medium. Acetone is not considered to be
    genotoxic or mutagenic.

         In a study of pregnant rats and mice exposed to acetone vapour
    during days 6-19 of gestation, slight developmental toxicity was
    observed following exposures of rats to 26 100 mg/m3 (11 000 ppm) for
    6 h/day (increased percentage of litters with at least one fetal
    malformation) and following exposures of mice to 15 670 mg/m3 (6600
    ppm) for 6 h/day (small decrease in fetal weight and small increase in
    percentage incidence of late resorptions). An atmospheric
    concentration of 5200 mg/m3 (2200 ppm) was identified as a NOAEL for
    developmental toxicity in both mice and rats. In a gavage study,
    treatment at 3500 mg/kg per day during organogenesis impaired
    reproduction in a screening test in mice. Negative results  in vivo
    in two different species, using oral and intraperitoneal routes,
    indicated that no mutagenic changes were produced in mammals exposed
    to acetone.

         Reports of other reproductive effects of acetone include
    observations of testicular effects and changes in sperm quality in
    rats administered drinking-water containing 50 g acetone/litre for 13
    weeks. No investigations of the effect of oral doses of acetone on
    fetal development (fetotoxicity and teratogenicity) were available.

         Acetone has been used extensively as a solvent vehicle in skin
    carcinogenicity studies and is not considered carcinogenic when
    applied to the skin.

    1.7  Effects on humans

         Acetone is relatively less toxic than many other industrial
    solvents; however, at high concentrations, acetone vapour can cause
    CNS depression, cardiorespiratory failure and death. Acute exposures
    of humans to atmospheric concentrations as high as approx. 4750 mg/m3
    (approx. 2000 ppm) have been reported to produce either no gross toxic
    effects or minor transient effects, such as eye irritation. More
    severe transient effects (including vomiting and fainting) were
    reported for workers exposed to acetone vapour concentrations >25 500
    mg/m3 (>12 000 ppm) for approx. 4 h. Acute exposures to acetone have
    also been reported to alter performance in neurobehavioural tests in

    humans at 595 mg/m3 (250 ppm). Females exposed to atmospheric
    concentrations of 2370 mg/m3 (1000 ppm) were reported to suffer
    menstrual irregularities.

    1.8  Effects on other organisms in the laboratory and field

         For most freshwater and saltwater animal species, 48- and 96-h
    LC50 and EC50 values are >5540 mg/litre.

         Growth of the alga  Chlorella pyrendoidosa exposed to acetone at
    257.4 mg/litre for 76 h was inhibited. There was inhibition of growth
    of  Chlamydomonas eugametos exposed to acetone for 48 h at 790
    mg/litre. Photosynthesis was increased in  Scendesmus quadricauda and
     C. pyrenoidosa exposed to 79.0 and 790 mg/litre.

         The 7- to 8-day toxicity thresholds for the green alga
     S. quadricauda and the cyanobaeterium (blue-green alga)
     Microcystis aeruginosa were 7500 and 530 mg/litre, respectively,
    indicating that the green alga was more resistant to the toxic action of
    acetone. The diatom  Nitzschia linearis also seemed very resistant,
    with a 5-day EC50 of 11 493 to 11 727 mg/litre. Similarly, the saltwater
    diatom  Skeletonema costatum was very resistant with 5-day EC50
    values of 11 798 and 14 440 mg/litre.

         Bacteria appear more resistant to acetone than protozoans.
     Photobacterium phosphoreum,  Pseudomonas putida and a mixed
    microbial culture had EC50 values of 1700 to 35 540 mg/litre, and the
    protozoan  Entosehon sulcatum had an EC50 of 28 mg/litre. This may
    be related to cell wall differences.

         Quails and pheasants had oral 5-day LC50 values > 40 g/kg
    diet. Fertile mallard eggs were not affected when immersed in 10%
    acetone for 30 seconds; however, immersion in 100% acetone resulted in
    decreases in survival, embryonic weight and embryonic length, but it
    is not clear if this was due to the toxic or the solvent properties of
    acetone. White Leghorn chicken eggs injected with 5 µl acetone did not
    appear to have any significant changes in mortality or malformations.


    2.1  Chemical identity

    Chemical name                 acetone
    Synonym(s)                    dimethyl ketone; 2-propanone;
    Chemical formula              C3H6O
    Chemical structure            
                                  H3C - C - CH3

    Identification numbers:
         CAS registry             67-64-1

         NIOSH RTECS              AL3150000

         EPA Hazardous Waste
         (RCRA)                   U002; F003

         OHM/TADS                 7216568

         DOT/UN/NA/IMCO shipping  UN1090

         HSDB                     41

         EINECS                   200-662-2

    Relative molecular mass  58.08

    2.2  Physical and chemical properties

    2.2.1  Physical properties

         Acetone is a clear and colourless liquid with a strong "fruity"
    odour. It is miscible with water and organic solvents such as ether,
    methanol, ethanol and esters (Nelson & Webb, 1978). The physical
    properties of acetone, such as high evaporation rate, low viscosity
    and miscibility, make it suitable for use as a solvent (Krasavage et
    al., 1982). The physical properties of acetone are shown in Table 1.

    2.2.2  Chemical properties

         Acetone shows reactions typical of saturated ketones (SRI, 1996).
    These reactions include addition, oxidation-reduction and
    condensation, and yield alcohols, ketals, acids and amines (Papa &
    Sherman, 1981). The chemical reactivity of acetone is commercially
    important for the synthesis of methyl methacrylate, diacetone alcohol,
    bisphenol A and other derivatives (SRI, 1996).

        Table 1. Physical and chemical properties of acetone


    Property                          Value/descriptiona           Reference

    Relative molecular mass           58.08                        Riddick et al, (1986)

    Colour                            Clear colourless             Sax & Lewis (1987)

    Physical state                    Liquid                       Sax & Lewis (1987)

    Melting point                     -95.35°C                     Weast (1987}

    Freezing point                    -94.7°C at 1 atm             Riddick et al. (1986)

    Boiling point                     56.2°C at 1 atm              Weast (1987)
                                      (760 torr)


    at 20°C                           0.78996 g/ml                 Riddick et al. (1986)

    at 26°C                           0.78440 g/ml                 Riddick et al. (1966)

    at 30°C                           0.78033 g/ml                 Riddick et al. (1986)

    Odour threshold:

    Acetone in water                  20 mg/litre                  Amoore & Hautala

    Air (absolute)                    30-48 mg/m3                  Amoore & Hautala
                                      (13-26 ppm (v/v))            (1983)

    Air (detection)                   9.5 mg/m3 (4 ppm)            Wysocki et al. (1997)

    100% odour recognition            237-332 mg/m3                Hellman & Small
                                      (100-140 ppm)                (1974); Leonardos et
                                                                   al. (1969)

    Table 1 (contd).
    Property                          Value/descriptiona           Reference

    Water at 20°C                     Completely miscible          Windholz (1963)

    Organic solvent(s)                Soluble in organic
                                      solvents                     Windholz (1983)

    Viscosity at 25°C                 0.303 cP                     Riddick et al. (1986)

    Partition coefficients:

    Log Kow                           -0.24                        Sangster (1989)
    Log Koc                           0.73b                        Lyman (1982)
    KB/A                              301 ± 22                     Dills et al. (1994)

    Vapour pressure                   181.72 mmHg (at 20°C)        Riddick et al. (1986)
                                      231.06 mmHg (at 25°C)        Riddick et al. (1986)

    Henry's law constant:             4.26 × 10-5 atm-m3/mol       Rathbun & Tai (1987)
    at 25°C

    Flashpoint (closed cup)           -17°C                        Riddick et al. (1986)
    (open cup)                        -9°C                         Riddick et al. (1986)

    Flammability limits               Lower, 2.2%;                 Clayton & Clayton
    in air at 25°C                    upper, 13.0%                 (1982)

    Minimum ignition                  465°C                        Riddick et al. (1986)

    Explosive limits                  Lower, 2.6% in air (v/v);    Sax & Lewis (1987)
                                      upper, 12.8% in air (v/v)    Sax & Lewis (1987)

    a w/v = weight per volume, v/v = volume per volume.
    b Estimated by regression equation 4-13 in Lyman (1982).

    2.3  Conversion factors

    Conversion factors in air at 25°C:
         1 ppm = 2.374 mg/m3
         1 mg/m3 = 0.421 ppm

    2.4  Analytical methods

         A number of analytical methods is available for the detection,
    sampling and monitoring of acetone and its metabolites in the various
    media. Acetone is a well-studied chemical and is used frequently in
    the laboratory. This section is a review of the more established and
    standard practices in use today.

    2.4.1  Biological media

         Methods for determining the presence of acetone in biological
    organisms are listed in Table 2. Acetone is found in almost every
    tissue and organ in the human body. Acetone and two other chemicals,
    beta hydroxybutyrate and acetoacetate, are collectively referred to as
    "ketone bodies". In the last 30 years much has been learned of acetone
    in biological tissue since the discovery that acetone levels in
    diabetes mellitus patients with severe hyperketonaemia may be
    significant (Trotter et al., 1971). Higher acetone levels may be found
    in the blood levels of individuals or animals after strenuous exercise
    or prolonged dieting. Acetone production is also increased in animals
    in disease states such as diabetes and anorexia.

         The development of biological analytical methods can be done to
    measure, but this does not distinguish acetone from either endogenous
    and exogenous sources or from acetone in ketone levels in body fluids,
    since acetone is produced within the biological system by breaking
    down lipids and stored fats. Most of the methods for measuring acetone
    in expired air use gas chromatography (GC/FID) and involve the
    breakdown of beta-hydoxybutyrate and acetoacetate into acetone, which
    is isolated and quantified by any of the techniques listed in Table 2.
    The differences between these methods have been mainly concerned with
    the nature of the column packing and with the various methods of
    sample collection.

         The determination of acetone in blood is difficult because it is
    a metabolite and the quantity produced depends on storage time, even
    when the blood samples are stored at 4°C (Trotter et al., 1971). The
    delay between sample collection and analysis could lead to spuriously
    elevated acetone concentrations because of the spontaneous
    decarboxylation of acetoacetate (Van Stekelenburg & Koorevaar, 1972).
    One method for the determination of acetone in the clinical laboratory
    involves deproteinizing with acetonitrile and derivitization of the
    sample with 2,4-dinitrophenylhydrazine, followed by isolation and
    quantification of the hydrazone by high pressure liquid chromatograph

        Table 2. Analytical methods for determining acetone in biological media
    Sample matrix            Preparation method                 Analytical         Sample detection     Reference
                                                                method             limit
    Whole blood, urine       Centrifuged and deproteinized     GC-HPLC            33 µg/ml            Gavino et al. (1986)
                             with acetonitdle and 2,4-DNPH

    Whole blood              Deproteinized with HClO4 and      GC-FID             0.4 µmol/litre      Mangani & Ninfali
                             subjected to purge-and-trap                                                (1988)

    Whole blood              Purge-and-trap                    GC-MS              0.2 µg/ml           Ashley et al. (1992)

    Serum                    Deproteinized with sodium         HRGC-FID           <58 µg/ml           Smith (1984)
                             tungstate and cupric sulfate                         (<1 nmol/litre)

    Serum                    Sample centrifuged and clear      GC-FID             5.8 mg/ml            Cheung & Lin
                             filtrate injected                                    (0.1 nmol/ml)        (1987)
                             into GC

    Urine                    Diluted sample derivatized with   GC-FID             0.2 µg/ml            Kobayashi et al.
                             pentafiuorobenzyloxyl ammonium                       (3.45 µmol/ml)       (1983)
                             chloride and extracted with

    Liver perfusate,         Reduction to isopropanol using    GC-HPLC            33 µmol/ml           Gavino et al. (1987)
    blood, urine             sodium borohydrid and
                             separation by HPLC

    Liver                    Liver perfusion medium reduced    GC-FID             3.78 µg/ml in       Holm & Lundgren
                             with NaBH4 and an aliquot of                         perfusate           (1984)
                             reduced solution injected                            (65 µmol/litre)
                             into GC

    Liver, kidney, lung      Purge-and-trap                    GC-FID             No data              Holm & Lundgren
    and adipose tissue                                                                                 (1984)

    Breath                   Direct injection into GC          GC-FID             No data              Trotter et al. (1971);
                                                                                                       Jansson & Larsson (1969)

    (HPLC) (Brega et al., 1991). This method prevents acetoacetate, which
    is present in plasma, from being thermally degraded to acetone on the
    column when using a GC method (Gavino et al., 1987). The HPLC method
    can also be used to measure acetone in urine or liver perfusate. This
    method can be used in experiments requiring multiple samples and thus
    can be used for diabetic patient monitoring, as well as for
    occupational exposure monitoring.

    2.4.2.  Environmental media

         Analytical methods for determining acetone in air, water and soil
    are presented in Table 3. The commonly used methods are direct GC/MS
    of a sample concentrate or HPLC of the 2,4-dinitrophenyl-hydrazine
    derivative. In the United Kingdom, the 2,4-dinitrophenyl-hydrazine
    HPLC method is applied to the analysis of acetone in water and there
    is a standardized validated method (UK SAC, 1988).

         When sampling for acetone, the incorrect use of Tedlar bags and
    activated carbon may lead to spurious results.

        Table 3 Analytical methods for determining acetone in environmental samples

    Sample matrix           Preparation method                                         Analytical method    Sample detection   Reference

    Air (occupational)      Air passed through charcoal and components                 GC-FID (NIOSH        7 µg/litre         NIOSH (1994)
                            desorbed with CS2                                          method 1300)

    Air                     Air passed through a cryogenic trap and the                GC-RGD               10 ppt             O'Hara & Singh
    (ambient)               trapped component injected into GC                                                                 (1988)

    Air                     Air passed through                                         HPLC-UV              <3 µg/litre        Risner (1995)
    (ambient)               2,4-dinitrophenylhydrazine-coated cartridge and eluted     reversed-phase
                            with acetonitrile and tetrahydrofuran                      column

    Air (indoor)            Diffusive sampler with silica gel tape impregnated with    HPLC-UV              15 µg/litre        Brown et al.
                            2,4-dinitrophenylhydrazine and eluted with acetonitrile                         (1994)

    Air                     Air passed through a 1% sodium bisulfite solution and      Spectrophotometry    <0.5 ppm (in       Amlathe & Gupta
                            absorbed acetone reacted with alkaline vanilla solution                         solution)          (1990)

    Rural air               Air passed through silica gel coated with                  HPLC-UV              No data            Shepson et al.
                            2,4-dinitrophenylhydrazine and eluted with acetonitrile                                            (1991)

    Water                   Sample reacted with alkaline diazotized anthranilic        Spectrophotometry    500 µg/litre       Rahim & Bashir
                            acid solution                                                                                      (1981)

    Fresh and seawater      Sample derivatized with 2,4-dinitrophenylhydrazine         HPLC-UV detection    0.5 nmol/litre     Kieber & Mopper
                            passed through a C18 cartridge and absorbed                                     (0.03 µg/litre)    (1990)
                            compound eluted with acetonitrile

    Waste water, soil or    Sample or sample mixed with reagent water subjected        GC-MS                100 µg/litre       US EPA (1986b)
    sediment                to purge-and-trap                                          (EPA method 8240)    (water)
                                                                                                            100 µg/k9
                                                                                                            (sediment and

    Fresh fruit             Vacuum distillation followed by solvent extraction         HRGC-MS              No data            Takeoka et al.
                            of pulp                                                                                            (1988)


    3.1  Natural occurrence

         Acetone occurs as a metabolic component in blood, urine and human
    breath (Conkle et al., 1975). Because endogenous acetone formation is
    so closely linked with the utilization of stored fats as a source of
    energy, background levels can fluctuate depending on an individual's
    health, nutrition, and level of activity (Morgott, 1993). The acetone
    level in the human body at any instant is reflective of acetoacetate
    production and ketogenesis. It occurs naturally as a biodegradation
    product of sewage, solid wastes and alcohols and as an oxidation
    product of humic substances. Acetone has been detected in a variety of
    plants and foods, including onions, grapes, cauliflower, tomatoes,
    morning glories, wild mustard, milk, beans, peas, cheese and chicken
    breast (Day & Anderson, 1965; Grey & Shrimpton, 1967; Palo & Ilkova,
    1970; Lovegren et al., 1979). Natural emissions from a variety of tree
    species contain acetone vapour (Isidorov et al., 1985) and another
    source is direct emission from the ocean (Zhou & Mopper, i990).

    3.2  Anthropogenic sources

         There are many anthropogenic sources of acetone, with various
    levels and concentrations that cover a broad range. Human sources of
    emissions to the aquatic environment include wastewater discharges
    from many industries (Perry et al., 1978; NLM, 1992) and leaching from
    industrial and municipal landfills (Sabel & Clark, 1984; Brown &
    Donnelly, 1988). A major source of emission to the air is from
    evaporation of acetone solvent from coating products such as paints,
    cleaners, varnishes and inks. Acetone is an emission product from the
    combustion of wood, refuse and plastics (Lipari et al., 1984; Graedel
    et al., 1986), and is emitted in exhaust from automobile, diesel and
    turbine engines (Barber & Lodge, 1963; Lloyd, 1978; Jonsson ct al.,
    1985; Graedel et al., 1986; Westerholm et al., 1988; Zweidinger et
    al., 1988).

         Other important anthropogenic sources of acetone in the air are
    chemical manufacture (Graedel et al., 1986), tobacco smoke (Manning et
    al., 1983), wood burning and pulping (Lipari et al., 1984; Graedel et
    al., 1986; Kleindienst et al., 1986), polyethylene burning (Hodgkin et
    al., 1982), refuse combustion (NAS, 1976), petroleum production
    (Graedel, 1978), and certain landfill sites (LaRegina et al., 1986;
    Militana & Mauch, 1989; Hodgson et al., 1992). Acetone is formed in
    the atmosphere from the photochemical oxidation of propane (Singh &
    Hanst, 1981; Arnold et al., 1986) and possibly from propylene oxide
    and epichlorohydrin (Spicer et al., 1985).

         In a US EPA-sponsored survey of household products analysed by
    purge-and-trap GC/MS for volatile organic compounds, acetone was found

    in 314 of 1005 products (31.2%). Of the eight product categories, the
    highest categories were paint-related (51.5% contained acetone),
    adhesive-related (24.3%) and automotive (22.7%) products (Sack et al.,

    3.2.1  Production levels and processes

         In 1994, world acetone capacity amounted to almost 3.83 million
    tonnes (SRI, 1996). Since approximately 80% of acetone is produced as
    a co-product of phenol, demand for phenol largely determines acetone
    production levels. World production in 1994 was estimated to be 3.22
    million tomes, and demand for acetone was expected to grow at an
    average annual rate of 3.3% annually from 1994 to 1999 (SRI, 1996).

         The USA is the largest producer of acetone. Table 4 depicts the
    capacity of the largest manufacturers in the USA in 1995, while Table
    5 shows the capacity of other countries. The annual capacity in the
    European Union in 1992-1994 was 1.1-1.2 million tonnes.

         Most acetone is manufactured by one of two processes, cumene
    peroxidation (94% yield) or isopropyl alcohol dehydrogenation (IPA)
    (95% yield) (SRI, 1996). In the peroxidation process, cumene is
    oxidized to hydroperoxide, which is cleaved to yield acetone and
    phenol. In the dehydrogenation process, isopropyl alcohol is
    catalytically dehydrogenated to yield acetone and hydrogen (Nelson &
    Webb, 1978). The cumene peroxidation process accounts for 96%; IPA
    accounts for the other 4%. Production grade acetone is 99.5% acetone,
    0.5% water. Fermentation of corn starch and molasses to produce
    acetone, using  Clostridium acetobutylicium, is utilized in several
    countries, including Russia, Egypt, Brazil and India (Sifniades,
    1985). Although acetone is more costly to produce by the IPA process,
    this process has no benzene contamination. Acetone produced through
    the cumene process contains benzene at concentrations < 10 ppm
    (SRI, 1996).

         Some companies recover acetone as a by-product (SRI, 1996). For
    example, in the United Kingdom there is a plant producing 52 000
    tonnes per year that recovers acetone as a by-product of acetic acid
    manufacture, and two Japanese manufacturers recover acetone from
    cresol production.

    3.2.2  Uses

         Acetone is used primarily as an intermediate in chemical
    production and as a solvent (SKI, I996). It is used as a solvent for
    resins, paints, inks, varnishes and lacquers and in adhesives,
    thinners and clean-up solvents. Pharmaceutical applications of acetone
    include use as an intermediate and solvent for drags, vitamins and
    cosmetics (Nelson & Webb, 1978). It has uses as an extraction solvent
    for fats and oils and a precipitation agent in the purification of
    starches and sugars (FAO/WHO, 1971).

        Table 4: Major manufacturers of acetone in the USA in 1995a

    Manufacturer                  Location                 Annual capacity
                                                           (thousands of tonnes)

    Allied Signal, Inc,           Philadelphia, PA         280
    Aristech Chemical Corp.       Ironton, OH              180
    Dow Chemical USA              Oyster Creek, TX         161
    Eastman Chemical Co.          Kingsport, TN            13
    Mt. Vernon Partnership        Mount Vernon, IN         191
    Georgia Gulf Corp.            Pasadena, TX             45
                                  Plaquemine, LA           123
    Goodyear Tire & Rubber Co.    Bayport, TX              7
    JLM Chemicals, Inc.           Blue Island, IL          26
    Shell Chemical Co.            Deer Park, TX            182
    Texaco, Inc.                  El Dorado, KS            26
    Union Carbide Corp.           Institute, WV            77

    Total                                                  1281

    a  SRI (1996)

    Table 5: Production capacity of acetone in 1995 (excluding the USA)a
    Country                       Annual capacity
                                  (thousands of tonnes)

    Germany                       388
    Italy                         235
    France                        168
    United Kingdom                97
    Netherlands                   80
    Spain                         75
    Brazil                        71
    Finland                       65
    Mexico                        22
    Argentina                     20
    Venezuela                     10

    TOTAL                         1185

    a  SRI (1996)
         In 1995 the USA use pattern for acetone was as follows: acetone
    cyanohydrin/methyl methacrylate, methacrylic acid and higher
    methacrylates (45%); solvent applications (17%); bisphenol A (18%);
    aldol chemicals/methyl isobutyl ketone and others (12%); and
    pharmaceutical and other applications (8%) (SKI, 1996).

         The largest solvent application for acetone is as a surface
    coating, including use as a thinner and wash solvent. In 1995,
    greatest use of acetone as a solvent was in automotive coatings, both
    original equipment and automotive refinishing (SKI, 1996). The next
    greatest use for acetone is the production of acetone cyanohydrin
    which is used to produce an acrylic resin monomer, methyl
    methacrylate. Bisphenol A is produced from acetone and used in
    polycarbonate resins.

         Acetone is also used in food processing as an extraction solvent
    for oils and fats and as a precipitation agent in the purification of
    starches and sugars.

    3.2.3  Releases  Air

         Atmospheric emissions are likely from the many consumer products
    containing acetone (US EPA, 1989). Such products include nail polish
    removers, particle board (Tichenor & Mason, 1988), carpet backing
    (Hodgson et al., 1993), some paint removers, a number of liquid/paste
    waxes or polishes, some detergents/cleansers, adhesives (Knöppel &
    Schauenburg, 1989; Sack et al., 1992) and carburetor and choke
    cleaners (US EPA, 1989).

         Atmospheric emissions from the phenol/acetone production process
    are approximately 0.44 g per kg of acetone produced (Sifniades, 1985).  Water

         Acetone is released into surface water as wastewater from certain
    chemical manufacturing industries (Jungclaus et al., 1978; Hites &
    Lopez-Avila, 1980; Gordon & Gordon, 1981). It is also released in
    water from energy-related industries, such as coal-gasification
    (Pellizzari et al., 1979; Mohr & King, 1985) and oil shale processing
    (Pellizzari et al., 1979; Hawthorne & Sievers, 1984). Acetone was
    found in 27 of 63 effluent water samples from a wide range of chemical
    industries in the USA (Perry et al., 1979). It has been detected in
    effluents from various industrial production processes including
    paper, plastic, pharmaceutical, specialty cleaning and polishing
    products, paint and allied products, gum and wood chemicals, cyclic
    intermediates, industrial organic chemicals, gypsum products, and
    paper board products.

         Acetone can be released to groundwater as a result of leaching
    from municipal and industrial landfills (Gould et al., 1983; Steelman
    & Ecker, 1984; Sawhney & Raabe, 1986; Brown & Donnelly, 1988). It may

    also leach from solvent cement used in joining polyethylene and other
    plastic pipes used in drinking-water distribution and domestic
    plumbing (Anselme et al., 1985). One of the sources of acetone in
    seawater is the sensitized photoreaction of dissolved organic matter
    (Mopper & Stahovec, 1986).  Soil

         Acetone leaches readily in soil. The US Agency for Toxic
    Substances and Disease Registry (ATSDR, 1994) found the amount of
    acetone released into soil from landfills in the USA accounted for
    approximately 0.1% of the total environmental release of acetone.
    Sources of acetone release into soil include disposal of agricultural
    and food waste, animal wastes, and atmospheric wet deposition. Acetone
    was detected in 43% of the soil from designated waste disposal sites
    tested for acetone. Household septic tank effluents are another source
    of acetone in soil (DeWalle et al., 1985).


    4.1  Transport and distribution among media

         Acetone is commonly found in air, water, soil and biological
    samples, and these background levels can he from both human-made and
    natural sources. Acetone occurs naturally in trees, plants, forest
    fires and volcanic gases. When animals and humans catabolize body fat,
    acetone is exhaled and metabolized. Human-made sources include tobacco
    smoke, combustive engine exhaust and waste incineration. The exchange
    of carbonyl compounds (including acetone) between air and natural
    waters is governed by the appropriate partition coefficients, in
    addition to production and loss processes in both media (Benkelberg et
    al., 1995).

    4.1.1  Air

         The significant environmental fate processes for the degradation
    of acetone in the ambient environment are photolysis and reaction with
    hydroxyl radicals (Meyrahn et al., 1986; Kerr & Stocker, 1986).
    Meyrahn et al. (1986) measured the quantum yields of acetone
    photolysis at environmental wavelengths and projected the following
    rate constants for the lower troposphere at 40°N latitude: in January,
    3.3 × 10-8/sec; in July, 1.8 × 10-7/sec; yearly average,
    1.0 × 10-7/sec. These rate constants correspond to half-lives of
    243, 45 and 80 days for January, July and the yearly average,
    respectively. These rate constants intentionally neglect reaction of
    excited acetone molecules with oxygen. Based on the photodecomposition
    data of Gairdner et al. (1984), the rate constants of Meyrahn et al.
    (1986) would be about twice as great if the neglected reaction were
    included. Using this factor of 2, the total yearly average photolysis
    half-life (plus reaction of excited acetone molecules) is about 40
    days. The rate constant for the reaction of hydroxyl radicals with
    acetone at 25°C is in the range of 2.2-2.6 × 10-13 cm3/molecule-sec
    (Kerr & Stocker, 1986; Wallington & Kurylo, 1987). Probable pathways
    for the reaction of acetone with hydroxyl radicals in the troposphere
    have been postulated, and methyl-glyoxal is the primary product of
    this reaction (Altshuller, 1991). The primary products of acetone
    photolysis in sunlight are carbon dioxide and acetylperoxynitrate
    (Altshuller, 1991). The photochemical oxidation of acetone in the
    presence of nitrogen oxides produces small amounts of peroxyacetic
    acid and peroxyacetyl nitrate (Hanst & Gay, 1983).

         The photolysis lifetimes of acetone under cloudless conditions at
    40°N latitude, and at sea level during winter and summer were
    estimated to be 83 and 19 days, respectively (Martinez et al., 1992).
    Other investigators have estimated that the average atmospheric
    lifetime of acetone due to photolysis at 40°N latitude is 80 days/year
    and varies from 243 in January to 45 in July (Meyrahn et al., 1986).
    Meyrahn et al. (1986) estimated the average lifetime of acetone at

    40°N due to combined hydroxyl radical reaction and photolysis to be 32
    days/year, corresponding to a half-life of approx. 22 days. The
    decomposition rate showed a pronounced dependence on latitude, with
    greater losses of acetone occurring near the equator compared to the
    poles. In very polluted air, the hydroxyl radical concentration
    increased by an order of magnitude, which would lower the half-life by
    an order of magnitude.

         The complete miscibility of acetone in water suggests that
    physical removal from air by wet deposition (rainfall, dissolution in
    clouds, etc.) is probable (Aneja, 1993). The reactions of acetone
    vapour with nitrogen oxides, hydroxyl radicals (OH), singlet molecular
    oxygen (1 Delta g), singlet atomic oxygen (O(3P)), and nitrate
    radicals have been studied. Given the second order rate constants for
    the reactions of acetone with 1 Delta g (Datta & Rao, 1979) and O(3P)
    (Lee & Timmons, 1977), and the concentrations of singlet molecular and
    atomic oxygen in the atmosphere (Graedel, 1978), these reactions are
    insignificant in determining the fate of acetone in the atmosphere.
    However, Grosjean & Wright (1983) detected acetone in rain, cloud,
    mist and fog water that was collected in Southern California, USA. In
    certain instances, physical removal by wet deposition may be
    environmentally significant, especially since the degradation rate is
    not very fast. The reaction of acetone with nitrate radicals in the
    atmosphere was also determined to be insignificant (Boyd et al.,
    199l). Smog chamber studies with acetone and nitrogen oxides have
    shown that acetone has low reactivity in terms of ozone and nitrogen
    dioxide formation and that the rate of disappearance of acetone by
    this process is low (Altshuller & Cohen, 1963; Dimitriades & Joshi,

         Using 72-h back trajectories, Aneja (1993) studied organic
    compounds transported in cloud water whose origin was an industrial
    valley. Acetone was found in cloud water at an average of 460 ng/litre
    (range 0-4100 ng/litre), in clouds of low pH (2.78).

    4.1.2  Water

         The miscibility of acetone in water and the estimated low value
    of 0.73 for log Koc (see Table 1) suggests that adsorption of acetone
    to sediments and suspended solids is not significant. When water is
    not present, acetone vapour adsorbs rather strongly to the clay
    component of soil by hydrogen bonding (Goss, 1992; Steinberg &
    Kreamer, 1993). The sorption is inversely dependent on relative
    humidity, so increasing the humidity decreases sorption drastically.
    In water-saturated soil or sediment, Koc values (organic carbon), and
    not hydrogen bonding, may control the sorption of acetone (Steinberg &
    Kreamer, 1993). The experimental adsorption studies with Kaolinite,
    montmorillonite, and stream sediments showed very little or no loss of
    acetone from water to the adsorbents (Rathbun et al., 1982).

    The transport of acetone from the water column to the atmosphere
    depends on the Henry's law constant. The Henry's law constant for
    acetone is 4.26 × 10-5 atm-m3/mol (see Table 1), which suggests that
    volatilization of acetone from water, although not very fast, could be
    significant (Thomas, 1982), and likely to be important in determining
    the fate of acetone in streams (Rathbun et al., 1982). The
    volatilization rate of a chemical depends on the characteristics of
    the chemical and the presence of water, and on other ambient
    conditions (e.g., water depth, suspended solid concentration, water
    current, wind speed, temperature). Based on an estimation method
    (Thomas, 1982) and the Henry's law constant value, the volatilization
    half-life of acetone from a model river 1 m deep, flowing at a current
    of 1 m/second with a wind velocity of 3 m/sec is between 18 and 19 h.
    The mean volatilization coefficient for acetone in a model outdoor
    stream was found to be in the range of 7.15 × 10-4 to 14.8 × 10-4/min
    (Rathbun et al., 1989, 1991). Therefore, the volatilization half-life
    of acetone from the model stream is in the range of 8-16 h. It was
    concluded that volatilization will control the fate of acetone in
    water (Rathbun et al., 1989, 1991). Using a computer simulation model
    the volatilization half-life from a model pond (2 m deep) was
    estimated to be around 9 days.

