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

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

    First draft prepared by Dr K. Hashimoto (Kanazawa University, Japan),
    Dr. K. Morimoto (National Institute of Hygienic Sciences, Japan) and
    Dr. S. Dobson (Institute of Terrestrial Ecology, Monks Wood
    Experimental Station, United Kingdom)

    World Health Orgnization
    Geneva, 1993

         The International Programme on Chemical Safety (IPCS) is a
    joint venture of the United Nations Environment Programme, the
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    toxicology. Other activities carried out by the IPCS include the
    development of know-how for coping with chemical accidents,
    coordination of laboratory testing and epidemiological studies, and
    promotion of research on the mechanisms of the biological action of

    WHO Library Cataloguing in Publication Data


        (Environmental health criteria ; 154)

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

        ISBN 92 4 157154 3        (NLM Classification: QV 633)
        ISSN 0250-863X

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    1. SUMMARY

         1.1. Properties, uses and analytical methods
         1.2. Environmental levels and sources of human exposure
         1.3. Environmental distribution and transformation
         1.4. Environmental effects
         1.5. Absorption, distribution, biotransformation and
         1.6. Effects on laboratory mammals
         1.7. Effects on humans


         2.1. 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. Determination of acetonitrile in ambient air
               Sampling methods
               Measurement of acetonitrile in
                                collected air samples
               2.4.2. Monitoring methods for the determination of
                       acetonitrile and its metabolites in
                       biological materials
               Acetonitrile in urine
               Acetonitrile in serum
               Acetonitrile metabolites in tissues
                                and biological fluids


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


         4.1. Transport and distribution between media
               4.1.1. Water
         4.2. Transformation
               4.2.1. Biodegradation
               Water and sewage sludge
               4.2.2. Abiotic degradation


         5.1. Environmental levels
               5.1.1. Air
               5.1.2. Water and bottom sediment
               5.1.3. Food
               5.1.4. Tobacco smoke
               5.1.5. Other sources of exposure
         5.2. Occupational exposure
         5.3. Acetonitrile in various solvent products


         6.1. Absorption
               6.1.1. Human studies
               6.1.2. Experimental animal studies
               Intake through inhalation
               Dermal absorption
               Intake via the gastrointestinal tract
         6.2. Distribution
               6.2.1. Human studies
               6.2.2. Experimental animal studies
         6.3. Biotransformation and elimination
               6.3.1. Human studies
               6.3.2. Experimental animal studies and
                        in vitro studies
               Cyanide liberation from acetonitrile
               The oxidative pathway of acetonitrile
         6.4. Biological monitoring of acetonitrile uptake


         7.1. Acute toxicity
               7.1.1. Single exposure
               7.1.2. Clinical observations
               Effect on skin
               Effect on the eyes
               Effect on respiration
               Effect on adrenals
               Effect on the gastrointestinal tract
               7.1.3. Biochemical changes and mechanisms of
                       acetonitrile toxicity
               Effect on cytochrome oxidase
               Effect on glutathione
               7.1.4. Antidotes to acetonitrile
         7.2. Subchronic toxicity
               7.2.1. Inhalation exposure
               7.2.2. Subcutaneous administration
         7.3. Teratogenicity and embryotoxicity
         7.4. Mutagenicity
               7.4.1. Bacterial systems
               7.4.2. Yeast assays
               7.4.3.  Drosophila melanogaster
               7.4.4. Mammalian  in vivo assays
               7.4.5. Chromosome aberrations and sister chromatid
         7.5. Carcinogenicity
         7.6. Cytotoxicity testing


         8.1. Acute toxicity
               8.1.1. Inhalation exposure
               8.1.2. Dermal exposure
               8.1.3. Oral exposure
         8.2. Chronic toxicity
         8.3. Mutagenicity and carcinogenicity
         8.4. Occupational exposure to cyanide
         8.5. Chronic poisoning by cyanides
               8.5.1. Ingestion


         9.1. Microorganisms
         9.2. Aquatic organisms


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









    Dr  R. Bruce, System Toxicants Assessment Branch, Office of Research
        and Development, Environmental Criteria and Assessment Office,
        US Environmental Protection Agency, Cincinnati, Ohio, USA
         (Joint Rapporteur)

    Dr  R.J. Bull, College of Pharmacy, Washington State University,
        Pullman, Washington, USA

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

    Dr  K. Hashimoto, Department of Hygiene, School of Medicine,   
        Kanazawa University, Kanazawa, Japan

    Dr  P. Lauriola, Local Hygiene Unit, Office of Public Hygiene,   
        Modena, Italy

    Dr  M. Lotti, Institute of Occupational Medicine, University of   
        Padua, Padua, Italy  (Chairman)

    Dr  K. Morimoto, Division of Biological Chemistry and Biologicals,
        National Institute of Hygienic Sciences, Tokyo, Japan  (Joint

    Dr  Y.F. Panga, Department of Standard Setting, Chinese Academy of
        Preventive Medicine, Beijing, China

    Dr  S.A. Soliman, Department of Pesticide Chemistry, College of   
        Agriculture and Veterinary Medicine, King Saud University,
        Al-Qasseem, Bureidah, Saudi Arabia


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

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


    a  Invited but unable to attend.


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

                                   *  *  *

        A detailed data profile and a legal file can be obtained from
    the International Register of Potentially Toxic Chemicals, Case
    postale 356, 1219 Châtelaine, Geneva, Switzerland (Telephone
    No. 9799111).

                                   *  *  *

        This publication was made possible by grant number
    5 U01 ES02617-14 from the National Institute of Environmental Health
    Sciences, National Institutes of Health, USA.


        A WHO Task Group on Environmental Health Criteria for
    Acetonitrile met in Modena, Italy, from 24 to 28 November 1992.
    Mr Giorgio Baldini, the President of the Province of Modena, opened
    the meeting and greeted the participants on behalf of the Province
    of Modena.  Dr B.H. Chen of the International Programme on Chemical
    Safety (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 acetonitrile.

        The first draft of this monograph was prepared by Dr K.
    Hashimoto, Kanazawa University, Japan, Dr K. Morimoto, National
    Institute of Hygienic Sciences, Japan, and Dr S. Dobson, Institute
    of Terrestrial Ecology, Monks Wood Experimental Station, United
    Kingdom.  The second draft was prepared by Dr K. Morimoto
    incorporating comments received following the circulation of the
    first draft to the IPCS Contact Points for Environmental Health
    Criteria monographs.  Dr M. Lotti (Institute of Occupational
    Medicine, University of Padua, Italy) made a considerable
    contribution to the preparation of the final text.

        Dr B.H. Chen and Dr P.G. Jenkins, both members of the IPCS
    Central Unit, were responsible for the overall scientific content
    and technical editing, respectively.  The efforts of all who helped
    in the preparation and finalization of the document are gratefully

                                   *  *  *

        Financial support for this Task Group meeting was provided by
    the Province of Modena, Communes of Mirandola and Medolla, Local
    Hygiene Units N. 16 of Modena and N. 15 of Mirandola, Association of
    Business and Industries of the Province of Modena and ENICHEM
    (National Organization of Industrialization for Chemistry) in Italy.


    CLD      chemiluminescence nitrogen detector
    GC       gas chromatography
    HPLC     high performance liquid chromatography
    NPD      nitrogen-phosphorus selective detector
    TCD      thermal conductivity detection
    TEA      thermal energy analyser

    1.  SUMMARY

    1.1  Properties, uses and analytical methods

        Acetonitrile (CH3CN) is a by-product of acrylonitrile
    manufacture.  It may also be formed by the combustion of wood and
    vegetation.  It is a liquid with an ether-like odour.  Acetonitrile
    is a volatile, highly polar  solvent used to extract fatty acids and
    animal and vegetable oils. It is used in the petrochemical industry
    in extractive distillation based on its selective miscibility with
    organic compounds.  It is used as a solvent for spinning synthetic
    fibres and in casting and moulding plastics.  In laboratories, it is
    widely used in high-performance liquid chromatographic (HPLC)
    analysis and as a solvent for DNA synthesis and peptide sequencing.

        The most widely used analytical technique for acetonitrile is
    gas chromatography.

    1.2  Environmental levels and sources of human exposure

        Very few data on acetonitrile levels in the environment are
    available.  Worldwide, acetonitrile concentrations in air of 200 to
    42 000 ng/m3 have been reported.  Slightly higher values were
    obtained for urban than rural air in one study.  Single measurements
    before and after burning of bush and straw showed a 10-fold increase
    in acetonitrile air concentration.

        Acetonitrile was not detected in 72 water samples from Japan but
    was found in 11 out of 60 aquatic sediment samples at
    concentrations between 0.02 and 0.54 mg/kg.  Acetonitrile has not
    been detected in food.

        Tobacco smoke contains acetonitrile and burning polyurethane
    foam releases acetonitrile and hydrogen cyanide.

        Whilst production of acrylonitrile offers the greatest potential
    for exposure, this is carried out in a closed system.  Practical
    uses of acetonitrile lead to greater exposure.

    1.3  Environmental distribution and transformation

        Acetonitrile volatilizes from water and would also volatilize
    from soil surfaces.  It is readily biodegraded by several strains of
    bacteria common in sewage sludge, natural waters and soil. 
    Acclimatization of bacteria to acetonitrile or petroleum wastes
    increases the rate of degradation.  Anaerobic degradation appears to
    be limited or absent.

        Hydrolysis of acrylonitrile in water is extremely slow.  There
    is no significant photodegradation in either water or the
    atmosphere.  Reaction with ozone is slow as is reaction with singlet
    oxygen.  The major mechanism for removal of acetonitrile from the
    troposphere is reaction with hydroxyl radicals;  residence times
    have been estimated at between 20 and 200 days.

        Acetonitrile does reach the stratosphere where it is
    characteristically associated in positive ion clusters in the upper

    1.4  Environmental effects

        Acetonitrile has low toxicity to microorganisms (bacteria,
    cyanobacteria, green algae and protozoans) with thresholds at
    500 mg/litre or more.  Freshwater invertebrates and fish acute
    LC50s are 700 mg/litre or more.  Acute tests have been conducted
    under static conditions without analytical confirmation of
    concentrations.  Similar results obtained from 24- and 96-h tests
    suggest volatilization of acetonitrile.

    1.5  Absorption, distribution, biotransformation and elimination

        Acetonitrile is readily absorbed from the gastrointestinal
    tract, through the skin and the lungs.  All three routes of exposure
    have been reported to lead to systemic effects.

        Postmortem examination of tissues from poisoned humans has
    revealed that acetonitrile distributes throughout the body.  This is
    supported by animal studies in which acetonitrile distribution has
    been found to be fairly uniform throughout the body.  There are no
    indications of accumulation in animal tissues following
    repeated administrations of acetonitrile.

        There are substantial data to suggest that most of the systemic
    toxic effects of acetonitrile are mediated through its metabolism to
    cyanide, which is catalysed by the cytochrome P-450 monooxygenase
    system.  Cyanide is subsequently conjugated with thiosulfate to form
    thiocyanate which is eliminated in the urine.  Peak concentrations
    of cyanide in the blood of rats following administration of near
    lethal doses of acetonitrile approximate to the concentrations
    observed following the administration of an LD50 dose of potassium
    cyanide.  However, the peak concentration of cyanide after
    administration of acetonitrile is delayed by up to several hours as
    compared to other nitriles.  Moreover, the more rapid rate at which
    cyanide is produced in the mouse appears to account for the much
    greater sensitivity of this species to the toxic effects of
    acetonitrile.  Cyanide and thiocyanate have been identified in human
    tissues after exposure to acetonitrile.  A portion of the
    acetonitrile dose is also eliminated unchanged in expired air and in

    1.6  Effects on laboratory mammals

        Acetonitrile induces toxic effects similar to those observed in
    acute cyanide poisoning, although the onset of symptoms is some-what
    delayed compared to inorganic cyanides or other saturated nitriles. 
    The 8-h inhalation LC50 in male rats is 13 740 mg/m3 (7500 ppm). 
    The oral LD50 in the rat varies from 1.7 to 8.5 g/kg depending on
    the conditions of the experiment.  Mice and guinea-pigs appear to be
    more sensitive, with an oral LD50 in the range of 0.2-0.4 g/kg. 
    The main symptoms in animals appear to be prostration followed by

        Dermal application of acetonitrile causes systemic toxicity in
    animals and has been implicated in the death of one child.  The
    percutaneous LD50 in rabbits is 1.25 ml/kg.

        Subchronic exposure of animals to acetonitrile produces effects
    similar to those seen after acute exposures.

        Acetonitrile is not mutagenic in assays using  Salmonella
     typhimurium, both with and without metabolic activation.  It
    induces aneuploidy in a diploid yeast strain at very high
    concentrations. No animal studies on chronic or carcinogenic effects
    of acetonitrile have been reported.

    1.7  Effects on humans

        The levels causing toxicity in man are unknown but are
    probably in excess of 840 mg/m3 (500 ppm) in air.  Symptoms and
    signs of acute acetonitrile intoxication include chest pain,
    tightness in the chest, nausea, emesis, tachycardia, hypotension,
    short and shallow respiration, headache, restlessness,
    semiconsciousness, and seizures.  Other non-specific symptoms may be
    due to the irritant effects of the compound.  The systemic effects
    appear to be largely attributable to the conversion of acetonitrile
    to cyanide.  Blood cyanide and thiocyanate levels are elevated
    during acute intoxication.  Two fatalities after exposure to
    acetonitrile vapour in the workplace and one fatal case of a child
    ingesting an acetonitrile-containing cosmetic have been reported. 
    Elevated tissue cyanide concentrations were found in postmortem
    examin-ation of these cases.

        No epidemiological study of cancer incidence relating to
    acetonitrile exposure has been reported.

        Acetonitrile can cause severe eye burns.  Skin contact with
    liquid acetonitrile should be avoided.  An employee's exposure to
    acetonitrile in any 8-h shift has been recommended in many
    countries not to exceed a time-weighted average of 70 mg/m3 air
    (40 ppm).


    2.1  Identity

    Chemical formula:            CH3CN

    Chemical structure:


    Relative molecular mass:     41.05 

    CAS chemical name:           acetonitrile

    CAS registry number:         75-05-8

    Synonyms:                    cyanomethane, ethanenitrile, nitrile of
                                 acetic acid, methyl cyanide, ethyl
                                 nitrile, methanecarbonitrile

         Specifications for commercial acetonitrile are given in
    Table 1.  The principal organic impurity in commercial acetonitrile
    is propionitrile, although small amounts of allyl alcohol may also
    be present (Grayson, 1985).

    2.2  Physical and chemical properties

    2.2.1  Physical properties

         Acetonitrile is a volatile, colourless liquid with a sweet,
    ether-like odour (Grayson, 1985).  It is infinitely soluble in water
    and readily miscible with ethanol, ether, acetone, chloroform,
    carbon tetrachloride and ethylene chloride (Clayton & Clayton,
    1982).  It is immiscible with many saturated hydrocarbons (petroleum
    fractions) (Budavari, 1989).

         Important physical constants and properties of acetonitrile are
    summarized in Table 2.

    Table 1.  Commercial acetonitrile specificationsa


    Specific gravity (at 20 °C)                       0.783-0.787

    Distillation range (°C)
     initial point, minimum                               80.5
     end point, maximum                                   82.5

    Purity (minimum), % by weight                         99.0

    Acidity (as acetic acid, maximum % by weight)          0.05

    Copper (maximum), ppm                                  0.5

    Iron (maximum), ppm                                    0.5

    Water (maximum), % by weight                           0.3

    Colour (maximum), Pt-Co                                15

    a  From: Grayson (1985)

    2.2.2  Chemical properties

         Although acetonitrile is one of the most stable nitriles, it
    undergoes typical nitrile reactions and is used to produce many
    types of nitrogen-containing compounds.  It can be trimerized to
     S-trimethyltriazine and has been telomerized with ethylene and
    copolymerized with alpha-epoxides (Grayson, 1985).

         Acetonitrile produces hydrogen cyanide when heated to
    decomposition or when reacted with acids or oxidizing agents
    (Reynolds, 1982).

    2.3  Conversion factors

    1 ppm   = 1.68 mg/m3 (25 °C, 760 mmHg)

    1 mg/m3 = 0.595 ppm (25 °C, 760 mmHg)    (Clayton & Clayton, 1982)

        Table 2.  Physical properties of acetonitrile


    Properties                 Value                   Reference


    Appearance                 colourless liquid       Budavari (1989)

    Odour                      ether-like              Budavari (1989)

    Boiling point              81.6 °C (760 mmHg)      Budavari (1989)

    Freezing point             -45.7 °C                Grayson (1985)
                               -44 to -41 °C           Verschueren (1983)

    Specific gravity           0.78745 (15/4 °C)       Grayson (1985)
                               0.7138 (30/4 °C)        Grayson (1985)

    Vapour density             1.42 (air = 1)          Clayton & Clayton (1982)

    Refractive index (ND)      1.34604 (15 °C)         Clayton & Clayton (1982)
                               1.33934 (30 °C)         Clayton & Clayton (1982)

    Solubility in water        infinitely soluble      Clayton & Clayton (1982)

    Vapour pressure
        at (15.5 °C)           7.32 kPa (54.9 mmHg)    US EPA (1984)
        at (20.0 °C)           (74.0 mmHg)             Verschueren (1983)
        at (30.0 °C)           (115.0 mmHg)            Verschueren (1983)

    Water azeotrope            boiling point 76 °C
                               water content 16%       US EPA (1984)

    Log P (octanol/water       -0.38                   Leo  et al. (1971)
     partition coefficient     -0.34                   Verschueren (1983)

    Table 2 (contd)


    Properties                 Value                   Reference


    Flash point                5.6 °C (open cup)       Reynolds (1982)
                               12.8 °C (closed cup)    Reynolds (1982)

    Ignition temperature       524 °C                  Sax & Lewis (1989)

    Explosive limits           lower 4.4               Grayson (1985)
     in air (% by volume)            3.05              Prager (1985)
                               upper 16.0              Grayson (1985)
                                     17.0              Prager (1985)
    2.4  Analytical methods

    2.4.1  Determination of acetonitrile in ambient air  Sampling methods

         The use of absorption tubes to trap acetonitrile from ambient
    air with subsequent thermal or liquid desorption prior to gas
    chromatographic (GC) analysis has been reported in many references. 
    The National Institute of Occupational Safety and Health (NIOSH,
    1977, 1984) recommended the use of a glass tube (9 cm long and 6 mm
    internal diameter) containing two sections of 20-40 mesh activated
    (600 °C) coconut charcoal (front = 400 mg and back = 200 mg)
    separated by 3 mm section urethane foam and held in place with plugs
    of silanized glass wool.  The tube is then flame-sealed at both ends
    until it is used for air sampling.  Other sampling tubes containing
    different sorbents (i.e. porous polymer beads) have also been
    recommended (Campbell & Moore, 1979; Berg  et al., 1980; Rigby,
    1981; Kashihira, 1983; Kashihira  et al., 1984; Wood, 1985; Cobb
     et al., 1986).  Measurement of acetonitrile in collected air samples

         Several methods have been used to measure acetonitrile in
    environmental samples.  Most of the reported methods are based on
    the use of GC.

    a)  Gas chromatography

         GC is frequently used for determining acetonitrile using
    different kinds of detectors in conjunction with the charcoal or
    porous polymer beads sampling technique.  A number of detectors have
    been recommended.  Until recently, almost all of the
    published work involved the use of flame ionization detection (FID). 
    However, it was found that FID did not respond to acetonitrile in a
    repeatable way even with the use of internal standards (Joshipura
     et al., 1983).

         Attention has therefore turned to the use of thermal
    conductivity detection (TCD) (Joshipura  et al., 1983) and to
    nitrogen-phosphorus selective detector, NPD (Cooper  et al., 1986). 
    Rounbehler  et al. (1982) described a modification for the thermal
    energy analyser (TEA), a highly sensitive nitrosyl-specific GC
    chemiluminescence detector, which allows it to be used as a highly
    selective one in detecting nitrogen-containing compounds.  They
    concluded that the modified TEA was as sensitive as the alkali-bead
    flame ionization detection (AFID) but had a much higher selectivity
    toward nitrogen-containing compounds.  Using the TEA, these
    investigators were not able to detect any acetonitrile in bacon or
    beer. Kashihira  et al. (1984) used a chemiluminescence nitrogen
    detector GC (CLD-GC) method to measure acetonitrile and

    acrylonitrile in air.  The method was able to detect as little as
    20 ng of acetonitrile per injection.

         Cooper  et al. (1986) developed a very sensitive method of
    measuring nitrogen-containing hazardous pollutants in complex
    matrices by GC with NPD and were able to detect 1.5 pg acetonitrile.

         Table 3 summarizes the different types of detectors used in GC
    analysis of acetonitrile along with the conditions employed and
    their corresponding detectability.

    b)  High-performance liquid chromatography (HPLC)

         The use of HPLC to determine trace amount of acetonitrile in
    environmental samples has not been reported.

    c)  Microwave spectrometry

         Kadaba  et al. (1978) analysed toxic constituents including
    acetonitrile in tobacco smoke by microwave spectroscopy and were
    able to measure acetonitrile down to 2 ppm.

    2.4.2  Monitoring methods for the determination of acetonitrile and
           its metabolites in biological materials  Acetonitrile in urine

         Mckee  et al. (1962) determined acetonitrile in urine samples
    obtained from 20 male nonsmokers and 40 male smokers by a
    modification of the method reported by Rhoades (1958, 1960) for the
    analysis of coffee volatiles.  The modification permitted the
    stripping of urinary volatiles at 37 °C and at reduced pressure. 
    The stripped volatiles were collected in a liquid nitrogen trap,
    vapourized, and analysed by GC with a thermal conductivity detector.
    The column, which was packed with 15% Carbowax 1500 and silicone oil
    200 (ratio 2:1) on 40-60 mesh Chromosorb P, was operated at 40 °C. 
    The carrier gas was helium at a pressure of 4 pounds per square
    inch.  Acetonitrile concentrations as low as 2.9 µg/litre could be
    measured in urine using this method.

        Table 3.  Gas chromatographic conditions for acetonitrile determination


    Packing               Conditions                            Detection    Reported level of    References

    Porapak               250 x 0.25 cm, 160 °C injector           FID       10 ppm in            Thomson (1969)
                          150 °C helium, 70 ml/min                           acrylonitrile

    Porapak Q             122 x 0.63 cm, 180 °C injector           FID       10 mg/m3 in air      NIOSH (1977)
                          270 °C nitrogen, 50 ml/min                         (6 ppm)

    Porapak Q             305 x 0.32 cm, 200 °C injector           FID       0.01 ppm in air      Campbell & Moore (1979)
                          200 °C nitrogen, 20 ml/min

    0.1% SP 1000          200 x 0.19 cm, 35-235 °C injector        FID       0.07 ppm in air      Berg et al. (1980)
    on Carbopack C        125 °C nitrogen, 21 ml/min

    20% Carbowax          180 x 0.2 cm, 90-145 °C injector         TEA       0.041 ppm            Rounbehler et al. (1982)
    20 M                  120 °C

    Chromosorb 103        90 x 0.3 cm, 85 °C injector              CLD       1 ppb in air         Kashihira et al. (1984)
                          150 °C helium, 60 ml/min

    Porapak Q             508 x 0.32 cm, 170 °C injector           FID       0.2 ppm in air       Wood (1985)
                          200 °C nitrogen, 30 ml/min

    20% SP-1200W/0.1%     305 x 0.32 cm, 180 °C injector           NPD       1.5 ppb              Cooper et al. (1986)
    Carbowax 1500         190 °C nitrogen, 30 ml/min or
                          helium, 35 ml/min

    FID = Flame ionization detection; CLD = Chemiluminescent nitrogen detection; NPD =
    Nitrogen-phosphorous detection; TEA = Thermal energy analyser
  Acetonitrile in serum

         Freeman & Hayes (1985a) determined serum acetonitrile
    concentrations in rats dosed orally with acetone, acetonitrile, and
    a mixture of acetone and acetonitrile by GC equipped with FID.  The
    analysis was performed isothermally (150 °C) at a helium flow rate
    of 30 ml/min using a 2 mm x 1.22 m Chromosob 104 column (100/120
    mesh) with a 15-cm precolumn.  Propionitrile was added to the serum
    samples as an internal standard prior to injection, and the samples
    were injected directly into the column.  Under the conditions of
    this study, the retention times of acetone, acetonitrile and
    propionitrile were 2.05, 3.65 and 6.20 min, respectively.  The limit
    of detection was not reported.  However, it was reported that the
    serum acetonitrile concentrations of animals in the control group
    were all below 1 mg/litre.  Acetonitrile metabolites in tissues and biological fluids

    a)  Cyanide

         Since hydrogen cyanide is a reactive and volatile nucleophile,
    a variety of problems are encountered in its assay in biological
    materials due to tissue binding or diffusibility (Troup &
    Ballantyne, 1987).  To reduce artefacts due to simple evaporative
    losses, cyanide should be extracted under alkaline conditions.

         Amdur (1959) determined the cyanide level in the blood of 16
    workers, who were accidentally exposed to acetonitrile, by the
    method of Feldstein & Klendshoj (1954), which uses a Conway
    microdiffusion approach (Conway, 1950).  The sensitivity of this
    method is as low as 0.1 µg cyanide in a 1 ml sample.  Willhite &
    Smith (1981) measured cyanide concentrations in the liver and brain
    of mice challenged by acetonitrile using the method of Bruce  et al.
    (1955), which is capable of determining 0.05 µg cyanide in a 1 ml
    sample.  Haguenoer  et al. (1975a,b) determined free cyanide in the
    tissues and urine of rats using the pyridine-benzidine method
    described by Aldridge (1944); the sensitivity of this method was
    0.7 µg hydrogen cyanide in a 1 ml sample.  Ahmed & Farooqui (1982)
    determined the tissue and blood cyanide levels in rats by the Conway
    diffusion method described by Pettigrew & Fell (1973).  Willhite
    (1983) determined tissue cyanide level in hamsters by the procedure
    of Bruce  et al. (1955).  A combination of the aeration procedure
    of Bruce  et al. (1955) with the colorimetric method of Epstein
    (1947), which can determine 0.2 µg of cyanide in a 1 ml sample, has
    been used to determine the cyanide level in brain (Tanii &
    Hashimoto, 1984a) and in liver microsomes of mice (Tanii &
    Hashimoto, 1984b).  The aeration apparatus consists of three serial
    tubes containing 25 ml 20% NaOH, 5 ml 20% trichloroacetic acid and
    0.5 ml 0.1 N NaOH.  An aliquot of samples is added to the tube
    containing trichloroacetic acid, which is then aerated at a flow
    rate of 600 ml/min, passing from the tube containing 20% NaOH for

    10 min toward the tube containing 0.1 N NaOH.  An aliquot from the
    tube containing 0.1N NaOH is then removed, neutralized with acetic
    acid and subjected to analysis for cyanide.  Under these conditions,
    the recovery of known amounts of cyanide is 97-100%.  Freeman &
    Hayes (1985a) determined cyanide in the blood of rats  by a
    microdiffusion method modified from Feldstein & Klendshoj (1954). 
    Samples were analysed colorimetrically at 586 nm using
    pyridine-barbituric acid reagent as described by Blanke (1976). 
    Cyanide concentrations as low as 0.1 mg/litre could be reproducibly
    detected by these methods.  Zamecnik & Tam (1987) reported an
    improved GC method for cyanide analysis in blood with acetonitrile
    as an internal standard.  GC with NPD was used with a 180 x 0.2 cm
    column packed with 100/120 mesh Porapak Q.  Other conditions were:
    temperature, column 120 °C, detector 250 °C, and a helium gas flow
    rate of 20 ml/min.  The blood samples containing cyanide were
    pipetted into disposable vials.  Samples were then sealed and
    glacial acetic acid was injected into the vials.  These were then
    vortexed and allowed to equilibrate for 30 min at room temperature. 
    The head space was injected into the gas chromatograph.  The typical
    retention times for the cyanide and acetonitrile peaks were 0.6 min
    and 2.5 min, respectively.  The sensitivity for cyanide was
    0.05 ppm.  Three procedures for the determination of cyanide in
    biological fluids have been reported with full detail (Rieders &
    Valentour, 1975).  The first procedure is qualitative, the second
    colorimetric (chloramine-T and barbituric acid and pyridine), and
    the third depends on GC using electron capture detection.

         Table 4 summarizes the methods which have been used for cyanide
    analysis in biological samples.

    b)  Thiocyanate

         Pozzani  et al. (1959a) determined urinary thiocyanate levels
    in various animals by means of the colorimetric method of Chesley
    (1941).  Using this method, 25-180 mg thiocyanate/litre urine could
    be measured with a ± 4% error.  Silver  et al. (1982) determined
    thiocyanate in the urine of rats dosed with acetonitrile. 
    Thiocyanate was first isolated from urine by separation on an ion
    exchange column (10 x 1 cm) of Amberlite CG-400 as described by
    Kanai & Hashimoto (1965) and then measured colorimetrically
    according to the method of Epstein (1947).  Willhite (1983)
    determined the tissue thiocyanate levels in hamsters using the
    method described by Bruce  et al. (1955).

        Table 4.  Analysis of cyanide in biological materials


                                    Analytical methods                                            Application

    Principle                  Detectability        References                   Biological materials        References

    Conway diffusion method         0.1        Feldstein & Klendshoj (1954)      human blood                 Amdur (1959)

                                    0.1        Pettigrew & Fell (1973)           rat tissues and blood       Ahmed & Farooqui (1982)

                                    0.1        Feldstein & Klendshoj (1954);     rat blood                   Freeman & Hayes (1985a)
                                               Blanke (1976)

    Benzidine and pyridine          0.1        Aldridge (1944)                   rat tissues and             Haguenoer et al.
    methods, colorimetry                                                         urine                       (1975a,b)

    Aeration procedure and          0.2        Bruce et al. (1955);              mouse brain                 Tanii & Hashimoto
    colorimetry                                Epstein (1947)                                                (1984a,b)

                                    0.05       Bruce et al. (1955)               mouse liver and brain       Willhite & Smith (1981)

                                    0.05       Bruce et al. (1955)               hamster tissues             Willhite (1983)

    GC, nitrogen-phosphorus         0.05               -                         blood                       Zamecnik & Tam (1987)

         Pereira  et al. (1984) used the method of Contessa & Santi
    (1973) to determine thiocyanate levels in urine samples collected
    from rats treated with different nitriles.  The method was able to
    detect thiocyanate concentrations as low as 100 µg in a 0.2 ml urine

         Table 5 summarizes the methods reported for analysis of
    thiocyanate in biological samples.

        Table 5.  Analysis of thiocyanate in biological materials


                                    Analytical methods                                            Application

    Principle                  Detectability        References                   Biological materials        References

    Colorimetry                    25          Chesley (1941)                    animal urine                Pozzani (1959a)

                                    0.6        Bruce et al. (1955)               hamster tissues             Willhite (1983)

    Ion exchange separation         0.5        Kanai & Hashimoto (1965);         rat urine                   Silver et al. (1982)
    and colorimetry                            Epstein (1947)


    3.1  Natural occurrence

         Acetonitrile may be formed by combustion of wood, straw and
    other vegetation.  However, the rate of formation and the
    contribution to atmospheric acetonitrile has not been quantified
    (Becker & Ionescu, 1982).

    3.2  Anthropogenic sources

    3.2.1  Production levels and processes

         Acetonitrile is a by-product of acrylonitrile synthesis.  This
    process is known as the SOHIO (Standard Oil Company of Ohio) process
    and involves a high temperature catalytic reaction between propylene
    and ammonia.  The SOHIO process is the principal route to both
    acrylonitrile and acetonitrile, produced in the ratio of 0.035 kg
    acetonitrile/kg acrylonitrile (Lowenheim & Moran, 1975).

         Acetonitrile can be synthesized by several other routes.  Good
    yields are obtained by dehydration of an acetic acid and ammonia
    mixture, acetamide or ammonium acetate.

               CH3COOH + NH3 -> CH3CN + 2H2O
               CH3CONH2 -> CH3CN + H2O
               CH3CO2NH4 -> CH3CN + 2H20

         A 90% yield of acetonitrile is obtained by the reaction of
    ethanol and ammonia in the presence of catalyst such as Ag, Cu,
    MoO3, and ZnS at moderate temperatures.  Acetonitrile is also
    produced by the reaction of cyanogen chloride with methane, ketones,
    ethanol, alkylene epoxides, and paraffins or olefins.

         The principal organic impurity in commercial acetonitrile is
    propionitrile, together with a small amount of allyl alcohol (US
    EPA, 1992).

         Reported production of acetonitrile in the USA during the
    period 1980-83 (US EPA, 1985) was:

            Year             Production (millions of kg)

            1980                        10.1
            1981                         9.5
            1982                         9.4
            1983                        11.4

    3.2.2  Uses

         Being a volatile highly polar solvent, acetonitrile finds its
    greatest use as an extracting fluid for fatty acids and animal and
    vegetable oils.

         Acetonitrile has been widely used as an extractive distillation
    solvent in the petrochemical industry for separating olefin-diolefin
    mixtures and for C4-hydrocarbons.  When acetonitrile is used in this
    way, recycling is effected by water dilution of the extract and
    condensate with subsequent phase separation, after which the
    acetonitrile is azeotroped from the aqueous phase.