         The average of four experimentally determined rate constants for
    the reaction of acetone with hydroxyl radicals in water (pH 6-7) is
    1.1 × 10-8 litres/mol-sec (Buxton et al., 1988). Assuming the
    hydroxyl radical concentration in brightly sunlit natural water is 1.0
    × 10-17 mol/litre, the half-life for the reaction is almost 20 years.
    Thus, photo-oxidation reactions of acetone in environmental waters do
    not appear to be a significant removal process. Also, photolysis of
    acetone in water, based on a rate constant for the reaction of acetone
    with hydroxyl radicals in water at pH 7 of 5.8-7.7 × 107
    litres/mol-sec and a concentration of hydroxyl radicals in eutrophic
    waters of 3 × 10-17 M (Mill & Mabey, 1985), will not be significant.
    Rathbun & Tai (1982) measured the mass transfer coefficient (KL for
    acetone in water and reported values ranging from 0.310 to 0.537. When
    distilled water or natural water containing acetone was exposed to
    sunlight for 2-3 days, no photodecomposition of acetone was observed
    (Rathbun et al., 1982). Experimental hydrolysis data for acetone have
    not been found in the available literature. However, ketones generally
    resist aqueous environmental hydrolysis (Harris, 1982) and hydrolysis
    of acetone is not expected to be significant in the environment.

         Bacterial degradation of acetone occurs, and the rate is
    increased if acclimatization of the bacteria is achieved before higher
    concentrations are present (see section Both volatilization
    and biodegradation are likely to play a part in the loss of acetone
    from surface waters. The most significant process will depend on
    particular circumstances, such as depth and amount of aeration.

    4.1.3  Soil

         The two significant transport properties for acetone in soil are
    volatilization and leaching, and acetone is also expected to
    biodegrade rapidly. Leaching transports acetone from soil to
    groundwater, with the rate of leaching from soil by rainwater
    depending on the sorption characteristics of acetone in the various
    types of soil. Since acetone may be controlled by Koc in
    water-saturated soil and has a low Koc value, sorption of acetone
    in such soil will be weak. A sorption study with moist clay soils
    indicated that aqueous acetone causes swelling in these soils (Green
    et al., 1983), and this process may allow the retention of a small
    fraction of acetone. Volatilization transports acetone from soil to
    the atmosphere. The volatility rate of acetone from soil depends on
    the soil characteristics (moisture content, soil porosity, etc.).
    Since acetone is weakly sorbed to soil, the volatility depends
    primarily on fire moisture content of the soil. In dry soil, the
    volatilization rate from soil surfaces is high due to the high vapour
    pressure of acetone. In moist soil, the rate of volatilization is
    similar to that of acetone in water and depends on the Henry's law
    constant. Acetone volatilizes moderately under these conditions. The
    detection of acetone at higher concentrations in downwind air of a
    landfill site, compared to upwind air (Militana & Mauch, 1989),
    indicates that acetone can volatilize from soil.

         No data regarding the transport or uptake of acetone from soil to
    plants are available.

         While acetone is expected to biodegrade readily in soil, no data
    are available to suggest that any degradation process in soil, other
    than biodegradation, is significant.

         Acetone has been detected in leachates from municipal and
    industrial landfills (Sabel & Clark, 1984; Sawhney & Kozloski, 1984;
    Brown & Donnelly, 1988), demonstrating that leaching through soil can
    occur. The presence of other leachate constituents can adversely
    affect the biodegradation efficiency of microbes to use acetone.

         Acetone has a relatively high vapour pressure (231.06 mmHg at
    25°C) (Riddick et al., 1986) and is used as an evaporative solvent in
    a variety of applications. Because of its volatile properties, acetone
    can be expected to evaporate from dry surfaces, particularly in spills
    on the soil surface. Although evaporation from dry surfaces should be
    a significant process, sufficient data are not available to predict
    the relative significance of evaporation from moist soils, where
    biodegradation and leaching will compete with evaporation as a removal

    4.2  Biotransformation

    4.2.1  Bioconcentration and biomagnification

    The very low log Kow value of -0.24 (see Table 1) suggests that
    bioconcentration (a process leading to a higher concentration of a
    chemical in an organism relative to that in its environment) of
    acetone in either aquatic or terrestrial organisms, and
    biomagnification (series of processes in an ecosystem by which higher
    concentrations of a chemical are attained in organisms at higher
    trophic levels) of acetone from animals of lower to higher trophic
    levels is unlikely.

    4.2.2  Biodegradation

         Many aerobic biodegradation screening studies with mixed
    microorganisms from waste-treatment plant effluents, activated sludge,
    or sewage have examined the biodegradability of acetone (Lamb &
    Jenkins, 1952; Heukelekian & Rand, 1955; Stafford & Northup, 1955;
    Ettinger, 1956; Hatfield, 1957; Gaudy et al., 1963; Price et al.,
    1974; Thom & Agg, 1975; Bridie et al., 1979; Urano & Kato, 1986a,b;
    Babeu & Vaishnav, 1987; Bhattacharya et al., 1990). These strutues
    indicate that acetone is easily biodegradable with acclimatized
    microorganisms or after a suitable lag period (approx. 1 day) (Urano &
    Kato, 1986a,b), as long as the initial concentration of acetone is not
    at a toxic level. For example, acetone at a concentration of 500
    mg/litre was toxic to microorganisms when biooxidation of acetone by
    activated sludge was attempted (Gerhold & Malaney, 1966).
    Biodegradation of acetone was similar in seawater and fresh water
    (Takemoto et al., 1981 ). The 20-day biochemical oxygen demand (BOD)
    for acetone for fresh water and saltwater was 78% and 76%,
    respectively (Lamb & Jenkins, 1952; Price et al., 1974). After a
    suitable lag period (5 days), acetone biodegraded quantitatively under
    anaerobic conditions with anaerobic acetate-enriched culture medium
    (Chou et al., 1979). A biodegradation study of acetone in natural
    water collected from Lago Lake near Athens, Georgia, determined that
    the biodegradation kinetics were multiphasic in nature and depended on
    the substrate concentration. The determined rate of degradation was
    faster at higher initial concentrations (the maximum concentration
    used was 0.5 mg/litre) (Hwang et al., 1989).

         In a laboratory experiment with natural stream water and
    sediment, no acetone was lost in 338 h under sterile conditions in
    closed flasks. However, with non-sterile natural sediment, 100% of the
    acetone was lost in 500 h following a lag period of 90 h. (Rathbun et
    al., 1982). The authors of this study concluded that biodegradation
    was one of the important processes for the loss of acetone in streams.
    Rathbun et al. (1982) separated his study into two groups to observe
    the effects of pre-exposure acclimatization. One group was pre-treated
    with a small concentration of acetone overnight and the other did not
    get pre-treatment. The treatment reduce the lag time, and degradation
    coefficients were much lower for the pre-treated groups. First-order

    rate coefficients for the bacterial degradation of acetone at 25°C
    ranged from 0.43-0.9 days-1 (not pre-treated), giving half-lives of 2
    days. Significant loss of acetone due to biodegradation was not
    observed in a later study when acetone was injected continuously in an
    outdoor model stream (Rathbun et al., 1988, 1989, 1991, 1993).
    Attempts to induce biodegradation by adding glucose and a nutrient
    solution containing bacteria acclimated to acetone were unsuccessful.
    The authors concluded that the residence time of acetone in the model
    stream (6 h) was too short for the bacteria to become acclimated in
    the water before initiation of biodegradation. However, this
    explanation may not be valid if attached bacteria, rather than
    free-floating bacteria, dominate the biodegradation process. As an
    alternative explanation, the authors indicated that the observed
    limitation in the nitrate concentration in the stream may be
    responsible for the lack of acetone biodegradation.  Microbial degradation

         Many aerobic biological screening studies have examined the
    biodegradability of acetone and have found it to be readily
    biodegradable (Lamb & Jenkins, 1952; Heukelekian & Rand, 1955;
    Stafford & Northrup, 1955; Ettinger, 1956; Hatfield, 1957; Ludzack &
    Ettinger, 1960; Price et al., 1974; Bridie et al., 1979; Takemoto et
    al., 1981; Urano & Kato, 1986a,b; Vaishnav et al., 1987; Hwang et al.,
    1989). One of these studies examined acetone biodegradation in a
    natural water experiment and found acetone to be readily biodegraded
    in Lago Lake water collected near Athens, Georgia, USA (Hwang et al.,

         Platen et al. (1990) studied the enrichment, isolation,
    characterization and the stoichiometry of acetone and its degradation.
    In their study, acetone was oxidized completely by
     Desulfococcus biacutus, a gram negative, anaerobic sulfate-reducing
    bacterium using acetone as its sole organic substrate. Enzyme studies
    indicated that acetone was metabolized by condensation with carbon
    dioxide to a C4 compound (possibly free acetoacetate) and moved into
    intermediary metabolism as acetoacetyl-coenzyme A. Acetoacetyl-CoA is
    cleared by a thiolase reaction to acetyl-CoA which is completely
    oxidized by the carbon monoxide dehydrogenase pathway. In
    acetone-amended slurries, 76% of the theoretically-expected sulfate
    was depleted, and in nitrate-amended slurries > 100% of the
    theoretically-expected amounts of nitrate were consumed after 85 days
    of incubation. Chou et al. (1979) also showed that acetone can be
    degraded by anaerobic biodegradation.

         Waggy et al. (1994) compared a USA 20-day biochemical oxygen
    demand (BOD) test with the Organization for Economic Cooperation and
    Development (OECD) closed bottle biodegradation test (Test 301D)
    (OECD, 1981). In the 20-day BOD test, the results were 56, 76, 83 and
    84%, at 5, 10, 15 and 20 days, respectively, and in the OECD test were
    68, 72 and 78% for 5, 15 and 28 days, respectively, indicating good
    correlation (Waggy et al., 1994). These test results classify acetone

    as readily biodegradable. In a laboratory study using a microbial
    culture from domestic waste water without acclimation, Price et al.
    (1974) measured fresh water BODs (% biooxidation) to be 76, 82, 85 and
    96% for 5, 19, 15 and 20 days, respectively. In "synthetic" saltwater,
    the values for the same periods were 66, 88, 88 and 100%.

    4.3  Bioavailability from environmental media

         Acetone is expected to be bioavailable.

    4.4  Interaction with other physical, chemical or biological factors

         The atmospheric degradation of volatile organic compounds (VOCs)
    in the presence of nitrogen oxides (NOx) leads to the production of
    ozone. During complete oxidation of the VOCs free radical reactions
    occur in the presence of sunlight with acetone (and other ketones),
    participating as an intermediate with ozone as a byproduct. One method
    of measuring the contribution of acetone is by the reactivity of it
    with the hydroxyl radical (OH*).

         The degradation of acetone in the lower troposphere may be
    initiated by photolysis or reaction with OH* radicals. The reactions
    with ozone (OD) or NOx are too slow to be important under
    tropospheric conditions (Johnson & Jenkin, 1991). The rate of the
    initiating reaction of OH* with acetone is well established at
    2.26 × 10-13cm3/ molecule per sec (Atkinson, 1985).
    Accordingly, the tropospheric lifetime of acetone with respect to
    removal by OH radicals is approximately one month; therefore, the loss
    of acetone by photooxidation is the major removal process of acetone
    in the troposphere (Johnson & Jenkin, 1991).

         The mechanism for acetone photodissociation has been reviewed by
    Gardner et al. (1984). At 40°C, using the Gardner equations, the
    average tropospheric lifetime would be halved to about 15 days, In
    summary, the ozone concentrations predicted by the model were not
    significantly affected by removal of the acetone emissions (Johnson &
    Jenkin, 1991). Chatfield et al. (1987) examined the effect of
    atmospheric pressure on the photolytic lifetime of acetone, and then
    compared the result with losses caused by hydroxyl radical reactivity.
    Reactions with hydroxyl radicals were much higher at ground level than
    at increasing altitude where photolysis was more important in
    degrading acetone.

         The formation of ground-level ozone has become an air pollution
    problem, especially in crowded, urban areas. Ozone is formed from the
    complex photochemical interaction of some VOCs and NOx compounds.
    Andersson-Sköld et al. (1992) calculated photochemical ozone creation
    potentials (POCP) for 75 organic compounds, while Carter (1994)
    developed maximum incremental ozone reactivity (MIR) scales to measure
    the potential of VOCs to create ozone. Both research groups found that

    ketones are weak producers of ozone, with acetone having one of the
    lowest ozone formation potentials. Derwent et al. (1996) calculated a
    POCP for acetone using a European model, which takes into account the
    difference in conditions between European and North American cities;
    the MIR model is considered more appropriate for North American
    conditions. Andersson-Sköld et al. (1992) found similar values to
    Derwent et al. (1966), indicating that acetone has "a remarkably low
    POCP". Because of the low POCP, acetone has been suggested as a
    potential substitute for high POCP aromatic hydrocarbons or the
    chlorine-containing solvents.

    4.5  Ultimate fate following use

         The environmental fate of acetone can be predicted, since many of
    the major fate processes have been investigated. When released to the
    atmosphere, acetone will degrade through a combination of photolysis
    and reaction with hydroxyl radicals (Meyrahn et al., 1986). Acetone
    can be removed from the air by rainfall (wet deposition), as shown by
    its detection in rainwater samples (Grosjean & Wright, 1983), but this
    does not appear to be a significant route most of the time. In soil,
    many studies have shown that acetone is readily biodegradable.
    However, leaching may occur, especially if other chemicals are present
    that may destroy or hinder microorganisms from degrading acetone.
    Acetone can volatilize from water, as well as soil surfaces (Rathbun
    et al., 1982). Since acetone is miscible with water and has a low
    Koc, it leaches rather than adsorbs to soil. Where biodegradation is
    inhibited or limited, acetone may reach the groundwater as a result of
    leaching from spills or landfills (Steelman & Ecker, 1984; Brown &
    Donnelly, 1988). Manufacturing and processing facilities may also
    release acetone to air and water through discharges, and through other
    wastes transported to landfills.


    5.1  Environmental levels

    5.1.1  Air

         Acetone is a commonly found volatile contaminant. It is one of
    the more long-lived intermediates that are produced in the oxidation
    of light non-methane hydrocarbons (Henderson et al., 1989). Monitoring
    data, covering rural, urban, remote and other areas, are available;
    values depend upon where the sampling was done, as well as the time of
    the year and sampling technique. Examples arc presented in Table 6.

         Grosjean et al. (1989) collected samples in three large urban
    areas in Brazil (Sao Paulo, Rio de Janeiro, Salvador) with populations
    ranging from 2 to 13 million people. In Sao Paulo, acetone levels were
    in the range of 0.5-7 µg/m3 (0.2-3 ppb), in Rio 1.2-9 µg/m3 (0.5-3.8
    ppb), and in Salvador 0-49.9 µg/m3 (0-21 ppb). In 1975, Brazil
    initiated a nationwide programme of production of ethanol from sugar
    cane, and by 1988, when these samples were taken, approximately
    one-third of the vehicles in use were ethanol-fuelled. Formaldehyde,
    acetaldehyde and acetone were the three carbonyls with the highest
    values, but these levels were still not higher than levels in other
    parts of the world.

         Acetone was one of the VOCs identified in the air of the storage
    section of a municipal waste truck (Wilkins, 1994). Although the exact
    measurement was not given in the study report, the author stated that
    the concentration was below 1780 mg/m3 (750 ppm) (the TLV value).
    Brosseau & Heitz (1994) measured the gases emitted from a municipal
    landfill site and found acetone in two samples: one at 77 µg/m3 (32.5
    ppbv) and the other at 16 µg/m3 (6.84 ppbv).

         Chatfield et al. (1987) studied the behaviour of acetone in the
    troposphere. Over the Atlantic Ocean (35°N), the mean concentration of
    acetone in the lower troposphere is approximately 1.2 µg/m3 (0.5
    ppb). Chatfield et al. (1987) stated that a significant amount of
    carbon appeared to be cycled as acetone, with attack by hydroxyl
    radicals and photolysis as the chief loss mechanisms, and that propane
    may contribute nearly half of the acetone observed in the upper
    atmosphere. Henderson et al. (1989) continued this work by showing
    that the effects of surface sources of higher order alkanes, alkenes
    and terpenes play a major role in the amount of acetone in the

         Granby et al. (1997) measured acetone levels simultaneously in a
    busy Copenhagen street (22 000 cars/day) and a semi-rural site 30 km
    west and found little difference in mean concentrations (2.4 µg/m3
    vs. 2.1 µg/m3; 1 ppb vs. 0.9 ppb). They found very weak correlations
    with carbon monoxide and NOx; indicating sources other than
    automobile exhaust, the most likely being oxidation of reactive
    hydrocarbons from long-range transport of polluted air masses. Since

        Table 6. Environmental air levels in various locations

    Sampling Area                     Concentrationa               Sampling dates              Reference
                                      µg/m3          ppb

    City/Tucson, Arizona, USA         28.5           12            February-September 1982     Snider & Dawson (1985)
    Urban/Tulsa, OK, USA              11.4-125.4     4.8-52.8      1978                        Arnts & Meeks (1981)
    Urban/South and Central America   0.5-49.9       0.2-21        1988                        Grosjean et al. (1989)
    Rural/Arizona, USA                6.7            2.8           February-September 1982     Snider & Dawson (1985)
    Rural/Colorado, USA               12.1-56.3      5.1-23.7      1978                        Arnts & Meeks (1981)
    Rural/Egbert, Ontario             0.9-8.8        0.39-3.6      1989                        Shepson et al. (1991)
    Rural/Dorset, Ontario             1.5-10.2       0.65-6.3      1989                        Shepson et al. (1991)
    Forest/Texas, USA                 6.9-46         2.9-19.4      January 1978                Seila (1979)
    Remote/Alaska                     0.7-6.9        0.3-2.9       1967                        Cavanagh et al. (1969)
    Mountains/Tennessee, USA          5-28.5         2.1-12        1978                        Arnts & Meeks (1981)
    Mountains/Bavaria, Germany        approx. 1.2    0.54b         August 1995                 Leibrock & Slemr (1997)
    Ocean/Atlantic 35°N               1.2            0.5                                       Chatfield et al. (1987)

    a  Some sampling in the above studies may have been conducted using Tedlar bags that are known to contaminate
       air samples with acetone (Henderson et at., 1989). Non-range values are mean values.
    b  Measured as propylene equivalents of oxygenated hydrocarbons in ppbC (ppb of carbon).

    the acetone concentrations in this study are only slightly higher than
    those found in rural, remote and ocean atmospheres, it appears that
    the acetone is probably not transported a great distance in the lower

         Arnold et al. (1997) measured upper tropospheric concentrations
    of acetone at 9000 m over the northeastern Atlantic, near Ireland in
    1993. Measured acetone concentration was found to correlate positively
    with that of sulfur dioxide (SO2), reaching a maximum abundance of
    approx. 7 µg/m3 (3 ppb). This concentration is markedly higher than
    the concentration of 1.2 µg/m3 (0.5 ppb) in the lower troposphere
    reported by Chatfield et al. (1987). As the SO2 level decreased, so
    did the acetone concentration. Either the acetone was transported from
    direct emissions from the USA, or a photochemical hydrocarbon
    conversion had occurred.

         In a review of earlier studies, Singh et al. (1994) found acetone
    at a range of approx. 0.9-5.2 µg/m3 (approx. 0.4-2.3 ppb), with a
    mean of 3.1 µg/m3 (1.14 ppb), in the troposphere. Using a three
    dimensional photochemical model, Singh et al. (1994) found that the
    greatest source of acetone was the oxidation of precursor hydrocarbons
    (51%); other sources were biomass burning (26%), biogenic emissions
    (21%) and an anthropogenic emission (approx. 3%). Atmospheric removal
    was mainly by photolysis (64%), followed by reaction with OH*
    radicals (24%) and deposition (12%). Other important points were:

    *    there is substantial variability in atmospheric abundance
    *    the concentration of acetone appears to vary with altitude
    *    upper atmospheric transport is possible since the half-life is
         >10 days
    *    acetone appears to be the most abundant non-methane organic
         species in the atmosphere
    *    the geochemical background of acetone appears to be 1.2 µg/m3
         (approx. 0.5 ppb)  Indoor air

         Shah & Singh (1988) reported a concentration of 19 µg/m3 (8 ppb)
    in household indoor air. These authors compiled available data to
    calculate an average outdoor concentration of 16.4 µg/m3 (6.9 ppb).
    Other investigators reported similar results (Jarke et al., 1981).
    Tichenor & Mason (1988) measured acetone levels in the range of 37-41
    µg/m3 (approx. 15-17 ppb) per hour being emitted from low-density
    particle board used in home construction in the USA. The reason for
    the higher indoor air concentration was the use of acetone-containing
    consumer products inside homes. The potential for intrusion of acetone
    present as Soil gas into a house adjacent to a landfill was
    characterized by Hodgson et al. (1992), but the measurement was for
    only a single house. The average concentration was 47.5 µg/m3 (20

         Hodgson et al. (1991) collected air samples in a 
    newly-constructed building at four different times over a period of
    14 months. The major source of VOCs was not the new construction
    materials, but the liquid-process copiers and plotters where acetone
    concentrations ranged from 28.8 to 66.6 µg/ms (12-28 ppb).

    5.1.2  Water

         Acetone has been qualitatively detected in drinking-water in
    various cities in the USA, including Miami, FL; Ottumwa, IO;
    Philadelphia, PA; Cincinnati, OH; Calhoun, GA; Dalton, GA; Gastonia,
    NC; Durham, NC; New Orleans, LA; Rome, GA; and Tuscaloosa, AL (Bertsch
    et al., 1975; US EPA, 1975; Shackelford & Keith, 1976). In the US EPA
    National Organics Reconnaissance Survey (NORS), involving
    drinking-water supplies from 10 cities in the USA, acetone was
    qualitatively detected in all the cities. An acetone concentration of
    1 µg/litre was found in drinking-water samples from Seattle, WA (US
    EPA, 1975).

         Acetone was detected in 33/204 surface water samples collected
    from sites near heavily industrialized areas in the USA during
    1975-1976 (Ewing et al., 1977). It was detected in 12.4% of all
    groundwater samples analysed from 178 USA hazardous waste (Superfund)
    sites as part of a national programme to investigate and remedy
    potential problems at these sites (Plumb, 1987).

         Acetone is released to water in wastewater discharges from
    industry and sewage treatment. It was found in 23/63 effluent waters
    from a wide range of chemical manufacturers around the USA at
    concentrations ranging from < 10 to 100 µg/litre (Perry et al.,
    1978). A comprehensive survey of wastewater from 4000 industrial and
    publicly owned treatment works detected acetone in a wide range of
    wastewater from industries such as leather tanning, petroleum
    refining, nonferrous metals, paint and ink, printing and publishing,
    coal mining, organics and plastics, inorganic chemicals, textile
    mills, pulp and paper, robber processing, pesticide manufacture,
    photographic industries, pharmaceuticals, porcelain/enamels,
    mechanical products and transportation equipment. The highest effluent
    concentration of acetone from all industries was 37.7 mg/litre, which
    was detected in the paint and ink industry; however, the median
    acetone level was 0.89 mg/litre (NLM, 1992).

         Acetone can be released to groundwater by leaching from municipal
    and industrial landfills. Leachate collected from a Minnesota (USA)
    municipal landfill contained as much as 13 mg acetone/litre (Sabel &
    Clark, 1984). Levels of 2.94.8 mg/litre were detected in leachate
    samples collected in the USA from an industrial landfill in
    Connecticut in 1982-1983 (Sawhney & Kozloski, 1984) and from one in
    Michigan that contained up to 62 mg acetone/litre (Brown & Donnelly,

         Acetone has also been detected at 0.2-0.7 µg/litre in water from
    several artesian wells adjacent to a landfill in Wilmington, Delaware,
    USA (DeWalle & Chian, 1981). The concentration of acetone was up to 3
    mg/litre in a drinking-water well in New Jersey (Burmaster, 1982;
    Steelman & Ecker, 1984).

         The concentration of acetone in open ocean water (Tongue of the
    Ocean, Bahamas) was approx. 0.35 µg/litre (Kieber & Mopper, 1990).
    Corwin (1969) measured VOCs in seawater and found acetone levels in
    the Florida Straits (USA) of 14-52 µg/litre at depths ranging from 0
    to 160 metres at approx. 35% salinity. Similar concentrations were
    found in the Mediterranean where the measurements were 18-52 µg/litre
    at slightly higher salinity (approx. 39%).

    5.1.3  Soil and sediment

         There are few data regarding the level of acetone in soil and
    sediment. Acetone has been detected in 43% of the soil samples in
    designated waste disposal sites in the USA for which acetone
    determination has been made (ATSDR, 1994). The maximum concentration
    of acetone in soils from Vega Alta Public Supply well sites in Puerto
    Rico and the mean concentration of acetone in soil from Summit
    National Site, Ohio, was 9.5 mg/kg (ATSDR, 1994). Because of its high
    water solubility and low sediment adsorption coefficient, acetone in
    an aquatic system is predominantly found in water, rather than in

    5.1.4  Food

         Acetone has been qualitatively detected in blue cheese (Day &
    Anderson, 1965), baked potatoes (Coleman et al., 1981), roasted
    filbert nuts (Kinlin et al., 1972), chicken breast muscle (Grey &
    Shrimpton, 1967) and nectarines (Takeoka et al., 1988). Acetone
    concentrations of 795 mg/kg and 11 mg/kg were identified in
    Czechoslovakian milk samples and milk cream culture, respectively
    (Palo & Ilkova, 1970). Milk samples from Swedish dairy cattle were
    found to contain acetone concentrations ranging from 18 to 226
    mg/litre (0.32-3.89 µmol/litre) (Andersson & Lundstrom, 1984).
    Pellizzari et al. (1982) qualitatively identified acetone in all 8
    selected human milk samples collected from volunteers in Bayonne, NJ,
    Jersey City, NJ, Bridgeville, PA, and Baton Rouge, LA. A variety of
    bean types (common, lima, mung and soy) contained acetone levels
    ranging from 260-2000 µg/kg, with a mean level of 880 µg/kg, and
    levels of 530 and 230 µg/kg were detected in split peas and lentils,
    respectively (Lovegren et al., 1979). Acetone has also been detected
    in onions, grapes, cauliflower, tomatoes and wild mustard (NLM, 1992).

    5.1.5  Other environmental levels

         Acetone is ubiquitous in the environment and is found at a wide
    range of concentrations.

    5.2  General population exposure

         Acetone is readily absorbed from the lung and gastrointestinal
    tract following inhalation and ingestion (see chapter 6). It can also
    be absorbed through the skin. The low values for Koc (see Table 1)
    and a moderate value for Henry's law constant (Rathbun & Tai, 1987)
    suggest that the bioavailability of acetone from contaminated water
    and soil as a result of contact may be significant. However,
    quantitative data regarding the rate and extent of dermal absorption
    of acetone from contaminated water and soil are lacking. The high
    water solubility and low Koc value for acetone suggest that
    bioavailability from ingested soil (e.g., children playing at or near
    contaminated sites) will be high, but, again, quantitative absorption
    data are lacking. Data on bioavailability of acetone from ingested
    plant food are not available.

         Exposure to acetone occurs from both natural and anthropogenic
    sources, and it is endogenously produced by all humans. The general
    population is exposed to acetone by inhaling ambient air, ingesting
    food, and drinking-water containing acetone. Dermal exposure to
    acetone may result from skin contact with consumer products (e.g.,
    certain nail polish removers, paint removers, and household cleaning
    and waxing products). Assuming concentrations of acetone are 19 µg/m3
    (8.0 ppb) in indoor air and 16.4 µg/m3 (6.9 ppb) in outdoor air (Shah
    & Singh, 1988) and that an average person inhales 15 m3/day of indoor
    air and 5 m3/day of outdoor air daily, the estimated exposure to
    acetone by inhalation is 0.37 mg/day. This value is much lower than an
    estimate based upon an earlier exposure level found by one of these
    researchers. Singh & Hanst (1981) estimated that an acetone
    concentration of 0.26 µg/m3 (0.111 ppb) will occur in the lower
    troposphere as a result of atmospheric oxidation of naturally
    occurring propane, with levels of 35 ng/m3 (15 ppt) in the upper
    troposphere and 7 ng/m3 (3 ppt) in the stratosphere. Since the
    sampled atmospheric concentrations of acetone are 0.723-127.25 µg/m3
    (0.3-52.8 ppb), and maintaining that the average adult human inhales
    20 m3 air/day, the average daily exposure of acetone from inhalation
    can be estimated to be 14.5-2545.0 µg, or up to 2.5 mg/day.

         Wang et al. (1994) measured acetone concentrations in 89
    non-occupationally exposed subjects and found acetone mean values of
    840 µg/litre in blood, 842 µg/litre in urine, 715 ng/litre in alveolar
    air and 154 ng/litre in environmental air. The researchers found no
    significant difference in blood levels between smokers (896 µg/litre)
    and nonsmokers (792 µg/litre), and likewise between hospital staff
    (719 µg/litre) and blood donors (966 µg/litre). The results are
    similar to those of Pezzagno et al. (1986) who measured 760 µg
    acetone/litre in urine.

         The endogenous acetone level in the body at any instant reflects
    acetoacetate production (Morgott, 1993). The concentration of acetone
    in whole blood does not differ from that in plasma (Gavino et al.,
    1986). Even in healthy subjects, the level of acetone in blood or

    plasma varies with fasting or non-fasting conditions and depends on
    the weight of the subject. Generally, the blood or plasma acetone
    concentrations are higher in fasted than non-fasted subjects and
    higher in subjects who are not obese, compared to obese subjects (Haff
    & Reichard, 1977). It should be noted that normal and abnormal
    physiological conditions and disease states may increase ketogenesis
    and the body burden of acetone. Acetone levels in athletes and
    pregnant women (among many groups) may be elevated because these
    groups of people have greater energy requirements. Ashley et al.
    (1994) measured blood concentrations in non-occupationally exposed
    populations. The mean concentration in a control group in the USA was
    3.1 mg/litre. In a group of nine volunteer subjects, the mean blood
    concentration before entering a van designed for clinical examinations
    for a health survey was 1.9 mg/litre and after 3 h in the van the mean
    blood concentration was virtually unchanged at 2 mg/litre, although
    the range before entry was 1 3.6 mg/litre and after 3 h was 0.9-5
    mg/litre, i.e. the high end of the range was over 1.4 mg/litre higher
    when the subjects were tested after breathing the same air for 3 h.

         Individuals with uncontrolled diabetes mellitus or diabetic
    ketoacidosis may have plasma acetone levels as high as 750 mg/litre
    (Trotter et al., 1971). The acetone concentrations in body fluids and
    expired air in studies of healthy individuals and diabetic patients
    are shown in Table 7. Clinical findings in eases of acute acetone
    intoxication suggest that acetone blood levels over 1000 mg/litre are
    necessary to cause unconsciousness in humans (Ramu et al., 1978), but
    lower levels may interrupt physiological processes in diabetics.