         Acetonitrile has been used as a solvent for polymer spinning
    and casting because of the combination of high solubility and
    desirable intermediate volatility.  It is also used as a solvent for
    isolating components from crude products such as crude wool resin. 
    Acetonitrile is used as a common laboratory solvent for
    recrystallizing various chemicals and is widely used as a solvent in
    HPLC analysis.  Acetonitrile is also used in biotechnology research
    as a solvent in the synthesis of DNA and peptide sequencing (Borman,

         Acetonitrile can be used to remove tars, phenols and colouring
    matter from petroleum hydrocarbons that are not soluble in

         Acetonitrile is also used as a starting material for the
    synthesis of many chemicals such as acetophenone, alpha-naphthyl
    acetic acid, thiamine and acetomidine (Hawley, 1971).

         The use patterns of acetonitrile are summarized in Table 6.

    Table 6.  Main use patterns of acetonitrilea


    Extraction of fatty acids and animal and vegetable oils

    Extraction of unsaturated petroleum hydrocarbons

    Solvent for polymer spinning and casting

    Moulding of plastics

    Removal of tars, phenols and colouring matter from petroleum

    Purification of wool resin

    Recrystallization of steroids

    Starting material for synthesis of chemicals

    Solvent in DNA synthesis and peptide sequencing

    Medium for promoting reactions

    Solvent in non-aqueous titrations

    Non-aqueous solvent for inorganic salts

    High-pressure liquid chromatographic analysis

    Catalyst and component of transition-metal complex catalysts

    Extraction and refining of copper

    Stabilizer for chlorinated solvents

    Perfume manufacture

    Pharmaceutical solvents

    a  From: Veatch  et al. (1964); NIOSH (1978); Toxic Substances
       Control Act (1979); Smiley (1983); Borman (1990)


    4.1  Transport and distribution between media

    4.1.1  Water

         Hine & Mookerjee (1975) reported that the ratio of
    concentration in the water phase to the gas phase of a dilute
    aqueous solution of acetonitrile at equilibrium at 25 °C is 891:1. 
    The inverse of this ratio (1.1 x 10-3) is the unit-less Henry's
    Law constant.  Conversion to units, using an RT value of 2.4 x
    10-2-m3 atm/mol (where R is the gas constant and T is the
    temperature in K), yields a Henry's Law constant of
    2.6 x 10-5-m3 atm/mol.  This value of Henry's Law constant
    indicates that the volatilization of acetonitrile is probably
    significant for most environmental bodies of water (Lymann  et al.,
    1982).  The concentration of acetonitrile in river water decreased
    to 5% of the original level after 72 h in a study carried out under
    stable conditions (Chen  et al., 1981).

    4.2  Transformation

    4.2.1  Biodegradation  Water and sewage sludge

         Ludzack  et al. (1958, 1959) measured the biodegradation of
    acetonitrile in Ohio River water and in aged sewage by measuring
    CO2 production.  Degradation in the river water occurred at a
    faster rate than in the sewage; the 12-day biological oxygen demand
    (BOD) was 40% in river water but only 20% in the sewage.
    Acclimatization of microorganisms was examined by reculturing, and
    the degradation was found to occur 5 times more rapidly using
    acclimatized microorganisms.  The effect of temperature on
    biodegradation was also studied; degradation at 5 °C took 2.5-5
    times longer than at 20 °C.  Ludzack  et al. (1961) examined the
    degradation of acetonitrile by activated sludge in a continuous feed
    test at 22-25 °C; 82-94% BOD was removed during 4 weeks of test
    operation.  Anaerobic digestion does not appear to be an effective
    means of removing the compound from waste water (Ludzack  et al.,

         Using the Japanese MITI (Ministry of International Trade and
    Industry) test, Sasaki (1978) reported that acetonitrile is "readily
    biodegradable", meaning that oxygen consumption is > 30% in 2
    weeks.  Thom & Agg (1975) reported that acetonitrile should be
    degradable by biological sewage treatment with appropriate
    acclimatization.  Mimura  et al. (1969) isolated the bacterium
     Corynebacterium nitrilophius from activated sludge and found that
    this microorganism was capable of assimilating acetonitrile.  Kelly
     et al. (1967) found virtually no degradation of acetonitrile using
    a nitrogenase from  Azotobacter chroococcum.

         Goud  et al. (1985) isolated bacteria of several genera from
    various points in an effluent treatment plant at a petrochemical
    installation.   Azobacter spp and, more particularly,  Pseudomonas
    spp were able to degrade acetonitrile, added to the culture medium
    at 1% as sole carbon source.   Aeromonas spp and  Bacillus spp,
    however, were unable to degrade acetonitrile.  The authors pointed
    out that many of the bacterial species tested are common in the
    environment, and that regular exposure to petrochemicals selects
    strains that are able to degrade such compounds.

         Chapatwala  et al. (1992) investigated mixed cultures of
    bacteria isolated from an area contaminated with organic cyanide and
    polychlorinated biphenyls and found that they readily utilized
    acetonitrile as sole carbon and nitrogen source.  Nearly 70% of
    14C-labelled acetonitrile was recovered as CO2, the remainder
    being incorporated into bacterial growth.  The mixed culture lost
    its capacity to degrade biphenyl when repeatedly recultured with
    acetonitrile, indicating more ready degradation of the nitrile.

         Ludzack  et al. (1961) observed high levels of nitrates in
    effluents from activated sludge degrading acetonitrile.  Firmin &
    Gray (1976) used a species of  Pseudomonas capable of utilizing
    acetonitrile as sole carbon source to show that acetonitrile
    undergoes direct enzymatic hydrolysis.  These authors postulated the
    following metabolic pathway based on their results with [2-14C]
    acetonitrile: acetonitrile -> acetamide -> acetate -> tricarboxylic
    acid cycle intermediates (citrate, succinate, fumarate, malate,
    glutamate, etc.).  Soil

         DiGeronimo & Antoine (1976) isolated  Nocardia rhodochrus
    Ll100-21 from barnyard soil and demonstrated that the
    microorganism was capable of using acetonitrile as a source of
    carbon and nitrogen.  A decrease in acetonitrile content within the
    culture medium was correlated with an increase in acetamide and
    acetic acid levels; ammonia was also detected.  Under the test
    conditions, the initial concentration of acetonitrile was reduced by
    14% in 3 h and by 52% in 8 h.  Crude cell-free extracts were also
    found to degrade acetonitrile by an enzymatic hydrolysis
    mechanism that was reported to be inducible.  Kuwahara  et al.
    (1980) found that  Aeromonas species BN 7013 could be grown
    using acetonitrile as a nitrogen source; the microorganism was
    isolated from soil.  Harper (1977) isolated a strain of the fungus
     Fusarium solani from soil and found that cell-free extracts,
    containing the nitrilase enzyme, were capable of hydrolysing
    acetonitrile enzymatically.

    4.2.2  Abiotic degradation  Water

         Brown  et al. (1975) reported that the hydrolysis rate
    constant for acetonitrile in an aqueous solution of pH 10 is 1.195 x
    10-8 M-1 sec-1.  Assuming a constant pH of 10, the half-life
    for this process would be > 18 000 years.

         Anbar & Neta (1967) reported that the rate constant for the
    reaction of acetonitrile with hydroxyl radicals in aqueous solution
    at pH 9 and room temperature is 2.1 x 106 M-1 sec-1; assuming
    an environmental hydroxyl radical concentration at 10-17 M, a
    half-life of 1042 years can be calculated.  Dorfman & Adams (1973)
    reported a similar hydroxyl radical rate constant of 3.5 x 106
    M-1 sec-1.

         The absorption maximum for acetonitrile in the UV range is
    < 160 nm (Silverstein & Bassler, 1967); therefore, the direct
    photolysis of acetonitrile in the aquatic environment is not
    expected to occur.  Air

         Harris  et al. (1981) found in laboratory studies that the
    rate of reaction of acetonitrile with ozone was relatively slow, the
    rate constant being < 1.5 x 10-19 cm3 molecule-1 sec-1. 
    Assuming a typical atmosphere concentration of 1012 ozone
    molecules/cm3, a half-life of > 54 days can be calculated from
    this rate constant.

         The reaction rate constant between singlet oxygen and
    acetonitrile is reported to be 2.4 x 10-16 cm3 molecule-1
    sec-1 (Graedel, 1978); this predicts an atmospheric half-life of >
    5000 years for acetonitrile.

         Dimitriades & Joshi (1977) reported on the reactivity of
    acetonitrile as measured in an US EPA smog chamber with 22
    blacklights, 7 sunlamps, 4 ppm acetonitrile and 0.2 ppm NOx. 
    Acetonitrile was found to be unreactive with respect to ozone yield. 
    The average rate of disappearance of acetonitrile was found to be
    0.02% per hour, i.e. 100 times slower than that measured for
    propane.  Kagiya  et al. (1975) measured the photochemical
    decomposition rate of acetonitrile (300-2000 ppm) in air saturated
    with water in a reaction cell irradiated with a mercury lamp.  No
    degradation was observed, however, when chlorine gas (2000 ppm) was
    added to the cell, the decomposition rate being 1.32% per second. 
    Reaction between chlorine radicals and acetonitrile in the
    atmosphere is not thought to be significant in relation to hydroxyl
    radical reaction (Arijs  et al., 1983).

         The absorption maximum for acetonitrile in the UV range is
    < 160 nm (Silverstein & Bassler, 1967).  Therefore, the direct
    photolysis of acetonitrile in the ambient atmosphere is not expected
    to occur.

         The major mechanism for removal of acetonitrile from the
    troposphere is reaction with hydroxyl radicals.  The rate constant
    for the gas-phase reaction of acetonitrile with hydroxyl radicals
    has been experimentally determined by Harris  et al. (1981) to be
    0.494 x 10-13 cm3 molecule-1 sec-1 at 24.2 °C; in the
    temperature range 298-424 °K (25-151 °C), the rate constant was
    described by the equation k = 5.86 x 10-13 exp (-1500 cal
    mole-1/RT).  From this rate constant data, Harris  et al. (1981)
    calculated the tropospheric destruction rate of acetonitrile at
    25 °C to be approximately 5 x 10-7 sec-1 for a mean
    concentration of 107 hydroxyl radicals/cm3 in a moderately
    polluted troposphere; this rate yielded a tropospheric lifetime of
    approximately 20 days.  In a more average atmosphere of 106
    hydroxyl radicals/cm3, the lifetime will be 10 times longer. 
    Guesten  et al. (1981) reported the rate constant for the reaction
    between hydroxyl radicals and acetonitrile in the gas phase to be
    approximately 0.2 x 10-13 cm3 molecule-1 sec-1 at room
    temperature, which agrees reasonably well with the findings of
    Harris  et al. (1981).  The Arrhenius activation energy of
    approximately 1500 cal mole-1, as determined by Harris  et al.
    (1981), indicates that the reaction proceeds largely or entirely by
    abstraction of a hydrogen atom.

         Acetonitrile does reach the upper atmosphere.  It is
    characteristically associated in positive ion clusters of the form
    H+(CH3CN)m (H2O)n.  These ions do not occur in the
    ionosphere but become important at 35 km altitude.  At lower
    altitudes still (about 12 km), acetone ions become evident (Arijs
     et al., 1983; Huertas & Marenco, 1986).


    5.1  Environmental levels

    5.1.1  Air

         Becker & Ionescu (1982) monitored air near to the ground in
    both urban and rural areas and detected acetonitrile at
    concentrations of 3360 to 11 960 µg/m3 (2-7 ppb by volume) using
    GC/MS.  There was some indication that results from city centre
    samples were higher than general rural samples; acetonitrile at
    concentrations of 7.4 ± 2.4 ppb was reported for the city centre in
    Wuppertal, Germany.  Given the small number of samples, however, a
    comparison of the sites is difficult.  A rural site was sampled in
    the air before and after burning of bush and grass by farm workers
    and results showed an increase in acetonitrile concentration from
    4.0 to 34.9 ppb.  This seems to be the only reported demonstration
    of non-anthropogenic sources of atmospheric acetonitrile. 
    Acetonitrile has also been reported to be present in the upper
    stratosphere (Arijs  et al., 1983).  It was detected at
    concentrations of 210 to 42 000 ng/m3 in the Environmental Survey
    of Chemicals in Japan (Office of Health Studies, Environment Agency,

         In the USA, two samplings of air over a period of 24 h in a
    rural area gave daily mean levels of 0.048 ppb by volume.  A single
    sampling of urban air was below the detection limit of the
    analytical method (US EPA, 1988).

    5.1.2  Water and bottom sediment

         Acetonitrile was not detected in water but was detected in
    bottom sediment in the Environmental Survey of Chemicals in Japan
    (Office of Health Studies, Environment Agency, 1990).  The sampling
    was conducted in all 47 prefectures of Japan, but no information is
    available concerning the nature of the sampling sites.  It is not
    known, therefore, whether the high ends of the ranges in air and
    aquatic sediment were associated with industrial production and
    release (Table 7).

    5.1.3  Food

         No report has been published showing contamination of food by

    Table 7.  Environmental levels in Japan of acetonitrile in 1987a

               Concentration       Frequency of   Detection limit

    Water      not detected            0/72       3 µg/litre

    Sediment   0.021 to 0.54 mg/kg    11/60       0.021 mg/kg

    Air        210 to 42 000 ng/m3    44/70       200 ng/m3

    a  From: Office of Health Studies (1990)
    b  Number of detections/number of samples

    5.1.4  Tobacco smoke

         The absorption of acetonitrile from smoke has been confirmed by
    GC/MS analysis of a composite sample of the urine of 40 smokers
    (Mckee  et al., 1962).  The average acetonitrile level was
    117.6 µg/litre urine, while the average level for 20 nonsmokers was
    2.9 µg/litre urine.

    5.1.5  Other sources of exposure

         Nitrogen-containing products such as hydrogen cyanide,
    acetonitrile and acrylonitrile, and some other toxic gases have been
    detected from the thermal decomposition of flexible polyurethane
    foams (Woolley, 1972).  The yield of hydrogen cyanide and
    acetonitrile, respectively, from 10 mg foam was 26.4 and 21.4 µg at
    800 °C, where a volatile yellow smoke was produced, and 522 and
    30.5 µg at 1000 °C, where the yellow smoke was decomposed.

    5.2  Occupational exposure

         Synthesis of acetonitrile is usually carried out in a closed
    system.  Therefore, occupational exposure would only be accidental. 
    NIOSH estimated that 23 000 workers may be exposed to acetonitrile
    in the USA.  Since much of the acetonitrile produced has noncaptive
    uses, the general population may also be exposed (NIOSH, 1979).

         The occupational exposure limit for acetonitrile in various
    countries is shown in Table 8.

    Table 8.  Occupational exposure limits for various countriesa


    Country                TWA              STEL
                      (ppm)  (mg/m3)    (ppm)  (mg/m3)

    Australia           40      70        60      105

    Belgium             40      67        60      101

    Denmark             40      70         -       -

    Finland             40      70        60      105

    France              40      70         -       -

    Germany             40      70         -       -

    Hungary              -      50         -      100

    Switzerland         40      70        80      140

    United Kingdom      40      70        60      105


      (ACGIH)           40      67        60      101
      (NIOSH/OSHA)      40      70        60      101

    USSR                 -       -         -       10

    a  From: ILO (1991)

    5.3  Acetonitrile in various solvent products

         After a nationwide survey in Japan of organic solvent
    components in various solvent products, acetonitrile was not
    detected in either thinners (321 samples) or miscellaneous solvents
    (56 samples), but was detected in 1% of the degreasers (145 samples)
    (Inoue  et al., 1983).


    6.1  Absorption

    6.1.1  Human studies

         Acetonitrile is well absorbed by inhalation.  There is little
    information on absorption of inhaled acetonitrile in humans.

         Studies on smokers showed that 91 ± 4% of the acetonitrile
    inhaled in cigarette smoke was retained (Dalhamn  et al., 1968a). 
    A significant portion of this could have been retained in the mouth,
    as 74% of the acetonitrile was retained as a result of holding smoke
    in the mouth for 2 sec (Dalhamn  et al., 1968b).

         There are no absorption studies concerning dermal or oral
    exposure.  However, human poisoning cases indicate that acetonitrile
    is well absorbed by both routes.

    6.1.2  Experimental animal studies  Intake through inhalation

         Although there is information that acetonitrile is easily
    absorbed from the lungs of animals exposed to acetonitrile vapour,
    no quantitative analytical data is available on the pulmonary
    absorption of acetonitrile.  Dermal absorption

         Pozzani  et al. (1959a) studied the skin penetration of
    undiluted or diluted acetonitrile under polyethylene sheeting in
    rabbits (the site of application was not reported).  The dermal
    LD50 value was decreased when application was made as a 75% (by
    volume) aqueous solution, i.e. from 1.25 (0.84 to 1.85) ml/kg in the
    case of the undiluted compound to 0.5 (0.37 to 0.67) ml/kg in the
    case of the diluted aqueous solution.  These LD50 values are
    similar or even lower than those obtained after oral administration
    in other animal species, indicating effective skin absorption of
    acetonitrile.  Intake via the gastrointestinal tract

         Although there is information that acetonitrile is easily
    absorbed from the gastrointestinal tract, no quantitative analytical
    data are available.

    6.2  Distribution

    6.2.1  Human studies

         A postmortem investigation on a man accidentally exposed to
    acetonitrile suggested that acetonitrile absorbed through inhalation
    or skin contact is distributed in the body as shown in Table 21
    (section 8.1.1).

    6.2.2  Experimental animal studies

         Ahmed  et al. (1992) studied by means of whole body
    auto-radiography the distribution of radioactivity derived from
    2-14C-acetonitrile in the body of ICR mice at time points between
    5 min and 48 h after administration of a single intravenous dose. 
    Irreversible association of label was determined in co-precipitated
    protein and nucleic acids and extracted lipid.  No attempt was made
    to distinguish between metabolically incorporated or adducted label. 
    The highest concentrations of non-volatile radioactive compounds
    were generally found in the liver, kidney and the contents of the
    upper gastrointestinal tract.  A significant fraction (40-50%) of
    the radioactivity found in liver at 24 and 48 h was bound to the
    macromolecular fractions of the tissues.  The radioactivity contents
    of other organs were, in large part (40-50% of total), present in
    the lipid fraction of the tissue.

    6.3  Biotransformation and elimination

    6.3.1  Human studies

         There is no specific human study describing acetonitrile
    biotransformation and elimination.  However, accidental poisoning
    cases indicate that acetonitrile is biotransformed to cyanide and
    thiocyanate, which are then excreted from urine (see section 9).

    6.3.2  Experimental animal studies and  in vitro studies  Cyanide liberation from acetonitrile

         The release of cyanide from acetonitrile and its subsequent
    metabolism to thiocyanate have been studied under a number of
    experimental conditions and in several animal species.

         Biotransformation of acetonitrile to cyanide and thiocyanate
    has been demonstrated in a variety of  in vitro preparations. 
    Liver slices obtained from male golden hamsters show an increasing
    generation of cyanide and thiocyanate as the concentration of
    acetonitrile increases (Willhite, 1983).  Release of cyanide from
    acetonitrile is also catalysed by liver microsomes of hamster in a
    concentration-dependent manner (Willhite, 1983).  Production of
    cyanide from acetonitrile has been demonstrated in isolated

    hepatocytes from female SD rats; the Km and Vmax values (mean ±
    SD) were 3.4 ± 0.8 mM and 1.1 ± 0.1 nmol cyanide/106 cells per
    10 min, respectively (Freeman & Hayes, 1987).  The release of
    hydrogen cyanide from acetonitrile has also been demonstrated in
    mouse liver microsomes, both with and without NADPH (Ohkawa  et al.,
    1972).  The Km and Vmax values obtained from male ddY mouse
    microsomes were 4.19 mM and 14.3 ng cyanide formed in 15 min per mg
    protein, respectively (Tanii & Hashimoto, 1984a).

         Dahl & Waruszewski (1989) studied the metabolism of
    aceto-nitrile to cyanide in rat nasal and liver tissues and found
    that the maximum rates of cyanide production from acetonitrile by
    nasal maxilloturbinate and ethmoturbinate microsomes and liver
    microsomes were 0, 0.9 ± 0.2 and 0.098 ± 0.008 nmol cyanide/mg
    protein per min, respectively.

          In vivo metabolism of acetonitrile to cyanide and thiocyanate
    was first demonstrated by Pozzani  et al. (1959a).  Studies were
    conducted in rats, monkeys and dogs under a number of experimental
    conditions.  Fifteen male and fifteen female rats were exposed to
    acetonitrile vapour (166, 330, and 655 ppm) 7 h/day, 5 days/week for
    90 days.  During the 5-day sampling period (inhalation days 59 to
    63), thiocyanate concentrations in urine ranged from 27 to 79 and 29
    to 60 mg/100 ml for the 166 and 330 ppm exposure groups,
    respectively.  Thiocyanate was not completely eliminated between
    daily exposures, but was almost completely excreted during the
    2.5-day rest period over weekends.  The excretion of thiocyanate in
    the higher exposure group was not reported.

         The concentrations of thiocyanate in the urine of three dogs
    exposed to 350 ppm acetonitrile in air increased from 69 to
    252 mg/litre over the same 5-day inhalation period as described
    above for rats.  Unlike the rats, dogs continued to eliminate
    thiocyanate beyond the 2.5-day rest period over the weekend.  When
    three monkeys were exposed to 350 ppm acetonitrile in the same
    manner as the dogs, the urinary thiocyanate concentration ranged
    from 60 to 114 mg/litre.  Thiocyanate was also excreted after the
    2.5-day rest period.

         Rhesus monkeys were injected intravenously either with
    acetonitrile (0.1 ml/kg) or with thiocyanate (1.55 ml/kg of a 10%
    solution in saline).  The percentages of the dose excreted as
    thiocyanate were 12% and 55%, respectively.  It seems therefore that
    more than 12% of the injected acetonitrile was converted into
    thiocyanate (Pozzani  et al., 1959a).

         After a single intraperitoneal administration of acetonitrile
    (780 mg/kg) in rats, all animals died in 3 to 12 h, and acetonitrile
    was found to be distributed in various organs (Dequidt & Haguenoer,
    1972).  The free cyanide varied from 170 µg/kg in the liver to

    3.5 mg/kg in the spleen.  Concentrations of combined cyanide in the
    liver, spleen, stomach and skin were 3.6, 13.5, 17.6 and 10.5 mg/kg
    tissue, respectively.

         Haguenoer  et al. (1975a,b) studied the pharmacokinetics of
    acetonitrile in male Wistar rats after a single intraperitoneal
    acetonitrile injection or inhalation exposure.  Rats given 2340 or
    1500 mg/kg died within 3 to 28 h after the intraperitoneal
    injection, but rats given 600 mg/kg survived with no apparent
    symptoms.  After administration of 2340 mg/kg, concentrations of
    acetonitrile and free and combined cyanide in various organs ranged
    from 900 to 1700 mg/kg, 200 to 3500 µg/kg, and 3.5 to 17 mg/kg
    tissue, respectively.  Mean total urinary acetonitrile and free and
    combined cyanide (essentially all thiocyanate) excreted during the
    11 days following an intraperitoneal injection of 600 mg/kg were 28,
    0.2 and 12 mg, respectively.  These values were equivalent to 3,
    0.035 and 2.3% of the acetonitrile dose, respectively.  Urinary
    acetonitrile was detectable for 4 days after dosing, whereas free
    and combined cyanide were detectable until 11 days, at which time
    the animals were sacrificed.  Rats inhaling 25 000 ppm died within
    30 min from the beginning of exposure.  The concentration of
    acetonitrile in muscle and kidney ranged from about 1.4 to 24 mg/kg,
    and that of free cyanide in liver and spleen from 0.3 to 4 mg/kg
    tissue.  When three rats were exposed to 2800 ppm (2 h/day for
    3-5 days) the concentrations of acetonitrile and free cyanide in
    various tissues at the time of death were 1000-2900 mg/kg and
    0.5-10 mg/kg tissue, respectively.

         The liver and brain cyanide levels of male CD-1 mice (n = 9-10)
    that died 2.5 h after intraperitoneal administration of 175 mg
    acetonitrile/kg were found to be 47.8 ± 36.1 and 13.4 ± 4.8 µmol/kg,
    respectively (Willhite & Smith, 1981).  Sprague-Dawley rats
    administered an oral LD50 of acetonitrile (2460 mg/kg) were found
    to have cyanide levels of 16 ± 6 mg/kg in liver, 102 ± 39 mg/kg in
    kidney and 28 ± 5 mg/kg in brain (Ahmed & Farrooqui, 1982).

         Freeman & Hayes (1985a) found that the peak blood cyanide
    concentration (5.2 ± 0.5 mg/litre) was achieved 35 h after oral
    administration of 1470 mg/kg to female SD rats.  Silver  et al.
    (1982) reported that urinary thiocyanate excretion for a 24-h period
    following oral or intraperitoneal adminstration of acetonitrile
    (30.8 mg/kg) in SD rats was 11.8 ± 2.5 and 4.4 ± 0.5% of the dose,
    respectively.  Inhalation studies on male and female Wistar rats
    exposed to 166 and 330 ppm (660 ppm was fatal) indicated that the
    amount of thiocyanate in urine was not proportional to the
    concentration of acetonitrile inhaled (Pozzani  et al., 1959a).

         Table 9 shows that acetonitrile is converted to cyanide at a
    slower rate than other nitriles.  In fact, one hour after
    acetonitrile administration the blood level of cyanide was much
    lower than those after acute toxic doses of other nitriles. Peak

    concentrations of blood cyanide were found 7.5 h after acetonitrile
    dosing and were comparable to those of other nitriles measured one
    hour after dosing.

         Brain cyanide concentration one hour after acetonitrile dosing
    was also lower than those after exposure to potassium cyanide (KCN)
    or other nitriles.  Urinary excretion of thiocyanate after exposure
    to various nitriles indicated that for acetonitrile the percentage
    of the dose excreted was lower than for other nitriles, even though
    the absolute given amount of acetonitrile, based on its oral LD50
    value, was much higher.  These data, taken together, indicate that
    the toxicity of acetonitrile is lower than those of cyanide and
    other nitriles, as shown by oral LD50 values in Table 9.  The
    reason for this is most probably the slower transformation of
    acetonitrile to cyanide and consequently the more efficient
    detoxification via thiocyanate excretion.

         The relevance of acetonitrile pharmacokinetics is further
    illustrated by examining the relationship between symptoms produced
    by acetonitrile one hour after exposure and the amounts of cyanide,
    as well as the effect on cytochrome  c oxidase in the brain
    (Table 10).  Animals treated with acetonitrile were asymptomatic at
    this time, but animals treated with other nitriles or KCN at LD50
    doses were symptomatic.  In fact, the inhibition of brain cytochrome
     c oxidase paralleled brain cyanide concentrations.  In the case of
    acetonitrile, the brain cyanide concentration was too low to affect
    cytochrome  c oxidase activity and therefore to cause symptoms.

         In conclusion, the data reported in Tables 9 and 10 indicate
    that the apparent lack of relationship, assessed shortly after
    dosing, between acetonitrile toxicity and cyanide production is due
    to the slow transformation of acetonitrile to cyanide.

         There is sufficient evidence from all animal species studied
    that the toxicity of acetonitrile is due to cyanide.  Interspecies
    variations, as shown in Tables 11 and 12, are probably related to
    the relative speed of cyanide formation from acetonitrile (data of
    Willhite & Smith, 1981 in mice versus the data of Ahmed & Farooqui,
    1982 in rats).

        Table 9.  Metabolism of nitriles to cyanide in relation to their lethal effects


    Compound                       Cyanide concentration              Urinary thiocyanate           Oral LD50
                                  (1 h after an oral LD50)                 excretion           (mg/kg body weight)c
                             Blood (mg/litre)a     Brain (mg/kg)c        (% dose/24 h)d

    Potassium cyanide              6.3                748 ± 200            not measured                  10

    Acetonitrile                   0.3b                28 ± 5               11.8 ± 2.5                 2460

    Propionitrile                  4.0                508 ± 84              65.1 ± 2.9                   40

    Butyronitrile                  3.8                437 ± 106             64.9 ± 3.5                   50

    Malononitrile                  6.5                649 ± 209            not measured                  60

    Isobutyronitrile          not measured          not measured            74.0 ± 2.6                  160

    Acrylonitrile                  4.1                 395-106              37.3 ± 1.9                   90

    a  Estimated from: Ahmed & Farooqui (1982)
    b  7.5 h after oral administration (1470 mg/kg body weight), the blood cyanide level was found to
       be 7.3 mg/litre (Estimated from: Freeman & Hayes, 1985a)
    c  Ahmed & Farooqui (1982) 1 h after oral LD50
    d  Silver et al. (1982)
  The oxidative pathway of acetonitrile metabolism

         Following the observation of acetonitrile metabolism to cyanide
    and thiocyanate by Pozzani  et al. (1959a), many authors reported
    the same results in humans as well as in experimental animals both
     in vitro and  in vivo (Amdur, 1959; Ohkawa  et al., 1972;
    Willhite & Smith, 1981; Ahmed & Farooqui, 1982; Silver  et al.,
    1982; Willhite, 1983; Pereira  et al., 1984; Tanii & Hashimoto,
    1984a,b, 1986; Freeman & Hayes, 1985a,b; Ahmed  et al., 1992). 
    They all suggested a metabolic pathway in which acetonitrile is
    bio-transformed by cytochrome P-450 monooxygenase system initially
    to cyanohydrin, which then spontaneously decomposes to hydrogen
    cyanide and formaldehyde as shown in Fig. 1. Formaldehyde has not
    been identified in all of these studies, but this could be due to
    its high reactivity and rapid conversion into a simple metabolite

         Acetone, an inducer of cytochrome P-450 isozyme LM3a (Koop &
    Casazza, 1985; Johannsen  et al., 1986), has been demonstrated to
    stimulate the metabolism of acetonitrile to cyanide  in vivo in
    rabbits (Freeman & Hayes, 1985a).  In an  in vitro  study, liver
    microsomes were isolated and pooled 24 h after pretreatment of
    female Sprague-Dawley rats with acetone. Microsomal metabolism of
    acetonitrile to cyanide was found to be NADPH-dependent and
    heat-inactivated tissue was unable to catalyse this reaction
    (Freeman & Hayes, 1985b).  The metabolism of some nitriles,
    including acetonitrile to cyanide by mouse hepatic microsome system,
    has been shown to be NADPH-dependent and enhanced by pretreatment
    with ethanol (Tanni & Hashimoto, 1986).  Ohkawa  et al. (1972)
    found that the amount of hydrogen cyanide released in mouse liver
    microsomal preparations was increased greatly by the addition of
    NADPH.  It is known that treatment of rats with cobalt-heme
    effectively depletes liver cytochrome P-450 concentrations (Drummond
    & Kappas, 1982).  Freeman & Hayes (1987) demonstrated a marked
    decrease in acetonitrile metabolism in isolated hepatocytes prepared
    from rats pretreated subcutaneously with cobalt-heme (90 µmol/kg)
    48 h before killing.  However, the rate of acetonitrile
    biotransformation into cyanide by liver microsomal preparation
    obtained from cobalt-heme-treated rats was 13% of controls, while
    the total cytochrome P-450 content was reduced by only 41% compared
    to the controls.

        Table 10.  Biochemical and clinical effects in Sprague-Dawley male rats dosed with cyanide and nitrilesa


    Compound                 Brain cyanide     Brain cytochrome c        CNS          Convulsionb     Respiratory
                             concentration     oxidase activity       depressionb                       failureb
                                (mg/kg)        (% of control)

    Control                       0                  100                  no              no               no

    Potassium cyanide         748 ± 200               29                   4               4                4

    Acetonitrile               28 ± 5                 92                  no              no               no

    Propionitrile             508 ± 54                47                   3               1                1

    Butyronitrile             437 ± 106               41                   2               1                1

    Malononitrile             649 ± 209               73                   3               3                2

    a  Measured 1 h after an LD50; data from: Ahmed & Farooqui (1982)
    b  Physiological changes were graded on a scale of 1 (lowest) to 4 (highest)

            NADPH, O2            spontaneous

    CH3CN   ------->   HOCH2CN   -------> [HCHO] + CN-       (1)



    CN-     ------->   SCN-                                  (2)


                      [HCHO] has not been identified
                      CN- and SCN- have been identified both
                       in vitro and  in vivo

    Fig. 1.  Oxidation (1) and conjugation (2) reactions in acetonitrile

         Treatment of rats with inducers of P-450 IIE1, such as
    pyrazole, 4-methylpyrazole and ethanol, resulted in a 4- to 5-fold
    increase in cyanide production from acetonitrile by isolated
    microsomes (Feierman & Cederbaum, 1989).  Phenobarbital treatment
    had a small stimulatory effect, whereas 3-methylcholan-threne
    treatment decreased microsomal oxidation of acetonitrile.  Cyanide
    production was inhibited by carbon monoxide, ethanol, 2-butanol,
    dimethyl sulfoxide (DMSO) and 4-methylpyrazole  in vitro. 
    Oxidation of acetonitrile to cyanide by microsomes from rats treated
    with pyrazole or 4-methylpyrazole was nearly completely inhibited by
    an antibody (IgG) against P-450 3a.

         These results imply a role for P-450 in the oxidation of
    acetonitrile to cyanide and suggest that P-450 IIE1 may be the
    specific catalyst for this oxidation.  Acetonitrile oxidation was
    not affected by hydroxyl radical scavengers or by desferrioxamine.

         The results of human and animal studies indicate that cyanide
    formed  in vivo is subsequently conjugated with thiosulfate to form
    thiocyanate, which is then eliminated in urine.  This conjugation is
    catalysed by the enzyme rhodanese (thiosulfate cyanide sulfur
    transferase: EC (Pozzani  et al., 1959a; Takizaw &
    Nakayama, 1979; Silver  et al., 1982; Willhite, 1983; Pereira
     et al., 1984).