         Approximate reference concentrations for human plasma acetone are
    < 10 mg/litre for a "healthy" individual, < 100 mg/litre for an
    occupationally exposed individual, 100-700 mg/litre for an individual
    with diabetic ketoacidosis and > 200 mg/litre for an individual
    showing symptoms of "toxic" exposure (Tietz, 1983).

    5.3  Occupational exposure

         Kiesswetter et al. (1994) investigated occupational acetone
    exposure using two groups of eight healthy male workers on nine shift
    days. Using personal sampling, exposure was higher in the first half
    of the shift (2730 mg/m3) than in the second half (1720 mg/m3).
    For monitoring purposes, the researchers studied the relationship of
    acetone in air versus three urine parameters: (1) concentration of
    acetone in urine; (2) concentration of urine related to creatinine
    excretion; and (3) concentration of acetone in urine in relation to
    time (sampling period) and excreted urine volume. The concentration of
    acetone in urine was moderately correlated to that in air. Some of the
    ratings of well-being in the workers con-elated with the acetone
    concentrations in the urine but not with the acetone concentrations in
    the workplace air.

        Table 7. Concentrations of acetone in body fluids and expired air of humans

    Medium          Subject                 Concentration            Reference

    Blood           Healthy (non-fasted)    0.93 mg/litre            Gavino et al. (1986)

    Blood           Health (non-fasted)     0.84 mg/litre            Brugnone et al. (1994)

    Blood           Healthy (non-fasted)    1.8 mg/litre (median)    Ashley et al. (1994)

    Plasma          Healthy (3-day fasted)  46.5 mg/litre            Haff & Reichard (1977)

    Plasma          Healthy (non-fasted)    1.74 mg/litre            Trotter et al. (1971)

    Plasma          Obese (3-day fasted)    17.4 mg/litre            Haff & Reichard (1977)

    Plasma          Ketoacidotic            424 mg/titre             Trotter et al. (1971)

    Plasma          Ketoacidotic            290 mg/litre             Haff & Reichard (1977)

    Urine           Healthy                 0.23-0.41 mg/litre       Kobayashi et al. (1983)

    Urine           Healthy                 0.84 mg/litre            Brugnone et al. (1994)

    Urine           Healthy (endogenous)    0.76 mg/litre            Pezzagno et al. (1986)

    Urine           Diabetic                0.64-9.0 mg/litre        Kobayashi et al. (1983)

    Expired air     Healthy                 1.23 µg/litre            Jansson & Larsson (1969)

    Expired air     Healthy                 1.16 µg/litre            Trotter et al. (1971)

    Expired air     Healthy                 1.3 µg/litre             Phillips & Greenberg (1987)


         Wang et al. (1994) calculated a blood-air coefficient for acetone
    of 146. On average, the blood acetone levels of workers were 56 times
    higher than those of subjects only exposed environmentally. These
    researchers calculated the half-life of acetone in blood to be 5.8 h
    for the interval between the end of one shift and the beginning of the
    next (approx. 16 h). Analyses were made of workers before the start of
    their shift, and mean acetone levels were 3.5 mg/litre in blood and 13
    mg/litre in urine. Wigaeus (1981) calculated the acetone half-life to
    be 6.1 h. These values indicate that the 16-h period between
    workshifts did not allow for complete elimination of acetone absorbed
    from the previous workshift.

         In a study of environmental tobacco smoke (ETS) and its
    contribution to VOC concentrations, Heavner et al. (1996) measured
    acetone levels in smoking and non-smoking workplaces and homes. The
    mean levels were: non-smoking workplace, 59.77 µg/m3 (SD 79.78);
    smoking workplace, 952.86 µg/m3 (SD 3988.25); non-smoking home, 50.12
    µg/m3 (SD 58.5); smoking home, 71.19 µg/m3 (SD 118.17).
    Approximately 6% of the acetone found in the air of smoking workplaces
    and homes was attributed to ETS.

         Workers in industries that manufacture and use acetone can be
    exposed to much higher concentrations of acetone than the general
    population. For example, the concentrations of acetone in the
    breathing zone air in a paint factory, a plastics factory, and an
    artificial fibre factory in Italy were > 3.48 mg/m3 (Pezzagno et
    al., 1986). The concentration of acetone in a plastic plant in Japan,
    where bathtubs were produced, was > 100 mg/m3 (Kawai et al., 1990a).
    The inhalation exposure of workers to acetone in a shoe factory in
    Finland ranged from 25.4-393.4 mg/m3 (Ahonen & Schimberg, 1988). The
    concentration of acetone in the air of a solvent recycling plant was
    as high as 42 mg/m3, the mean exposure being 1 mg/m3 (Kupfersehmid &
    Perkins, 1986).

         Exposure to acetone may also occur indirectly. For example,
    isopropyl alcohol is known to oxidize in the liver and is converted to
    acetone (Kawai et al., 1990b). Therefore, occupational exposure
    (printing plants) or accidental ingestion of isopropyl alcohol can
    produce acetone in expired air, blood and urine (Lacouture et al.,


         There is extensive information regarding acetone and its
    metabolism within animals and humans. Because acetone has a low
    relative molecular mass and is miscible with water, it is absorbed and
    uniformly distributed throughout the non-adipose tissues of the body.
    There are absorption and tissue distribution studies, radiolabelled
    metabolic and kinetic studies and elimination/excretion data. Other
    variables such as diet, exercise and alcohol consumption affect the
    kinetics of acetone.

    6.1  Absorption

    6.1.1  Inhalation exposure  Human studies

         In humans exposed to acetone concentrations of up to 2970 mg/m3
    (1250 ppm) for < 7.5 h/day in a complex protocol for < 6 weeks,
    the concentration of acetone in venous blood was directly related to
    the vapour concentration and duration of exposure, and inversely
    related to the time elapsed following exposure (Stewart et al., 1975).

         Data on the actual distribution of acetone in the human body are
    scarce. Digs et al. (1994) measured  in vitro blood/air partition
    coefficients (KB/A) in blood samples from 73 humans. The average
    KB/A (±SD) for acetone was 301 ± 22, with a range of 250-410, and
    was normally distributed. Since acetone is absorbed into the blood
    from the respiratory tract and is highly water soluble, it is to be
    expected that there will be distribution to tissues with high water

         Acetone vapour is rapidly taken up by the tissue of the
    respiratory tract and absorbed into the bloodstream during inhalation
    exposure. This rapid uptake was shown by Haggard and co-workers when
    substantial concentrations of acetone appeared in the blood only 30
    min after exposure (Haggard et al., 1944). This is probably due to its
    high blood-air partition coefficient (167-330) (Haggard et al., 1944;
    Sate & Nakajima, 1979; Fiserova-Bergerova & Diaz, 1986; Paterson &
    Mackay, 1989; Dills et al., 1994). Studies in humans exposed to up to
    10 940 mg/m3 (4607 ppm) for up to 4 h showed measured pulmonary
    uptakes ranging widely from -30% to 80% (Landahl & Herrmarm, 1950;
    DiVincenzo et al., 1973; Nomiyama & Nomiyama, 1974a; Wigaeus et al.,
    1981; Pezzagno et al., 1986). The reason for the wide range in
    reported values involves the aqueous wash-in/wash-out effect when
    acetone is inhaled, which can lead to spurious results (Schrikker et
    al., 1985, 1989). During this phase, acetone, which is highly water
    soluble, will dissolve in epithelial cells during inspiration
    (wash-in) and evaporate during expiration (wash-out). This could
    account for the lower than expected pulmonary absorption based on the
    high blood/air partition coefficient (Wigaeus et al., 1981).

         There have been a number of studies on highly soluble vapours
    (such as acetone) and expiration from the respiratory tract. Cander &
    Forster (1959) stated that a substantial portion of the acetone
    adsorbed into the pulmonary tissue during inspiration was removed
    during expiration, thus mixing with any expired alveolar sample that
    was used as a measurement for analysis. Schrikker et al. (1985, 1989)
    performed a series of measurements and found several interesting
    results. There was an appreciable difference in alveolar air expired
    at the beginning and ending of any breath during the wash-in cycle. At
    first, acetone level was greatest at the beginning of a breath, but
    when work load (exercise) started, the levels of the end started
    rising, until after approximately 8 breaths, acetone level was higher
    at the end of a breath. Part of the explanation was that the upper
    airway linings give off the acetone during the initial breaths, and
    the deeper portions of the respiratory tract give off the acetone in
    the later breaths. Schrikker et al. (1989) found that the pulmonary
    excretion of acetone is dependent upon the exchange of vapour between
    the respiratory tract tissues and the inspired air, and is a
    substantial proportion of the excretion of acetone via the respiratory

         The turnover of acetone is highly dependent upon the organism's
    state. Schrikker et al. (1989) and Jakubowski & Wieczorek (1988)
    showed, as exercise increased, so did the amount of acetone being
    expired and the rate of acetone uptake by the body was also directly
    proportional to the ventilation rate. Haggard et al. (1944) compared
    resting and exercising males and found that a ninefold increase in the
    metabolic rate was required to account for a less-than-expected rise
    in acetone blood levels. They also approached the idea that there was
    a limit to the amount of acetone that can be accumulated in the body.

         Exhaled breath levels of acetone in humans rise during exposure
    to acetone and reach a steady state within approximately 2 h
    (DiVincenzo et al., 1973; Nomiyama & Nomiyama, 1974a; Brown et al.,
    1987). Uptake is directly proportional to exposure concentration and
    duration (DiVincenzo et al., 1973; Wigaeus et al., 1981). Uptake also
    increases as the level of physical activity increases, i.e. during
    exercise, due to increased pulmonary ventilation (Haggard et al.,
    1944; DiVincenzo et al., 1973; Wigaeus et al., 1981; Jakubowski &
    Wieczorek, 1988). Lungs (including the mouth and trachea) were shown
    to retain a greater percentage of inspired acetone (55%) than the
    nasal cavity (18%) in two humans exposed to acetone vapour
    concentrations of 0.3-3.0 mg/litre and 0.8-11.0 mg/litre for nasal and
    lung retention measurements, respectively, with a flow rate of 18
    litres/min. This might indicate that the nasal cavity absorbs acetone
    less readily than the rest of the respiratory system (Landahl &
    Herrmann, 1950). Blood levels of acetone rose rapidly during exposure
    for up to 4 h with no indication that a steady state was reached
    (DiVincenzo et al., 1973; Brown et al., 1987; Dick et al., 1989),
    suggesting that during exposure, the rate of absorption exceeded the
    rate of distribution and elimination. During short-term (2-4 h)
    exposure to 240 or 1190 mg acetone/m3 (100 or 500 ppm), 75-80% of
    the amount of acetone inspired was absorbed by blood after 15 mm of

    exposure, and 20-25% remained in the dead space volume (DiVincenzo et
    al., 1973). Higher inspired amounts resulted in higher blood levels
    (Haggard et al., 1944; Matsushita et al., 1969a; DiVincenzo et al.,
    1973; Pezzagno et al., 1986). Pezzagno et al. (1986) similarly
    reported that an approximate average of 53% of administered acetone
    was retained during exposure of 15 humans to acetone vapour
    concentrations of 964-8610 mol/m3 (56-500 mg/m3) for 2-4 h in an
    exposure chamber. In contrast to other studies, moderate exercise did
    little to change the net retention of acetone. The mean net retention
    was 54% during exposure at rest and 53% during exposure with exercise.
    A correlation between blood level at the end of exposure and exposure
    concentration was found in humans exposed to 55-495 mg/m3 (23-208
    ppm) for 24 h (Pezzagno et al., 1986). No significant difference in
    uptake or retention was found between men and women (Brown et al.,
    1987).  Experimental animal studies

         Animals also absorb acetone rapidly during inhalation exposure.
    Measurement of blood acetone levels in rats after 4-6 h of exposure to
    various concentrations shows that blood levels correlate well with
    exposure concentrations (Charbonneau et al., 1986a, 1991; NTP, 1988)
    and are highest immediately after exposure (NTP, 1988). In rats
    exposed to 355 mg/m3 (150 ppm) for 0.5-4 h, measurement of blood
    acetone concentrations during exposure revealed that blood levels
    increased steadily for 2 h and then remained constant for the next 2 h
    of exposure (Geller et al., 1979). Blood acetone levels also
    correlated well with exposure concentration in dogs exposed for 2 h
    (DiVincenzo et al., 1973). Blood levels were 4, 12 and 25 mg/litre
    after exposures to 240, 1190 and 2375 mg/m3 (100, 500 and 1000 ppm),
    respectively. In anaesthetized dogs allowed to inhale concentrated
    vapour of acetone spontaneously from a respirator at various
    ventilation rates, uptake by the respiratory tract was 52% at flow
    rates of 5-18 litres/min and 42% at ventilation rates of 21-44
    litres/min (Egle, 1973). Retention in the lower respiratory tract was
    48% at 5-18 litres/mm and 37.5% at 21-40 litres/min. Retention by the
    upper respiratory tract was 57% at 4-18 litres/min. The effect of
    exposure concentration on total uptake was studied at a range of
    ventilation rates equated with exposure concentrations. Percentage
    uptakes were 52.1% at a mean concentration of 503 mg/m3 (212 ppm),
    52.9% at 672 mg/m3 (283 ppm), and 58.7% at 1553 mg/m3 (654 ppm).
    These results indicate the respiratory uptake of acetone by dogs is
    similar to human uptake values reported by Landahl & Herrmann (1950).
    Comparison of data from dogs and humans by ATSDR (1994) revealed that
    the amount absorbed in humans was greater in absolute quantity under
    comparable exposure conditions, but when expressed in terms of kg body
    weight, the amount absorbed in dogs was five times more than in
    humans. The retention in the upper respiratory tract was higher than
    in the lower respiratory tract of dogs (Egle, 1973). Exposure
    concentration had little effect on retention. The absorption of
    acetone by the nasal walls of anaesthetized dogs, in which the nasal

    passage was isolated, increased when the airflow rate was increased
    (Aharonson et al., 1974), but the percentage uptake actually

         In rats exposed continuously to 5250 mg/m3 (2210 ppm) for 9
    days, peak acetone blood levels were approximately half the exposure
    concentration, were reached in 3-4 days, and remained at this level
    for the duration of exposure (Haggard et al., 1944) In rats exposed to
    10 200 mg/m3 (4294 ppm) for 12 days, acetone blood levels slightly
    greater than half the initial concentration were reached in 4 days and
    continued to day 12. Blood levels in rats exposed to these
    concentrations for 8 h/day were about half of those reached during 
    continuous exposure. The amount of acetone absorbed in the first 8 h
    exceeded the amount eliminated in the next 16 h of exposure to fresh
    air, meaning them was a small accumulation.

         Studies with laboratory animals illustrate the absorption of
    acetone by the nasal cavity (Morris et al., 1986). Absorption
    efficiencies (i.e. relative net uptake) were measured in the upper
    respiratory tracts of two strains of rat and a single strain of
    guinea-pig. At flow rates approximately 3 times the normal minute
    volumes, upper respiratory tract retention of acetone vapour averaged
    7, 12 and 21% for guinea-pigs, Fischer-344 rats and Sprague-Dawley
    rats, respectively.

         As in the case of humans (Landahl & Herrmann, 1950) and dogs
    (Egle, 1973), the disposition of acetone in the upper respiratory
    tract of other animals, including rats, mice, guinea-pigs and
    hamsters, indicates that relatively little acetone is absorbed from
    the upper respiratory tract (Morris et al., 1986; Morris & Cavanagh,
    1986, 1987; Morris, 1991). The absorption efficiency was greater in
    Sprague-Dawley rats than in Fischer-344 rats, but there was no
    difference between male and female Sprague-Dawley rats (Morris, 1991).
    Deposition was similar in B6C3F1 mice and Fischer-344 rats, and was
    greater than in Hartley guinea-pigs and Syrian golden hamster. The
    differences between strains and species could not be attributed to
    differences in metabolism, because acetone is not significantly
    metabolized in the upper respiratory tract of these species. The
    reason was thought to be differences in perfusion rates (Morris &
    Cavanagh, 1987; Morris, 1991).

    6.1.2  Oral exposure  Human studies

         In a series of experiments conducted in male volunteers given
    acetone orally at 40-80 mg/kg, an estimated 65-93% of the administered
    dose was metabolized, with the remainder being eliminated in the urine
    and expired air in about 2 h, indicating rapid and extensive
    gastrointestinal absorption (Haggard et al., 1944). Early research
    demonstrated that after oral exposure, acetone moved quickly through
    the body. In a human who ingested 137 mg acetone/kg on an empty

    stomach, the blood level of acetone rose sharply to a peak 10 min
    after dosing (Widmark, 1919). In another example, a subject ingested
    the same dose 10 or 12 min after eating porridge. The blood acetone
    level rose slowly over 48-59 min to levels of about one-half to
    two-thirds that achieved after taking acetone on an empty stomach. The
    presence of food in the gastrointestinal tract led to a slower rate of

         Measurement of acetone in blood and urine of patients who
    accidentally or intentionally ingested acetone indicated that acetone
    was absorbed, but the percentage absorbed cannot be determined from
    the data. A man ingested liquid cement (approximate acetone dose of
    231 mg/kg) (Sakata et al., 1989) causing his plasma acetone level to
    be approx. 110 mg/litre and his urinary level to be 123 mg/litre 5 h
    after ingestion. In another study, a woman who had ingested nail
    polish remover had a blood acetone level of 2.5 g/litre (Ramu et al.,
    1978). The authors estimated that her body burden was 150 g acetone at
    the time of admission to the hospital. The serum acetone level of a
    30-month-old child was (4.45 g/litre) 1 h after ingestion of a 6-ounce
    bottle of nail polish remover (65% acetone) (Gamis & Wasserman, 1988).  Experimental animal studies

         Acetone appears to be absorbed by the gastrointestinal tract as
    indicated by early studies of laboratory animals. Price & Rittenberg
    (1950), administered orally a dose of 14C-acetone (0.22 mg/189 g
    body weight, in 1 ml water) to a female rat and collected respiratory
    14CO2: for 13.5 h. During this period, 47.4% of the administered
    dose was accounted for by exhaled 14CO2. In a separate experiment,
    a rat (152 g body weight) was given seven daily oral doses of
    14C-acetone (1.08 mg), and radioactivity in carbon dioxide collected
    during 24-h post-administration periods accounted for 67-76% of the
    administered radioactivity. Radioactive acetone was detected in
    expired air in the first 20-min period following the first
    administration; however, radioactive acetone, exhaled during 24-h
    post-administration periods, accounted for a maximum of 7% of a daily
    dose. In an experiment in which a 210 g rat was given 1.30 mg of
    radioactive acetone, the rate of exhalation of radioactivity as
    acetone was maximal approx. 2 h after administration, but declined
    thereafter, suggesting that gastrointestinal absorption was rapid
    (Price & Rittenberg, 1950).

         Experiments in rats indicate that acetone is rapidly and almost
    completely absorbed from the gastrointestinal tract after oral
    exposure. A rat expired 97.4% of a 1.16 mg/kg oral dose over a 13.5-h
    period, while another rat given 7 mg/kg 14C-acetone expired 67-76%
    of the administered dose over a 24-h period after the last dose (Price
    & Rittenberg, 1950). From these data, absorption of least 74-83% of
    the administered dose can be inferred. In other studies where rats
    were given similar or higher doses of acetone, plasma acetone levels
    rose proportionately with dose in rats given acetone as single doses
    by gavage (Lewis et al., 1984; Charbonneau et al., 1986a) or in the
    drinking-water for 7 days (Skutches et al., 1990).

         In a study comparing the blood levels of acetone achieved after
    fasting with those after oral dosing, peak blood levels of acetone of
    approx. 35 and 110 mg/litre were reached within about 3 h after dosing
    of rats with 78 and 196 mg acetone/kg, respectively (Miller & Yang,
    1984). The levels declined to near background levels within the next
    16 h. At an acetone dose of 20 mg/kg, the blood level increased to
    about 5 mg/litre over 19 h, when the rats were sacrificed. In rats
    fasted for 48 h, blood acetone levels increased continuously to about
    13 mg/litre. While the maximal blood concentrations of the treated
    rats differed considerably from those of the fasting group, the
    calculated areas under the curve for the 78 and 196 mg/kg groups were
    comparable to those of the fasting groups (ATSDR, 1994).

         There are conflicting data regarding the effect of vehicle on the
    gastrointestinal absorption of acetone. In the one study where water
    was used as the vehicle, maximum blood levels were higher and achieved
    earlier in rats given acetone by gavage as compared to those given
    acetone by gavage in corn oil (Charbonneau et al., 1986a). The slower
    absorption of acetone in corn oil may have resulted from a delayed
    gastric emptying due to the presence of corn oil in the stomach. In a
    later repetition of this study, very little difference in blood and
    liver levels of acetone were found in rats given the same dose of
    acetone in water or in corn oil (Charbonneau et al., 1991).

    6.1.3  Dermal exposure  Human studies

         Dermal absorption of acetone is known to occur in humans.
    Application of cotton soaked in acetone to a 12.5 cm2 uncovered area
    of skin of volunteers for 2 h/day for 4 days resulted in blood levels
    of acetone of 5-12 mg/litre, alveolar air levels of 12-28 mg/m3 (512
    ppm), and urinary concentrations of 8-14 mg/litre on each day
    (Fukabori et al., 1979). When the daily exposure increased to 4 h/day,
    body concentrations more than doubled with 26-44 mg/litre in blood,
    59-81 mg/m3 (25-34 ppm) in alveolar air, and 29-41 mg/litre in
    urine. The absorption was mediate, with peak blood levels appearing at
    the end of each daily application. The authors noted that it was not
    possible to completely prevent exposure from inhalation; the acetone
    concentration in the breathing zone of one subject was found to be
    0.95-1.4 mg/m3 (0.4-0.6 ppm). From the alveolar air and urine
    concentrations, it was estimated that a 2-h dermal exposure was
    equivalent to a 2-h inhalation exposure to 120-355 mg/m3 (50-150
    ppm), and a 4-h dermal exposure was equivalent to a 2-h inhalation
    exposure to 590-1190 mg/m3 (250-500 ppm).  Experimental animal studies

         In a study using isolated perfused pig skin and 14C-labelled
    acetone, 60% of the acetone evaporated in the first 2 min, but
    approximately 33% remained after 2 h, and around 20% was still present
    after 8 h (Williams et al., 1994). The findings of cataract formation
    in guinea-pigs exposed dermally to acetone 0.5 ml applied daily for 5
    days per week for 6 weeks to the back was attributed to dermal
    absorption of acetone (Rengstorff et al., 1972; Rengstorff & Khafagy,
    1985). These authors suggested an association between cataract
    formation and significant depression of the antioxidant, ascorbate, in
    the aqueous humour. To study this relationship in more depth, Taylor
    et al. (1993) fed albino hairless guinea-pigs diets containing low
    (4.9 mg/day) and high (55 mg/day) levels of ascorbate. Daily dermal
    exposure to acetone occurred over the next 6 months, with a total
    applied dose of 65 ml. No cataracts were found in any of the
    guinea-pigs from either group even though Taylor et al. (1993) used
    four times the dose of Rengstorff & Khafagy (1985).

    6.1.4.  Absorption summary

         From the information presented, acetone is absorbed rapidly no
    matter which route of exposure. It appears that acetone is absorbed by
    all parts of the respiratory system, and that oral and dermal
    absorption can also occur. However, absorption can be affected by the
    stomach contents.

    6.2  Distribution

    6.2.1  Inhalation exposure  Human studies

         Human  in vitro tissue-blood partition coefficients of acetone
    for cadaver muscle, kidney, lung and brain grey matter range from 0.74
    to 0.82, indicating nearly complete tissue distribution
    (Fiserova-Bergerova & Diaz, 1986). Dills et al. (1994) measured
     in vitro blood/air partition coefficients (KB/A) of acetone in
    blood samples from 73 subjects. The mean value was 301 ± 22; the range
    was 250-410 and was normally distributed.  Experimental animal studies

         The distribution of acetone has been studied in mice exposed to
    acetone by inhalation (Wigaeus et al., 1982). Mice were exposed to
    1190 mg/m3 (500 ppm) 14C-acetone for 1, 3, 6, 12 and 24 h or for 6
    h/day for 1, 3 or 5 consecutive days and sacrificed. Radioactive
    unmetabolized acetone and total radioactivity were found in blood,
    heart, pancreas, spleen, kidney, brain, liver, thymus, testis, vas
    deferens, lung, muscle, brown adipose tissue, subcutaneous adipose
    tissue and intraperitoneal adipose tissue. Acetone levels generally
    peaked from about 145.2 to 203.3 µg/g tissue except in adipose tissues

    for total radioactivity. Peak levels of metabolized acetone were
    generally < 58.0-75.5 µg/g tissue. Exposure for longer than 6 h
    resulted in no further accumulation of total radioactivity except in
    the liver and brown adipose tissue, where levels rose to 278.8 µg/g in
    the liver and 151.0 µg/g in brown adipose tissue at 24 h. Only about
    10% of the radioactivity in the liver at 24 h was unmetabolized
    acetone. When file mice were exposed intermittently on 3 or 5
    consecutive days, most tissues showed no or only a small additional
    increase in radioactivity after more than 1 day of exposure; however,
    the concentration in adipose tissue increased significantly with
    increasing exposure duration up to 5 days. The ratio of acetone in the
    tissues to that in blood was < 1 at all exposure times except for the
    lungs (the site of exposure). However, the ratio of total
    radioactivity in the tissues to that in the blood showed that after 1
    and 3 h exposure, only the lung had a ratio > 1, whereas the ratios
    in the kidneys and liver were > 1 after 6 h. Only the muscle and
    subcutaneous and intraperitoneal adipose tissue levels rose
    continuously. Elimination of acetone was complete in all tissues by
    24 h after exposure, but total radioactivity, indicative of
    metabolites, was still present in all tissues except blood and muscle.
    These data indicate that acetone is not selectively distributed to any
    tissues but is more evenly distributed in body water. It appears that
    acetone does not accumulate with repeated exposure. The continued
    accumulation of radioactivity in the liver and brown adipose tissue is
    probably the result of high metabolic turnover in these tissues.

    6.2.2  Oral exposure

         No studies were located regarding the distribution of acetone or
    its metabolites in humans or animals after oral exposure except that
    acetone was found in the liver of rats after oral exposure
    (Charbonneau et al., 1986a, 1991). Acetone is absorbed from the
    gastrointestinal tract and is highly water soluble. Therefore,
    distribution to tissues with high water content is to be expected.

    6.2.3  Injection exposure

         Intravenous injection of 100 mg acetone/kg body weight to
    pregnant rats on gestational day 19 resulted in high levels of
    1,2-propanediol and acetol in the fetuses (Peinado et al., 1986).
    Whether these findings reflect transfer of the metabolites from the
    dams or metabolism of transferred or endogenous acetone by the
    fetuses was not resolved.

    6.2.4  Distribution summary

         There are few studies on the distribution of acetone. Since
    acetone is highly water soluble, it has been shown to be widely
    distributed to tissues with a high water content.

    6.3  Metabolism

    6.3.1  Human studies

         Acetone is a normal product of intermediary metabolism. The
    metabolism of acetone appears to be independent of route of
    administration and involves at least three separate gluconeogenic
    pathways, with ultimate incorporation of carbon atoms into glucose and
    other products and substrates of intermediary metabolism with the
    generation of carbon dioxide. As previously mentioned, acetone is one
    of three ketone bodies produced by acetyl coenzyme A within the liver.
    The metabolic pathways appear to be similar in humans and animals. The
    primary pathway involves hepatic metabolism of acetone to acetol,
    followed by metabolism of acetol to methylglyoxal, while two secondary
    (minor) pathways are partially extrahepatic, involving the
    extrahepatic reduction of acetol to L-1,2-propanediol. Some exogenous
    acetone is unmetabolized and is excreted primarily in the expired air.
    Little acetone is excreted in urine.

         Metabolic studies in humans were conducted in normal fasted,
    obese fasted, and diabetic patients (Reichard et al., 1979, 1986). The
    involvement of gluconeogenesis was demonstrated in normal patients
    fasted for 3 days, obese patients fasted for 3 days, and obese
    patients fasted for 21 days before intravenous injection of
    2-[14C]-acetone (Reichard et al., 1979). According to the
    researchers, fasted individuals had a daily intake of one multivitamin
    capsule and at least 1500 ml of water. The percentages of 14C-glucose
    in plasma derived from 14C-acetone were 4.2, 3.1 and 11.0% in the
    three respective groups, suggesting the involvement of gluconeogenesis.
    Cumulative 14C-carbon dioxide excretion by the lungs during the 6-h
    collection period accounted for 17.4, 21.5 and 4.9% in the three
    respective groups. Radioactivity was also incorporated into plasma
    lipids and plasma proteins. Unmetabolized acetone in the expired air
    accounted for 14.7, 5.3 and 25.2%, urinary excretion of acetone
    accounted for 1.4, 0.6 and 1.3%, respectively, and  in vivo
    metabolism accounted for 83, 94.1 and 73%, respectively, of the
    radioactivity, Intravenous infusion of 2-[14C]-acetone into patients
    with diabetic ketoacidosis resulted in a mean plasma acetone turnover
    rate of 6.45 µmol/kg/min (Reichard et al., 1986). Analysis of glucose
    in urine revealed a labelling pattern in five of the six patients
    consistent with the involvement of pyruvate in the gluconeogenic
    pathway, while a different pathway may have been followed in the other
    patient. Acetol and 1,2-propanediol were also detected in the plasma
    and the concentrations of these metabolites were directly related to
    the plasma level of acetone. The results demonstrated high plasma
    acetone levels in decompensated diabetic patients with moderate to
    severe ketoacidosis. The proposed pathway of acetone metabolism in
    these patients is acetone to acetol to 1,2-propanediol to pyruvate and
    ultimately to glucose, but other pathways may exist.

         Jones & Andersson (1995) reported on a man arrested and suspected
    of drunken driving. Both isopropyl alcohol (0.17 mg/ml) and acetone
    (0.45 mg/ml) were found in his blood, but one of the breath tests
    identified that an interferant was present. The case history showed
    that the man was being treated for hyperglycaemia with a controlled

         Jones et al. (1993) examined blood concentrations of acetone in
    three groups: drunk drivers, type-1 diabetic outpatients and healthy
    blood donors. The median concentrations were 2.03 mg/litre, 1.90
    mg/litre and 1.26 mg/litre, respectively. While previous research
    indicated that during fasting and uncontrolled diabetes mellitus
    acetone increases, Jones et al. (1993) indicated that controlled
    diabetes results in near normal acetone concentrations.

         Kundu et al. (1993) studied acetone and established a correlation
    between rate of fat loss and breath acetone concentration. The study
    consisted of 58 men and women, 10-30% above their ideal body weight on
    special diets of 1000 and 1200 calories per day. Breath acetone
    concentrations were taken immediately upon wakening and increased in
    the first few days to a plateau at approx. 7 days.

    6.3.2  Experimental animal studies

         The metabolism of acetone has been studied extensively in
    laboratory animals, primarily in rats, and three separate pathways of
    gluconeogenesis have been elucidated (Fig. 1). In many experiments,
    rats, mice or rabbits have been exposed by inhalation, gavage,
    drinking-water, or by intravenous, subcutaneous or intraperitoneal
    injection of non-radiolabelled acetone or acetone labelled with 14C
    in the methyl groups, number 2 carbon atom, or all three carbon atoms
    (Price & Rittenberg, 1950; Rudney, 1954; Mourkides et al., 1959;
    Casazza et al., 1984; Hetenyi & Ferrarotto, 1985; Koop & Casazza,
    1985; Johansson et al., 1986; Kosugi et al., 1986a,b; Puccini et al.,
    1990; Skutches et al., 1990). In these experiments, identification of
    metabolites in liver, plasma or urine, the labelling patterns of 14C
    incorporation into metabolites from 14C-acetone in plasma or in
    liver, or the results of enzyme reactions using microsomes from
    acetone-treated animals have led to the known metabolic pathways
    illustrated in Fig. 1. Initially, acetone is oxidized (hydroxylation
    of a methyl group) to acetol by acetone monooxygenase, an activity
    associated with the cytochrome P-450IIE1, and requiring oxygen and
    NADPH (Casazza et al., 1984; Koop & Casazza, 1985; Johansson et al.,
    1986; Puccini et al., 1990). Cytochrome P-450IIE1 can be induced by
    fasting, experimental diabetes, or exposure to ethanol or acetone
    (Patten et al., 1986; Johansson et al., 1988; Puccini et al., 1990).
    When the rate of acetone oxidation was evaluated in microsomes with
    acetone added to the incubation system, microsomes from rats
    (Johansson et al., 1986) and mice (Puccini et al., 1990) pretreated
    with acetone had a 7-8 times greater rate than microsomes from control
    rats or mice, indicating that acetone induces its own metabolism.

    FIGURE 2

         The relative importance of the three pathways in the metabolism
    of acetone may depend upon the amount of acetone administered. When a
    trace amount of [2-14C]-acetone was administered intravenously to
    rats, the pattern of incorporation of 14C into glucose was
    consistent with the production of glucose via the
    methylglyoxal/lactate pathway (Kosugi et al., 1986a). When a higher
    dose of [2-14C]-acetone (325 mg/kg) was injected, the pattern of
    incorporation was more consistent with the 1,2-propanediol pathway.
    These results suggest that at low doses of acetone or endogenous
    acetone, the methylglyoxal and lactate pathways predominate, but at
    higher doses, these pathways become saturated and metabolism is
    shunted to the formate-acetate branch of the 1,2-propanediol pathway.

         Methylglyoxal can then be converted to D-glucose by an
    unidentified pathway (Fig. 1), and/or possibly by catalysis by
    glyoxalase I and II and glutathione to D-lactate, which is converted
    to D-glucose (Casazza et al., 1984). This formation of D-lactate from
    acetone provides the body with a mechanism for recovering a portion of
    the energy that is lost when acetone is formed from acetoacetate
    (Morgott, 1993). The conversion of methylglyoxal to D-lactate by the
    actions of glyoxalase I and II is well established (Racker, 1951), but
    may represent a minor pathway in the metabolism of acetone (Casazza et
    al., 1984; Kosugi et al., 1986a; Thomalley, 1990). In addition,
    methyl-glyoxal is converted to D-glucose via conversion of
    methylglyoxal to pyruvate by 2-oxoaldehyde dehydrogenase, an activity
    identified using aqueous extracts of sheep liver acetone powders
    (Monder, 1967).

         In the second and third pathways, acetol is converted to
    L-1,2-propanediol by an extrahepatic mechanism that has not been
    characterized (Rudney, 1954; Casazza et al., 1984; Kosugi et al.,
    1986a,b; Sktuches et al., 1990). The two pathways then diverge from
    the point of production of 1,2-propanediol. In the second pathway,
    1,2-propanediol formed extra-hepatically returns to the liver where it
    is converted to L-lactaldehyde by nicotinamide adenine dinucleotide
    (NADH)-dependent alcohol dehydrogenase (Casazza et al., 1984; Kosugi
    et al., 1986a,b), and L-lactaldehyde, in mm, is converted to L-lactate
    (Rudney, 1954; Ruddick, 1972; Casazza et al., 1984) by NADH-dependent
    aldehyde dehydrogenase (Casazza et al., 1984). L-lactate can then be
    converted to D-glucose (Casazza et al., 1984). In the third pathway,
    the L-1,2-propanediol formed extra-hepatically returns to the liver
    where it is degraded by other mechanisms to acetate and formate
    (Sakami & Rudney, 1952; Ruddick, 1972; Casazza et al., 1984),

         Several studies have traced the labelling patterns of 14C from
    [2-14C]-acetone or [1,3-14C]-acetone to gluconeogenic precursors
    and formate to incorporation of 14C into glycogen, glycogenic amino
    acids, fatty acids, haem, cholesterol, choline and urea (Price &
    Rittenherg, 1950; Sakami & LaFaye, 1950; Mourkides et al., 1959). The
    pattern of labelling suggested the involvement of the pathway to
    acetate and formate. Fatty acids, amino acids and glycogen may also
    enter stages of intermediary metabolism. Factors affecting the

    formation and release of long-chain fatty acids from adipose tissue
    during lipolysis can affect the circulatory levels of acetone
    (Morgott, 1993).

         Although the liver is the primary site of acetone metabolism,
    radioactive unmetabolized acetone and total radioactivity have been
    found in many other mice tissue and organs after inhalation exposure
    to 14C-acetone (Wigaeus et al., 1982). The fraction of total
    radioactivity that was not unchanged acetone represented metabolites.
    Elimination of acetone was complete in all tissues by 24 h after
    exposure, but total radioactivity, indicative of metabolites, was
    still present in all tissues except blood and muscle. Whether these
    tissues (other than the liver) were capable of metabolizing acetone or
    whether the metabolites themselves were distributed to the tissues was
    unclear. However, microsomes from the lungs of hamsters exposed to
    acetone in drinking-water for 7 days had a 500% increased activity of
    aniline hydroxylase activity, an enzyme associated with cytochrome
    P-450IIE1 (Ueng et al., 1991). The level of cytochrome P-450IIE1
    increased 6-fold in microsomes from the nasal mucosa of rabbits
    exposed to acetone in drinking-water for 1 week (Ding & Coon, 1990).
    In hamsters given drinking-water containing acetone for 7 days (Ueng
    et al., 1991) or 10 days (Menicagli et al., 1990), the microsomes
    prepared from kidneys had increased levels of cytochrome P-450 and
    cytochrome b5. These results suggest that acetone metabolism, which
    involves cytochrome P-450IIE1, may occur in the lungs and kidneys of
    hamsters and the nasal mucosa of rabbits. Incubation of acetone with
    homogenates of nasal mucosa from mice indicated that acetone was
    metabolized via a NADPH-dependent pathway  in vitro, but no evidence
    of  in vivo metabolism of acetone by the upper respiratory tract was
    found in mice, rats, guinea-pigs or hamsters (Morris, 1991 ).

         Diet as well as physiological or genetic status may alter the
    metabolism of acetone. When non-diabetic and diabetic rats were
    treated by gavage with acetone at doses of 1000, 2000 or 4000 mg/kg,
    isopropyl alcohol was detected in the blood (Lewis et al., 1984). The
    levels of isopropyl alcohol and acetone increased with higher doses in
    the diabetic rats, although with plateaus for both acetone and
    isopropyl alcohol at 1000 and 2000 mg/kg doses, but levelled off in
    the non-diabetic rats, indicating either saturation of the metabolic
    pathway from acetone to isopropyl alcohol or a reversibility of the
    conversion at high doses. It was suggested that in the diabetic rats,
    acetone and NADH+, both needed for isopropyl alcohol production from
    acetone, presumably by alcohol dehydrogenase, may be diverted to
    gluco-neogenic pathways to meet the diabetic rat's need for glucose,
    resulting in the short plateau. The subsequent rises of both compounds
    at the high dose of acetone in the diabetic rats could be accounted
    for by greater generation of NADH+ from fatty acid oxidation in the
    diabetic rat, which reduces acetone to isopropyl alcohol, accounting
    for the rising level of isopropyl alcohol. Liver homogenates from mice
    heterozygous for the obesity gene treated with acetone were more
    effective in converting acetone to lactate than liver homogenates from
    normal homozygous mice treated with acetone (Coleman, 1980).

         In pregnant or virgin rats (either fed or fasted) injected
    intravenously with acetone, plasma acetol levels were not
    significantly different between fasted and non-fasted rats, but
    pregnant rats had significantly lower levels than virgin rats (Peinado
    et al., 1986). Liver levels of acetol were also significantly lower in
    pregnant rats than in virgin rats, Methylglyoxal levels were very high
    in the livers and plasma of non-fasted rats (pregnant or virgin), but
    fasting resulted in much lower levels. In contrast, no major
    differences were found in the expiration of carbon dioxide between
    fasted and diabetic rats injected intraperitoneally with acetone
    (Mourkides et al., 1959) or in the labelling pattern of 14C derived
    from 14C-acetone into glucose among non-fasted diabetic, fasted
    diabetic, normal non-fasted and normal fasted rats injected
    intravenously with 14C-acetone (Kosugi et al., 1986a,b).

    6.3.3  Metabolism summary

         As shown in Fig. 1, acetone is oxidised to acetol, which is then
    metabolized by at least three different pathways and is independent of
    the route of exposure. Glycogenesis is a driving force and acetone is
    one of three ketone bodies produced by acetyl coenzyme A in the liver.

         The relative importance of each pathway is probably dependent on
    both the amount and route of exposure. Diet, physiological and genetic
    status, and diabetes may affect the metabolism of acetone. Acetone is
    either metabolized or excreted in both humans and animals, and the
    time taken for elimination depends on the amount of acetone absorbed.

    6.4  Elimination and excretion

         Exhalation accounts for the elimination of about 20% as breath
    acetone at low plasma acetone concentrations. Approximately 75% is
    metabolized, only small amounts appearing in the urine. However, at
    high plasma acetone concentrations, 80% can be accounted for by breath
    acetone with only 20% being metabolised  in vivo. The main route of
    excretion of acetone is by the lung regardless of the route of
    exposure (Owen et al., 1982).

    6.4.1  Human studies

         The clearance of acetone from blood was constant regardless of
    blood acetone concentration (DiVincenzo et al., 1973). Halftimes for
    blood elimination of 3-3.9 h have been estimated in humans exposed to
    240-590 mg/m3 (100-500 ppm) for 2-4 h (DiVincenzo et al., 1973;
    Wigaeus et al., 1981; Brown et al., 1987). Elimination half-times
    between 3.9 and 6.2 h have been estimated for blood (Wigaeus et al.,
    1981, Wang et al., 1994), and no differences in elimination half-times
    were found between men and women (Brown et al., 1987). Because the
    elimination rate depends on the metabolism, the effect of induction of
    P450-dependant monooxygenase hydroxylase by acetone itself (Puccini et
    al., 1989) or other specific inducers of the isozymes involved could
    change the half-time. Longo et al. (1993) have shown that the set of

    isozymes differs among animal species, and some have not been isolated
    and characterized (Puccini et al., 1989). The elimination from blood
    was found to be complete in 24 h after a 6-h exposure in subjects
    exposed to 470 mg/m3 (250 ppm), in 32 h in subjects exposed to 1190
    mg/m3 (500 ppm), and in 48 h in subjects exposed to 2370 mg/m3
    (1000 ppm) (Matsushita et al., 1969b). When volunteers were exposed
    for 6 h/day for 6 days, the blood levels of acetone rose each day and
    declined to background levels by the following morning each day when
    the exposure concentration was 470 mg/m3 (250 ppm) (Matsushita et
    al., 1969a). At an exposure concentration of 1190 mg/m3 (500 ppm),
    however, the blood levels declined each day, but not to pre-exposure
    levels. At the end of the 6-day exposure, blood acetone levels
    declined to pre-exposure levels within 2 days for the 470 mg/m3
    group and declined within 3 days for the 1190 mg/m3 group. From the
    half-life and the data on time for decline to pre-exposure levels, it
    appears that at higher concentrations, acetone may accumulate slightly
    in the blood during daily intermittent exposure, as would be
    experienced by workers.

         The rate and pattern of respiratory excretion of acetone is
    influenced by exposure concentration, duration, the level of physical
    activity during exposure and gender. In humans exposed to acetone
    concentrations of < 2970 mg/m3 (< 1250 ppm) for < 7.5 h/day
    in a complex protocol for < 6 weeks, the rate of respiratory
    excretion was a function of the duration, and the concentration of
    acetone in breath after exposure was directly related to the
    time-average concentration during exposure, with constant duration
    (Stewart et al., 1975). The length of time after exposure in which
    acetone could be detected in the expired air was related to the
    magnitude of exposure, with acetone still readily detectable 16 h after
    exposure to 2370 or 2970 mg/m3 (1000 or 1250 ppm) for 7.5 h.
    Excretion of acetone by the lungs was complete within 20 h post-exposure
    in humans exposed to 560 mg/m3 (237 ppm) for 4 h (Dick et al.,
    1989). During exposure for 2 h, the acetone concentration in expired
    air rose to 50 mg/m3 (20 ppm) in humans exposed to 240 mg/m3 (100
    ppm) and to 215-240 mg/m3 (90-100 ppm) in those exposed to 1190 mg/m3
    (500 ppm) (DiVincenzo et al., 1973). After exposure to 240 mg/m3, the
    expired air concentration of acetone declined biphasically over the
    next 7 h to 12 mg/m3 (5 ppm). However, after exposure to 1190 mg/m3
    (500 ppm), the expired air concentration dropped sharply to 5 mg/m3
    (2 ppm) and declined to 2 mg/m3 (1 ppm) over the next 7 h. Prolonging
    the exposure duration to 4 h resulted in less than a 2-fold increase
    in acetone levels in post-exposure expired air, which may reflect a
    greater loss of acetone through metabolism and urinary excretion.
    Exercise during the exposure period increased the elimination almost
    2-fold. In humans exposed to acetone at rest, during exercise at a
    constant workload, or during exercise with step-wise increments in
    workload, expiration of acetone via the lungs amounted to 70, 80 and
    200 nag, respectively, at 4 h post-exposure and to 50, 80 and 200 mg,
    respectively, over the next 4-20 h (Wigaeus et al., 1981). Excretion
    of acetone from the lungs and kidneys (combined) amounted to 16, 20
    and 27% of the amount absorbed in the three respective groups of

    subjects. Urinary excretion amounted to only 1% of the total uptake.
    Women expired acetone more slowly than men after a 4-h exposure to
    300-310 mg/m3 (127-131 ppm), but the percentages excreted by the
    lungs were not statistically significantly different between men and
    women (17.6% for men, 15.0% for women) (Nomiyama & Nomiyama, 1974b).

         Very little acetone is excreted in the urine (DiVincenzo et al.,
    1973; Wigaeus et al., 1981; Vangala et al., 1991; Kawai et al., 1992).
    Urinary excretion is biphasic (Pezzagno et al., 1986). Peak urinary
    excretion occurred between 1 and 3.5 h after exposure (Matsushita et
    al., 1969b; Wigaeus et al., 1981). In male volunteers exposed by
    inhalation to 1180-2350 mg/m3 (497 or 990 ppm) acetone for 4 h,
    cumulative acetone excretion in urine at 18 h after cessation of
    exposure was 89.5 mg, suggesting slow excretion of acetone in the
    urine (Vangala et al., 1991). Again, the amount of acetone excreted in
    the urine will be influenced by the exposure concentration, the
    duration of exposure, and the level of physical activity during
    exposure. The acetone concentration in the urine ranged from 0 to 17.5
    mg/litre at the end of the 8-h work shift in 45 workers exposed to
    0-165 mg/m3 (0-70 ppm) acetone (background urinary concentration in
    343 non-exposed subjects averaged 1.5 mg/litre) (Kawai et al., 1992).
    Acetone levels in the preshift urine samples were significantly higher
    than background levels when acetone exposure on file previous day was
    above 35 mg/m3 (15 ppm). There was no significant difference between
    background urine levels and preshift urine levels when the previous
    day's exposure was < 35 mg/m3 (< 15 ppm). Total 24-h urine
    content of acetone was 1.25 mg in subjects exposed to 240 mg/m3 (100
    ppm) for 2 h and 3.51 mg in subjects exposed to 1190 mg/m3 (500 ppm)
    for 2 h (DiVincenzo et al., 1973). Prolonging the duration to 4 h in
    the 240 mg/m3 group resulted in a total of 1.99 mg acetone in the
    urine. A slight increase in the urinary content of acetone (1.39 nag)
    was found when humans exposed to 240 mg/m3 for 2 h exercised during
    the exposure. The nature of physical activity during exposure also
    influenced the urinary excretion. At 3-3.5 h after exposure, 8.5, 8.5
    and 13.4 mg were excreted by the kidney in subjects exposed at rest,
    during exercise at a constant workload, and during exercise with
    step-wise increments in workload, respectively (Wigaeus et al., 1981).
    Urinary excretion amounted to only 1% of the total uptake.

         In volunteers who ingested 40-60 mg/kg acetone, the elimination
    of acetone in expired air and urine was determined 2 h later, and a
    rate of metabolism of 1.82 mg/kg per h along with the excretion data
    was used to calculate that 3.54-7.38 mg/kg had been excreted and
    metabolized (Haggard et al., 1944). The authors estimated that 65-93%
    of the administered dose was metabolized, the remainder being
    eliminated in the urine and expired air.

         The only other information regarding excretion of acetone in
    humans after oral exposure is from case reports of accidental or
    intentional ingestion of materials containing acetone plus other
    components that may have influenced the elimination of acetone. In a
    man who ingested liquid cement containing 18% acetone (231 mg/kg), 28%

    2-butanone and 29% cyclohexanone, and 720 ml sake, the plasma level of
    acetone was approx. 1120 mg/litre 5 h after ingestion and declined to
    65 mg/litre at 18 h, 60 mg/litre at 24 h and < 5 mg/litre at 48 h
    (Sakata et al., 1989). A first-order plasma elimination rate constant
    of 0.038/h and a half-time of 18.2 h were calculated. The urinary
    level of acetone decreased gradually from about 123 mg/litre at 5 h
    after ingestion to about 61 mg/litre at 19 h. In a case of a known
    alcoholic who had ingested nail polish remover and whose blood acetone
    level was 2.5 g/litre) upon admission to the hospital, the blood level
    of acetone declined in a log-linear manner to about 0.6 g/litre about
    86 h after admission, with a half-life of 31 h (Ramu et al., 1978).
    The calculated clearance of acetone from the lungs was 29 ml/min or
    0.39 ml/min per kg. A half-time of 25 h for lung clearance was
    calculated, which is in agreement with the observed plasma elimination
    half-tune of 31 h. The serum acetone level of a 30-month-old child was
    4.45 g/litre 1 h after ingestion of a 6-ounce bottle of nail polish
    remover (65% acetone) and declined to 2.65 g/litre at 117 h, to 0.42
    g/litre at 48 h, and to 0.04 g/litre at 72 h (Gamis & Wasserman,
    1988). The half-time of acetone in this patient was 19 h in the severe
    early stage and 13 h in later stages of intoxication, which suggested
    to the authors greater metabolism and/or excretion in children,
    compared with adults.

         Information regarding excretion of acetone after dermal exposure
    of humans is limited, but the main route of excretion is via the
    lungs, with little excreted in the urine. Application of an
    unspecified quantity of acetone to a 12.5 cm2 area of skin of
    volunteers for 2 h/day for 4 days resulted in alveolar air levels of
    12-30 mg/m3 (5-12 ppm) and urinary concentrations of 8-14 mg/litre
    on each day (Fukabori et al., 1979). These levels declined to
    background levels by the next day after each exposure. Higher alveolar
    air and urinary levels were obtained when the daily exposure increased
    to 4 h/day: 60-80 mg/m3 (25-34 ppm) in alveolar air and 29-41
    mg/litre in urine. However, these levels also returned to background
    each day.

         As determined in humans (Reichard et al., 1979), physiological
    status may influence the disposition of endogenous and exogenous
    acetone. In groups of non-obese patients fasted for 3 days, obese
    patients fasted for 3 days, and obese patients fasted for 21 days and
    injected intravenously with 14C-acetone, 8-29% of the urinary
    acetone was derived from plasma radioactive acetone (Reichard et al.,
    1979). The concentrations of urinary acetone were 1.2, 0.4 and 151
    mg/litre in 3-day-fasted non-obese, 3-day-fasted obese, and
    21-day-fasted obese patients, respectively. The rates of urinary
    acetone excretion were 2962, 1800 and 3542 µg/min, respectively,
    suggesting marked renal reabsorption or back-diffusion. The percentages
    of measured acetone production that could be accounted for by excretion
    via the lungs were 14.7, 5.3 and 25.2%, respectively. The percentages
    that could be accounted for by urinary excretion were 1.4, 0.6 and
    1.3%, respectively. Cumulative excretion of 14C-carbon dioxide
    during the 6-h turnover study periods accounted for 17.4, 21.5 and

    4.9%, respectively. Thus, non-obese subjects fasted for 3 days
    excreted more acetone at higher rates than did obese subjects fasted
    for 3 days. However, excretion by the obese patients fasted for 21
    days exceeded that by both 3-day-fasted groups. These differences are
    probably related to the effect that the degree of starvation ketosis
    has on the metabolism and overall disposition of acetone.  Occupational exposure studies

         There are many reports in the literature regarding exposure to
    solvents, many of which are confounded for risk assessment purposes by
    exposure to a mix of several solvents. The following information takes
    the essence of these studies to give the reader an understanding of
    the various exposure scenarios and the measured acetone

         Satoh et al. (1995) studied male shift workers at a Japanese
    acetate fibre manufacturing facility. The first group was 110
    acetone-exposed (AE) workers, while the control groups (CG) consisted
    of 67 workers in the same factory area but not engaged in acetone
    manufacturing (background concentration < 12 µg/m3; < 5 ppb).
    Levels were measured in the breathing zone and in samples of alveolar
    air, blood and urine. Mean levels were reported as 857 mg/m3 (361
    ppm), 216 mg/m3 (91 ppm), 67 mg/litre and 37 mg/litre, respectively.
    They evaluated whether exposure to acetone during the previous day
    affects the biological monitoring value at the end of a work day, i.e.
    urinary values of acetone from monitoring do not revert to levels seen
    with normal background exposure. Matsushita et al. (1969a,b) observed
    that humans exposed to 1190 mg/m3 (500 ppm) of acetone had higher
    than background levels the next morning. According to Satoh et al.
    (1995), the extent of previous exposure and the sampling time
    influenced the biological monitoring value and were very critical.
    Additionally, other factors such as alcohol consumption, could give
    rise to more than 30 mg/litre of acetone in the urine. When the
    exposure concentration of the workers was 595 mg/m3 (250 ppm), the
    urinary level of acetone returned to background the next morning. When
    the exposure concentration was raised to 1190 mg/m3 (500 ppm), the
    following morning's acetone levels were higher than background. Wang
    et al. (1994) reported similar results. The next morning, 16 h after
    the end of a workshift, with a mean occupational exposure to acetone
    of 336 mg/m3, blood and urinary concentrations of 3.5 mg/litre and
    13.0 mg/litre, respectively, were much higher than levels in
    non-exposed subjects.

         Fujino et al. (1992) also investigated the relationship between
    the environmental concentration and the concentration in urine,
    alveolar air and blood. The environmental air concentration to which
    each of the 110 subjects were exposed was closely correlated with all
    body concentrations. The authors also found that urinary acetone
    concentration is probably the best biological index of exposure
    because it shows the strongest correlation.

         Kawai et al. (1992) studied 45 acetone-exposed male workers
    together with 343 non-exposed men to examine the quantitative
    relationship between the levels of acetone vapour exposure and the
    concentration of acetone in urine. Up to a vapour concentration of 35
    mg/m3 (15 ppm), there was no increase in acetone concentration in
    end-of-shift urine, but above this concentration there was an increase
    in urinary acetone concentration in proportion to the acetone vapour
    concentration. The authors reported that urinary acetone
    concentrations collected at the shift-end and those before the shift
    of the next morning were similar among those exposed to < 35
    mg/m3 (15 ppm) acetone. However, among those exposed to acetone at
    more than 35 mg/m3, acetone levels in the shift-end samples were
    significantly higher than those in the pre-shift samples.

         Mizunuma et al. (1993) and DeRosa et al. (1993) reported
    different results in factory workers exposed to styrene and acetone.
    Mizunuma et al. (1993) studied 41 workers in a factory making
    fibre-reinforced plastics who were exposed to mixed styrene and
    acetone vapour and 20 non-exposed workers. Acetone and styrene
    concentrations in blood and urine correlated significantly with
    intensity of exposure. Acetone was found to distribute evenly in blood
    and urine, and was also distributed evenly between the cellular and
    non-cellular fractions of the blood. DeRosa et al. (1993) monitored 22
    workers exposed to styrene and acetone in two fibreglass industries to
    determine if excretion of styrene metabolites differed over a working
    week and if it was modified by simultaneous exposure to acetone.
    Acetone exposure had no affect on styrene metabolism.

    6.4.2  Experimental animal studies

         As in humans, acetone is excreted mainly by the lungs of
    experimental animals. Studies in animals have followed the elimination
    of acetone from blood and tissues, excretion of acetone and carbon
    dioxide in expired air, and the urinary excretion of formic acid.

         Blood levels of acetone were highest immediately after a 4-h
    exposure of rats to acetone (Charbonneau et al., 1986a). In rats
    exposed to 23 700 mg/m3 (10 000 ppm), the blood level dropped from
    2114 to 5 mg/litre in 25 h. In rats exposed to 35 600 mg/m3 (15 000
    ppm), the blood level dropped from 3263 mg/litre to 50 mg/litre after
    25 h. Elimination from blood was biphasic in rats exposed to 23 700
    and 35 600 mg/m3. Elimination from blood was triphasic in rats
    exposed to 2370, 5940 or 11 900 mg/m3 (1000, 2500 or 5000 ppm) and
    was complete within 17-25 h. In dogs exposed to 240, 1190 or 2370
    mg/m3 (100, 500 or 1000 ppm) acetone for 2 h, blood levels declined
    in a log-linear manner with a half-time of 3 h, similar to that
    observed m humans (DiVincenzo et al., 1973). Blood levels declined
    from 25 mg/litre immediately after exposure to 10 mg/litre at 5 h
    post-exposure for the 2370 mg/m3 (1000 ppm) group, from 12 to 3
    mg/litre for the 1190 mg/m3 (500 ppm) group, and from 4 to 1.5
    mg/litre for the 240 mg/m3 (100 ppm) group. Elimination of
    radioactivity and 14C-acetone was fastest from blood, kidney, lungs,

    brain and muscle tissues of mice exposed to 1190 mg/m3 (500 ppm)
    14C-acetone for 6 h, with half-times of 2-3 h during 6 h
    post-exposure (Wigaeus et al., 1982). Elimination of acetone was
    complete in 24 h in all tissues, but radioactivity (indicative of
    metabolites) was still present in all tissues except blood and muscle.
    When rats were exposed for 5 days, acetone tended to slowly attain
    steady state in adipose tissue.

         Excretion of acetone in air followed pseudo-first-order kinetics
    in rats exposed to up to 50 mg/m3 (< 20 ppm) acetone for 1-7 days,
    while at higher concentration saturation kinetics were observed
    (Hallier et al., 1981). In rats exposed to 1190 mg/m3 (500 ppm)
    14C-acetone for 6 h, 42 µmol of radioactive acetone and 37 µmol
    14C-carbon dioxide were excreted in the expired air during a 12-h
    post-exposure period, 95% and 85%, respectively, being recovered in
    the first 6 h post-exposure (Wigaeus et al., 1982). Radioactive
    acetone accounted for 52% and radioactive carbon dioxide accounted for
    48% of the expired radioactivity. The concentration of acetone in the
    expired breath of dogs exposed to 240, 1190 or 2370 mg/m3 (100, 500
    or 1000 ppm) acetone for 2 h declined in a log-linear manner
    (DiVincenzo et al., 1973). The breath levels were directly related to
    the magnitude of exposure. Breath levels declined from 3.8 mg/m3
    (1.6 ppm) at 30 min after exposure to 0.7 mg/m3 (0.3 ppm) at 300 mm
    in the 240 mg/m3 (100 ppm group), from 16.1 to 3.5 mg/m3 (6.8 to
    1.5 ppm) in the 1190 mg/m3 (500 ppm) group, and from 35.6 to 9.5
    mg/m3 (15 to 4 ppm) in the 2370 mg/m3 (1000 ppm) group.

         Urinary excretion of formic acid was followed for 7 days in rats
    exposed by inhalation to 147 200 mg/m3 (62 000 ppm) acetone for 2
    days. The rate of formic acid excretion was 344 µg/h compared with 144
    µg/h in controls (Hallier et al., 1981).

         For experimental animals, information regarding the excretion of
    acetone after oral exposure is available only for rats. As is the case
    after inhalation exposure, acetone, mainly as carbon dioxide, is
    excreted primarily by the lungs. In a rat given 1.16 mg/kg
    14C-acetone by gavage in water, expiration of 14C-carbon dioxide
    totalled 47.4% of the administered radioactivity over the 13.5-h
    collection period (Price & Rittenberg, 1950). In another experiment, a
    rat was given 7.11 mg/kg radioactive acetone. A small amount of
    radioactive acetone (10%) was found in the expired air. Radioactive
    carbon dioxide and acetate were also detected. In a rat made diabetic
    by alloxan and given 6.15 mg/kg 14C-acetone, a total of 7.29% of the
    administered radioactivity was expired as acetone and 51.78% as carbon
    dioxide. Radioactive acetate was detected in the urine. These data
    indicate that very little acetone (< 10%) was excreted by the lungs
    after small doses of acetone. A major fraction was oxidized to carbon
    dioxide and some of the derived carbon was used for acetylation. The
    diabetic rat was also able to oxidize acetone, but only to approx. 70%
    of that in the normal rat.

         The dose of acetone influences the elimination of acetone from
    blood (Plaa et al., 1982). At a dose of 78.44 mg/kg, the maximum blood
    level of 200 mg/litre at 3 h declined to 10 mg/litre at 12 h, where it
    remained for the next 12 h (data inadequate to evaluate total body
    clearance). At a dose of 196.1 mg/kg body weight, the maximum blood
    level of 400 mg/litre at 6 h declined biphasically to 50 mg/litre at
    12 h and to 30 mg/litre at 18 h where it remained until 24 h (total
    body clearance = 64 ml/h). At a dose of 784.4 mg/kg body weight, the
    maximum blood level of 900 mg/litre at 1 h declined to 300 mg/litre at
    12 h, to 110 mg/litre at 18 h, and to 50 mg/litre at 24 h (total body
    clearance = 86 ml/h). At a dose of 1961 mg/kg body weight, the maximum
    blood level of 1900 mg/litre at 3 h declined slowly to 400 mg/litre at
    24 h (total body clearance = 75 ml/h). Thus total body clearance was
    independent of dose, but the half-time for elimination increased from
    2.4 h for 196.1 mg/kg to 4.9 h for 784.4 mg/kg, and 7.2 h for 1961

         The vehicle (corn oil or water) in which acetone is administered
    has little influence on the elimination of acetone from blood
    (Charbonneau et al., 1986a). After gavage treatment of rats with 78
    196, 392, 784 or 1177 mg/kg acetone in corn oil or water, elimination
    was biphasic for the two higher doses and triphasic for the lower
    doses. Acetone elimination from blood declined to <5 to <10 µg/ml by
    18-26 h at all dose levels, but minor differences were found between
    water and corn oil as vehicle. The blood concentration curves from
    rats given acetone in water more closely resembled those from rats
    exposed by inhalation.