         Acetone inhibits acetonitrile metabolism when the two compounds
    are administered simultaneously.  Blood cyanide concentrations were
    maximally elevated 9 to 15 h after female SD rats were dosed with
    acetonitrile alone at 1470 mg/kg.  In rats dosed concomitantly with

    acetonitrile (1470 mg/kg) and acetone (1960 mg/kg), blood cyanide
    concentrations measured 0 to 24 h after dosing were much lower than
    those in rats given the same dose of acetonitrile alone.  Blood
    cyanide levels, however, reached peak concentration 39 to 48 h after
    dosing with the two compounds and were 50% higher than those
    measured in rats treated with acetonitrile only (Freeman & Hayes,

         From these time courses of blood cyanide it was postulated that
    acetone has a biphasic effect on acetonitrile metabolism, causing an
    initial inhibition and a subsequent stimulation of cyanide
    generation from acetonitrile.  Freeman & Hayes (1985b) also found
    that the  in vitro metabolism of acetonitrile to cyanide by either
    hepatic microsomal preparations or by isolated liver cells
    (hepatocytes) from rats pretreated with acetone (2.5 ml/kg) was
    significantly increased (2 fold).  However, when acetone was
    incubated with hepatocytes, it inhibited acetonitrile metabolism
    without affecting cell viability.

         Ethanol has also been shown to affect the  in vitro metabolism
    of some nitriles, including acetonitrile (Tanii & Hashimoto, 1986). 
    A 1.8-fold increase in cyanide liberation from acetonitrile was
    observed in hepatic microsomes from male ddY mice pretreated with
    ethanol (4.0 g/kg) 13 h prior to the study.

         Freeman & Hayes (1988) further investigated the metabolism of
    acetonitrile  in vitro and the effects of acetone and other
    compounds.  They suggested that the conversion of acetonitrile to
    cyanide is mediated by specific acetone-inducible isoforms of
    cytochrome P-450 and cytochrome P-450j (LM3, LMeb).  Acetone,
    dimethylsulfoxide and ethanol competitively inhibited this
    conversion.  Aniline HCl has been shown to reduce acetonitrile

    6.4  Biological monitoring of acetonitrile uptake

         Workers accidentally exposed to acetonitrile vapour showed
    increased serum cyanide and thiocyanate levels but the exposure
    concentrations were unknown (Amdur, 1959).  In three human
    volunteers exposed at different times to concentrations of up to
    160 ppm for 4 h (Pozzani, 1959a), no significant changes in urinary
    blood cyanide and thiocyanate levels were observed compared to those
    measured prior to exposure.  In experimental animal studies using
    various routes of exposure, blood cyanide and thiocyanate levels
    showed increases but they were not proportional to the exposures
    (Pozzani, 1959a).  It should be noted that there is a delay of
    several hours in the formation of cyanide following exposure to
    acetonitrile, and the timing of blood sampling is therefore

         From these data it is not possible to derive biological indices
    for exposure monitoring.


    7.1  Acute toxicity

    7.1.1  Single exposure

         The LD50 values for acetonitrile in mammals are summarized in
    Table 11; they range between 175 and 5620 mg/kg body weight.  The
    mouse and the guinea-pig seem to be the most sensitive species.  No
    consistent effects of sex, administration route or vehicle were
    observed.  An experiment using four different age groups of rats
    showed that new-born rats (24 to 48 h old, 5-8 g) are the most
    sensitive.  Significant differences in LD50 values were found
    between 14-day-old and adult rats, but not between young adults
    (80-160 g body weight) and older adults (300-470 g body weight)
    (Kimura  et al., 1971).

         The acute inhalation toxicity of acetonitrile in various animal
    species is shown in Table 12. The LC50 values range between about
    2700 ppm for a 1-h inhalation or 2300 ppm for a 2-h inhalation in
    mice and 16 000 ppm for a 4-h inhalation or 12 000 ppm for an 8-h
    inhalation in rats.  Mice appear to be the most sensitive species to
    acetonitrile inhalation.  In Nelson rats, the LC50 value for an
    8-h inhalation was significantly lower in males (7551 ppm with 5975
    to 9542 confidence interval) than in females (12 435 ppm with 11 036
    to 14 011 confidence interval), while that for a 4-h inhalation was
    the same in both sexes (16 000 ppm with 13 070 to 19 636 confidence
    interval) (Pozzani  et al., 1959a).

         Pozzani  et al. (1959b) studied the relationship between the
    observed and predicted LD50 of acetonitrile given in combination
    with other chemicals to rats exposed orally or by inhalation. 
    Predictions were made using the method of Finney (1952).  The
    mixture of acetonitrile and acetone seemed to show effects that were
    greater than additive.  Results are summarized in Table 13.

    7.1.2  Clinical observations

         Signs and symptoms of acute acetonitrile intoxication are
    similar in different animal species.  Verbrugge (1899) described
    signs of acute acetonitrile toxicity in rabbits.  One to three hours
    after a subcutaneous acetonitrile injection of 90 to 150 mg/kg,
    rabbits showed rapid and irregular respiration, immobilization and
    convulsions, and two out of seven animals died.  Monkeys exposed to
    2510 ppm acetonitrile vapour appeared normal after the first day of
    inhalation but showed poor coordination followed by prostration and
    laboured breathing during the second day.  Death occurred a few
    hours later (Pozzani  et al., 1959a).  Mice exposed to
    concentrations of acetonitrile ranging from 500 to 5000 ppm (the
    LC50 for a 60-min exposure was 2693 ppm) displayed dyspnoea,
    tachypnoea, gasping, tremors, convulsions and corneal opacity
    30-300 min after the beginning of the exposure.  Exposure of mice to

    5000 ppm acetonitrile for 60 min killed all the animals within 2 h. 
    The syndrome of acute acetonitrile toxicity was indistinguishable
    from that observed after exposure to cyanide or other nitriles
    (Willhite, 1981; Willhite & Smith, 1981).

         In a study by Willhite (1983), pregnant hamsters were exposed
    to acetonitrile concentrations from 3800 to 8000 ppm for one hour. 
    The number of hamsters showing tremors, hypersalivation, ataxia,
    hypothermia, lethargy and coma increased with increasing dose. 
    Hamsters died about 3 h after exposure to 5000 ppm acetonitrile and
    within 90 min after exposure to 8000 ppm acetonitrile.

         In a study by Johansen  et al. (1986), all of five pregnant
    rats treated with acetonitrile at doses of 750 mg/kg or more per day
    by gavage on gestation days 6-15 died, whereas only three out of
    five animals treated with 375 mg/kg per day died.  Four out of six
    rats treated with 275 mg/kg had reduced body weight at parturition,
    while two others died.

         Ahmed & Farooqui (1982) measured cyanide levels one hour after
    administration of LD50 doses of several saturated and unsaturated
    nitriles to male SD rats.  Few symptoms were noted with acetonitrile
    in this study because little cyanide was released within the first
    hour following treatment.  The tissue concentrations of cyanide
    after lethal doses of propionitrile, butyronitrile and malononitrile
    were very similar and approximately those observed with a lethal
    dose of KCN.

         In female SD rats given an oral dose of acetonitrile
    (1770 mg/kg), acute toxic effects appeared after 30 h (Freeman &
    Hayes, 1985a).  Effect on skin

         The skin irritation of acetonitrile in Sherman rats was
    reported by Smyth & Carpenter (1948) to be comparable to that of
    acetone, although no precise description of the technique used for
    testing skin irritation was provided.  Effect on the eyes

         Eye injury caused by acetonitrile, reported by Smyth &
    Carpenter (1948), is of intermediate intensity and similar to that
    produced by acetone (Carpenter & Smyth, 1946).  Corneal opacity has
    been observed after either inhalation or intraperitoneal
    administration of acetonitrile in male mice (Willhite, 1981;
    Willhite & Smith 1981).  Pregnant hamsters exposed to 8000 ppm
    acetonitrile via inhalation for 60 min showed eye irritation
    (Willhite, 1983).

        Table 11.  LD50 values of acetonitrile for various species and different routes of administration


    Species (strain)            Sex       Observation     Route                LD50 (mg/kg or       Vehicle       References
                                         period (days)                       ml/kg body weightb

    Mouse (Kunming)             male          -a          gavage                 453 mg/kg          water         Chen et al. (1981)
    Mouse                                      1          intraperitoneal        520.79 mg/kg                     Yoshikawa (1968)
    Mouse                                      -          intraperitoneal        0.25 ml/kg         saline        Pozzani et al. (1959a)
    Mouse (NMRI)                               7          intraperitoneal        400 mg/kg          water         Zeller et al. (1969)
    Mouse (CD-1)                male           7          intraperitoneal        175 mg/kg          water         Willhite & Smith (1981)
    Mouse (ddY)                 male           7          oral                   269 mg/kg          water         Tanii & Hashimoto (1984a)

    Rat (Sherman)                              -          oral                   3800 mg/kg         -a            Smyth & Carpenter (1948)
    Rat (Wistar) or albino      male           -          gavage                 1.68 ml/kg         undiluted     Pozzani et al. (1959a)
    Rat (Wistar) or albino      male           -          gavage                 2460 mg/kg         water         Pozzani et al. (1959a)
    Rat (Wistar) or albino      male           -          intravenous            1.68 ml/kg         undiluted     Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          gavage                 2230 mg/kg         1% Tgc        Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          gavage                 1730 mg/kg         corn oil      Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          gavage                 8.56 ml/kg         undiluted     Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          intraperitoneal        7.96 ml/kg         undiluted     Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          intraperitoneal        5620 mg/kg         saline        Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          intraperitoneal        0.85 ml/kg         undiluted     Pozzani et al. (1959a)
    Rat (Wistar) or albino      female         -          intravenous            1.68 ml/kg         undiluted     Pozzani et al. (1959a)
    Rat (SD)                                   -          oral                   3200 mg/kg         water         Zeller et al. (1969)
    Rat (SD) 14-day old         male           -          oral                   0.2 ml/kg          undiluted     Kimura et al. (1971)
    Rat (SD) young adult        male           -          oral                   3.9 ml/kg          undiluted     Kimura et al. (1971)
    Rat (SD) older adult        male           -          oral                   4.4 ml/kg          undiluted     Kimura et al. (1971)
    Rat (SD)                    female         3          oral                   4050 mg/kg         undiluted     Freeman & Hayes (1985a)

    Table 11 (contd).


    Species (strain)            Sex       Observation     Route                LD50 (mg/kg or       Vehicle       References
                                         period (days)                       ml/kg body weightb

    Guinea-pig                  male           -          gavage                 0.177 ml/kg        undiluted     Pozzani et al. (1959a)

    Rabbit                                     -          skin                   5.0 ml/kg          undiluted     Smyth & Carpenter (1948)
    Rabbit                      male           -          skin                   1.25 ml/kg         undiluted     Pozzani et al. (1959a)
    Rabbit                      male           -          skin                   0.50 ml/kg         water         Pozzani et al. (1959a)

    a  - = not reported
    b  1 ml acetonitrile = 783-787 mg at 20 °C
    c  Tg = Tergitol 7 in water

        Table 12.  Acute inhalation toxicity of acetonitrilea


    Species (strain)      Sex         Concentration    Exposure      Mortality
                                          (ppm)        time (h)      measuresb

    Mouse (Kunming)                        2300            2         LC50
    Mouse (Kunming)                        5700            2         LC50
    Mouse (CD-1)          male             2700            1         LC50
                          male             5000            1         10/10

    Rat (Nelson)          male             7551            8         LC50
                          female         12 435            8         LC50
                          male           16 000            4         LC50
                          female         16 000            4         LC50
    Rat (Wistar)                         12 000            2         MLC

    Guinea-pig            male +           5655            4         LC50
    Guinea-pig                             7400            2         MLC

    Rabbit                male             2800            4         LC50
    Rabbit                                 4500            2         MLC

    Dog                   male           32 000            4         1/1
                          male           16 000            4         3/3
                          male             8000            4         0/1
                          male             2000            4         0/2

    a  From: Willhite (1981), Pozzani  et al. (1959a,b), Wang  et al. (1964)
    b  MLC = minimum lethal concentration

    Table 13.  Predicted and observed LC50 and LD50 values of acetonitrile in
               combination with other solvents in rata


                                    4-h inhalation (g/m3)          Oral (ml/kg)

                                    PLC50          OLC50        PLD50         OLD50

    Acetonitrile                      -            26.9          -             8.27

    Acetonitrile + n-hexane         45.6           74.1          -              -  

    Acetonitrile + acetone          39.7           14.6         9.99           2.75

    Acetonitrile + ethyl            32.4           51.4         9.40           14.1

    Acetonitrile + carbon           31.5           45.5         4.35           6.77

    Acetonitrile + toluene          22.3           44.4         8.68           3.73

    a  From: Pozzani  et al. (1959b)
       PLC50 or PLD50 = predicted LC50 or LD50
       OLC50 or OLD50 = observed LC50 or LD50  Effect on respiration

         Animals exposed to acetonitrile via different routes of dosing
    always showed respiratory symptoms: rapid and irregular respiration
    after subcutaneous administration in rabbits (Verbrugge, 1899),
    laboured or difficult breathing after inhalation exposure in monkeys
    (Pozzani  et al., 1959a) or rats (Haguenoer  et al., 1975b), and
    intense dyspnoea after either inhalation or intraperitoneal
    administration in mice (Willhite, 1981; Willhite & Smith, 1981). 
    Histopathological investigations of rat lungs after acetonitrile
    inhalation showed haemorrhage and congestion (Haguenoer  et al.,
    1975b).  After inhaling 660 ppm acetonitrile for 2 h, two monkeys
    showed focal areas of emphysema and atelectasis, with occasional
    proliferation of alveolar septa (Pozzani  et al., 1959a).  Effect on adrenals

         Szabo  et al. (1982) studied structure-activity relationships
    of 56 chemicals, including acetonitrile, with respect to their
    potential for causing adrenocortical necrosis in rats.  The dose was
    selected on the basis of preliminary experiments and was aimed to
    lead to 70 to 100% mortality in 4 to 5 days.  The compounds were
    given 3 times per day for 4 days, and surviving animals were
    sacrificed on the 5th day.  Acetonitrile, along with 13 other
    compounds out of 56 test chemicals, did not show any
    adrenocorticolytic effect in rats.  Effect on the gastrointestinal tract

         Rats that inhaled acetonitrile at a concentration of 2800 ppm
    (2 h/day for 2 days) showed temporary diarrhoea (Haguenoer  et al.,

         Acetonitrile did not produce duodenal ulcers in female SD rats
    after oral or subcutaneous administration 3 times per day for 4
    days, the total dose being 432 mmol/kg (Szabo  et al., 1982).

    7.1.3  Biochemical changes and mechanisms of acetonitrile toxicity  Effect on cytochrome oxidase

         An  in vitro study carried out by Willhite & Smith (1981)
    showed that high concentrations of acetonitrile (up to 0.47 M) did
    not inhibit cytochrome  c oxidase activity.  Ahmed & Farooqui
    (1982) investigated the ability of acetonitrile and other nitriles
    to inhibit cytochrome  c oxidase one hour after they were
    administered at the LD50 to male SD rats.  There was no direct
    evidence for the inhibition of cytochrome oxidase after the
    administration of acetonitrile.  However, very little increase in
    tissue or blood cyanide concentrations was observed one hour after
    dosing with acetonitrile.  Symptoms had not occurred within this
    time period, and the evidence from other studies indicates that peak

    cyanide levels are achieved much later than one hour (in 9-15 h)
    (Freeman & Hayes, 1985a).  The need to consider the different
    pharmacokinetic and metabolic factors involved in making such
    comparisons was emphasized by Willhite & Smith (1981).  Effect on glutathione

         Levels of glutathione (GSH) in liver, kidney and brain were
    unaffected one hour after oral administration of acetonitrile (at
    the LD50 level) in male SD rats (Ahmed & Farooqui, 1982).  Aitio &
    Bend (1979) studied the  in vitro effect of 12 organic solvents,
    including acetonitrile, on the activity of rat liver soluble
    glutathione S-transferase.  They demonstrated that in the presence
    of 630 mM acetonitrile, the conjugation of styrene oxide,
    benzo[ a]pyrene-4,5-oxide and 1,2-dichloro-4-nitrobenzene by GSH
    was reduced to 79.0 ± 5.2, 92.6 ± 3.0 and 59.2 ± 1.4%,
    respectively, of the control values.