    6.4.3  Elimination/excretion summary

         Following single exposure, endogenous acetone is eliminated from
    the body at low doses via metabolic pathways and at high doses via the
    lungs with the urine as a minor pathway. In general, acetone is
    eliminated from the body within 24 h, unless exposure is continuous or

         At low exposure levels, acetone is primarily eliminated by
    metabolism, while at higher exposure levels it is mainly eliminated by
    the lungs. Very little acetone is excreted in the urine. The
    elimination rate is highly dependent upon exposure level, duration of
    exposure, metabolism, genetic and pathophysiological conditions, and
    physical activity.

    6.4.4  Physiologically based pharmacokinetic model

         A physiologically based pharmacokinetic model has been developed
    to study the kinetic behaviour of acetone (Kumagai & Matsunaga, 1995).
    In this model, acetone can be distributed into eight tissue groups:
    the mucous layer of the inhaled air tract, the mucous layer of the
    exhaled air tract, a compartment for gas exchange (alveolus of the
    lung), a group of blood-vessel-rich tissues including the brain and

    heart, a group of tissues including muscles and skin that have low
    blood perfusion rates, a group of fatty tissues, an organ for
    metabolism (liver), and a compartment for urinary excretion (kidney).

         With an appropriate value for the volume of mucous layer, the
    simulated acetone concentration in arterial blood, and exhaled air,
    urine, and fatty tissue were found to agree well with the experimental
    data. The volume of mucous layer and rate of respiration were critical 
    for the appropriate simulation.

         This model is suitable for occupational exposure assessments.

    6.5  Retention and turnover

         Reichard et al. (1979) studied acetone production in obese and
    non-obese patients during starvation-induced ketonaemia. The
    elimination and metabolism of acetone were measured, as well as urine
    and plasma concentrations by radioactive labels in order to calculate
    a plasma turnover rate for acetone. This was 20-77 µmol/m2 body
    surface area per min. Owen et al. (1982) and Reichard et al. (1986)
    furthered the original study in patients with severe diabetic
    ketoacidosis. Owen et al. (1982) measured rates of acetone production
    ranging from 68 to 581 µmol/min (using a standard human body surface
    area of 1.73 m2), with plasma concentrations ranging from 1.55 to
    8.91 mmol/litre. In the Reichard et al. (1986) study, the plasma
    concentrations ranged from 0.50 to 6.02 mmol/litre, and the acetone
    remover rate was linearly related to the plasma concentration up to a
    level of 7.61 mmol/litre. The two studies found opposite relationships
    between acetone turnover rate and plasma concentration.


    7.1  Short-term toxicity

         A summary of short-term inhalation toxicity studies of acetone is
    given in Table 8, acute oral studies are in Table 9, and dermal
    studies in Table 10. In the studies on rats and guinea-pigs, very high
    levels of acetone were required to cause death. In rats, a 4-h LC50
    of 76 mg/m3 and a 8-h LC50 of 50.1 mg/m3 have been reported
    (Pozzani et al., 1959). A range of LD50 values was found for rats.
    Kimura et al. (1971) stated that the lethality of acetone decreases
    with age to a certain point in the rat life cycle. However, the
    difference in values from older to younger adult rats was not found to
    be statistically significant.

         In acute oral studies, signs of narcosis usually precede death
    (ATSDR, 1994). In the EHRT (1987) study, mice that were dosed by
    gavage at 4800 mg/kg per day or more for 10 days displayed wheezing
    and rapid/laboured breathing. Narcosis was present before death.
    Savage treated rats were found to have increased haematocrit and
    haemoglobin in high-dose males (2500 mg/kg per day), but not in
    females. As will be seen below, these effects change with increasing
    dose and duration. Considering all the studies, it appears that there
    are sex and species differences for haematological effects from
    exposure to acetone.

         Acetone is known to be only mildly toxic to the liver, unless
    physiological processes are compromised (e.g., diabetes mellitus). It
    is known to potentiate and antagonize the effects of other chemicals
    by inducing microsomal enzymes that metabolize other chemicals to
    reactive intermediates. Acetone has been shown to increase the
    activity of glutathione S-transferase (Sippel et al., 1991 ).
    Induction of microsomal enzymes has been considered as a normal
    physiological response to xenobiotics when it does not cause other
    adverse effects such as increased liver weight, enzyme changes or
    other hepatic effects.

         In the NTP (1991) study, Dietz and co-workers found increased
    liver weights at doses > 965 mg/kg per day, and in higher dose
    groups (> 3896 mg/kg per day) hepatocellular changes accompanied
    this effect. A 14-day drinking-water study of F344/N rats and B6C3F1
    mice served as a preliminary study to the 13-week NTP (1991) study
    discussed in section 7.2. Five animals/sex of each species were
    administered drinking-water at concentrations of 0, 5, 10, 20, 50 or
    100 g/litre (NTP, 1991; Dietz et al., 1991). Based upon water
    consumption data, the authors estimated doses as follows: 0, 714,
    1616, 2559, 4312 and 6942 mg/kg per day for male rats; 0, 751, 1485,
    2328, 4350 and 8560 mg/kg per day for female rats; 0, 965, 1579, 3896,
    6348 and 10 314 mg/kg per day for male mice; and 0, 1569, 3023, 5481,
    8804 and 12 725 mg/kg per day for female mice.

         At necropsy, body weights were decreased, compared with controls,
    in male rats exposed to concentrations of > 50 g/litre and female
    rats exposed to 100 g/litre. The report for the 14-day study did not
    provide the collected organ weight data but stated that increased
    relative weights of kidneys and liver were measured for exposed rats
    and mice (dose level was not specified). No histopathological changes
    were observed in the kidneys or livers of exposed rats or in the
    kidneys of mice. Centrilobular hepatocellular hypertrophy was noted in
    ali male mice at concentrations > 20 g/litre and in female mice at
    concentrations of > 50 g/litre (NTP, 1991; Dietz et al., 1991).
    The hypertrophy was described as "minimal" in female mice, but
    increased incidence was noted with increasing concentration 2/5 and
    5/5 for 50 g/litre and 100 g/litre, respectively. The incidences of
    male mice with more severe hypertrophy (classified by the authors as
    either "mild" or "moderate") increased with increasing concentrations
    > 20 g/litre. The authors hypothesized that male mice may develop
    a tolerance to acetone because hepatic changes were not observed in
    male mice in the second study, the 13-week NTP study presented in the
    next section. Thus, in evaluating oral studies of the effects of
    acetone, the data indicated that changes occurred in the liver. The
    determination of whether or not these were adverse depends more on the
    determination of the severity of the effects. Acetone induced
    microsomal enzymes and increased liver weights. It caused liver injury
    with increased serum levels of liver enzymes and hepatocellular
    hypertrophy. As will be seen later, acetone potentiates other
    chemicals, which may increase these adverse effects or potentiate
    adverse effects caused by other chemicals. Oral exposure to acetone
    has also caused effects on the kidney in mice and rats, as shown in
    the NTP (1991) study (see also section 7.2). The best-known effects of
    acetone ingestion are the diabetes-like symptoms of hyper-glycaemia
    and glycosuria.

    7.1.1  Skin and eye irritation

         Smyth et al. (1962) applied 1.0 ml acetone to the shaved dorsal
    skin of rabbits without occlusion. After 24 h there was no evidence of
    irritation. In CD-1 mice, a single application of 0.2 ml acetone to
    shaved skin produced increased DNA synthesis and moderate hyperplasia
    of the epidermis that was considered to be evidence of slight
    irritation, In hairless mice treated with twice weekly application of
    0.1 ml acetone for 18 weeks, moderate hyperplasia of the epidermis was
    noted (Iversen et al., 1988)

         In rabbits, severe eye inflammation and corneal necrosis followed
    instillation of 0.005 ml acetone into the eye (Carpenter & Smyth,
    1946; Smyth et al., 1962). A 3-min application of 3.9 ml caused
    conjunctival oedema (Larson et al., 1956).

        Table 8. Short-term animal inhalation exposure to acetone

    Species       Exposure              NOAELb             LOAELb              Critical effect                          Reference
                  duration/frequencya   mg/m3(ppm)         mg/m3(ppm)

    Guinea-pig    2 days                                   23 700 (10 000)     5/5 died; spleen and lung congestion;    Specht et al.
                  24 h/day                                                     fatty liver; renal tubular distension    (1939)
    Guinea-pig    22-26 h                                  47 500 (20 000)     8/9 died; congestion and haemorrhage     Specht et al.
                                                                               of spleen and lung                       (1939)
    Guinea-pig    25 min-23.4 h                            51 750 (21 800)     2/10 died; narcosis, paralysis           Specht et al.
    Guinea-pig    3-8.75 h                                 118 700 (50 000)    8/8 died; pulmonary congestion,          Specht et al.
                                                                               oedema, glomerular distension            (1939)
    Rat           2 h                                      120 120 (50 600)    5/5 died                                 Bruckner &
                                                                                                                        Peterson (1981)
    Rat           3 h                                      29 900 (12 600)     CNS depression                           Bruckner &
                                                                                                                        Peterson (1981)
    Rat           4 h                                      76 000 (32 000)     LC50                                     Pozzani et al.
    Rat           4 h                                      38 000 (16 000)     1/6 died                                 Smyth et al.
    Rat           4h                    2850 (1200)        7100 (3000)         Audiogenic seizures depressed            Frantik et al.
    Rat           8 h                                      50 100 (21 050)                                              Pozzani et al.
    Rat           14 days               5200 (2200)        26 100 (11 000)     Reduced body weight, uterine weight,     NTP (1988)
                  7 days/week                                                  decreased fetal weight;
                  6 h/day
                  GD 6-19
    Rat           2 weeks               7100 (3000)        14 240 (6000)       inhibition of avoidance behaviour        Goldberg et al.
                  5 days/week                                                  in over 1/3 of rats                      (1964)
                  4 h/day
    Mouse         6h                                       26100(11000)        Severe narcosis                          NTP (1988)
    Mouse         1 day                 2370 (1000)        7100 (3000)         Decreased behavioura[ response           Glowa & Dews

    Table 8. (Continued)

    Species       Exposure              NOAELb             LOAELb              Critical effect                          Reference
                  duration/frequencya   mg/m3(ppm)         mg/m3(ppm)

    Mouse         12 days               5200 (2200)        15 650 (6600)       Decreased fetal weight, reduced                  NTP (1988)
                  7 days/week                                                  sternal ossification
                  6 h/day
                  GD 6-17

    a  GD = gestation day.
    b  Dose levels for all studies are included in this table or the text only.

    Table 9. Short-term oral exposure to acetone

    Species    Route            Exposure            NOAEL          LOAEL        Critical effect                               Reference
                                duration/frequency  (mg/kg)        (mg/kg)

    Rat        drinking-water   3-7 days                           3214         reduced insulin production, less              Skutches et al.
                                                                                serious systemic problems                     (1990)

    Rat        drinking-water   14 days           4312 (male)      6942 (male)  bone marrow hypoplasia                        NTP (1991)
                                                  8560 (female)

    Rat        drinking-water   10 days                            3500         induction of hepatic cytochrome               Puccini et al.
                                                                                P450, aminopyrineN-demethylase,               (1989)
                                                                                ethoxycourmarin O-deethylase,
                                                                                p-nitrophenol hydroxylase, acetone
                                                                                hydroxylase, diethyl-ngrosamine

    Rat        drinking-water   14 days           3500                          induction of dealkylation of                  Fiodo & Bronzetti
                                                                                amino-pyrine; induction of dealkylation       (1995)
                                                                                of anisole, hydroxylation of aniline;
                                                                                decreased survival of tissue culture
                                                                                cells treated with 
                                                                                dimethylnitros-amine; increased mutation
                                                                                rate of tissue culture cells treated with

    Rat        gavage           once              --               15 mmol/kg   induction of hepatic P450EI,                  Barnett et al.
                                                                   (871 mg/kg)  P450IB, P45OIIB, P45OIA2                      (1992)

    Rat        gavage           once                               1726         LD50                                          Kimura et al.
    (newborn)                                                                                                                 (1971)

    Rat        gavage           once                               4393         LD50                                          Kimura et al.
    (14 day)                                                                                                                  (1971)

    Table 9. (Continued)

    Species    Route            Exposure            NOAEL          LOAEL        Critical effect                               Reference
                                duration/frequency  (mg/kg)        (mg/kg)

    Rat(young  gavage           once                               7138         LD50                                          Kimura et al.
    adult)                                                                                                                    (1971)

    Rat        gavage           once                               6667         LD50                                          Kimura et al.
    (older adult)                                                                                                             (1971)

    Rat        gavage           once                               5806         LD50 15% body weight loss,                    Freeman &
                                                                                prostration                                   Hayes (1985)

    Mouse      drinking-water   10-12 days                         3500         induction of hepatic cytochrome               Puccini et al.
                                                                                P450, cytochrome b5,                          (1990)
                                                                                ethoxy-courmarin O-deethylase,
                                                                                p-nitrophenol, hydroxylase,
                                                                                diethylnitrosamine deethylase
    Mouse      drinking-water   14 days           1579 (male)      3896 (male)  mild hepatocellular hypertrophy               NTP (1991)
                                                  12 725 (female)

    Mouse      gavage with      10 days                            3500         reduced maternal body weight;                 EHRT (1987)
               water            (GD 6-15)                                       reduced reproduction index;
                                once/day                                        decreased pup survival

    Hamster    water            10 days                            2100         induction of cytochrome P450                  Puccini et al,

    a  GD = gestation day.
       Dose calculated on the assumption taken from Puccini et al. (1992) that 1% acetone in drinking-water is equivalent to 700 mg/kg per day.

    7.2  Longer term toxicity

         A limited number of oral animal studies are reviewed in Table 10.
    Only one longer-term dermal study was available.

         Bruckner & Peterson (1981) exposed male ARS/Sprague-Dawley rats
    to acetone vapour concentrations of 0 or 45 100 mg/m3 (0 or 19 000
    ppm), 3 h/day, 5 days/week for < 8 weeks. Groups of five rats were
    killed and examined at 2, 4 and 8 weeks and at 2 weeks after
    termination of exposure. No significant (p<0.05) effects were
    noted in blood chemistry (blood urea nitrogen (BUN), serum
    glutamic-oxaloacetic transaminase (SGOT), lactate dehydrogenase (LDH),
    liver triglyceride levels and histology of heart, lung, kidney, brain
    and liver. Small, statistically significant (p<0.02) decreases in
    absolute weights of the brain at 4 and 8 weeks and kidney at 4 weeks
    (but not at 8 weeks) were observed compared with controls. Without
    providing quantitative data, the authors stated that the organ-to-body
    weight ratios were slightly increased, suggesting that the effect on
    absolute organ weight reflected a slight but statistically
    insignificant reduction in rate of body weight gain. Two weeks after
    termination of exposure, no significant differences in organ weights
    were observed between treated and control rats.

         Sollman (1921) exposed three rats to 2.5% acetone in
    drinking-water for 18 weeks and reported that body weights and
    consumption of food and water were decreased, compared with normal
    values; the report cited normal values for consumption of food and
    fluid and for body weight, but did not indicate whether these were
    historical control values or values from concurrent control animals.
    No deaths were noted during the experimental period, No other
    end-points were examined.

         Acetone was administered by gavage (as an aqueous solution) to
    groups of 30 Sprague-Dawley rats/sex for 90 days at dose levels of 0,
    100, 500 or 2500 mg/kg per day (US EPA, 1986a). At the highest dose
    level, significantly increased values of RBC parameters were measured
    at 46 and 90 days for males (haemoglobin, haematocrit, corpuscular
    volume) and at 90 days for females (haemoglobin, haematocrit), Females
    in the 500 and 2500 mg/kg per day groups had significantly increased
    absolute kidney weights. Both sexes showed increased relative weights
    of kidney and brain and increased absolute and relative liver weights
    at the 2500 mg/kg per day dose. Body weights were unaffected in males,
    but transient, significantly elevated body weights were observed in
    females in the 500 and 2500 mg/kg per day groups. Statistically
    significant clinical chemistry alterations, possibly attributable to
    acetone, included increased alanine aminotransferase activities in
    both sexes at 2500 mg/kg per day and decreased platelet counts, serum
    glucose and potassium levels in males at 2500 mg/kg per day.

        Table 10. Longer-term oral exposure to acetone

    Species  Route               Exposure             NOAEL             LOAEL         Critical effect               Reference
                                 duratron/frequency   (mg/kg/day)       (mg/kg/day)

    Rat      gavage with water   46-47 days           500 (male)        2500          excessive salivation;         US EPA (1986a)
                                                      (once/day)                      increased haemoglobin,
                                                                                      haematocrit and mean cell
    Rat      gavage with water   93-95 days           500 (female)      2500          decreased brain weight;       US EPA (1986a)
             (once/day)                                                               increased blood parameters
                                                                                      (as above)
    Rat      water               13 weeks             900 (male)        1700          increased incidence/severity  NTP (1991)
                                                      1600 (female)     3100          of nephropathy in males;
                                                                                      haematological effects
    Mouse    water               13 weeks             4858 (male)       -             -                             NTP (1991)
                                                      11 298 (female)

    Histological examinations were made of all major tissues and organs
    from control and high-dose rats. For the low-dose (100 mg/kg) and
    middle-dose (500 mg/kg) rats, histological examinations were
    restricted to the heart, liver, kidneys and any tissues with gross
    changes. Increasing doses were associated with increasing intensity of
    tubular degeneration of the kidneys and hyaline droplet accumulation.
    The Task Group noted that these changes were observed in all groups,
    including controls. These changes were accentuated in males at the 500
    and 2500 mg/kg per day dose levels and in females at the 2500 mg/kg
    per day dose level. No other chemical-related histological changes
    were noted. There were no effects on urinalysis or ophthalmological
    parameters examined before sacrifice. No acetone-related effects were
    seen at the 100 mg/kg per day dose level.

         In a 13-week drinking-water study (NTP, 1991; Dietz et al.,
    1991), groups of 10 F344/N rats of each sex and 10 female B6C3F1
    mice were administered drinking-water containing 0, 2.5, 5, 10, 20 or
    50 g/litre acetone. Groups of 10 male mice were exposed to
    drinking-water containing 0, 1.25, 2.5, 5, 10 or 20 g/litre.
    Corresponding TWA doses in treated animals were estimated by the
    authors as 200, 400, 900, 1700 and 3400 mg/kg per day for male rats;
    300, 600, 1200, 1600 and 3100 mg/kg per day for female rats; 892,
    2007, 4156, 5945 and 11 298 mg/kg per day for female mice; and 380,
    611, 1353, 2258 and 4858 mg/kg per day for male mice.

         Necropsy was performed on all animals and histological
    examinations were conducted on all major tissues and organs of animals
    from control and high-dose groups. For lower dose groups, tissues
    examined included heart, kidneys and spleen of male rats at the 10 and
    20 g/litre dose levels; kidneys of male rats at 5 g/litre; bone marrow
    of male rats at 20 g/litre; nasal cavity and turbinates of all groups
    of female rats; mandibular lymph nodes of female rats at 20 g/litre;
    and liver of all female mice. At necropsy, organ weights were obtained
    and haematological examinations and examinations of sperm morphology
    and vaginal cytology were performed.

         No mortalities or overt clinical signs of toxicity were observed
    for any of the rats within the experimental period. Depressed water
    consumption and body weight gain were noted in rats of both sexes at
    the highest concentration. Significantly increased (p<0.05) relative

    weights of kidney, liver and lung were noted in rats of both sexes
    exposed to 50 g/litre. Relative testis weights were also increased at
    the highest concentration. Also noted at 50 g/litre were significant
    decreases in caudal and epididymal weights and in sperm motility and
    increased counts of morphologically abnormal sperm. Administration of
    20 g/litre was associated with increased relative liver weights in
    both sexes and increased relative kidney weights in female rats,
    compared with controls.

         "Mild but statistically significant" (p<0.05) alterations in
    haematological parameters (haematocrit, haemoglobin and mean
    corpuscular haemoglobin) were noted in rats of both sexes given 50
    g/litre (increased leukocytes and lymphocyte counts, mean corpuscular
    haemoglobin and mean cell volume, and decreased platelet counts) (NTP,
    1991; Dietz et al., 1991). At 20 g/litre, haematological alterations
    were restricted to male rats with the exception that females also
    showed decreased platelet counts. The haematological alterations in
    males were accompanied by increased pigmentation in the splenic red
    pulp of all males exposed to concentrations >20 g/litre, compared with

         "Mild" nephropathy was noted in male rats, including controls.
    The incidence and intensity of the kidney lesions increased with
    increasing drinking-water concentrations of acetone, particularly at
    20 g/litre. However, the criteria for distinguishing between "minimal"
    and "mild severity" for the observed nephropathy were not described.
    Based on accentuated nephropathy in male rats, the LOEL was considered
    by the Task Group to be 1700 mg/kg per day.

         During the 13-week exposure of mice to drinking-water containing
    acetone, no deaths or clinical signs of toxicity were recorded (NIP,
    1991; Dietz et al., 1991). Body weights, growth, sperm morphology and
    vaginal cytology also were unaffected in exposed mice. Significant
    organ weight changes (p<0.05) were restricted to female mice
    administered 50 g/litre; absolute and relative weights were increased
    for liver and decreased for spleen. Small changes in a few
    haematological parameters were noted in female mice (increased
    haematocrit and haemoglobin) and male mice (increased haemoglobin and
    mean corpuscular haemoglobin) exposed to their highest respective
    concentrations. The authors did not consider the changes to be
    toxicologically significant. The only histopathological alteration
    noted for acetone-exposed mice was centrilobular hepatocellular 
    hypertrophy (liver cells with abundant eosinophilic cytoplasm and
    slightly enlarged nuclei) in 2 of the 10 female mice administered 50

    7.3  Reproductive toxicity, embryotoxicity and teratogenicity

         NTP (1988) examined the in vivo developmental toxicity of inhaled
    acetone in mice and rats. Groups of pregnant Sprague-Dawley rats
    (26-29 rats/group) were exposed to 0, 1045, 5200 or 26 100 mg/m3 (0,
    440, 2200 or 11 000 ppm) acetone vapour, 6 h/day, 7 days/week for 14
    days (days 6-19 of gestation). Groups of pregnant Swiss CD-1 mice
    (28-31 mice/group) were exposed to 0, 1045, 5200 or 15 670 mg/m3 (0,
    440, 2200 or 6600 ppm) with the same protocol for 12 days (days 6-17
    of gestation). Maternal body weights were obtained throughout the
    experimental period. Uterine and fetal body weights were recorded at
    sacrifice (gestation days 20 and 18 for rats and mice, respectively).
    Live fetuses were examined for gross, visceral, skeletal and soft
    tissue craniofacial defects.

         No signs of maternal toxicity were noted in the pregnant rats
    except that statistically significant reductions in body weight at 14,
    17 and 20 days gestation, in cumulative body weight gain and in
    uterine weight were observed for the 26 100 mg/m3 group. The
    following were unaffected by exposure to acetone: absolute and
    relative liver and kidney weights of the dams; number of
    implantations; percentage of live pups/litter; percentage of
    resorptions/litter; and the fetal sex ratio. Fetal weights were
    significantly decreased in the 26 100 mg/m3 group compared with the
    control group. The incidences of fetal malformations were not
    significantly increased in any of the acetone-exposed groups compared
    with controls, although the percentage of litters with at least one
    malformed pup was greater in the 26 100 mg/m3 group (11.5%) compared
    with the control group (3.8%). NTP (1988) concluded that acetone had
    not caused a teratogenic effect in the rats in this study.

         The only significant acetone-related effect in the pregnant mice
    was increased relative liver weights in the 15 670 mg/m3 group
    compared with controls. Developmental and reproductive indices were
    unaffected in the acetone-treated groups of mice with the exceptions
    of a statistically significant decrease in fetal weight and a slight,
    but statistically significant, increase in the percentage incidence of
    late resorptions, both in the 15 670 mg/m3 group of mice. The
    authors concluded that slight developmental toxicity occurred at the
    respective highest exposure levels in the studies of Swiss mice and
    Sprague-Dawley rats, and that 5200 mg/m3 (2200 ppm) was the
    no-observed-effect level (NOEL) for maternal and developmental
    toxicity in both species (NTP, 1988).

         Ten male Wistar rats were exposed to 11 870 mg/m3 (5000 ppm)
    acetone in drinking-water for 8 weeks (Larsen et al., 1991). During
    the sixth week, the treated males were mated with untreated females.
    Numbers of pregnancies, numbers of fetuses and testes weights were
    recorded and histopathology of the seminiferous tubules and testes was
    undertaken. Acetone appeared to have no effects on these parameters.

         Negative and positive results have been obtained in  in vitro
    tests of the teratogenic potential of acetone. Guntakatta et al.
    (1984) reported that acetone at concentrations as high as 100 mg/ml
    did not alter the cellular incorporation of radiolabelled sulfate or
    thymidine in an  in vitro mouse embryo limb bud culture system.
     In vitro growth of rat embryos also was unaffected by the presence
    of 0.1 or 0.5% acetone (v/v), but the presence of 0.5% caused
    increased incidence of morphological abnormalities in the embryos;
    2.5% caused embryo death (Kitchin & Ebron, 1984).

         In a 13-week drinking-water study (NTP, 1991 Dietz et al., 1991),
    small changes in sperm motility and incidence of morphologically
    abnormal sperm were noted in rats exposed to concentrations of 50
    g/litre (3400 mg/kg per day). Reproductive performance of these
    animals, however, was not examined.

         EHRT (1987) evaluated acetone in a reproduction screening test
    using mice. Acetone in distilled water was administered by gavage to
    groups of 50 mated CD-1 mice on days 6-15 of gestation at doses of 0
    or 3500 mg/kg per day. Parameters of toxicity evaluated included
    maternal toxicity (mortality, body weight and clinical signs), number
    of live and dead offspring, pup body weight at birth, survival and
    litter weight at postpartum day 3. Although two treated dams exhibited
    clinical signs and eventually died, the authors did not consider that
    maternal mortality had been increased by treatment with acetone.
    Survivors exhibited no clinical signs or effects on body weight.
    Effects attributed to acetone included decreased reproductive index,
    increased gestation length, reduced birth weights, decreased neonatal
    survival and increased neonatal weight gain.

    7.4  Mutagenicity

         Table 11 presents relevant genotoxicity studies and their
    corresponding data for acetone. The data are almost entirely negative;
    only one report of positive genetic activity was located. Exposure of
     Saccharomyces cerevisiae to approx. 7% concentrations caused
    aneuploidy (Zimmermann et al., 1985). Abbondandolo et al. (1980)
    reported no forward mutations in a test on
     Schizosaccharomyces pombe. In prokaryotes, acetone did not induce
    reverse mutations in  Salmonella typhiraurium (McCann et al., 1975;
    NTP, 1991). Acetone did not induce DNA-cell binding with
     Escherichia coli or ascites cells (Kubinski et al., 1981). Negative
    results were reported for assays in animal systems  in vitro and
     in vivo, including mutation at the TK locus in mouse lymphoma cells
    (Amacher et al., 1980), sister chromatic exchange or chromosome
    aberrations in Chinese hamster ovary cells and human lymphocytes
    (Norppa et al., 1981; NTP, 1991), cell transformation in Fischer rat
    embryo cells (Freeman et al., 1973) and micronucleated erythrocytes in
    mice and Chinese hamsters (Basler, 1986; NTP, 1991).

        Table 11. Genotoxicity testing of acetone


    Assay           Indicator organism      Application     Purity  Concentration     Activating            Response  Comment        Reference
                                                            (%)     or dose           system

    Reverse         Salmonella typhimurium  plate           NR      10, 100, 1000,    +/- Aroclor-induced   -/-       NC             McCann et al.
    mutation        TA1535, TA1537, TA98,   incorporation           10 000 µg/plate   rat liver S9                                   (1975)

    Reverse         S. typhimurium, TA97,   liquid          NR      <10mg/plate       +/-Aroclor-induced    -/-       NC             NTP (1991);
    mutation        TA98, TA100, TA1535,    suspension                                rat, Syrian hamster                            Dietz et al.
                    TA1537                                                            liver S9                                       (1991)

    Forward         Schizosaccharomyces     liquid          NR      3.75%             +/-phenobarbital-     -/-       3ml 5%         Abbondandolo
    mutation        pombe                   suspension                                induced mouse                   acetone        et al. (1980)
                                                                                                                      plus 1 ml

    Aneuploidy      Saccaharomyces          liquid          >97     6.98, 7.41,       -                     +         Expression     Zimmermann
                    cerevisiae diploid      suspension              7.83%                                             of             et al. (1985)
                    D61.M                                                                                             aneuploidy
                                                                                                                      on ice

    Forward         mouse lymphoma          cell culture    NR      0.134-0.421       -                     -         Cytotoxicity   Amacher
    mutation        L5178Y TK +/- cells                             mol/litre                                         prevented      et al. (1980)
                                                                                                                      use of

    Sister          Chinese hamster ovary   cell culture    NR      <5000           +/- Aroclor-induced      -         NC            NTP (1991)
    chromatid       cells                                           mg/litre        rat liver S9                                     Dietz et al.
    exchange                                                                                                                         (1991)

    Table 11. (Continued)
    Assay           Indicator organism      Application     Purity  Concentration     Activating            Response  Comment        Reference
                                                            (%)     or dose           system
    Chromosomal     Chinese hamster ovary   cell culture    NR      <5000 mg/lltre   +/- Aroclor-induced                             NTP (1991);
    aberrations     cells                                                            rat liver S9           -         NC             Dietz
                                                                                                                                     et al.(1991)

    Cell            Rauscher leukaemia      cell culture    NR      0.001-100         -                     -         NC             Freeman et al.
    transformation  virus/Fischer rat                               mg/litre                                                         (1973)
                    embryo cells

    DNA-cell        binding of E. coli      liquid          NR      50, 100 mg/litre  +/- S9                -         Radiolabelled  Kubinski
    binding         DNA to                  suspension                                                                DNA is         et al
    assay           Ehrlich ascites or                                                                                incubated      (1981)
                    E. coli cells                                                                                     with cells in
                                                                                                                      the presence
                                                                                                                      of test

    Sister          cultured human          whole blood     99.5    2.7, 12.8         -                     -         NC             Norppa et al.
    chromatid       lymphocytes             cell culture            mmol/litre                                                       (1981)

    Chromosomal     cultured human          whole blood     99.5    12.8              -                     -         NC             Norppa
    aberrations     lymphocytes             cell culture            mmol/litre                                                       et al. (1981)

    Micronucleus    mouse peripheral        drinking-water  NR      5-20 g/litreb     NA                    -         NC             NTP (1991)
    test            blood normochromatic                                                                                             Dietz et al
                    or polychromatic                                                                                                 (1991)

    Micronucleus    Chinese hamster         intraperitoneal NR      865mg/kgc         NA                    -         NC             Basler (1986)
    test            polychromatic           injection

    a NA = Not applicable; NC = no comment; NR = not reported.
    b For 13 weeks.
    c Single dose.