    7.1.4  Antidotes to acetonitrile

         Multiple intraperitoneal administrations of 1 g sodium
    thiosulfate per kg at the rate of one injection every 100 min over a
    10-h period or two intraperitoneal injections of 75 mg sodium
    nitrite per kg significantly reduced mortality in CD-1 mice exposed
    to 3800 or 5000 ppm acetonitrile by inhalation for 60 min (Willhite,
    1981).  Treatment of animals with thiosulfate at a dose rate of
    1 g/kg every 100 min for an 8-h period was effective in providing
    significant protection against the lethal effect of an
    intraperitoneal injection of acetonitrile (575 mg/kg) in male CD-1
    mice (Willhite & Smith, 1981).  An intraperitoneal injection of
    sodium thiosulfate (300 mg/kg) 20 min prior to inhalation of
    8000 ppm acetonitrile in pregnant hamsters abolished the overt signs
    of acetonitrile poisoning and reduced mortality from 3 out of 12
    hamsters to zero (Willhite, 1983).  Repeated intraperitoneal
    administrations (6 injections in 10 h) of sodium thiosulfate
    (1 g/kg), which started at the onset of acute toxicity about 30 h
    after oral administration of acetone (1960 mg/kg) and acetonitrile
    (1770 mg/kg) given simultaneously, provided significant protection
    against mortality in female SD rats (Freeman & Hayes, 1985a).

         Two intraperitoneal injections of 75 mg sodium nitrite did not
    provide CD-1 mice with any significant protection against the lethal
    effect of acetonitrile (575 mg/kg) (Willhite & Smith, 1981).

    7.2  Subchronic toxicity

    7.2.1  Inhalation exposure

         In a rat study, the body weight gain and organ weights of male
    and female rats which inhaled 166, 330 or 655 ppm acetonitrile
    (7 h/day, 5 days/week, for a total of 90 days) did not differ

    significantly from those of the controls (Pozzani  et al., 1959a). 
    Histopathological examination showed that of the 28 rats that
    inhaled 166 ppm, one had histiocyte clumps in the alveoli and
    another had atelectasis.  Of 26 rats that inhaled 330 ppm, three
    showed bronchitis, pneumonia, atelectasis and histiocyte clumps in
    the alveoli.  After the inhalation of 655 ppm acetonitrile vapour,
    10 out of 27 animals showed alveolar capillary congestion and/or
    focal oedema in the lung, often accompanied by bronchial
    inflammation, desquamation and hypersecretion.  Tubular cloudy
    swelling of the kidneys in eight rats and swelling of the livers of
    seven rats were observed.  These effects were statistically
    significant (lungs, P < 0.001; kidney, P < 0.005; liver,
    P < 0.04) compared with control animals.  No lesions were found in
    the adrenals, pancreas, spleen, testes or trachea.  Focal cerebral
    haemorrhage was observed in one of the five brains examined.

         Wang  et al. (1964) reported that there was no change of
    iodine levels in the thyroid of Wistar rats exposed to 80 or 400 mg
    acetonitrile/m3 (4 h/day, 6 days/week) for 10 weeks. Degenerative
    changes in the epithelial cells of thyroid follicles were observed
    in rabbits exposed to 400 mg/m3 (4 h/day, 6 days/week) for 16

         In an inhalation study (7 h/day) on four Rhesus monkeys, one
    female monkey was exposed to 2510 ppm, two females to 660 ppm and
    one male to 330 ppm (Pozzani  et al., 1959a).  The monkey exposed
    to 2510 ppm appeared normal during the first inhalation day but on
    the second day showed incoordination and laboured breathing and died
    a few hours later.  In the two monkeys exposed to 600 ppm there was
    also incoordination from the second week.  One monkey died on day 23
    and the other on day 51.  The monkey exposed to 330 ppm showed
    overextension reflexes and hyperexcitability towards the end of the
    99-day inhalation period and was sacrificed then.  At autopsy, the
    monkey exposed to 2510 ppm had engorgement of the dural capillaries,
    and the animals exposed to 660 and 330 ppm showed focal dural or
    subdural haemorrhage in the parietal and/or occipital tissues
    adjacent to the superior sagittal sinus.  The monkey exposed to
    2510 ppm had pleural effusion, and those exposed to 660 ppm had
    focal areas of emphysema and atelectasis with occasional
    proliferation of alveolar septa, and cloudy swelling of the proximal
    and convoluted tubules of the kidneys.  The monkey exposed to
    330 ppm had pneumonitis as shown by diffuse proliferation of
    alveolar septa, monocytic infiltration and pleural adhesions.

         In another inhalation study (Pozzani  et al., 1959a), three
    male Rhesus monkeys were exposed to 350 ppm acetonitrile (7 h/day,
    5 days/week) for 91 days, and at the end of the study the animals
    were sacrificed.  At autopsy, haemorrhages of the superior and
    inferior sagittal sinuses were found in the brains of all three
    monkeys.  Small discrete caseous nodules were seen in the lungs of

    two monkeys and one monkey had a pale liver.  Histological
    investigations of the lung showed focal emphysema, diffuse
    proliferation of alveolar septa, and focal accumulations of
    pigment-bearing macrophages.  In two of the monkeys there was cloudy
    swelling of the proximal tubules of the kidney.

         One female and two male dogs inhaled 350 ppm acetonitrile
    (7 h/day, 5 days/week) for 91 days.  The haematocrit and haemoglobin
    values of the three dogs were depressed by the fifth week of
    inhalation, but with the exception of one dog, there was a return to
    pre-inhalation values toward the end of the 91-day inhalation
    period.  No significant deviation of the erythrocyte counts was seen
    in any dogs.  Histopathological examination of these dogs showed
    some focal emphysema and proliferation of alveolar septa.

         Roloff  et al. (1985) exposed groups of male and female rats
    (strain unspecified) to acetonitrile vapour (0, 1038, 3104 and
    10 485 mg/m3) for one month (6 h/day, 5 days/week).  Death and
    reduced body weight gains were observed at the highest exposure
    level.  Respiratory and/or ocular irritation were noted in animals
    exposed to 3104 and 10 485 mg/m3.

         In a 13-week inhalation study of acetonitrile (100, 200 and
    400 ppm) in 25 male mice and male rats, there were no effects on
    body weight or on testicular weight and sperm motility (Morrissey
     et al., 1988).

         In a 13-week inhalation study on acetonitrile in mice and rats,
    ten mice (B6C3F1) and ten rats (F-344/N) of each sex were exposed
    to acetonitrile vapour at 0, 100, 200, 400, 800 and 1600 ppm
    (6 h/day, excluding weekends and holidays) for 13 weeks (Battelle,
    Pacific Northwest Laboratories, 1986a,b).  At 400 ppm one female
    mouse, at 800 ppm one male and four female mice, and at 1600 ppm ten
    female and ten male mice were found dead during the study.  The
    majority of the mortality occurred after two weeks of exposure. 
    Clinical signs observed were hypoactivity and a hunched rigid
    posture.  Body weight gains were comparable to control values for
    all surviving mice.  An increase in absolute and relative liver
    weight was attributed to acetonitrile exposure.  The maximum
    tolerated concentration determined by this 13-week subchronic study
    was 200 ppm.  Significant changes were observed in the liver and
    stomach of male mice exposed to 400 ppm of acetonitrile and female
    mice exposed to 200 ppm or more.  At 800 ppm one male rat and at
    1600 ppm six male and three female rats were either moribund (and so
    sacrificed) or found dead during the study.  The clinical signs
    observed were hypoactive, abnormal posture, ataxia, bloody crusts on
    nose and/or mouth and a rough haircoat.  The moribund, sacrificed
    rats exhibited tonic/clonic convulsions. Reductions in body weight
    gain were observed in rats exposed to 1600 ppm.  Minimum to mild
    lesions were found in the lungs and brain of some rats exposed to
    800 ppm (Table 14).

         In a 92-day study, reported as an abstract, acetonitrile was
    administered by inhalation to B6C3F1 mice and Fischer-344 rats at
    concentrations of (25, 50, 100, 200 and 400 ppm) for a total of 65
    days (Hazleton, 1990b).  In mice, one male in each of the 50, 200
    and 400 ppm groups died.  There was an increase in body weight gain
    in all males exposed to 50, 100, 200 and 400 ppm acetonitrile and in
    the females of the 200 and 400 ppm groups.  Body weight gain was
    decreased by comparison with controls in the 25, 50 and 100 ppm
    female groups.  Liver/body weight ratio was increased in males at
    400 ppm group and in females at 100, 200 and 400 ppm groups. 
    Liver/brain weight ratio was increased in males at the 400 ppm and
    in female at 100 and 400 ppm groups.  There was slight cytoplasmic
    vacuolization of hepatocytes in both males and females in the 200
    and 400 ppm groups. Mean haemato-crit and erythrocyte counts were
    marginally reduced in females at 200 and 400 ppm group. In females
    of the 200 and 400 ppm groups haematocrit, haemoglobin, red and
    white blood cell counts, and serum IgG were all depressed.  In rats,
    one male in the 400 ppm group died during the study.  There was
    slight cytoplasmic vacuolization of hepatocytes in females at
    400 ppm.  Marginal decreases in mean leucocyte counts were reported
    in males at 100 and 200 ppm and in both males and females at
    400 ppm.

    7.2.2  Subcutaneous administration

         Marine  et al. (1932a) gave daily subcutaneous injections of
    0.1 ml acetonitrile to 4-month-old rabbits for 21 days.  Two groups
    of four male rabbits developed pronounced (more than twice normal
    size) thyroid hyperplasia whereas one group of four females showed
    no effect.  Allyl-benzyl and phenyl nitriles produced less
    pronounced hyperplasia or no effect on thyroids at up to 4 times the
    dose of acetonitrile.  A further study (Marine  et al., 1932b)
    suggested that young rabbits were more susceptible than adults and
    that the effect varied with the strain.

    7.3  Teratogenicity and embryotoxicity

         In a study by Berteau  et al. (1982), mated rats were
    administered daily aqueous solutions of acetonitrile by gavage
    (125, 190 and 275 mg/kg) on gestation days 6-19.  Although maternal
    body weights were reduced and death occurred in the high-dose group,
    no other maternal effects were noted in any treated group. 
    Embryotoxic effects, as shown by increases in early resorptions and
    postimplantation losses, were also noted in the high-dose group. 
    However, no teratogenic responses were observed at any dose level.

        Table 14.  Subchronic inhalation toxicity of acetonitrile in mice and rats


    Species (strain)    Sex     Number of    Concentration    Duration        Effects                                  References
                                animals         (ppm)

    Mice (B6C3F1)       M, F    10, 10       100, 200, 400    6 h/day,        changes in liver and stomach at          Battelle, Pacific
                                             800, 1600        5 days/week,    > 400 ppm, hypoactivity, rigid           Northwest Laboratories
                                                              13 weeks        posture; NOEL for males 200 ppm,         (1986a)
                                                                              for females 100 ppm

    Mice (B6C3F1)       M, F    10, 10       25, 50, 100,     6 h/day,        increased body weight gain in male       Hazleton Laboratories
                                             200, 400         65/92 days      groups 50, 100, 200 and 400 ppm          (1990a)
                                                                              and female groups 200 and 400 ppm;
                                                                              liver/body weight ratio increased
                                                                              in 400 ppm males and 100, 200 and
                                                                              400 ppm females; liver/brain weight
                                                                              ratio increased in 400 ppm males and
                                                                              100 and 400 ppm females; minimal
                                                                              cytoplasmic vacuolization of
                                                                              hepatocytes in male and female 200
                                                                              and 400 ppm groups; no effects on
                                                                              male reproductive system

    Mice                M       25           100, 200, 400                    no effect on reproductive system         Morrissey et al.

    Rat (Carworth)      M, F    15, 15       166              7 h/day,        bronchitis, pneumonia, atelectasis,      Pozzani et al.
                                15, 15       330              5 days/week,    alveolar congestion, kidney and          (1959a)
                                15, 15       655              90 days         liver changes

    Table 14 (contd).


    Species (strain)    Sex     Number of    Concentration    Duration        Effects                                  References
                                animals         (ppm)

    Rat (F-344)         M, F    10, 10       25, 50, 100,     6 h/day,        minimal cytoplasmic vacuolization        Hazleton
                                             200, 400         65/92 days      of hepatocytes in 400 ppm females,       (1990b)
                                                                              slightly decreased mean leucocyte
                                                                              counts in 100 and 200 ppm males
                                                                              and 400 ppm males and females

    Rat                 M, F    not          1038, 3104,      6 h/day,        eye/nose irritation, body weight         Roloff et al.
                                specified    10 485           5 days/week,    loss, nervous system effects, mild       (1985)
                                                              1 month         anaemia at mid- and high-exposure

    Rat (F-344/N)       M, F    10, 10       100, 200, 400,   6 h/day,        hypoactive, ataxia at > 800 ppm,         Battelle, Pacific
                                             800, 1600        5 days/week,    body weight loss at > 1600 ppm           Northwest Laboratories
                                                              13 weeks                                                  (1986b)

    Dog (Basenji)       M, F    2, 1         350              7 h/day,        body weight drop on day 3 and 5          Pozzani et al.
                                                              5 days/week,    decreased Hb                             (1959a)
                                                              91 days

    Monkey (Rhesus)     F       2            660              7 h/day,        1 died on day 23 and 1 on day            Pozzani et al.
                                                              23 days and     51; brain haemorrhages, emphysema,       (1959a)
                                                              51 days         atelectasis, cloudy swelling
                                                                              of renal convoluted tubes

    Table 14 (contd).


    Species (strain)    Sex     Number of    Concentration    Duration        Effects                                  References

                                                                                                                                                                              animals          (ppm)

    Monkey (Rhesus)     M       3            350              7 h/day,        brain haemorrhages, focal emphysema,     Pozzani et al.
                                                              5 days/week,    cloudy swelling of renal convoluted      (1959a)
                                                              91 days         tubes

    Monkey (Rhesus)     M       1            330              7 h/day,        chronic pneumonitis, "excitability"      Pozzani et al.
                                                              5 days/week,                                             (1959a)
                                                              99 days

         When pregnant rabbits were given acetonitrile orally on
    gestation days 6-18 at dose levels of 0, 2, 15 and 30 mg/kg per day,
    animals given the highest dose showed anorexia and decreased body
    weight gain, and death occurred in 5 out of 25 rabbits at this
    level.  Body weight gain was also reduced in animals receiving
    15 mg/kg per day, but not at the lowest dose level.  With respect to
    the fetuses of the treated animals, evidence of toxicity was only
    observed at the highest dose level.  Therefore, acetonitrile is not
    considered to be toxic to fetuses at doses below those causing
    maternal toxicity (Argus Res Labs., 1984).

          In a study by Willhite (1983), pregnant golden hamsters were
    exposed by inhalation for one hour to 0, 1800, 3800, 5000 or
    8000 ppm acetonitrile on the 8th day of gestation.  There was a
    significant and dose-dependent increase in the number of abnormal
    fetuses from animals exposed to the two highest dose levels.

         Pregnant golden hamsters were exposed to a single gavage or a
    single intraperitoneal injection of 0, 100, 200, 300 or 400 mg/kg on
    the 8th day of gestation.  Animals exposed intraperitoneally were
    killed on day 14 while those exposed orally were killed on day 15. 
    An intraperitoneal injection of 200 to 400 mg/kg produced a
    significant increase in the average fetal body weight compared to
    controls.  A single gavage dose of 300 to 400 mg/kg produced a
    significant increase in the number of malformed fetuses
    (particularly rib malformations) or resorptions.  There was a
    significant decrease in the average fetal body weight, but not in
    maternal weight, at all dose levels.  The same dose given by gavage
    seemed to show greater toxic and teratogenic effects than when given
    intraperitoneally (Willhite, 1983).  The results of the teratologic
    studies are summarized in Table 15.

         When rats were orally administered acetonitrile, no changes in
    pregnancy rate, resorption of litters or perinatal toxicity in the
    offspring were found, even at doses of 300 and 500 mg/kg, which are
    toxic to the majority of females (Smith  et al., 1987).

    7.4  Mutagenicity

         Table 16 summarizes the short-term genotoxicity testing of
    acetonitrile.  Most of these tests have been performed using
    extremely high concentrations and therefore the interpretation of
    results is difficult.

        Table 15.  Teratogenic effects of acetonitrile on Syrian golden hamstera


    Route of           Dosage               Maternal effects                      Fetal effects

    Inhalation         1800 ppm, 60 min     none                                  none

    Inhalation         3800 ppm, 60 min     dyspnoea, tremors, etc., death        none
                                            in one out of six hamsters
                                            after 3 h

    Inhalation         5000 ppm, 60 min     irritation, dyspnoea, tremor,         6 out of 53 abnormal fetuses, exencephaly, encephalocoele,
                                            etc., death in one out of             rib fusions
                                            six hamsters after 5 h

    Inhalation         8000 ppm, 60 min     respiratory difficulty and ataxia     29 out of 115 abnormal fetuses, exencephaly, encephalocoele,
                                            in 4 out of 12 hamsters; death        extrathoracie ectopia cordis, severe axial skeletal dysraphic
                                            in 3 out of 4 hamsters after 1.5 h    disorders, reduced body weight

    Intraperitoneal    100-400 mg/kg        none                                  encephalocoele, retrocession of maxilla, increase in
                                                                                  average fetal body weight

    Oral               100-400 mg/kg        none                                  increase in malformed fetuses (12 out of 65 at 300 mg/kg;
                                                                                  14 out of 76 at 400 mg/kg) and resorptions, decrease
                                                                                  in body weight gain

    a   From: Willhite (1983)

    7.4.1  Bacterial systems

         Within a dose range up to 10 mg/plate, acetonitrile was not
    mutagenic toward Salmonella strains TA1535, TA1537, TA97, TA98 and
    TA100 either in the presence or the absence of the metabolic
    activation systems prepared from SD rats pretreated with Aroclor
    1254.  The test was performed in two different laboratories and
    showed good reproducibility (Mortelmans  et al., 1986). 
    Schlegelmilch  et al. (1988) reported that acetonitrile does not
    show any mutagenicity activity in the Ames test
    (Salmonella/microsome assay) performed with strains TA98 and TA100.