         The negative results in the  in vivo bone marrow micronucleus
    tests in mice and Chinese hamsters suggest that the aneuploidy which
    was detected in yeast is not expressed  in vivo in mammalian cells.
    As all of the other mutagenicity tests (covering a range of end-points
    including gene mutations and clastogenicity) were negative, it is
    concluded that acetone presents no mutagenic risk to humans.

         Acetone is widely used as a solvent in genotoxicity studies.
    There are no indications that acetone interacts with other chemicals
    to alter their genotoxic potential (ATSDR, 1994).

    7.5  Carcinogenicity

         There are no studies available on the carcinogenicity of acetone
    by either inhalation or oral dosing. Acetone has been used extensively
    as a solvent vehicle in skin carcinogenicity studies (NTP, 1991).
    Generally, acetone is not considered to cause or promote tumours when
    applied to the skin, but comprehensive examinations of tissue sites
    remote from the dermal site of application are not murine in these
    studies (Ward et al., 1986; NTP, 1991).

         In cultured Syrian hamster embryonic cells, there was no evidence
    of cellular transformation when the cells were cultured in the
    presence of 0.02% acetone (DiPaolo et al., 1969).

    7.6  Immunotoxicity

         In an investigation of acetone as a solvent vehicle for skin
    studies, Singh et al. (1996) examined the effects of topically applied
    acetone on immune function in SSIN mice. Acetone (200 µl) was applied
    to the dorsal trunk four or eight times. Responses in the sheep red
    blond cell plaque-forming assay were measured at the end of treatment.
    Responses were depressed in the 4x group but not in the 8x group,
    suggesting a temporary effect on humoral immunity. Plaque-forming
    response was further investigated using 50, 100, 200 and 300 µl
    acetone with one, four or eight applications. Response was depressed
    in mice treated one, four or eight times with 300 µl acetone. There
    were no changes in spleen cellularity, the CD4+ to CD8+ T cell
    ratio, or the alloantigen induced mixed lymphocytic response.
     In vitro proliferative responses to the mitogen concanavalin A were
    increased in the 200 µl 4x or 8x groups. The authors concluded that
    acetone can modulate humoral immunity.

         The effects of topically applied acetone on systemic immune
    function were analysed by Singh et al. (1996). SSIN mice, derived by
    inbreeding Sencar mice, were exposed to four or eight topical
    applications of 200 µl acetone. Plaque-forming assays were used to
    assess the effects of solvents on the development of humoral immunity.
    The responses in the 8x-treated group were indistinguishable from the
    controls, while in the 4x-treated group a retardation in the
    development of splenic B cells secreting IgM against SRBC occurred,
    The rate of loss of plaque-forming cells (PFCs) was not affected. A

    functional suppression of the development of humoral immunity had
    occurred. The researchers then assessed plaque-forming ability using
    50, 100, 200 and 300 µl of acetone in order to determine the effects
    of solvent dose and duration of treatment on the development of
    humoral immunity. In the 300 µl group, plaque formation 4 days after
    immunization was statistically suppressed in mice treated one, four or
    eight times. At the other concentrations, suppression of PFC
    development was schedule-dependent. The suppression was seen more
    after the first or fourth application, but the suppressive activity
    was lost following the eighth dose. While the reason is not known,
    Singh et al. (1996) speculated that it may be an adaptive response by
    the skin.

         Singh et al. (1996) showed that the modulation of humoral
    immunity was also dependent upon the nature of the antigen used for
    immunization. The capacity of the T cells to respond and to function
    following different stimuli does not appear to he suppressed in
    acetone-treated mice.

    7.7  Special studies

         Vodicková et al. (1995) studied the inhibition of electrically
    evoked seizures in male albino SPF Wistar rats (ages 0.5 to 1 year)
    and female albino H-strain mice (ages 24 months) exposed to acetone
    concentrations of 3630 mg/m3 (1530 ppm) (mice) and 4035 mg/m3 (1700
    ppm) (rats) for 2 h (mice) and 4 h (rats). The central nervous system
    (CNS) effect of inhibition of electrically evoked seizure discharge
    was measured immediately after exposure. Blood levels were also
    monitored, Frantik et al, (1994) used the same methodology and
    measured blood concentrations of 1190 mg/m3 (500 ppm) for mice and
    8300 mg/m3 (3500 ppm) for rats. In another study Frantik et al.
    (1996) exposed rats to constant or fluctuating air concentrations of
    acetone and measured inhibition of electrically evoked seizures.
    Four-hour exposures to air concentrations of 4 and 10 mg/litre
    resulted in blood levels of 183 and 520 mg acetone/line blood,
    respectively. Inhibition of seizures at these blood levels was 10% and
    50%, respectively. There were no significant differences between
    constant or fluctuating inhalation exposures. If a concentration
    depresses seizure discharge,  then generally it will inhibit behaviour
    in higher doses and provoke sleep and narcosis in still higher doses.
    In these studies, it appears that the acetone levels were below the
    concentration evoking behavioural inhibition. Furthermore, Vodicková
    et al. (1995) found that when mice were exposed to acetone and toluene
    in a binary mixture, the inhibiting neurotropic effect of the exposure
    was not increased, and when rats were exposed, the effect
    significantly decreased. The decline of blood toluene and xylene
    levels was slowed down by a simultaneous exposure to acetone. The
    authors of the studies concluded that the effects of solvents appear
    to be less than additive. The significance of these studies is

    7.8  Factors modifying toxicity; toxicity of metabolites

         Primarily, factors that may affect endogenously produced acetone
    toxicity are alterations in carbohydrate metabolism, accumulation of
    ketone bodies, interaction with ketone body metabolism, and
    interaction with ketone bodies. There are many secondary factors, such
    as an imbalance of hormones, e.g., insulin, that can effect the body
    burden and hence the toxicity of acetone (Ramu et al., 1978).

         Acetone can induce the enzymatic activity of a cytochrome P450
    isozyme, one which plays a role in the metabolism of endogenous and
    exogenous substrates. Acetone is metabolized by the same P450 isozyme
    that is induced during higher doses, thus making a homeostatic-type
    mechanism for decreasing acetone levels when higher body burdens

         Because acetone is non-ionic and miscible with water, it can
    passively diffuse across cell membranes. Normally, metabolism is the
    principal route of elimination from the body, and this metabolic
    breakdown is either through an intrahepatic or extrahepatic pathway.
    The metabolites of acetone include carbon dioxide, acetate, formate,
    glucose and 1,2-propanediol, with pyruvate and other compounds as
    intermediates. It does not appear that any of these compounds affect
    the toxicity of acetone. However, as shown in section 7.8, acetone can
    affect the toxicity of other compounds.

         Ruddick (1972) reviewed the toxicology, biochemistry and
    metabolism of 1,2-propanediol. The compound is used as a solvent for
    flavouring material in baking and candy production, as well as a
    humectant and preserver to keep packaged foods fresh. Oral LD50
    values of 1,2-propanediol in the rat are 21-30 mg/kg body weight, in
    the mouse 23.9, in the rabbit 18.0-19.0, in the guinea-pig 18.9, and
    in the dog 18.9-20.0.

         Another possible and relatively non-toxic metabolite is isopropyl
    alcohol. Lewis et al. (1984) showed that metabolism of acetone was
    different in normal and diabetic rats. These experiments indicated
    that high levels of blood acetone resulted in transformation to
    isopropyl alcohol.

    7.9  Mechanisms of toxicity - mode of action

         Within the liver, acetone is metabolized by three separate
    gluconeogenic pathways through several intermediates, but most of its
    intermediate or final metabolites are not considered toxic.
    Unmetabolized acetone does not appear to accumulate in any tissue, but
    is excreted mainly in the expired breath following high (> 1180
    mg/m3, > 500 ppb) exposures. Acetone is irritating to mucous
    membranes, possibly due to its lipid solvent properties, resulting ha
    eye, nose, throat and lung irritation following exposure to the
    vapour, and skin irritation upon dermal contact.

         Systemically, acetone is moderately toxic to the liver and
    produces haematological effects. The mechanism by which acetone
    produces these effects is unknown. The renal toxicity may be due to
    the metabolite, formate, which is known to be nephrotoxic (NTP, 1991)
    and is excreted by the kidneys (Hallier et al., 1981). Furthermore,
    the renal toxicity, which appears to be specific for male rats, may
    involve the alpha 2u-globulin syndrome, as hyaline droplet formation 
    was associated with the nephropathy observed in male rats in the US
    EPA (1986a) study. Acetone also causes increases in liver and kidney
    weight, probably through the induction of microsomal enzymes, which
    would increase the weight of the organs by virtue of the increased
    protein content. Acetone causes effects in the testes of male rats and
    is fetotoxic at high (approx. 15 670 mg/m3, approx. 6600 ppm)
    concentrations. Although the exact mechanism for many of the effects
    of acetone is not known, distribution studies in mice indicate that
    acetone and metabolites arc found in all of the target organs (Wigaeus
    et al., 1982). Acetone and some of its metabolites were also
    transferred to rat fetuses after the dams were exposed to acetone
    (Peinado et al., 1986).

         One of the major effects of acetone is the potentiation of the
    toxicity of other chemicals. Pretreatment with acetone has been shown
    to potentiate the hepatotoxicity and nephrotoxicity of carbon
    tetrachloride and chloroform (Plaa & Traiger, 1972; Traiger & Plaa,
    1972, 1974; Sipes et al., 1973; Plaa et al., 1973, 1982; Folland et
    al., 1976; Hewitt et al., 1980, 1987; Brown & Hewitt, 1984;
    Charbonneau et al., 1985, 1986a,b, 1988, 1991) by inducing particular
    forms of cytochrome P-450, especially cytochrome P-450IIE1, and
    associated enzyme activities (Johansson et al., 1988; Brady et al.,
    1989; Kobusch et al., 1989). The induction of these enzymes leads to
    the enhanced metabolism of carbon tetrachloride (CCl4) and chloroform
    to reactive intermediates capable of causing liver and kidney injury.
    Acetone enhances the formation of carboxyhemoglobin by dichloromethane
    via induction of cytochrome P-450IIE1, leading to enhanced metabolism
    of dichloromethane to carbon monoxide (Pankow & Hoffmann, 1989).
    Acetone, methyl ethyl ketone and methyl isobutyl ketone pretreatment
    was made in rats at a dosage of 6.8 mmol/kg given daily for 3 days.
    Acetone markedly potentiated CCl4-induced liver toxicity as indicated
    by a decrease in the CC14 ED50 to 3.4 mmol/kg compared to
    vehicle-pretreated rats (17.1 mmol ketone/kg). Pretreatment with
    acetone also potentiated chloroform kidney toxicity but to a lower
    degree; chloroform ED50 values for vehicle- and acetone-pretreated
    rats were 3.4 and 1.6 mmol/kg, respectively (Raymond & Plaa, 1995a).

         In a subsequent study, Raymond & Plaa (1995b) examined the role
    of monooxygenases induced by ketones as a mechanism for potentiating
    the CCI4 hepatotoxicity and chloroform nephrotoxicity. Hepatic and
    renal monooxygenase activities (aminopyrine and benzo-phetamine
     N-demethylase, aniline, hydroxylase) from rats pretreated with
    acetone or other ketones (6.8 or 13.6 mmoL/kg) were increased. This
    profile of induction was consistent with the ketone potentiation
    potency ranking profile observed  in vivo for liver but not kidney
    injury (Raymond & Plaa, 1995a).

         Acetone also potentiates the hepatotoxicity of acetaminophen
    (Moldetts & Gergely, 1980; Jeffery et al., 1991; Lin et al., 1991),
     N-nitrosodimethylamine and  N-nitrosodiethylamme (Sipes et al.,
    1978; Lorr et al., 1984; Hong & Yang, 1985), thiobenzamide (Chieli et
    al., 1990), oxygen (Tindberg & Ingelman-Sundberg, 1989), chromate
    (Ct[VI]) (Mikalsen et al., 1991), and benzene (Johansson et al., 1988;
    Johansson & Ingelman-Sundberg, 1988; Schnier et al., 1989); the
    genotoxicity of  N-nitrosodimethylamine (Glatt et al., 1981; Yoo &
    Yang, 1985; Yoo et al., 1990); and the lethality of acetonitrile
    (Freeman & Hayes, 1985, 1988) by inducing cytochrome P-450IIE1. The
    hepatotoxic and nephrotoxic effects of dibromochloromethane and
    bromodichloromethane (Hewitt & Plaa, 1983) and the hepatotoxic effects
    of 1,1,2-trichloroethane (MacDonald et al., 1982a,b),
    1,1-dichloroethene (Jaeger et al., 1975; Hewitt & Plaa, 1983) and
    dichlorobenzene (Brondean et al., 1989) are also enhanced by acetone.
    The details of the mechanisms for these interactions are not clear,
    hut the involvement of mixed-function oxidases has been implicated.
    The renal toxicity of  N-(3,5-dichlorophenyl)succinimide (a
    fungicide) is potentiated by acetone via the induction of cytochrome
    P-450IIE1 (Lo et al., 1987). Acetone in drinking-water increased lung
    toxicity of inhaled styrene (Elovaara et al., 1990). Ethanol at 10% in
    drinking-water had no adverse effect on mice, hut when 5% acetone was
    added, the mice lost weight and there were lipid droplets in
    hepatocytes (Forkert et al., 1991).

         In other interactions, acetone enhances the neurotoxicity of
    ethanol by a proposed mechanism whereby acetone inhibits the activity
    of alcohol dehydrogenase, a reaction responsible for 90% of the
    elimination of ethanol (Cunningham et al., 1989). Acetone also
    potentiates the neurotoxieity and reproductive toxicity of
    2,5-hexanedione (Ladefoged et al., 1989; Lam et al., 1991; Larsen et
    al., 1991). The exact mechanism for these interactions is not clear
    but appears to involve decreased body clearance of 2,5-hexanedione by
    acetone (Ladefoged & Perbellini, 1986). Acetone also antagonizes in
    that it decreases the incidence of liver necrosis in male Long-Evans
    rats treated with acetaminophen (Price & Jollow, 1983). The antagonism
    is possibly due to increased glutathione conjugation. No reasonable
    explanation was offered for the apparent ability of acetone to
    potentiate acetaminophen toxicity  in vitro and antagonize the
    hepatotoxicity  in vivo (Morgott, 1993).

         It appears that the potentiating effects of acetone may be
    occurring by any of three different mechanisms:

    a)   interference with uptake or elimination;
    b)   induction of microsomal enzymes, particularly cytochrome
    c)   additive interactions at the target site or toxic receptor

         The uneventful use of acetone as a carrier solvent in many
     in vitro genotoxicity assays that utilize microsomal activating
    enzymes suggests the third mechanism does not operate  in vitro.


    8.1  Effects on humans

         Acetone is produced endogenously within the human body during
    metabolism. It is released into the atmosphere by soil and water from
    a very wide range of natural and anthropogenic sources and is present
    in many household products. All humans will, therefore, be exposed to
    additional exogenous acetone in varying quantities, depending on
    specific circumstances (see sections 3 and 5).

    8.1.1  Non-occupational exposure

         The toxicity from inhalation and dermal/ocular exposure is listed
    in Tables 12 and 13.

         The 1991 Annual Report of the American Association of Poison
    Control Centers National Data Collection System documented 1137
    incidents of human exposure to acetone (Litovitz et al., 1992). This
    same report listed 1001 cases for 1988. Of these incidents, 1124 were
    due to accidental or intentional ingestion (the others were not
    clearly specified). No fatalities were reported, only three cases had
    a major acetone-related medical problem, 364 were treated in a health
    care facility, 233 cases were referred to hospitals but had no
    effects, 367 cases suffered minor effects, and 39 suffered from
    moderate effects. According to the classification of the AAPCC, none
    of the major, minor or moderate effects were further described, and
    the outcomes of the remainder of the incidents were not reported.

         Matsushita et al. (1969b) exposed 25 male volunteer students to
    acetone vapour for 3 h in the morning and 3 h in the afternoon during
    1 day at concentrations of 240, 590, 1190 and 2400 mg/m3 (100, 250,
    500 and 1000 ppm). The subjects were asked to describe any subjective
    symptoms, and most reported that exposure to concentration of 1190 and
    2400 mg/m3 for 6 h was irritating to the nose, eyes, throat and
    trachea. At concentrations of 240 and 590 mg/m3 only a few of the
    subjects complained of symptoms. Subjective symptoms also included the
    loss of the ability to smell acetone as exposure proceeded. In another
    controlled experiment, volunteer subjects were exposed to acetone
    concentrations of 475, 720 and 1190 mg/m3 (200, 300 and 500 ppm) for
    3-5 min in a chamber. Eye and throat irritation was experienced at 720
    and 1190 mg/m3, but the subjects estimated that they could tolerate
    an exposure level of 475 mg/m3 for an 8-h workshift (Nelson et al.,
    1943). Volunteers exposed to 1000 ppm acetone for 4 h reported more
    subjective complaints of throat irritation and "annoyance" (Seeber et
    al., 1992). However, the perceived irritation or annoyance associated
    with occupational and experimental exposures to acetone may be
    influenced by the perceived odour of acetone and unrelated to
    irritation and symptoms (Dalton et al., 1997; Wysocki et al., 1997).
    Pulmonary function testing of volunteers exposed to < 2970 mg/m3
    (< 1250 ppm) intermittently for various durations in a complex
    protocol revealed no abnormalities caused by the exposure (Stewart et
    al., 1975). The volunteers experienced sporadic throat irritation.

        Table 12. Short-term human inhalation exposure to acetone


    Exposure                    NOEL          LOEL                  Critical effect           Reference
    duration/frequency          mg/m3 (ppm)   mg/m3 (ppm)

    3-5 min                     475 (200)     1190 (500)            eye, nose and throat      Nelson et al. (1943)

    5.25 h                      240 (100)     590 (250)             eye, nose and throat      Matsushita et al.
    (6 h/day with 45-min break                                      irritation                (1969b)
                                                                    at 590 mg/m3

    5.25 h                                    1190 (500)            increased WBC and         Matsushita et al.
    (6 h/day with 45-min break)                                     eosinophil count,         (1969b)
                                                                    decreased phagocytic
                                                                    activity of neutrophils

    4 h                                       approx 560            behavioural changes       Dick et al. (1989)
                                              (approx 237)

    7 days (8 h/day)                          2370 (1000)           headache, dizziness,      Raleigh & McGee
                                                                    confusion                 (1972)

    5 days (7.5 h/day)          2370 (1000)   2970 (1250)           visual evoked response    Stewart et al. (1975)

    Table 13. Short-term human skin and eye exposure to acetone


    Exposure                Target          NOEL              LOEL               Critical effect        Reference
    duration/frequency                      mg/m3 (ppm)                                                 

    vapour: 3-5 min         skin/eyes       475 (200)         1190 (500)         eye irritation         Nelson et al. (1943)

    liquid: 30 or 90 min    skin                              1 ml               degenerative changes   Lupulescu et al.
                                                                                 in epidermis           (1973)

    liquid: 90 min          skin                              1 ml               decreased protein      Lupulescu &
                                                                                 synthesis              Birmingham (1975)

    vapour: 2-3 days        skin/eyes                         2140 mg/m3 (901)   eye irritation         Raleigh & McGee
    (8 h/day)                                                                                           (1972)

    vapour: 7 days          skin/eyes                         2390 mg/m3 (1006)  eye irritation         Raleigh & McGee
    (8 h/day)                                                                                           (1972)

    vapour: 4 and 8 h       skin/eyes       2375 (1000)                          no complaints of       Seeber et al. (1993)
                                                                                 skin or eye

    vapour: 4 h             skin/eyes                         2350 (990)         perceived irritation   Seeber et al. (1992)
                                                                                 of nose and throat
                                                                                 and "annoyance"

    vapour: 4 and 8 h       CNS             2375 (1000)                          mood change            Seeber et al. (1993)


         In the USA, the National Institute for Occupational Safety and
    Health (Stewart et al., 1975) sponsored a research study to determine
    physiological responses by humans exposed to acetone in air, and to
    develop a biological test to indicate the magnitude of exposure.
    Twenty adults of both sexes were exposed to acetone vapour
    concentrations of 0, 475, 2370 and 2970 mg/m3 (0, 200, 1000 and 1250
    ppm) for periods of 3 or 7.5 h for various durations up to 5 days. The
    results of this study showed that a predictable excretion pattern
    resulted for each of the tested vapour concentrations, and the rate of
    excretion of acetone in the breath was a function of the duration of
    exposure. After 3 h of exposure, the majority of the subjects could no
    longer detect the odour of acetone when breathing normally. No
    significant neurological abnormalities were noted, but there was a
    statistically significant amplitude change in the visual evoked
    response test. It was also noted that three out of four of the women
    had premature menstruation, early by one week or more, after four days
    of exposure to 2370 mg/m3 (1000 ppm) for 7.5 h/day, which the authors
    saw as worrisome.

         High pulse rates (120-160/min) were commonly found in patients
    exposed to acetone by inhalation and/or dermally, in most cases at
    concentrations sufficient to cause acute intoxications, after
    application of casts for which acetone was used in the setting
    solution (Chatterton & Elliott, 1946; Pomerantz, 1950; Renshaw &
    Mitchell, 1956; Hift & Patel, 1961). In a controlled laboratory study
    using a complex protocol, electrocardiography of volunteers exposed to
    atmospheric concentrations of 2970 mg/m3 (1250 ppm) for 6 weeks (2-5
    days; 7 h/day) revealed no alterations, compared with their
    pre-exposure electrocardiograms (Stewart et al., 1975).

         The acetone concentrations in the body fluids and expired air of
    healthy and diabetic patients can be very different. Even in healthy
    subjects, the level of acetone in blood/plasma varies according to
    fasting or non-fasting conditions and depends on the weight of the
    subject. Generally, the blood/plasma acetone concentrations are higher
    in fasted than non-fasted subjects and higher in subjects who are not
    obese, compared to obese subjects (Haff & Reichard, 1977). The
    narcotic effects of acetone occur after oral as well as inhalation
    exposure. Several case reports describe patients in minimally
    responsive, lethargic, or comatose conditions after ingesting acetone,
    but some of these cases are confounded by co-exposure to other
    possible narcotic agents. For example, a 30-mouth-old child ingested
    most of a 180 ml (6 ounce) bottle of nail polish remover containing
    65% acetone and 10% isopropyl alcohol (Gamis & Wasserman, 1988); a
    known alcoholic woman ingested nail polish remover (Ramu et al.,
    1978); and a man ingested 200 ml of sake prior to intentionally
    ingesting liquid cement containing a mixture of polyvinyl chloride,
    acetone, 2-butanone, and cyclohexanone (Sakata et al., 1989). Blood
    levels of acetone in some of these patients were 2.5 g/litre (Ramu et
    al., 1978) and 4.45 g/litre (Gamis & Wasserman, 1988). In the case
    reported by Sakata et al. (1989), the blood level of acetone was 110
    mg/litre and the urine level was 123 mg/litre 5 h after the ingestion,

    but the patient had been subjected to gastric lavage. A man who
    intentionally ingested about 200 ml of pure acetone (about 2241
    mg/kg) subsequently became deeply comatose, but responded to
    treatment (Gitelson et al., 1966). Six days later, he was ambulatory,
    but a marked disturbance of gait was observed. This condition had
    improved upon follow-up examination 2 months later.

         Acetone is reported to be irritating to mucous membranes. Raleigh
    & McGee (1972) listed eye irritation as a common complaint of workers
    exposed to acetone, and Matsushita et al. (1969a) reported the same
    finding for volunteers in their study. However, the complaints of
    irritation associated with exposure to acetone may be influenced by
    the strong odour of acetone (Dalton et al., 1997; Wysocki et al.,

         Lupulescu & Birmingham (1975, 1976) found that application of 0.1
    ml directly to the skin resulted in histological and degenerative
    epidermis changes in volunteers after 60 or 90 min of exposure. These
    changes were denoted by reduction as well as disorganization of the
    horny layers, intercellular oedema and vacuolization of the stratum
    spinosum. Haematological effects have been observed in humans after
    inhalation exposure to acetone in controlled laboratory studies of
    volunteers. A statistically significant increase in white blood cell
    counts and decrease in phagocytic activity of neutrophils, compared
    with controls, were observed in the volunteers after a single 6-h
    inhalation exposure or repeated 6-h exposures for 6 days to 1190
    mg/m3 (500 ppm) (Matsushita et al., 1969a,b). No significant
    difference was seen in haematological parameters in volunteers exposed
    to 590 mg/m3 (250 ppm) compared with controls. In contrast,
    haematological findings were within normal limits in volunteers
    exposed to 1190 mg/m3 (500 ppm) for 2 h (DiVincenzo et al., 1973) or
    to < 2970 mg/m3 (< 1250 ppm) repeatedly for 1-7.5 h/day for
    as long as 6 weeks (Stewart et al., 1975). Exposure to acetone vapour
    can also lead to increased pulse rates, gastrointestinal irritation,
    nausea, vomiting, and haemorrhage. However, the odour threshold of
    acetone (240-330 mg/m3, 100-140 ppm) and the feelings of irritancy
    are excellent warning properties that generally preclude serious
    inhalation overexposure. Accidental or intentional ingestion of
    acetone can cause erosions in the mouth, coma and diabetes-like

    8.1.2  Occupational exposure

         Most occupational exposure standards are in the range 1780-2370
    mg/m3 (750-1000 ppm). Occupations in which workers may be exposed to
    higher levels of acetone include paint manufacturing, plastics
    manufacturing, artificial fibre industries, shoe factories,
    professional painting, and commercial cleaning. As with the general
    population, there are case studies of accidental poisonings and
    inhalation of acetone fumes. Many of these situations are mixed
    exposures and not deemed relevant to this discussion, except where
    acetone potentiates or antagonizes the effects of another chemical
    present (see also section 8.3).

         Workers in industries that manufacture or use acetone are
    potentially exposed to higher concentrations of acetone than the
    general population. For example, the concentrations of acetone in the
    breathing-zone air in a paint factory, a plastics factory, and an
    artificial fibre factory in Italy were >3.48 mg/m3 (Pezzagno et al.,
    1986). The concentration of acetone in the breathing-zone air of a
    fibre-reinforced plastic plant in Japan, where bathtubs were produced,
    was < 108 mg/m3 (Kawai et al., 1990a). The inhalation exposure for
    workers to acetone in a shoe factory in Finland ranged from 25.4 to
    393.4 mg/m3 (Ahonen & Schimberg, 1988), and concentrations were
    similar in the breathing-zone air in shoe factories in Italy (Brugone
    et al., 1978). The concentration of acetone in the breathing-zone air
    of a solvent recycling plant in the USA ranged from not detectable to
    43 mg/m3 (Kupferschmid & Perkins, 1986). High levels of acetone were
    detected in the occupational air in other industries, including the
    chemical, plastic button, and paint manufacturing industries in Italy
    (Ghittori et al., 1987). Isopropyl alcohol is known to oxidize in the
    liver and is converted to acetone (Kawai et al., 1990b); therefore,
    occupational exposure (e.g., printing plants) or accidental ingestion
    of isopropyl alcohol also produces acetone in expired air, blood and

         Satoh et al. 0996) carried out a cross-sectional study on 110
    male (age range 18.7 to 56.8 years) acetone-exposed and 67 male (age
    range 20.7 to 57.5 years) non-exposed shift workers. The personal
    passive monitors and biological monitoring indices measured at the end
    of the workshift were 46.5-2583 mg/m3 (19.6-1088 ppm) (mean 864
    mg/m3, 364 ppm) in breathing-zone, 5.9-1002 mg/m3 (2.5-422 ppm)
    (mean 231 mg/m3, 97.3 ppm) in alveolar air, 4-220 mg/litre (mean 66.8
    mg/litre) in blood, and 0.75-170 mg/litre (mean 37.8 mg/litre) in
    urine. Symptoms at the end of the workshift showing good exposure
    response relationships were eye irritation, tear production and
    complaints of acetone odour. In acetone workers in the 30-44 year
    range, simple reaction time and digit span scores were significantly
    lower in acetone-exposed workers but exposure-relationships were not
    clear. Manifest Anxiety Scale Scores, Self-rating Depression Scale
    Scores, R-R internal variation on the ECG, haematological examinations
    and liver function tests did not show any significant differences
    between the two groups.

         In a retrospective mortality study of 948 employees (697 men, 251
    women) in a cellulose fibre plant where acetone was used as the only
    solvent, there was no significant excess risk of death from any cause
    (all causes, malignant neoplasm, circulatory system disease, ischaemic
    heart disease) compared with rates for the general population in the
    USA (Ott et al., 1983a,b). The workers had been employed at the plant
    for at least 3 months to 23 years. Industrial hygiene surveys found
    that median TWA acetone concentrations were 902, 1678 and 2540 mg/m3
    (380, 770 and 1070 ppm) based on job categories. All haematologieal
    parameters and all clinical blood chemistry parameters (aspartate
    aminotrausferase, alanine aminotransferase, lactic dehydrogenase,
    alkaline phosphatase, total bilirubin, and albumin) were within normal

         The only effect on the respiratory system observed in humans
    exposed to acetone vapour is irritation of the nose, throat, trachea
    and longs. The irritant properties of acetone in humans have been
    noted both in workers who were exposed to acetone occupationally
    (Raleigh & McGee, 1972; Ross, 1973) and in volunteers under controlled
    laboratory conditions (Nelson et al., 1943; Matsushita et al.,
    1969a,b). Complaints of irritation were reported by workers with
    average exposures to acetone in the workroom of 2140 mg/m3 (901 ppm)
    (Raleigh & McGee, 1972; Ross, 1973). Sallee & Sappington (1949), in a
    report of experience at the Tennessee Eastman Corporation on acetone
    concentrations not associated with injury, noted that acetone is
    mildly irritating to the eyes at 4750-7120 mg/m3 (2000-3000 ppm), but
    that no irritation persisted after exposure ceased.

         In an on-site medical appraisal of nine workers, in which the 
    exposure concentration was 2390 mg/m3 (1006 ppm), three of the
    workers mentioned headache and lightheadedness as subjective symptoms
    (Raleigh & McGee, 1972). In another on-site medical appraisal of four
    workers, in which the TWA exposure concentration was 2140 mg/m3 (901
    ppm), none of the workers complained of neurological effects (Raleigh
    & McGee, 1972). The medical examinations included the Romberg test,
    finger-to-nose test, and observations for nystagmus (involuntary rapid
    movement of the eyeball). These tests revealed no neurobehavioural
    effects in either study. Such symptoms as unconsciousness, dizziness,
    unsteadiness, confusion and headache were experienced by seven workers
    exposed to > 28 500 mg/m3 (> 12 000 ppm) while clearing out a pit
    containing acetone that had escaped from nearby tanks (Ross, 1973).
    The degree of the symptoms varied depending on the length of time that
    the workers had spent in the pit (2 min to 4 h).

    8.2  Subpopulations at special risk

         Because of higher exposure, workers in industries that
    manufacture or use acetone are one segment of the population at higher
    risk of acetone exposure compared to the general population (see
    section 5.3). Professional painters and commercial and household
    cleaners, using detergents, cleansers, waxes or polishes containing
    acetone, are also likely to be exposed to acetone at higher
    concentrations than the general population, although experimental data
    regarding the extent of exposures for this segment of workers are not
    available. Among the general population, high exposure to acetone may
    occur among several subgroups. Cigarette smoke contains < 0.54 mg
    acetone/cigarette (Manning et al., 1983); therefore, smokers are
    exposed to higher concentrations of acetone than non-smokers. The
    content of acetone in certain nail polish removers is high, and so
    individuals who frequently use nail polish removers, such as
    manicurists, are exposed to higher levels of acetone than the general
    population. People who live near landfill sites that emit acetone or
    those who live near industrial sources of emission (e.g., refinery,
    incinerator, close to high vehicular traffic areas) are also
    susceptible to higher exposure concentrations of acetone than the
    general population that does not reside near these sites.

         There is also a small possibility of ketone formation by
    ketoacidosis in humans. The most common form is diabetic ketoacidosis
    (DKA), which appears to require insulin deficiency coupled with a
    relative or absolute increase in glycogen concentration. Dieting has
    also been shown to cause starvation ketosis. Apart from these two
    types, the other common ketoacidotic state is alcoholic ketoacidosis.
    Presumably the liver is activated by kctogenesis as a result of
    starvation in cases of alcoholic ketoacidosis and driven to maximal
    rates of ketone formation by the high fatty acid levels (Wilson et
    al., 1991).

         The intrinsic toxicity of acetone and the results of the US EPA
    (1986a) animal studies suggest that male animals are more susceptible
    than female animals. Acetone at higher concentrations may exacerbate
    preexisting haematological, liver, kidney or reproductive disorders in
    humans. As with other chemicals, neonates and the elderly may be more
    susceptible to acetone because of immaturity or decrease function of
    their metabolic systems, respectively. Physiological disorders are
    exacerbated by higher exposure. Fasting and diabetes increases
    endogenous levels of acetone in humans, suggesting that dieters and
    diabetics may have a higher body burden, and additional exposure to
    acetone may make them more at risk. Results in animals suggest that
    the rate of acetone metabolism is slower during pregnancy (Peinado et
    al., 1986).

         One of the most-studied effects of acetone is the induction of
    mierosomal enzymes, particularly of cytochrome P-450IIE1. Acetone
    thereby induces its own metabolism, and it potentiates the toxicity of
    numerous other chemicals by enhancing the metabolism, which depends on
    cytochrome P-450IIE1, to reactive intermediates, The indnction of
    cytochrome P-450IIE1 by acetone has been documented in many species,
    and therefore poses a concern for humans exposed to acetone or to
    those chemicals whose toxicity is potentiated or antagonized by
    acetone. The observed potentiation following acetone ingestion
    generally causes a quantitative increase in the extent of damage to
    the affected tissues or organs.

         Acetone pretreatment has been shown to potentiate halogenated
    solvent hepatotoxicity and nephrotoxicity, and is related to the
    induction of microsomal enzymes that metabolize these solvents to
    reactive intermediates (Morgott, 1993), People with altered
    physiological states can have permanent potentiating effects of
    acetone. These states include starvation, alcoholism, diabetes
    mellitus, hypoglycaemia, eating disorders, prolonged vomiting or
    inborn errors of metabolism (Morgott, 1993). This potentiation has
    been shown to occur with carbon tetrachloride, chloroform and
    1,1,2-trichloroethane (Traiger & Plaa, 1974), 1,1-dichloroethylene
    (Hewitt & Plaa, 1983), bromodichloromethane, dibromomethane (Hewitt &
    Plaa, 1983), 1,2-dichlorobenzene (Brondeau et al., 1989), and several
    other solvents.


    9.1  Aquatic organisms

    9.1.1  Acute toxic effects on aquatic fauna

         Data on the effects of acute exposure of aquatic organisms to
    acetone are summarized in Table 14. The four freshwater fishes tested,
     Salmo gairdneri, Lepomis macrochirus, Pimephales promelas and
     Gambusia affinis, had 96-h LC50s between 5540 and 13 000 mg/litre,
    indicating low toxicity for these species (Wallen et al., 1957; Cairns
    & Scheier, 1968; Patrick et al., 1968; Mayer & Ellersieck, 1980; Veith
    et al., 1983; Brooke et al., 1984). Similarly, the freshwater Asiatic
    clam ( Corbiculo manilensis) had a 96-h LC50 of 20 000 mg/litre
    (Chandler & Marking, 1979). Various species of the water flea
    ( Daphnia magna, D, pulex and  D. cuculata) had 48-h LC50s and
    EC50s of 7460 to 13 500 mg/litre; however, test conditions for these
    studies were scantily reported (Canton & Adema, 1978; Randall & Knopp,
    1980). Bringmann & Kühn (1982) found a 24-h EC50 (immobilization) of
    10 000 mg/litre for  Daphnia magna. Dowden & Bennett (1965) reported a
    48-h LC50 of 10 mg/litre for  D. magna, but they noted that tests
    had been done by several different investigators and that values might
    be erroneous. Ewell et al. (1986) also tested several freshwater
    species under static conditions for 96 h. All of the species; pillbug
    ( Asellus intermedius), waterflea ( Daphnia magna), flatworm
    ( Dugesia tigrina), sideswimmer ( Gammarus fasciatus), snail
    ( Helisoma trivolvis), segmented worm ( Lumbriculus variegatus) and
    fathead minnow ( Pimephales promelas) had 96-h LC50s >100 mg/litre,
    the highest concentration tested.

         Two saltwater species were tested by Linden et al. (1979). The
    copepod,  Nitocra spinipes, and the bleak ( Alburnus alburnus,
    tested under static conditions had 96-h LC50s of 16 700 and 11 000
    mg/litre, respectively.

         Slooff & Baerselman (1980) studied groups of 10 amphibians,
    axolotls ( Ambystoma mexicanus) and clawed toads ( Xenopus laevis),
    34 weeks after hatching. The animals were exposed to varying
    concentrations of acetone in standardized medium and 48-h LC50 values
    for the respective species were 20 and 24 mg/litre.

        Table 14  Acute toxicity of acetone to aquatic fauna


    Species                Test         Result             pH        Temperature    Hardness       Comments          Reference
                                        (mg/litre)                   (°C)           (mg/litre)
    Water flea             48-h LC50    9218               8.2       25             90-110         static, nominal   Cowgill & Milazzo (1991)
    (Daphniamagna)         24-h LC50    4068               8.2       25             90-110         static, nominal   Cowgill & Milazzo (1991)
                           NOEL         <403               8.2       25             90-110         static, nominal   Cowgill & Milazzo (1991)

    Water flea             48-h LC50    12 100 to 13 300                                           nominal           Canton & Aderna (1978)
    (Daphnia magna)

    Water flea             48-h EC50    13 500             7.7       22             154.5          nominal           Randall & Knepp (1980)
    (Daphnia magna)

    Water flea             24-h LC50    10                                                         nominal           Dowden & Bennett (1965)
    (Daphnia magna)        48-h LC50    10                                                                           Dowden & Bennett (1965)

    Water flea             96-h LC50    >100               6.5-8.5   20                            nominal           Ewell et al. (1986)
    (Daphnia magna)

    Water flea             24-h EC50    >10 000                                                    immobilization    Bringmann & Kühn (1982)
    (Daphnia magna)

    Water flea             48-h LC50    8800                                                       nominal           Canton & Adema (1978)
    (Daphnia pulex)

    Water flea             48-h LC50    7460-7810                                                  nominal           Canton & Adema (1978)
    (Daphnia cuculata)

    Water flea             48-h LC50    8098               8.2       25             90-110         nominal           Cowgill & Milazzo (1991)
    (Cesiodaphnia dubia)

                           240-h LC50   6693               8.2       25             90-110         nominal           Cowgill & Milazzo (1991)

    Pillbug                96-h LC50    >100               6.5-8.5   20                            static, nominal   Ewell et al. (1986)
    (Asellus intermedius)

    Table 14 (contd).
    Species                Test         Result             pH        Temperature    Hardness       Comments          Reference
                                        (mg/litre)                   (°C)           (mg/litre)
    Flatworm               96-h LC50    >100               6.5-8.5   20                            static, nominal   Ewell et al. (1966)
    (Dugesia tigrina)

    Side swimmer           96-h LC50    >100               6.5-8.5   20                            static, nominal   Ewell et al. (1986)
    (Gammarus fasciatus)

    Segmented worm         96-h LC50    >100               6.5-8.5   20                            static, nominal   Ewell et al. (1986)

    Snail                  96-h LC50    >100               6.5-8.5   20                            static, nominal   Ewell et al. (1986)
    (Helisoma trivolvis)

    Asiatic clam           96-h LC50    >20 000                      16             16-26          static, nominal   Chandler & Marking (1979)

    Crustacean             24-h LC50    64 300             7.8       25             250            static, nominal   Crisinel et al (1994)

    Copepod                96-h LC50    16 700             7.8       10                            static, nominal   Lindén et al (1979)
    (Nitocra spinipes)

    Brine shrimp           24-h LC50    2100               24.5                                    saltwater,        Price et al. (1974)
    (Artemia salina)                                                                               static, nominal
                           24-h LC50    6010               7.4       12             40             static, nominal   Mayer & Ellersieck (1980)

                           96-h LC50    5540               7.4       12             40             static, nominal   Mayer & Ellersieck (1980)

    Rainbow trout          24-h LC50    6100               8.0       10             90             flow-through,     Majewski et al. (1977)
    (Salmo gairdnen)                                                                               nominal

    Table 14 (contd).
    Species                Test         Result             pH        Temperature    Hardness       Comments          Reference
                                        (mg/litre)                   (°C)           (mg/litre)
    Rainbow trout          24-h CV50    36 500             18                                      CV50 is the       Segner & Lenz (1993)
    (Salmo gairdnen)                                                                               midpoint
                                                                                                   cytotoxicity of
                                                                                                   the R1 cell line

    Bluegill               96-h LC50    8300                         18             10             static, nominal   Cairns & Scheier (1968)
    (Lepomis macrochirus)

    Fathead minnow         96-h LC50    8120               7.58      25             48.5           measured          Brooke et al (1984)
    (Pimephales promelas)                                                                          exposure

                           96-h LC50    6880               6.93      25             535            measured          Brooke et al. (1984)

                           96-h LC50    6290               7.62      24             44.0           measured          Brooke et al. (1984)

    Fathead minnow         96-h LC50    >100               6.5-8.5                                 static, nominal   Ewell et al. (1986)
    (Pimephales promelas)

    Mosquito fish          24-h LC50    13 000             8.0-8.5   23-27          <100           static, nominal   Wallen et al. (1957)
    (Gambusia affinis)

                           48-h LC50    13 000             8.0-8.5   23-27          <100           static, nominal   Wallen et al. (1957)

                           96-h LC50    13 000             8.0-8.5   23-27          <100           static, nominal   WaIlen et al. (1957)

    Bleak                  96-h LC50    11 000             7.8       10                            static, nominal,  Linden et al (1979)
    (Alburnus alburnus)                                                                            saltwater

    9.1.2  Chronic effects on aquatic fauna

         Cowgill & Milazzo (1991) calculated EC50 values for two species
    of  Daphnia exposed to acetone using the three-brood test. For
     Daphnia magna, EC50 values for number of progeny, number of broods
    and mean brood size were 6369, 6406 and 6714 mg/litre, and the
    corresponding NOEL values were 3110, 5184 and 3110 mg/litre. The EC50
    values for  Ceriodaphnia dubia were 6469, 5908 and 6928 mg/litre, and
    the corresponding NOEL values were 5184 mg/litre for all three

    9.1.3  Effects on aquatic plants

         Freshwater diatoms and algae were tested with acetone.
     Chlorella pyrendoidosa, a green alga, was exposed to acetone at
    concentrations of 2574 and 25 740 mg/litre (3.3 and 33 ml/litre
    assuming an acetone density of approx. 790 mg/ml at 30°C) in culture
    tubes with 300 ml nutrient solution at 30°C under continuous light for
    76 h (Parasher et al., 1978). The lowest concentration bad a slight
    negative effect on algal growth; the high concentration caused
    disintegration of the cell membranes and cytoplasm.

         Hess (1980) examined the effects of acetone on
     Chlamydomonas eugametus, a green alga. The alga was exposed for 48 h
    at 25°C; pH and hardness were not reported. An acetone concentration
    of 0.5% (v/v; 3950 mg/litre) resulted in no inhibition of growth.
    Significant inhibition (a 15% growth reduction) occurred at 1.0% (7900
    mg/litre) and growth was only 24% of control values at 2.5% acetone
    (1975 mg/litre); at 5.0% (39 500 mg/litre), there was complete
    inhibition. Bringmann & Kühn (1978, 1980a) examined the effects of
    acetone on the green alga,  Scendesmus quadricauda. The alga was
    exposed at 27°C for 7-8 days. The toxicity threshold was 7500
    mg/litre. Bringmann & Kühn (1978) determined that the toxicity
    threshold for the cyanobacterium (blue-green alga)
     Microcystis aeruginosa exposed under similar conditions was only 530
    mg/litre. Stratton & Corke (1981) noted that acetone (0.1-1.0% v/v;
    790-7900 mg/litre; length of exposure not reported) actually
    stimulated photosynthesis in  S. quadricauda and  C. pyrendoidosa,
    perhaps by increasing the rate of CO2 diffusion into the cells.

         The freshwater diatom,  Nitzchia linearis, was tested in soft
    water (100 mg CaCO3/litre) for 5 days but temperature and pH were not
    reported (Patrick et al., 1968). The EC50 for cell multiplication was
    11 493 to 11 727 mg/litre.

         The marine diatom  Skeletonema costatum was also tested with
    acetone (Kleppel & McLaughlin, 1980; Cowgill et al., 1989). Following
    exposure to acetone for 5 days, EC50 values for decreases in total
    cell count and total cell volume were 11 798 and 14 440 mg/litre,
    respectively (Cowgill et al., 1989). Kleppel & McLaughlin (1980)

    exposed  skeletonema costatum (at cell densities of 3.8 × 102,
    3.8 × 103 and 3.8 × 104) to 1 ml acetone per litre of medium for 5
    days. There were no significant changes in cell growth and
    reproduction in cells exposed to acetone, compared with controls.

         Cowgill et al. (1991) estimated the NOEL and the EC50 (50%
    reduction in the number of plants or fronds as compared to controls)
    of acetone to  Lemna sp. (duckweed). Plants belonging to this genus
    have become "aquatic test organisms" because they are a part of the
    food chain of fish, water fowl and aquatic organisms. For
     Lemna gibba G-3, the EC50 for the 7-day test was 12.4 g/litre for
    plants and 10.2 g/litre for fronds. For  Lemna minor 6591, it was
    13.4 g/litre for plants and 11.4 g/litre for fronds. Three other
     Lemna species had EC50 values greater than 10 g/litre.

    9.2  Effects on bacteria and protozoa

         The effects of acetone have been studied with bacteria and
    protozoans. Protozoans seemed more sensitive to toxicological effects
    than bacteria. Bringmann & Kühn (1980a) exposed the bacterium
     Pseudomonas putida (for 16 h) and the protozoan
     Entosiphon sulcatum (for 72 h), to acetone at a temperature of 25°C
    in a cell multiplication test to determine toxicity. The toxicity
    thresholds for these two organisms were 1700 and 28 mg/litre,
    respectively. In another study, Bringmann & Kühn (1980b) determined a
    toxicity threshold for the protozoan  Uronema porduczi of 1710
    mg/litre. A mixed microbial culture from wastewater (specific biota
    not reported) tested with acetone for an unreported length of time
    resulted in an EC50 (decrease in biodegradation) of 0.612 mol/litre
    (35 540 mg/litre), indicating very low toxicity (Vaishnav, 1986). The
    bioluminescent bacterium  Photobacterium phosphoreum had an EC50
    (inhibition of luminescence) of 0.363 and 0.372 mol/litre (21 088 and
    21 579 mg/litre), also indicating very low toxicity (Kamlet et al.,
    1986). McFeters et al. (1983) reported a similar EC50 of 18 250
    mg/litre for  P. phosphoreum.

         Stratton (1987) estimated EC50 values in several species of
    cyanobacteria (blue-green algae). Acetone stimulated growth at
    concentrations less than 790-7900 mg/litre (0.1 to 1.0%), except for
     Anabaena sp. where levels above 5500 mg/litre (0.7%) caused total
    inhibition. Total growth inhibition occurred at acetone concentrations
    of 569 g/litre (72%) with  A. cylindrica, 31.6 g/litre (>4%) with
     A. inaegualis and > 63.2 g/litre (8%) with  A. variabilis and
     Nostoc sp. The estimated EC50 for these species ranged from 2.84 to
    34.6 g/litre (0.36 to 4.38% v/v).

         Ecotoxicological testing was done using the Microtox test, which
    is based upon the toxicant-based diminution of light emission of
     Photobacterium phosphoreum (Bulich, 1986). The parameter used to
    measure toxicity was the EC50, i.e. the toxicant concentration that
    diminishes light emission by 50% at 15°C. The EC50 for acetone has
    been measured at 14.7 g/litre (254 mmol/litre) for 5 min, 14.2 g/litre

    (245 mmol/litre) for 15 min and 14.1 g/litre (243 mmol/litre) for 25
    min (Chen & Que Hee, 1994). These EC50 values are very high compared
    to other compounds, indicating that acetone toxicity as reported by
    this test is low. These EC50 values can be compared to the results of
    a study by De Zwart & Slooff (1983), who determined an EC50 of 18.3
    g/litre (316 mmol/litre).

         In a series of studies on the toxicity of acetone to bacteria,
    Nirmalakhandan et al. (1994a,h) determined the IC50 in activated
    sludge cultures from a municipal wastewater treatment plan to be
    almost 4.9 g/litre.

         Blum & Speece (1991) found low inhibition, with IC50 values of
    1.2 g/litre for  Nitrosomonas, 50 g/litre in methanogens and 16
    g/litre for aerobic heterotrophs. Methanogens are generally the most
    sensitive bacteria that convert organic matter to carbon dioxide and
    methane in anaerobic environments.

         Rajini et al. (1989) examined the cytotoxicity to the protozoan
     Paramecium caudatum. The 10-min LC100 was 22.9 g/litre (2.9% v/v)
    with a concentration of 22.6 g/litre, and the 4-h LC50 was 5.37
    g/litre (0.68% v/v) with a concentration of 5.2 g/litre. The
    researchers also found that insecticides were more toxic to
     P. caudatum when they were dissolved in acetone.

    9.3  Terrestrial organisms

    9.3.1  Effects on fauna

         Hill et al. (1975) administered acetone for 5 days to both quail
    and pheasants. The LC50 for both of these birds was 40 g/kg diet, the
    highest dose administered. Acetone was also tested with mallard eggs
    (Hoffman & Eastin, 1981). Fertile eggs were immersed in 0, 10 or 100%
    acetone for 30 seconds at room temperature on days 3 or 8 of
    incubation. There were no significant effects with 10% acetone;
    however, 100% acetone caused a significant decrease in survival,
    embryonic weight and embryonic length for both exposure groups. It is
    unknown whether the mortality was due to the toxicity of acetone or to
    its solvent capabilities. White Leghorn chick embryos were also tested
    with acetone (Korhonen et al., 1983). The test article was injected
    into the eggs at 5 µl/egg. Statistical analysis was not performed and
    controls were not used; however, it appeared that acetone did not
    affect mortality or malformation of the embryos.

    9.3.2  Effects on flora

         Pertinent data regarding the effects of exposure of terrestrial
    flora to acetone have not been found. Acetone did not cause a
    significant decrease in seed germination or the percentage of normal
    seedlings of sweet corn (5h2 cultivars). However, with longer
    immersion times (8 h), it was detrimental (Hung et al., 1992).

         Gorsuch et al. (1990) tested the potential of acetone to affect
    germination and early growth of terrestrial plants. Plants were
    exposed to the chemical for 7 days and then germination, root length
    and plant heights were determined and compared with controls. Acetone
    had a no-observed-effect concentration of 100 mg/litre (nominal
    concentration) for ryegrass, radish and lettuce.


    10.1  Evaluation of human health effects

         Acetone is of a low order of acute toxicity. However a
    significant number of poisonings have occurred in humans following
    accidental or intentional misuse.

         Acetone can produce neurobehavioural and other changes, including
    headache, dizziness, confusion and, at high vapour concentrations, CNS
    depression and narcosis. Exposures to acetone vapour will cause
    irritation of eyes, nose and throat. Continuous exposure to vapour can
    lead to adaptation to the odour.

         Liquid acetone is an eye irritant and repeated exposure of skin
    will cause defatting, drying and cracking.

         It is considered that acetone is neither a skin nor a respiratory
    tract sensitizer.

         Acetone is formed endogenously from fatty acid oxidation and is
    uniformly distributed throughout the body among non-adipose tissues.
    It is rapidly cleared from the body by metabolism and excretion,
    mainly through the lungs. Acetone induces the hepatic mixed-function
    oxidase enzymes that bring about its own metabolism, and so the body
    has a homeostatic mechanism that has evolved to maintain acetone
    levels in the body at a "baseline" level. Induction of hepatic
    mixed-function oxidase enzymes can potentiate (and in some instances
    antagonise) the effects of other chemicals. People at most risk to
    potentiation include diabetics, alcoholics and those undergoing
    prolonged fasting. In common with other chemicals, metabolism of
    acetone may be reduced in neonates, the elderly and in hepatic

         In one study on human volunteers, increases in leucocyte count
    were reported. However, this has not been found in other studies, in
    an inhalation study, human female volunteers reported menstrual
    irregularities (delayed menstruation).

         Mild haematological effects were found in two strains of rats
    (F344 and Sprague-Dawley). The mean cell haemoglobin concentration and
    mean cell volume were elevated in both, but blood haemoglobin
    concentration was raised in Sprague-Dawley rats and decreased in F344
    rats. At an acetone dose of 50 000 mg/litre in the drinking-water,
    effects on sperm quality were observed in rats. At lower doses only
    small changes in sperm motility were seen. In a reproductive study in
    which males were exposed to 5000 mg/litre in drinking-water, there
    were no changes in reproductive index. High doses in animals produce
    minimal fetal toxicity although only at doses causing maternal
    effects. Acetone produced an increase in nephropathy in treated male

    rats over the levels found in controls: this is of uncertain
    significance to humans, Acetone is not genotoxic nor has it been shown
    to be carcinogenic in dermal bioassays in mice.

         No long-term experimental studies have been conducted. From the
    available shorter-term studies, a no-observed-effect level in a
    13-week drinking-water study in rats of 900 mg/kg body weight per day
    (male rats), based on parameters including changes in organ weights,
    was selected. Applying an uncertainty factor of 100 gives a guidance
    value of 9 mg/kg body weight per day.

         The relevance to humans of the liver, reproductive and
    developmental effects observed in animal studies is not known, and
    these end-points have not been sufficiently examined in humans.
    However, because few species differences exist in the toxicokinetics
    of acetone, these effects might be of concern for humans. The renal
    effects may be specific for male rats, and the cataract formation may
    be specific for guinea-pigs. The relevance of amyloidosis in
    completely unknown. Acetone appears to have no delayed toxic effects.
    The majority of genotoxicity assays on acetone were negative;
    therefore, acetone can be considered to present no potential genotoxic
    hazard to humans.

         It should be noted that the perception of "irritation" from
    acetone vapour by humans may be at a concentration in air as low as
    23.7 mg/m3 (100 ppm), which is at or near the odour threshold.

    10.2  Evaluation of effects on the environment

         Acetone is of low toxicity to both aquatic and terrestrial
    organisms. It is readily biodegraded in the environment and does not
    bioaccumulate or magnify through the food chain. Even if acetone is
    spilt in water, it is unlikely to have a major or lasting effect on
    the ecosystem. Owing to evaporation and dispersal, spills on land are
    likewise not expected to have any major or lasting effects on
    terrestrial organisms.


    a)   Reproductive effects need to be examined in animals and/or in
         humans. Clarification of the dose-response relationship is
         required with special reference to male reproductive effects at
         doses where abnormal sperm are found and to determine if there
         are complications during menstration, pregnancy and childbirth,
         as existing data are not conclusive.

    b)   Longer-term studies are required to determine whether the kidney
         effects are attributable to acetone or are exacerbating an
         existing condition. If they are acetone-related, the mechanism
         should be determined.

    c)   Clarification of the potentiation and antagonism mechanisms in
         humans is needed.

    d)   Clarification of the mechanisms of potential immunotoxic effects
         is required.


         Acetone was evaluated in 1970 as an extraction solvent for fats
    and oils and a precipitation agent in the purification of starches and
    sugars by the Joint FAO/WHO Expert Committee on Food Additives. The
    Committee recommended that its use as an extraction solvent should be
    restricted to that determined by good manufacturing practice, which is
    expected to result in minimum residues. Within these limits residues
    are unlikely to have any significant toxicological effect (FAO/WHO,
    1971; WHO, 1971).


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    1.  Propriétés

         L'acétone (masse moléculaire relative = 58,08) est un liquide
    inflammable, limpide et incolore (point d'éclair - 17°C en coupe
    fermée, -9°C en coupe ouverte; limites d'inflammabilité dans l'air à
    25°C = 2,15-13% v/v). Les limites d'explosion dans l'air sont de: 
    2,6-12,8% v/v). L'acétone s'évapore rapidement (tension de vapeur 
    181,72 mm Hg à 20°C) et présente une faible viscosité (0,303 cP à
    25°C). Elle est miscible à l'eau et aux solvants organiques.

    2.  Usages et sources d'exposition

    2.1  Production

         Industriellement, l'acétone se prépare principalement par
    peroxydation du cumène ou déshydrogénation de l'alcool isopropylique.
    La peroxydation du eumène produit également des traces de benzène.

    2.2  Usages et émissions dans l'environnement

         L'acétone est principalement utilisée comme solvant et comme
    intermédiaire dans la préparation de divers produits chimiques. Ses
    principaux usages consistent dans la production de méthacrylate de
    méthyle, acide méthacrylique et méthacrylates supérieurs, bisphénol A,
    méthylisobutylcétone, médicaments et dans des applications
    pharmaceutiques diverses. On l'utilise aussi comme solvant de
    l'acétate de cellulose et de divers enduits. Dans l'industrie
    alimentaire, on l'emploie comme solvant d'extraction des graisses et
    des huiles et comme agent de précipitation au cours de la purification
    du sucre et de l'amidon.

         Les émissions d'acétone dans l'atmosphère proviennent de produits
    de consommation qui en contiennent: dissolvants pour vernis à ongles,
    panneaux de particules, doublures de tapis, décapants pour peintures,
    cires et encaustiques liquides ou pâteux. Un certain nombre de
    détergents, produits de nettoyage (notamment pour certains éléments de
    moteurs d'automobile tels que carburateurs et starters) et adhésifs
    contiennent aussi de l'acétone.

         De nombreuses industries polluent les eaux superficielles par
    leurs rejets d'acétone dans les eaux résiduaires: papier, plastiques,
    produits pharmaceutiques, produits d'entretien, peintures et vernis,
    produits pour le traitement des gommes, colles et bois, intermédiaires
    cycliques, dérivés organiques industriels, produits de gypseuse,
    cartonnages, production d'énergie (gazéification de la houille et
    traitement de l'huile de schiste).

         La pollution des sols par l'acétone trouve son origine dans le
    rejet de déchets agricoles et alimentaires, les excréments d'animaux,
    les précipitations, les effluents de fosses septiques et les
    infiltrations provenant de décharges de produits chimiques.

    3.  Transport, distribution et transformation dans l'environnement

         L'acétone libérée dans l'atmosphère se décompose par voie
    photolytique et par réaction avec des radicaux hydroxyles. Sa demi-vie
    atmosphérique est dans ce cas d'environ 30 jours. Elle peut être
    éliminée physiquement de l'atmosphère par les précipitations. Dans les
    sols et dans l'eau, c'est la biodégradation qui constitue le principal
    mode de décomposition de l'acétone, ce composé étant facilement
    biodégradable, Sa volatilisation à partir de l'eau peut constituer une
    voie de transport environnemental non négligeable. En raison de sa
    volatilité, elle s'évapore des surfaces sèches sur lesquelles elle est
    déposée. En outre, sa miscibilité à l'eau en facilite le lessivage à
    partir de la plupart des sols. En cas de biodégradation suffisamment
    rapide, ce lessivage perd de son importance.

    4.  Concentrations dans l'environnement et exposition humaine

         L'exposition à l'acétone peut être d'origine naturelle ou
    artificielle. Elle est présente dans le sang, l'urine et l'haleine
    humaines par suite du métabolisme normal. Dans l'environnement, sa
    présence résulte entre autres de la biodégradation des effluents, des
    déchets solides et des alcools ainsi que de l'oxydation des substances
    humiques. On l'a mise en évidence dans diverses plantes et denrées
    alimentaires comme les oignons, le raisin, les choux-fleurs, les
    tomates, les volubilis, la moutarde sauvage, le lait, les haricots,
    les pois, le fromage et le blanc de poulet. Diverses espèces d'arbres
    émettent naturellement des vapeurs d'acétone. La pollution du milieu
    aquatique imputable à l'activité humaine est due au déversement des
    eaux résiduaires d'un grand nombre d'industries et au lessivage des
    décharges industrielles ou municipales. L'évaporation de l'acétone
    utilisée comme solvant dans les peintures, vernis, produits
    d'entretien et encres constitue une source importante de pollution de
    l'air. Sa présence dans l'atmosphère résulte également de la
    combustion du bois, de plastiques et de déchets divers. Elles est
    également émises avec les gaz d'échappement des moteurs à explosion et
    des moteurs diesel ou encore des turbines à gaz. Les concentrations
    relevées dans l'atmosphère vont de 0,5 à 125,4 µg/m3 (0,2-52,9
    parties par milliard).

    5.  Cinétique et métabolisme

         L'acétone est l'une des trois cétones qui sont présentes à l'état
    naturel dans l'organisme. Elle peut se former de manière endogène dans
    l'organisme des mammifères par oxydation des acides gras. Le jeûne, le
    diabète sucré et un exercice physique intense accroissent la formation
    endogène d'acétone. Dans les conditions normales, la production de
    corps cétoniques s'effectue presque exclusivement dans le foie et,
    dans une moindre proportion, dans les reins et les poumons. Il s'agit
    d'un processus continu et les trois produits, après être passés dans
    le sang, gagnent la totalité des tissus et des organes où ils peuvent
    être utilisés comme source d'énergie. Deux d'entre eux, l'acide

    acétoacétique et l'acide ß-hydroxybutyrique, sont des acides
    organiques susceptibles de provoquer une acidose lorsqu'ils sont
    produits en grande quantité, comme dans le cas du diabète sucré.
    L'acétone, en revanche, n'est pas ionisée et elle est produite de
    manière endogène par le clivage enzymatique ou spontané de
    l'acétoacétate. L'acétone endogène est éliminée de l'organisme soit
    par la voie urinaire, soit dans l'air expiré, soit par l'action
    d'enzymes. Dans les conditions normales, c'est la voie métabolique qui
    constitue le mode principal d'élimination de l'acétone (70 à 80% de la
    quantité totale présente dans l'organisme).

         L'acétone est rapidement résorbée au niveau des voies
    respiratoires et digestives de l'Homme et de l'animal, comme on peut
    le constater à la présence d'acétone dans le sang 30 minutes après
    inhalation et 20 minutes après ingestion. Les études effectuées sur
    des rats montant qu'après ingestion, l'acétone est absorbée dans une
    forte proportion, alors qu'après inhalation chez l'Homme, la
    proportion absorbée est d'environ 50% de la quantité initiale. Il est
    vrai cependant, que des valeurs plus fortes et plus faibles ont été
    relevées après inhalation. Il semblerait que les fosses nasales de
    l'Homme et des animaux de laboratoire n'aient qu'une capacité limitée
    à absorber et à excréter les vapeurs d'acétone, comparativement aux
    autres parties des voies respiratoires.