    7.4.2  Yeast assays

         Acetonitrile has been found to induce aneuploidy, but not
    recombination or point mutations, in a diploid yeast strain D61.M
    (Zimmermann  et al., 1985).

    7.4.3  Drosophila melanogaster

         FIX and ZESTE genetic test systems employing female  Drosophila
     melanogaster were performed by Osgood et al. (1991a,b).  Positive
    responses were obtained in these assays at acetonitrile
    concentrations of 0.2, 0.5, 2 and 5% (Osgood  et al., 1991a).  The
    Drosophila ZESTE system was used to monitor the induction of sex
    chromosome aneuploidy following inhalation exposure of adult females
    to acetonitrile.  Acetonitrile was a highly effective aneuploidogen,
    inducing both chromosome loss and gain following short exposure to a
    concentration of 131 ppm (Osgood  et al., 1991b).

    7.4.4  Mammalian  in vivo assays

         Schlegelmilch  et al. (1988) showed that a weak positive
    effect occurs with acetonitrile in the micronucleus assay 24 h after
    intraperitoneal injection of a dose equivalent to 60% of the LD50
    value to four male and four female NMRI mice (13 weeks old).

    7.4.5  Chromosome aberrations and sister chromatid exchange

         Galloway  et al. (1987) tested the ability of 108 chemicals,
    including acetonitrile, to induce chromosome aberration and sister
    chromatid exchange (SCE) in Chinese hamster ovary (CHO) cells both
    with and without a rat liver metabolic activation system.  At
    5000 mg acetonitrile/litre, there was a slight increase in SCE both
    with and without S9 activation, but chromosomal abberation tests
    yielded negative results.

        Table 16.  Short-term genotoxicity tests of acetonitrile


    Assay                                   Concentration            Experimental          Results     Reference

    Salmonella TA100                        3.8 µmol/plate                +S9                -         Maron et al. (1981)

    Salmonella TA100, TA1535                2.4-24.4 µmol/plate           +S9                -         Mortelmans et al. (1986)

    Salmonella TA98, TA100                  0.27 approx 1350 mM           -S9                -         Schlegelmilch et al. (1988)
                                                                          +S9                -

    Sister chromatid exchange               3.9-121.8 mM                  +S9                -         Galloway et al. (1987)
    in CHO cells                            121.8 mM                      -S9                ±

    Induction of aneuploidy in              553-904 mM                                       +         Zimmermann et al. (1985)
    Saccharomyces cerevisiae (D61.M)

    Induction of aneuploidy in              38-950 mM                FIX and ZESTE           +         Osgood et al. (1991a)

    Aneuploidy in Drosophila                131 ppm                  ZESTE system            +         Osgood et al. (1991b)
                                                                     (30, 50, 70 min)

    Micronucleus test in male               60% of LD50              24 h after              ±         Schlegelmilch et al. (1988)
    NMRI-mice                                                        intraperitoneal

    7.5  Carcinogenicity

         No data is available on the carcinogenicity of acetonitrile in
    experimental animals.  It is noteworthy, however, that the US
    National Toxicology Program has long-term oncogenicity studies
    underway in mice and rats.

    7.6  Cytotoxicity testing

         Table 17 summarizes the cytotoxicity of acetonitrile. The
    cytotoxicity to 3T3-L1, BCL-D1 and human hepatoma Hep G 2 was very
    weak.  The IC50 values in mouse neuroblastoma cells and in rat
    glioma cells, were 17.8 and > 20 mM, respectively.

        Table 17.  Cytotoxicity of acetonitrile


    Cell type               Method         Harvest time       Results         Reference


    Mouse 3T3-L1      FRAME Kenacid blue    after 72 h     IC50 = 562 mM    Clothier & Hulme (1987)

    BCL-D1                dye binding       after 72 h     IC20 > 24 mM     Knox et al. (1986)
                                                           IC50 > 24 mM
                                                           IC80 > 24 mM

    Human hepatoma    cellular protection   after 24 h     IC50 = 494 mM    Dierickx (1989)
    Hep G2                  content


    8.1  Acute toxicity

    8.1.1  Inhalation exposure

         Grabois (1955) reported on 16 workers at a chemical plant
    accidentally poisoned with acetonitrile vapour during the brush
    painting of the inside walls of a storage tank with
    corrosion-resistant paint.  One died after two days exposure, two
    were seriously ill and the remaining 13 workers were also affected. 
    Amdur (1959) studied this incident further.  The tank was of
    22 730 litre capacity, approximately 6 m high, and 2.75 m at its
    greatest diameter.  The paint contained 30-40% acetonitrile and the
    thinner contained 90-95% acetonitrile.  Because of the viscosity of
    the paint, the tank was heated to 25 °C and thinned on the second
    day before application.  Ventilation of the tank was stopped. 
    Details of the fatal case (Case 1), and the two seriously ill cases
    (Cases 2 and 3) are as follows:

         Case 1.  A 23-year-old man was painting within the tank during
    day 2.  He returned home without any symptoms but awoke shortly
    after midnight with malaise and chest pain.  Nausea, vomiting and
    blood-spitting were followed by convulsions, and he was admitted to
    hospital in a coma at about 9:15 a.m.  Respiration was shallow,
    irregular and infrequent and he died within one hour of admission. 
    Post-mortem examination revealed cerebral, thyroid, liver, splenic
    and renal congestion, and a "peach pit" odour of all tissues.  The
    blood and urine cyanide concentrations were 7960 and 2150 mg/litre,
    respectively.  There was a trace of cyanide in the gastric fluid. 
    Spleen, kidney and lung concentrations of cyanide were 3180, 2050
    and 1280 mg/kg tissue, respectively.  No cyanide was detected in the

         Case 2.  A 35-year-old man painted for 3 h inside the tank. 
    During the next day he began to feel ill and severe nausea and
    vomiting followed.  He was admitted to hospital with a slow pulse
    rate (55 per min), severe hypotension and slow shallow respiration. 
    He was treated with oxygen, intravenous fluids and whole blood,
    ascorbic acid, and sodium thiosulfate.  Twelve hours after admission
    he recovered and he returned to work after ten days.  The laboratory
    data are shown in Table 18.

    Table 18.  Laboratory data for case 2a


    Approximate        Blood cyanide     Serum thiocyanate
    time after
    exposure             (µg/litre)          (mg/litre)

    14 h                   3060                  ND
    23 h                   1930                  ND
    1 day                   ND                   160
    2 days                 2120                  150
    3 days                 2180                  ND
    4 days                  ND                   120
    5 days                 1020                  ND
    27 days                 ND                   30
    36 days            not detected              ND

    a  From: Amdur (1959); ND = not done

         Case 3.  A 28-year-old man painted outside and inside the tank. 
    In the night he felt unwell and had diarrhoea, and by morning he
    felt nauseated and weak and he was sent to hospital at 12:30 in a
    semiconscious state with a pulse rate of 45 per min and a blood
    pressure of 100/50 mmHg.  Respiration  was shallow and intermittent,
    motor power was severely impaired, and deep tendon reflexes were not
    elicited.  He was treated with oxygen, intravenous fluids and whole
    blood, ascorbic acid and sodium thiosulfate, and improved rapidly. 
    He was in hospital for 10 days and returned to work after 20 days. 
    The laboratory data are shown in Table 19.

         The laboratory data for twelve other workmen are summarized in
    Table 20, together with those for three severe cases described

         Dequidt  et al. (1974) reported a fatal case of acute
    acetonitrile poisoning in a 19-year-old male laboratory worker.
    After handling acetonitrile for 2 days without problems, he poured
    an unknown amount of acetonitrile and boiling water on the floor to
    clean it.  Four hours after work he complained of epigastric pain
    and nausea and vomited repeatedly.  Next day he became comatose and
    had convulsions.  On admission to hospital large amounts of cyanide,
    thiocyanate and acetonitrile were found in the blood and urine. 
    Treatment with dicobalt ethylenediaminetetraacetic acid (EDTA) and
    hydroxycobalamine was ineffective and he died 6 days after the
    poisoning.  Table 21 shows the results of clinical and postmortem
    examinations of cyanides in blood and tissues.

    Table 19.  Laboratory data for case 3a


    Approximate        Blood cyanide     Serum thiocyanate
    time after
    exposure             (µg/litre)          (mg/litre)

    24 h                   9700                  150
    2 days                10 880                 230
    3 days                 8800                  ND
    4 days                  ND                   200
    5 days                 2960                  ND
    8 days                 1400                  ND
    10 days                 ND                   100
    20 days                 35                   ND
    36 days            not detected              ND

    a  From: Amdur (1959); ND = not done

         In a human volunteer study, Pozzani  et al. (1959a) studied
    the acute inhalation toxicity of acetonitrile in three men between
    the age of 31 and 47.  They first inhaled 40 ppm acetonitrile vapour
    for 4 h in a 7900-litre chamber.  The two older subjects had no
    subjective response during or after the 4-h inhalation period. 
    There was no appreciable increase in urinary thiocyanate and no
    detectable blood cyanide.  The youngest subject experienced a slight
    tightness in the chest during the evening after inhalation.  The
    following morning he also reported a cooling sensation, which
    persisted for about 24 h and was similar to that experienced when
    menthol was inhaled.  There was only a slight increase in the
    urinary thiocyanate levels in this subject.  All three subjects
    detected the odour of acetonitrile for the first 2 or 3 h, after
    which they experienced some olfactory fatigue.

         The two older subjects then inhaled 80 ppm acetonitrile vapour
    for 4 h one week after the 40 ppm trial, with no symptoms.  No blood
    cyanide was detected in any of the samples taken after the
    inhalation period.  The urinary thiocyanate value in one subject was
    higher immediately before inhalation than it was after.  The values
    for the other subject were relatively constant.

         The same two subjects inhaled 160 ppm acetonitrile vapour for
    4 h, 9 days after the 80-ppm run.  One subject reported a slight
    transitory flushing of the face 2 h after inhalation, and a slight
    feeling of bronchial tightness about 5 h later, which disappeared
    overnight.  The blood cyanide and urinary thiocyanate levels of both
    subjects did not change significantly from pre-inhalation values.

        Table 20.  Summary of clinical findings of acute acetonitrile intoxication in mana


    Case No.   Age   Working condition        Symptoms and signs                    Outcome            Blood cyanide   Serum thiocyanate
                                                                                                       highest value   highest value
                                                                                                       (µg/litre)      (mg/litre)

       1       23    hand-brushing inside     chest pain, nausea, emesis, blood     death 14 h after       7960               -
                     of tank for 12 h         spitting, convulsions, shallow,       work
                                              irregular and infrequent

       2       35    hand-brushing inside     lightheaded, weakness, nausea,        returned to work       3060              160
                     of tank for 3 h          emesis, tachycardia, pallor,          after 11 days
                                              shallow respiration, abdominal

       3       28    hand-brushing outside    semiconsciousness, slate gray         returned to work      10 880             230
                     of tank for 12 h         colour, BP 100/50, shallow and        after 18 days
                                              intermittent respiration, impaired
                                              motor power, deep tendon reflexes
                                              absent, headache

       4       28    hand-brushing inside                    -                      returned to work        720              145
                     of tank for 2.5 h                                              after 10 days

    Table 20 (contd).


    Case No.   Age   Working condition        Symptoms and signs                    Outcome            Blood cyanide   Serum thiocyanate
                                                                                                       highest value   highest value
                                                                                                       (µg/litre)      (mg/litre)

       5       20    not clear                nausea, headache, lassitude,                 -                580              180

       6       18    sand-blasted and         headache, weakness, tightness         recovered after         330              100
                     mixed paint for 7 h      of chest and abdomen                  5 days

       7       42    mixed paint              nausea, tiredness                     returned to work        ND               135
                                                                                    within one week

       8       25    present in the work      severe pain of chest and              returned to work        ND                60
                     area for entire day      abdomen after 3 days,                 after two weeks

       9       24    mixed paint for 3 h      nausea, listlessness                         -                ND               100

     10-16     -     various                  no complaint                                 -                ND            under 30

    a   From: Amdur (1959); ND = not detected

        Table 21.  Cyanides in blood, urine and tissues after acetonitrile intoxicationa


    Sample         Days after        Free HCNb      Combined HCNb     Acetonitrileb

    Blood               2              1120              3760                  -
    Blood               3               870            10 380              11760
    Urine               4              4600              1050            311 000
    Heart               6             trace              2420               6130
    Lung                6               340            11 120               2870
    Liver               6               123              2670             11 840
    Spleen              6               440              3860               9340
    Kidney              6               270              2620             13 550
    Brain               6               220              2370                  -
    Pancreas            6               200              1090              trace
    Bladder             6             trace               910              trace

    a  From: Dequidt  et al. (1974)
    b  µg/litre for blood and urine, µg/kg for tissues
    8.1.2  Dermal exposure

         Caravati & Litovitz (1988) reported two cases of paediatric
    accidental exposure to an acetonitrile-containing cosmetic.  The
    exposure occurred both via the skin and by inhalation. 
    Approximately 30 ml of a nail remover (SuperNail Nail Off)
    containing 98-100% acetonitrile spilled on a 2-year-old 12-kg
    previously healthy boy and his bed (the actual amount of contact to
    the skin was not specified).  No symptoms were noted immediately
    after the exposure.  Eight hours later, the boy was moaning, poorly
    responsive, and had vomited.  On arrival at the emergency
    department, he was lethargic and pale.  Vital signs were as follows:
    temperature, 36.9 °C; pulse rate, 140/min; respirations 56/min; and
    blood pressure, 70/30 mmHg.  The electrocardiogram revealed a sinus
    tachycardia.  Therapy included oxygen by face mask, and an
    intraosseous line of 5% dextrose containing 0.2% potassium chloride
    and 20 mmol of sodium hydrogen carbonate.  Although the diagnosis
    was known, nitrites and thiosulfate were not given due to the
    patient's prompt response to supportive care.  Whole-blood cyanide
    levels were: 6 mg/litre 12 h after the exposure, 60-70 µmol/litre
    from 24 to 48 h and 15 µmol/litre after 60 h.  The patient was
    discharged 3 days later in good condition.

    8.1.3  Oral exposure

         Caravati & Litovitz (1988) reported on a 16-month-old 11.8-kg
    previously well boy who ingested 15 to 30 ml of SuperNail Nail Off
    (1-2 g acetonitrile/kg body weight).  The child vomited
    spontaneously about 20 min after the ingestion.  Telephone
    assistance from the poison centre and paediatrician was sought, but
    the product was mistaken for an acetone-containing  nail polish
    remover and toxicity was expected to be minimal.  The child was put
    to bed.  Later the mother noted that he was breathing heavily and
    noisily, but left him to sleep through the night.  He was found dead
    in his crib the next morning, about 12 h after the ingestion. 
    Postmortem examination showed moderately severe pulmonary oedema, a
    blood cyanide level of 119 (3.1 mg/litre), and brain cyanide level
    of 0.2 mg/kg.

         Jaeger  et al. (1977) reported a case of acute acetonitrile
    intoxication in a 26-year-old man who ingested 40 g of acetonitrile
    in a suicide attempt.  After a 3-h latent period, he suffered from
    vomiting, convulsions, coma, acute respiratory insufficiency, severe
    metabolic acidosis, and two cardiac arrests.  In addition to
    supportive treatment (oxygen, mechanical ventilation, correction of
    shock and acidosis), dicobalt EDTA, sodium nitrite, sodium
    thiosulfate and hydroxocobalamin were also administered.  His
    clinical course was complicated but he fully recovered 3 months

         Turchen  et al. (1991) reported the case of a 39-year-old
    woman, who was found vomiting and confused 7 h after ingesting 59 ml
    of nail polish remover containing 99% acetonitrile (4 g/kg).  About
    12 h after ingestion, she developed severe metabolic acidosis,
    seizures and shallow respiration.  Eight hours after ingestion she
    had a whole blood cyanide level of 3130 µg/litre.  At 65 h the serum
    cyanide level was 10 mg/litre and thiocyanate was 120 mg/litre,
    whereas at 77 h they were 12 mg/litre and 30 mg/litre, respectively. 
    She responded to the treatment with sodium nitrite and sodium
    thiosulfate.  Although she had several relapses, each time she
    responded to sodium thiosulfate administration.  On the fifth
    hospital day the cyanide level was 360 µg/litre and thiocyanate
    level 30 mg/litre and the patient was discharged on day six.