         L'acétone se répartit uniformément dans les tissus non adipeux et
    ne s'accumule pas dans les graisses. Chez la souris, la concentration
    maximale d'acétone dans les tissus adipeux s'est révélée égale au
    tiers de ce qu'elle était dans les autres tissus, après exposition des
    animaux par la voie respiratoire. L'acétone s'élimine rapidement de
    l'organisme par métabolisation et excrétion. Sa demi-vie dans l'air
    alvéolaire, dans le sang veineux et dans le sang artériel est
    respectivement égale à approx. 4, 6 et 4 h. La principale voie
    d'élimination de l'acétone et de son métabolite terminal, le CO2, est
    l'air expiré et la fraction du composé qui est rejetée inchangée
    dépend de la dose. Il y a aussi excrétion de l'acétone et de ses
    métabolites par la voie urinaire, mais il s'agit d'une voie mineure
    par rapport à l'expiration.

         L'acétone d'origine endogène prend part à nombre des réactions
    métaboliques qui se produisent dans les diverses parties de
    l'organisme, mais c'est le foie qui semble constituer le site
    métabolique le plus important. Le carbone provenant de l'acétone
    administrée par voie orale à des rat se retrouve dans le cholestérol,
    les acides aminés, les acides gras et le glycogène fistulaires ainsi
    que dans l'urée unanime. On le retrouve aussi dans l'acétone inchangée
    et dans le CO2 présents dans l'air expiré. L'acétone est métabolisée
    en acétate et en formiate; cela explique que le carbone acétonique
    entre dans le cholestérol, les acides gras, l'urée et les acides
    aminés et qu'il se forme des composés tricarbonés par gluconéogénèse.

         On a avancé que la gluconéogénèse à partir de l'acétone
    s'effectuait selon deux voies métaboliques. La première comporte
    l'action catalytique initiale de l'acétone-monooxygénase et de
    l'acétol-monooxygénase qui transforme respectivement l'acétone en
    acétol et l'acétol en méthylglyoxal. Ces deux enzymes sont induites
    par l'acétone et constituent des isozymes du cytochrome hépatique
    P-450IIE1 industriel par l'éthanol. Le deuxième mode de néoglucogénèse
    consiste dans la formation de 1,2-propanediol à partir de l'acétone,
    sous l'action de l'acétone-monooxygénase et d'une autre enzyme non
    caractérisée, capable de convertir l'acétol en 1,2-propanediol.

    6.  Effets sur les mammifères de laboratoire et les systèmes d'épreuve
    in vitro

         Chez le rat, la valeur de la DL50 par voie orale varie entre
    5800 et 7138 mg/kg. La CL50 par inhalation à 4 h est égale à 76 000
    mg/m3 (32 000 ppm).

         On a constaté, chez l'animal de laboratoire exposé à l'acétone,
    une moindre performance dans les tests neurocomportementaux, aux
    concentrations supérieures à 7765 mg/m3 (> 3270 ppm).

         On ne dispose pas de données sur les effets d'une exposition de
    longue durée à l'acétone par la voie orale ou respiratoire, sans doute
    parce que sa toxicité est faible et qu'il s'agit d'un composé

         En faisant inhaler de l'acétone à des rats pendant une longue
    période (45 000 mg/m3, soit 19 000 ppm, 3 h par jour, 5 jours par
    semaine, pendant 8 semaines), on a observé une diminution réversible
    du poids absolu du cerveau. Aucune modification systématique n'a été
    notée dans le poids du corps ou celui d'antres organes, au niveau des
    constantes hématologiques, dans le taux des triglycérides hépatiques
    ou dans l'aspect histologique du coeur, du poumon, du rein, du cerveau
    ou du foie.

         Lors d'une étude de 90 jours comportant l'administration
    d'acétone à des rats par gavage, on a observé une augmentation de
    certains paramètres hématologiques (hémoglobine, hématocrite) aux
    doses supérieures à 500 mg/kg par jour et on a déterminé une NOAEL
    (dose sans effet nocif observable) de 500 mg/kg par jour. Dans une
    autre étude, qui a duré 13 semaines et qui a consisté à ajouter de
    l'acétone à l'eau de boisson des rats, on a noté la présence d'effets
    toxiques chez les mâles exposés à des concentrations supérieures à 20
    g/litre (env. 1700 mg/kg p.c. par.jour), à savoir une augmentation du
    poids relatif des organes et une modification des constantes
    hématologiques, avec en outre une légère néphropathie. Chez les
    femelles soumises à la dose la plus forte, soit 50 g/litre (env. 3400
    mg/kg p.c. par jour), les effets consistaient en une augmentation du
    poids relatif des organes et une modification des constantes
    hématologiques. En outre, l'exposition à 50 g/litre pendant 13
    semaines a provoqué chez les mâles une modification du poids relatif

    des testicules et ainsi qu'une baisse de la motilité des
    spermatozoïdes accompagnée d'anomalies morphologiques. Des souris
    femelles exposées à la même concentration de 50 g/litre (env. 11 298
    mg/kg p.c. par jour) dans leur eau de boisson, présentaient une
    réduction du poids du foie et de la rate ainsi qu'une hypertrophie
    hépatique touchant les cellules centrilobulaires, mais dont
    l'augmentation d'incidence restait marginale. Aucun effet toxique n'a
    été relevé chez les souris mâles qui avaient reçu la plus forte dose
    d'acétone (20 g/litre, soit env. 4858 mg/kg p.c. par jour). Une
    exposition de 13 semaines à des doses inférieures ou égales à 10
    g/litre (900 mg/kg p.c. par jour), toujours par ingestion d'acétone
    mélangée à l'eau de boisson, n'a pas produit d'effets toxiques chez
    des rats mâles; les doses sans effets observables étaient < 20
    g/litre chez les rats (1600 mg/kg p.c. par jour) et les souris des
    deux sexes (mâles: 4858 mg/kg p.c. par jour; femelles: 5945 mg/kg p.c.
    par jour).

         Lors d'une étude préliminaire de 14 jours consistant à faire
    boire de l'eau additionnée d'acétone à des rats et à des souris, on a
    noté chez les mâles exposés aux concentrations de 20 à 100 g/litre,
    une hypertrophie hépatique affectant les cellules centrilobulaires.

         Chez les rongeurs, un prétraitement par l'acétone accroît les
    effets hépatotoxiques de certains composés, notamment ceux des dérivés
    halogénés des alcanes. On suppose que cette potentialisation de
    l'hépatotoxicité est due à l'augmentation, sous l'action de l'acétone,
    de l'activité de certaines enzymes (les oxydases hépatiques â fonction
    mixte), qui sont responsables de la production d'intermédiaires
    toxiques à partir des alcanes halogénés.

         Les épreuves de génotoxicité ont donné des résultats négatifs sur
    de nombreux systèmes mammaliens, tant  in vivo qu' in vitro. Il n'y
    a qu'une seule épreuve qui ait donné un résultat positif, à savoir la
    présence d'aneuploïdies chez une espèce de levure exposée à une forte
    concentration d'acétone (6,82%) dans son milieu de croissance. On
    considère que l'acétone n'est ni génotoxique, ni mutagène.

         Lors d'une étude portant sur des rats et des souris gravides, on
    a exposé les animaux à des vapeurs d'acétone du 6ème au 19ème jour de
    la gestation. De légers effets toxiques ont été observés sur le
    développement de la progéniture lorsque les rats étaient exposées à
    une concentration de 26 100 mg/m3 (11 000 ppm) à raison de 6 h par
    jour (augmentation de la proportion de portées comportant au moins une
    malformation foetale) et les souris à une concentration de 15 670
    mg/m3 (6600 ppm) à raison également de 6 h par jour (légère
    diminution du poids des foetus et petite augmentation de l'incidence
    relative des résorptions tardives). On a fixé à 5200 mg/m3 (2200 ppm)
    la concentration atmosphérique sans effet nocif observable sur le
    développement de la souris et du rat. Dans une étude par gavage, un
    traitement par l'acétone au cours de l'organogénèse à la dose
    quotidienne de 3500 mg/kg, a eu un effet négatif sur la reproduction
    lors d'un test de criblage sur des souris. Les résultats négatifs

    obtenus  in vivo chez deux espèces différentes, l'administration se
    faisant par la voie buccale et par la voie intrapéritonéale, montrent
    que l'exposition de mammifères à l'acétone n'a pas d'effets mutagènes.

         Les observations relatives aux effets de l'acétone sur la
    reproduction consistent en anomalies testiculaires et modification de
    la qualité des spermatozoïdes, qui ont été mises en évidence chez des
    rats dont l'eau de boisson avait contenu pendant 13 semaines 50 g
    d'acétone par litre. On n'a pu trouver aucune étude consacrée aux
    effets que pourrait avoir l'ingestion d'acétone sur le développement
    foetal (foetotoxicité et tératogénicité).

         L'acétone est largement utilisée comme solvant dans les études
    sur le pouvoir cancérogène cutané et on estime qu'en application sur
    la peau, elle est dénuée d'activité cancérogène.

    7.  Effets sur l'Homme

         L'acétone est relativement moins toxique que nombre d'autres
    solvants industriels; cependant, sous forte concentration, les vapeurs
    d'acétone peuvent provoquer une dépression du système nerveux central,
    un collapsus cardiorespiratoire et la mort. On connaît des cas
    d'exposition humaine aiguë à des concentrations d'acétone atteignant
    environ 4750 mg/m3 (soit à peu près 2000 ppm) qui n'ont été
    accompagnés d'aucun effet toxique majeur ou tout au plus d'effets
    mineurs et passagers, tels qu'une irritation oculaire. Des effets
    passagers plus sérieux (notamment des vomissement et une perte de
    conscience) ont le observés chez des travailleurs exposés à des
    vapeurs d'acétone dont la concentration dépassait 25 500 mg/m3 (>
    12 000 ppm) pendant environ 4 h. On a également fait état d'une baisse
    dans les résultats des tests neurocomportementaux chez l'Homme à la
    concentration de 595 mg/m3 (250 ppm). Des femmes exposées à une
    concentration atmosphérique de 2370 mg/m3 (1000 ppm) ont présenté des
    irrégularités du cycle menstruel.

    8.  Effets sur les autres êtres vivants au laboratoire et dans leur
    milieu naturel

         Pour la plupart des espaces animales dulçaquicoles ou marines,
    les valeurs de la CL50 et de la CE50 à 48 et 96 h se sont révélées >
    5540 mg/litre.

         Une exposition de 76 h à de l'acétone à la concentration de 257,4
    mg/litre a provoqué une inhibition de la croissance de l'algue
     Chlorella pyrendoidosa. Il en a été de même pour
     Chlamydomonas eugametos après 48 h d'exposition à 790 mg/litre. En
    exposant  Scendensemus quadricauda et  C. pyrendoidosa à de
    l'acétone aux concentrations respectives de 79,0 et 790 mg/litre, on a
    observé un accroissement de la photosynthèse.

         Les seuils de toxicité respectifs à 7 et 8 jours pour l'algue
    verte  S. quadricauda et pour la cyanobactérie (algue bleue)
     Microcystis aeruginosa se situent à 7500 et 530 mg/litre, ce qui
    traduit la plus grande résistance de l'algue verte à l'action toxique
    de l'acétone. La diatomée  Nitzschia linearis a également semblé
    faire preuve d'une grande résistance, avec une CE50 à 5 jours
    comprise entre 11 493 et 11 727 mg/litre. De même la diatomée marine
     Skelatonema costatum s'est aussi révélée lès résistante, avec une
    CE50 comprise entre 11 798 et 14 440 mg/litre.

         Les bactéries se révèlent plus résistantes à l'acétone que les
    protozoaires. Pour  Photobacterium phosphoreum,  Pseudomonas putida
    et une culture mixte, on a obtenu une valeur de la CE50 comprise
    entre 1700 et 35 540 mg/litre, contre 28 mg/litre dans le cas du
    protozoaire  Entosiphon sulcatum. Ce résultat pourrait s'expliquer
    par le fait que ces deux types de microorganismes ont une paroi
    cellulaire différente.

         Chez des cailles et des faisans, on a trouvé des valeurs de la
    CL50 à 5 jours supérieures ou égaies à 40 g par kg de nourriture. Des
    oeufs fécondés de colvert n'ont pas souffert d'une immersion de 30
    secondes dans de l'acétone à 10%; en revanche, l'immersion dans de
    l'acétone pneu a entraîné une diminution de la survie, du poids et de
    la taille des embryons sans que l'on puisse dire avec certitude si e'
    est la toxicité de l'acétone qui était en cause ou son caractère de
    solvant. L'injection de 5 µl d'acétone dans des oeufs de poules
    Leghorn ne semble pas avoir entraîné de mortalité ni de malformations
    chez les embryons.


    1.  Propiedades

         La acetona (masa molecular relativa = 58,08) es un liquido
    transparente, incoloro e inflamable (punto de inflamación - 17°C en
    crisol cerrado, -9°C en crisol abierto; limites de inflamabilidad en
    el aire a 25°C = 2,15-13% v/v). Los límites de explosión en el aire
    son 2,6-12,8% v/v. Tiene una elevada tasa de evaporación (presión de
    vapor 181,72 mmHg a 20°C) y baja viscosidad (0,303 cP a 25°C). Es
    miscible con el agua y con disolventes orgánicos.

    2.  Usos y fuentes de exposición

    2.1  Producción

         La acetona se fabrica principalmente mediante los procesos de
    peroxidación del cumeno o la deshidrogenación del isopropil alcohol.
    En el primer proceso se producen cantidades infamas de benceno como

    2.2  Usos y emisiones al medio ambiente

         La acetona se utiliza principalmente como disolvente y como
    intermedio en la producción de sustancias químicas. Sus principales
    aplicaciones son la producción de metil metacrilato, ácido metacrílico
    y metacrilatos de mayor tamaño, bisfenol A, metil isobutil cetona,
    aplicaciones farmacéuticas y medicamentosas, y como disolvente para
    revestimientos y para el acetato de celulosa. También tiene usos
    alimentarios como disolvente de extracción para grasas y aceites, y
    como agente de precipitación en la purificación del azúcar y el

         Las emisiones a la atmósfera proceden de los productos de
    consumo, como quitaesmalte para las uñas, tableros de conglomerado,
    revestimientos inferiores de moquetas, algunos decapantes de pinturas
    y ceras o abrillantadores líquidos o sólidos. Ciertos detergentes y
    limpiadores, adhesivos y limpiadores del carburador y el estrangulador
    en automóviles también contienen acetona.

         La acetona se vierte a las aguas superficiales en los efluentes
    de aguas residuales de una amplia gama de procesos e industrias de
    fabricación, como el papel, el plástico, productos farmacéuticos,
    limpiadores y abrillantadores químicos elaborados, pinturas y
    productos conexos, productos químicos del caucho y la madera,
    intermedios cíclicos, productos orgánicos industriales, productos del
    yeso, productos de cartón de papel e industrias de la energía, como la
    gasificación del carbón y el tratamiento de esquistos bituminosos.

         Entre las fuentes de incorporación de acetona al suelo figuran el
    vertido de residuos agrícolas y alimentarios, residuos animales,
    deposición húmeda desde la atmósfera, efluentes de fosas sépticas
    domésticas y vertederos de residuos químicos.

    3.  Transporte, distribución y transformación en el medio ambiente

         La acetona que ingresa en la atmósfera es degradada por una
    combinación de fotolisis y reacción con radicales hidroxilo. La
    semivida media para la degradación de la acetona en la atmósfera es de
    unos 30 días. La acetona puede ser eliminada por medios fiscos del
    aire por deposición húmeda. El principal proceso de degradación de la
    acetona en el suelo y el agua es la biodegradación; la acetona es
    fácilmente biodegradable. La volatilización de la acetona desde el
    medio acuático puede ser un proceso de transporte significativo. La
    acetona es un compuesto volátil que se evapora fácilmente de las
    superficies secas. Puesto que es miscible en agua, puede ser objeto de
    lixiviación en la mayoría de los tipos de suelo. La biodegradación
    concurrente puede reducir la importancia global de la lixiviación si
    aquélla se produce con la rapidez suficiente.

    4.  Concentraciones en el medio ambiente y exposición humana

         La exposición a la acetona procede de fuentes tanto naturales
    como antropogénicas. La acetona también aparece como compuesto
    metabólico en la sangre, la orina y el aire pulmonar del ser humano.
    Se produce en la biodegradación de las aguas residuales, los residuos
    sólidos y los alcoholes, así como por la oxidación de sustancias
    húmicas. Se ha detectado en muy diversas plantas y alimentos, como las
    cebollas, las uvas, la coliflor, los tomates, las convolvuláceas, la
    mostaza silvestre, la leche, las indias, los guisantes, el queso y la
    pechuga de pollo. Las emisiones naturales de varias especies de
    árboles contienen vapores de acetona. Las fuentes antropogénicas de
    emisión al medio acuático comprenden los vertidos de aguas residuales
    de muchas industrias y la lixiviación que tiene lugar en vertederos
    industriales y municipales. Una de las principales fuentes de emisión
    humana al aire es la evaporación de la acetona utilizada como
    disolvente en productos de revestimiento como pinturas, limpiadores,
    barnices y tintas. La acetona es un producto de emisión de la
    combustión de madera, basuras y plásticos. También se emite en los
    escapes de automóviles y de motores diesel y de turbina. Las
    concentraciones de acetona detectadas en la atmósfera varían entre 0,5
    y 125,4 µg/m3 (0,2-52,9 ppmm).

    5.  Cinética y metabolismo

         La acetona es uno de los tres cuerpos cetónicos que se producen
    naturalmente en el organismo humano. Puede formarse de modo endógeno
    en el organismo de los mamíferos por oxidación de los ácidos grasos.

    El ayuno, la diabetes mellitus y el ejercicio físico vigoroso
    incrementan la generación endógena de acetona. En condiciones
    normales, prácticamente todos los cuerpos cetónicos se producen en el
    hígado, y en menor medida en el pulmón y el riñón. El proceso es
    continuo y los tres productos son excretados a la sangre y
    transportados a todos los tejidos y órganos del cuerpo, donde pueden
    ser utilizados como fuente de energía. Dos de esos cuerpos cetónicos,
    el acetoacetato y el ß-hidroxibutirato, son ácidos orgánicos que
    pueden provocar acidosis metabólica cuando se producen en grandes
    cantidades, como en la diabetes mellitus. La acetona, en cambio, tiene
    carácter no iónico y se deriva de forma endógena de la degradación
    enzimática espontánea del acetoacetato. La acetona endógena se elimina
    del organismo por excreción en la orina y el aire exhalado o por
    metabolismo enzimático. En circunstancias normales, el metabolismo es
    la vía principal de eliminación y procesa el 70-80% de la carga total
    del organismo.

         La acetona es absorbida rápidamente por los tractos respiratorio
    y gastrointestinal del ser humano y los animales de laboratorio, como
    lo indica la detección de acetona en la sangre a los 30 minutos de la
    exposición por inhalación y a los 20 minutos de la exposición por vía
    oral. Los estudios efectuados en ratas indican que la acetona
    administrada por vía oral se absorbe fácilmente, mientras que en la
    exposición por inhalación el ser humano absorbe aproximadamente el 50%
    de la cantidad de acetona inhalada. Sin embargo, se han comunicado
    valores tanto menores como mayores de absorción por vía respiratoria.
    Las cavidades nasales de los seres humanos y los animales de
    laboratorio parecen tener una capacidad limitada de absorción y
    excreción de vapores de acetona, en comparación con el resto del
    tracto respiratorio.

         La acetona se distribuye uniformemente por los tejidos no
    adiposos y no se acumula en los tejidos adiposos. En el ratón, se
    comunicó que las concentraciones máximas de acetona en los tejidos
    adiposos eran aproximadamente la tercera parte de las observadas en
    los tejidos no adiposos tras la exposición por inhalación. La acetona
    se elimina rápidamente del organismo por vía metabólico y por
    excreción. Las semividas de la acetona en el aire alveolar y la sangre
    venosa y arterial en el ser humano son approx. 4, 6 y 4 horas,
    respectivamente. La exhalación es la principal vía de eliminación de
    la acetona y su metabolito terminal, el CO2, y la fracción de la
    acetona adminisáada que se exhala sin modificar depende de la dosis.
    También se produce excreción de acetona y sus metabolitos en la orina,
    pero esta vía de eliminación es menos importante que la exhalación de
    acetona y CO2 por vía respiratoria.

         La acetona de origen exógeno se incorpora a numerosas reacciones
    metabólicas en tejidos de todo el organismo, pero el hígado parece ser
    el órgano en el que se metabólico más intensamente. El carbono de la
    acetona administrada por veta oral se ha detectado en el colesterol,
    los amanecidos, los ácidos grasos y el glucógeno en tejidos de rata,

    la urea en la orina y acetona no modificada y CO2 en el aire
    exhalado. Desde el punto de vista metabólico, la acetona se degrada a
    acetato y formato; por esta vía se produce la incorporación de los
    átomos de carbono de la acetona al colesterol, los ácidos grasos, la
    urea y los amanecidos, así como la formación de compuestos
    gluconeogénicos de tres átomos de carbono.

         Se han propuesto dos posibles vías de gluconeogénesis a partir de
    la acetona. La primera vía comienza por la acción catalítica inicial
    de la acetona-monooxigenesa y la acetol-monooxigenesa, que convierten
    la acetona en acetol y el acetol en metilglioxal, respectivamente.
    Ambas actividades enzimáticas son inducidas por la acetona y han sido
    identificadas como isoenzimas del citocromo hepático P-450IIE1,
    inducible por el etanol. La segunda ruta gluconeogénica posible
    entraña la formación de 1,2-propanodiol a partir de la acetona,
    catalizada por la acetona monooxigenasa y una enzima no caracterizada
    capaz de convertir el acetol en 1,2-propanodiol.

    6. Efectos en mamíferos de experimentación y en sistemas in vitro

         Los valores de la DL50 en ratas adultas se encuentran en el
    intervalo 5800-7138 mg/kg. El valor de la CL50 a las 4 horas de la
    inhalación es de 76 000 mg/m3 (32 000 ppm).

         Se ha observado que la exposición aguda a la acetona altera los
    resultados de las pruebas necrológicas de conducta en animales de
    laboratorio cuando las concentraciones superan los 7765 mg/m3 (>3270

         No se dispone de datos en animales de experimentación para
    caracterizar los efectos de la exposición oral o por inhalación a
    largo plazo de la acetona, probablemente a causa de su escasa
    toxicidad y sus características endógenas.

         La exposición prolongada de ratas a la inhalación de acetona, a
    razón de 45 100 mg/m3 (19 000 ppm), durante 3 horas al día, 5 días a
    la semana durante 8 semanas, provocó una reducción reversible del peso
    cerebral absoluto. No se observaron cambios uniformes en el peso de
    otros órganos ni del organismo en conjunto, ni tampoco en los índices
    químicos de la sangre, en los niveles de triglicéridos hepáticos o en
    las características histológicas del corazón, el pulmón, el riñón, el
    cerebro o el higado.

         En un estudio de alimentación forzada de ratas durante 90 días,
    se determinó un aumento en los parámetros sanguíneos (aumento de la
    hemoglobina y el hematócrito) con concentraciones superioras a 500
    mg/kg al día, y una concentración sin observación de efectos adversos
    de 500 mg/kg al día. En un estudio de administración de acetona en el
    agua de bebida durante 13 semanas, se observaron efectos tóxicos en
    las ratas macho expuestas a concentraciones superioras a 20 g/litro
    (approx. 1700 mg/kg de peso corporal al día), a saber, aumento del
    peso relativo de algunos órganos, y alteración de los índices

    hematológicos y leve nefropatía. En hembras de rata a las que se
    administró la concentración más elevada, 50 g/litro (approx. 3400
    mg/kg de peso corporal al día), los efectos observados fueron un
    aumento de los pesos relativos de ciertos órganos y la alteración de
    los índices hematológicos. Además, la exposición durante 13 semanas a
    50 g/litro provocó una alteración del peso relativo de los testículos
    y de la mutualidad y morfología de los espermatozoides en ratas macho.
    Las hembras de ratón a las que se administraron 50 g/litro (approx. 11
    298 mg/kg de peso corporal al día) en el agua de bebida presentaron
    alteraciones del peso del hígado y el bazo y una incidencia
    ligeramente mayor de hipertrofia hepatocelular centrilobular. No se
    observaron efectos tóxicos en ratones macho a los que se administraron
    20 g/litro (4858 mg/kg de peso corporal al tila), la concentración de
    acetona más alta que se ha administrado a ratones macho. La exposición
    durante 13 semanas a concentraciones < 10 g/litro (900 mg/kg de
    peso corporal al día) administradas en el agua de bebida no se vio
    acompañada de efectos tóxicos en ratas macho; las concentraciones
    < 20 g/litro no produjeron efectos observables en hembras de rata
    (1600 mg/kg de peso corporal al día) ni en ratones de ambos sexos
    (machos: 4858 mg/kg de peso corporal al día; hembras: 5945 mg/kg de
    peso corporal al día).

         En un estudio preliminar en el que se administró acetona en el
    agua de bebida a ratas y ratones durante 14 alias, se observó
    hipertrofia hepatocelular centrilobular relacionada con la dosis en
    ratones machos expuestos a concentraciones de 20-100 g/litro.

         El tratamiento previo de roedores con acetona acentúa los efectos
    hepatotóxicos de varios compuestos, particularmente los alcanos
    halogenados. Una hipótesis es que la potenciación de la
    hepatotoxicidad está mediada por el aumento de las actividades
    enzimáticas mediadas por la acetona (oxidabas hepáticas de funcion
    mixta) que son responsables de la generación de productos intermedios
    tóxicos originados a partir de los alcanos halogenados administrados.

         La acetona ha dado resultados negativos en relación con la
    toxicidad genética en numerosos sistemas no mamíferos, así como en
    sistemas mamíferos  in vitro e  in vivo. Los resultados positivos se
    limitan a una sola prueba de aneuploidía en una especie de levadura
    expuesta a concentraciones elevadas de acetona (6,82%) en su medio de
    cultivo. No se considera que la acetona sea genotóxica ni mutagénica.

         En un estudio de hembras gestantes de ratón y rata expuestas a
    vapores de acetona durante los días ó a 19 de la gestación, se observó
    una ligera toxicidad para el desarrollo tras la exposición de las
    ratas a 26 100 mg/m3 (11 000 ppm) durante 6 horas al día (pequeña
    disminución en el peso del feto y pequeño aumento en la incidencia
    porcentual de retorciones tardías). Se determinó que una concentración
    atmosférica de 5200 mg/m3 (2200 ppm) era el nivel sin observación de
    efectos adversos respecto de la toxicidad para el desarrollo tanto en
    ratones como en ratas. En un estudio de alimentación forzada, el
    tratamiento con 3500 mg/kg al día durante la organogénesis

    obstaculizaba la reproducción en una prueba de detección en ratones.
    Los resultados negativos obtenidos  in vivo en dos especies
    diferentes, utilizando las vías oral e intraperitoneal, indicó que no
    se producían cambios mutagénicos en mamíferos expuestos a la acetona.

         Entre los datos comunicados acerca de otros efectos reproductivos
    de la acetona figuran observaciones de efectos testiculares y
    alteraciones de la calidad espermática en ratas a las que se
    administró agua de bebida con 50 g de acetona por litro durante 13
    semanas. No se dispuso de datos sobre investigaciones del efecto de
    dosis de acetona administradas por vía oral en el desarrollo fetal
    (fetotoxicidad y teratogenicidad).

    La acetona se ha utilizado ampliamente como vehículo disolvente en
    estudios de carcinogenicidad en la piel y no se considera
    carcinogénico cuando se aplica a la piel.

    7.  Efectos en el ser humano

         La acetona es relativamente menos tóxica que muchos otros
    disolventes industriales; sin embargo, en concentraciones altas, el
    vapor de acetona puede provocar depresión del sistema nervioso
    central, fallo cardiorrespiratorio y la muerte. Se ha comunicado que
    la exposición aguda del ser humano a concentraciones atmosféricas tan
    altas como approx. 4750 mg/m3 (approx 2000 ppm) no produce grandes
    efectos tóxicos ni efectos transitorios leyes, como irritación ocular.
    Se comunicaron efectos transitorios más graves (inclusive vómitos y
    desmayos) en trabajadores expuestos a concentraciones de vapor de
    acetona > 25 500 mg/m3 (250 ppm). Las mujeres expuestas a
    concentraciones atmosféricas de 2370 mg/m3 (1000 ppm) padecieron
    trastornos menstruales.

    8.  Efectos en otros organismos en el laboratorio y sobre el terreno

         En la mayoría de las especies animales de agua tanto dulce como
    salada, los valores de la CL50 y la CE50 a las 48 y las 96 horas son
    superiores a 5540 mg/litro.

         La exposición a una concentración de acetona de 257,4 mg/litro
    durante 76 horas inhibió el crecimiento del alga
     Chlorella pyrendoidosa. También se observó inhibición del
    crecimiento de  Chlamydomonas eugametos expuesta a acetona durante 48
    horas en una concentración de 790 mg/litro. En
     Scendesmus quadricauda y C pyrenoidosa expuestas a 79,0 y 790
    mg/litro de acetona se observo un aumento de la fotosíntesis.

         Los umbrales de toxicidad a 7 y 8 días para el alga verde
     S. quadricauda y la cianobacteria (alga verdeazulada)
     Microcystis aeruginosa fueron 7500 y 530 mg/litro, respectivamente,
    lo que indica que el alga verde era más resistente a la actividad
    tóxica de la acetona. La diatomea  Nitzschia linearis también resultó
    ser muy resistente, con una EC50 en cinco días de 11 493 a 11 727
    mg/litro. De modo similar, la diatomea de agua salada
     Skeletonema costatum resultó muy resistente, con valores de EC50
    a tos cinco días de 11 798 y 14 440 mg/litro.

         Las bacterias parecen ser más resistentes a la acetona que los
    protozoos.  Photobacterium phosphoreum,  Pseudomonas putida y un
    cultivo microbiano mixto presentaron valores de la CE50 de 1706 a 35
    540 mg/litro, mientras que el protozoo Entosiphon sulcatum presentó
    una CE50 de 28 mg/litro. Esto puede guardar relación con las
    diferencias en la pared celular.

         En codornices y faisanes se observaron valores de la CL50 por
    vía oral a los cinco días > 40 g/kg de dieta. Los huevos
    fecundados de pato silvestre no se vieron afectados por la inmersión
    en acetona al 10% durante 30 segundos; en cambio, la inmersión en
    acetona pura dio lugar a un descenso de la supervivencia, el peso y la
    talla del embrión, aunque no está claro si ello se debía a las
    propiedades tóxicas o a las propiedades disolventes de la acetona. Los
    huevos de gallina Leghorn blanca inyectados con 5 µl de acetona no
    mostraron cambios significativos en la mortalidad ni malformaciones.

    See Also:
       Toxicological Abbreviations
       Acetone (ICSC)
       Acetone (FAO Nutrition Meetings Report Series 48a)
       ACETONE (JECFA Evaluation)
       Acetone  (SIDS)