         Geller  et al. (1991) reported a case of acute acetonitrile
    poisoning of a 3-year-old 17.2-kg child who presented to the
    emergency department without any noticeable symptoms approximately
    30 min after ingesting an estimated 15-30 ml of a nail tip and glue
    remover containing acetonitrile.  The amount of ingested
    acetonitrile was estimated to be 0.7 to 1.4 g/kg.  Gastric lavage
    was performed with 1 litre of saline containing 20 g of activated
    charcoal.  Three hours and 45 min after ingestion, the cyanide blood
    level was 1.24 mg/litre and thiocyanate 11 mg/litre.  Eleven hours
    after ingestion the child was alert, but 2 h later the patient
    suddenly vomited, was confused and developed seizures.  A dose of
    35 ml of a 25% solution of sodium thiosulfate was intravenously
    administered over 30 min.  The patient recovered quickly and was
    discharged 42 h later.

         Kurt  et al. (1991) reported a case of a 15.8-kg 2-year-old
    girl who ingested 5-10 ml (0.25-0.5 mg/kg) of a nail glue containing
    84% acetonitrile.  Taken to the hospital, she was asymptomatic and
    discharged.  However, she later became restless and started
    vomiting.  Toxic clonic seizures also appeared about 14 h after
    ingestion.  She was admitted to the hospital comatose with
    hyperpnoea and tachycardia.  Gas analysis showed marked hypoxia and
    acidosis.  She was treated with oxygen and amyl nitrite by
    inhalation.  Activated charcoal was also administered.  She made a
    rapid recovery and was discharged after 2 days.

         Michaelis  et al. (1991) reported a case of suicidal oral
    acetonitrile ingestion in a previously healthy 30-year-old man.  He
    ingested about 5 ml (64 mg/kg) of acetonitrile (98%) and, 30 min
    later, about 1 ml of ammonia and vomited once.  Five hours later he
    was brought to the hospital because of increasing malaise.  On the
    way to the hospital he received 250 mg of  p-dimethyl aminophenol
    and 1 g of sodium thiosulfate.  The patient exhibited livid skin
    colour and excitation.  Gastric lavage with charcoal was performed
    5.5 h after ingestion, and treatment with oxygen and sodium
    thiosulfate (3/g intravenous) was given over 30 min.  He recovered
    quickly and was transferred to a psychiatric unit 30 h after

    ingestion.  Peak serum acetonitrile and blood cyanide levels were
    99.2 and 15.0 mg/litre.  Half-lives were calculated for acetonitrile
    and cyanide and found to be 32 and 15 h, respectively.

         Jones  et al. (1992) reported two fatal cases of a married
    couple who ingested acetonitrile by mistake.  They were found dead
    with traces of vomit.  Acetonitrile levels were 0.8 g/litre in
    blood, 1.0 g/litre in urine and 1.3 g/litre in stomach contents. 
    Blood inorganic cyanide levels were 4.5 mg/litre (male) and
    2.4 mg/litre (female).

         Table 22 summarizes the reports on human acetonitrile

    8.2  Chronic toxicity

         No data are available.

    8.3  Mutagenicity and carcinogenicity

         No data are available concerning the mutagenicity and
    carcinogenicity of acetonitrile in humans.

    8.4  Occupational exposure to cyanide

         El Ghawabi  et al. (1975) studied the effect of chronic
    cyanide exposure in the electroplating sections of three factories
    employing 9, 12 and 15 male workers and compared them with a control
    group.  The concentrations of cyanides to which the workers were
    exposed at the three factories were 10.87, 6.85 and 8.25 ppm,
    respectively.  The duration of exposure and the number of workers
    were: 5 years, 14; more than 5 years, 14; more than 10 years, 7; and
    more than 15 years, 1.  The symptoms listed in order of frequency
    were headache, weakness, changes in taste and smell, irritation of
    the throat, vomiting, effort dyspnoea, lacrymation, abdominal colic,
    and praecordial pain.  Disturbances of accommodation, salivation,
    and nervous instability were found in 8% of the exposed workers. 
    Two workers suffering from psychotic episodes worked in the part of
    the factory where the concentration of cyanides was the highest. 
    None of the 36 workers showed any clinical signs of hypo- or
    hyperthyroidism, but 20 (56%) had mild or moderate thyroid
    enlargement.  However, there was no correlation between duration of
    exposure and the incidence of enlargement, or size of the thyroid. 
    131I thyroid uptakes at 4 and 24 h were significantly higher than
    those in the controls (P < 0.001), while 131PBI (protein bound
    iodine) was unchanged.  There were increased haemoglobin and
    lymphocyte counts in all exposed workers, and punctate basophilia
    was reported in 28 workers.  Cyanmethaemoglobin was found only in
    the blood of the exposed workers, all of whom were non-smokers.  The
    concentration of thiocyanate in urine increased  towards the middle
    of the working week and then became almost stationary during the

    last three days.  The regression line between mean  values of
    urinary thiocyanate in the second half of each working week over 
    two successive months and the mean values of the concentration of
    cyanides in air was linear, being represented by the equation
    M = 0.65C (M = thiocyanate in total amount of urine  in 24 h per mg,
    and C = concentration of cyanide in air in ppm).

         Blanc  et al. (1985) studied acute and residual toxic
    reactions to cyanide in 36 former male workers, aged from 19 to 62
    (with mean age of 33.5 ± 11.4 (SD) years), in a silver-reclaiming
    facility with exposure to high levels of cyanide.  The median time
    since last employment at this facility was 10.5 months and the mean
    duration of employment was 11 ± 10.4 (SD) months (with a medium of
    8.5 months).  Mild abnormalities of vitamin B12 (P < 0.001), folate
    (P < 0.001) and T3 resin uptake (P < 0.01) were detected.

    8.5  Chronic poisoning by cyanides

    8.5.1  Ingestion

         Epidemiological studies suggested a correlation between chronic
    cyanide ingestion from cassava and certain neurological disorders
    (Wilson, 1983; WHO, 1992).

        Table 22.  Summary of reports on human acetonitrile poisoning


    Route of      Number    Estimated      Time of onset    Major symptom           Outcome             Toxicological           References
    exposure        of      doses           of symptoms     findings
                   cases                  after exposure

    Inhalation      16      unknown        several hours    nausea, vomiting,       one dead, others    cyanide and             Admur (1959)
                                                            respiratory failure,    recovered           thiocyanate in
                                                            hypotension                                 blood and urine

    Inhalation       1      unknown             4 h         epigastric pain,        dead                cyanide, thiocyanate    Dequidt et.
                                                            nausea, vomiting,                           and acetonitrile        al. (1974)
                                                            convulsions                                 in blood and urine

    Dermal/          1      approximately       8 h         moaning, poor           survived            cyanide in blood        Carvati &
    inhalation              30 ml                           response, vomiting,                                                 Litovitz (1988)

    Oral             1      15-30 ml       several hours    heavy and noisy         dead 12 h later     cyanide in blood        Carvati &
                                                            breathing                                   and urine               Litovitz (1988)

    Oral             1      40 g                3 h         vomiting, convulsion,   recovery after      not tested              Jaeger et al.
                                                            respiratory failure,    3 months                                    (1977)

    Table 22 (contd).


    Route of      Number    Estimated      Time of onset    Major symptom           Outcome             Toxicological           References
    exposure        of      doses           of symptoms     findings
                   cases                  after exposure

    Oral             1      59 ml              12 h         seizures, shallow       recovery after      cyanide in blood        Turchen et al.
                                                            respiration             5 days              (1991)

    Oral             1      15 to 30 ml        12 h         alert, frightened,      recovery after      cyanide and             Geller et al.
                                                            vomit, confusion        24 h                thiocyanate in          (1991)

    Oral             1      5 to 10 ml       10 - 14 h      moaning, restless,      recovery after            -                 Kurt et al.
                                                            vomiting, seizures      2 days                                      (1991)

    Oral             1      5 ml and            5 h         malaise                 recovery after      acetonitrile and        Michaelis et
                            1 ml ammonia                                            30 h                cyanide in blood        al. (1991)

    Oral             2      unknown           unknown       vomiting                dead                acetonitrile and        Jones et al.
                                                                                                        cyanide in blood        (1992)
                                                                                                        and urine


    9.1  Microorganisms

         Collins & Knowles (1983) reported that the bacterium  Nocardia
     rhodochrous was able to grow at an acetonitrile concentration of
    1.03 g/litre, apparently using acetonitrile as both carbon and
    nitrogen sources.

         Bringmann & Kuhn (1977a) calculated toxicity thresholds based
    on the first detectable inhibition of cell multiplication. For the
    bacterium  Pseudomonas putida the threshold was 680 mg/litre
    acetonitrile and for the green alga  Scenedesmus quadricauda it was
    7300 mg/litre.  Bringmann & Kuhn (1978) calculated a toxicity
    threshold for the cyanobacterium (blue-green alga)  Microcystis
     aeruginosa of 520 mg/litre. For the protozoan  Entosiphon sulcatum
    the threshold was 1810 mg/litre (Bringmann & Kuhn, 1980).

    9.2  Aquatic organisms

         The acute toxicity of acetonitrile to aquatic organisms is
    summarized in Table 23.  Due to the volatility of acetonitrile care
    must be taken when interpreting the test results, especially those
    based on nominal concentrations.

         Acute toxicity data for various fish and other freshwater
    species have been determined by a static bioassay to give an LC50. 
    Values range from 730 mg/litre for  Cyprinus carpio after a 48-h
    exposure to 6500 mg/litre for  Daphnia pulex after a 3-h exposure
    (Nishiuchi, 1981).  According to Bringmann & Kuhn (1977b), the 24-h
    LC50 for  Daphnia magna is more than 10 g/litre.

        Table 23.  Toxicity of acetonitrile to aquatic organisms


    Organism                  Size/age      Water      Temperature    Hardness        pH      Duration       LC50      References
                                         conditionsa      (°C)       (mg/litre)b                 (h)     (mg/litre)c

    Snail                     juvenile      stat          19-21          130        6.5-8.5      96         > 100 n    Ewell et al. (1986)
    (Helisoma trivolvis)

    Flatworm                  juvenile      stat          19-21          130        6.5-8.5      96         > 100 n    Ewell et al. (1986)
    (Dugesia tigrina)

    Segmented worm            juvenile      stat          19-21          130        6.5-8.5      96         > 100 n    Ewell et al. (1986)
    (Lumbriculus variegatus)

    Water flea                juvenile      stat                                                  3          6500
    (Daphnia pulex)           juvenile      stat          19-21          130        6.5-8.5      96         > 100 n    Ewell et al. (1986)

    Water flea                  24 h        stat          20-22                     7.6-7.7      24       > 10 000 n   Bringmann & Kuhn
    (Daphnia magna)                                                                                                    (1977b)

    Sideswimmer (scud)        juvenile      stat          19-21          130        6.5-8.5      96         >100 n     Ewell et al. (1986)
    (Gammarus fasciatus)

    Pillbug                   juvenile      stat          19-21          130        6.5-8.5      96         > 100 n    Ewell et al. (1986)
    (Asellus intermedius)

    Table 23 (contd).


    Organism                  Size/age      Water      Temperature    Hardness        pH      Duration       LC50      References
                                         conditionsa      (°C)       (mg/litre)b                 (h)     (mg/litre)c

    Fathead minnow              1.5 g       stat           25            20           7.4        24         1050 n     Henderson et al. (1961)
    (Pimephales promelas)       1.5 g       stat           25            20           7.4        48         1000 n     Henderson et al. (1961)
                                1.5 g       stat           25            20           7.4        96         1000 n     Henderson et al. (1961)
                                1.5 g       stat           25            380          8.2        24         1150 n     Henderson et al. (1961)
                                1.5 g       stat           25            380          8.2        48         1050 n     Henderson et al. (1961)
                                1.5 g       stat           25            380          8.2        96         1000 n     Henderson et al. (1961)
                              juvenile      stat          19-21          130        6.5-8.5      96         > 100 n    Ewell et al. (1986)

    Bluegill                    2.0 g       stat           25            20           7.4      24 & 96      1850 n     Henderson et al. (1961)
    (Lepomis macrohirus)

    Ctenopharyngodon            5-7 g       stat          10-11                       7.4        24         1950 n     Chen (1981)
    (C. idellus)                                                                                 48          880 n     Chen (1981)

    Guppy                       0.1 g       stat           25            20           7.4      24 & 96      1650 n     Henderson et al. (1961)
    (Poecilia reticulata)

    Medaka                      0.2 g       stat           25                                  24 & 48     > 1000 n    Tonogai et al. (1982)
    (Oryzias latipes)

    Carp                      juvenile                                                           48           730      Nishiuchi (1981)
    (Cyprinus carpio)

    Golden orfe                                                                                  48        5850-7050   Juhnke & Ludemann
    (Leuciscus idus melanotus)                                                                                         (1978)
    a   stat = static conditions (water unchanged for the duration of the test)
    b   Hardness measured as mg CaCO3/litre
    c   n = nominal concentration


    10.1  Evaluation of human health risks

         Acetonitrile is a colourless liquid with an ether-like odour. 
    It is found as a natural product and is manufactured for a variety
    of uses.  It is an excellent solvent for many inorganic and organic
    compounds, including polymers.  It is used for various purposes
    including the separation of butadiene from other C4 hydrocarbon, a
    solvent for spinning synthetic fibres, for casting and moulding
    plastics, for HPLC analysis, as a starting material for organic
    synthesis, and in products for removing artificial finger nails.

         Acetonitrile has not been detected in water but has been in
    bottom sediment in the environment in Japan.  It has also been
    detected in air at low concentrations in some urban and rural
    environments in Germany.  It has not been detected in food. 
    Acetonitrile is found in the stratosphere.  Along with hydrogen
    cyanide, acrylonitrile and other toxic products, acetonitrile is
    produced from the thermal decomposition of polyurethane foams.

         Acetonitrile is readily absorbed by all routes and rapidly
    distributed throughout the body.  It is converted enzymatically to
    cyanide, which is in turn conjugated with thiosulfate, forming
    thiocyanate, and eliminated via the urine.  Some acetonitrile is
    eliminated unchanged in the expired air and urine.  Acetonitrile
    does not accumulate in the body.

         Acute acetonitrile toxicity is due mainly to cyanide formation
    and the signs and symptoms are those of acute cyanide poisoning. 
    The toxic effects of acetonitrile usually appear after a latent
    period (lasting several hours) following exposure.

         In humans, ingestion of 1 to 2 g acetonitrile/kg causes death. 
    Animal experiments indicate that inhalation of acetonitrile at
    concentrations of 8400 to 16 800 mg/m3 (5000 to 10 000 ppm) for
    one hour is fatal.  It is irritant to the eyes and respiratory

         There are no available data on the chronic toxicity of
    acetonitrile in experimental animals or humans.

         High doses of acetonitrile are teratogenic and embryotoxic in
    rats and hamsters; maternal toxicity also occurs at these dose
    levels.  The mechanism for these effects is related to the
    production of cyanide.

         Tables in sections 6 and 7 indicate the reasons for the
    differences in toxicity between acetonitrile, cyanide and other
    nitriles.  These are based on the slow toxicokinetics of
    acetonitrile due to the slower rate of formation of free cyanide

    from acetonitrile compared with other nitriles.  These differences
    account for the different time course of blood cyanide and
    thiocyanate levels and of thiocyanate excretion, as well as for the
    different LD50 values.  It can also be predicted that any
    differences in toxicity across species are probably due to
    toxicokinetics.  Administration of cyanide antidotes such as sodium
    nitrite and sodium thiosulfate are effective.  Care needs to be
    taken in the use of sodium nitrite because of its toxicity.

         Occupational exposure in the production of acetonitrile is low
    because of the enclosed processes.  Poisoning has been associated
    with use and accidental exposure. A time-weighted average (TWA)
    occupational exposure limit of 67 mg/m3 (40 ppm) is used in many

    10.2  Evaluation of effects on the environment

         Acetonitrile has low toxicity to microorganisms and freshwater
    invertebrates and fish.

         The most sensitive species is the common carp  (Cyprinus
     carpio) with a 48-h LC50 of 730 mg/litre.  Application of an
    uncertainly factor of 100, to take into account static tests and
    lack of analytical confirmation, yields a value of 7.3 mg/litre.

         Acetonitrile is seldom present in the environment at measurable
    levels and has not been detected in water.  The highest measured
    level in sediment was 0.54 mg/kg.  It is, therefore, highly unlikely
    that acetonitrile poses any threat to organisms in the environment
    except locally after spills.


    a)   Acetonitrile and mixtures containing it should be clearly
         labelled with a warning of the toxicity of acetonitrile.

    b)   Clinicians should be aware of the delayed onset of signs and
         symptoms following exposure to acetonitrile.


    a)   The measurement of acetonitrile levels in expired air and urine
         should be investigated as a method for the biological
         monitoring of occupationally exposed populations.

    b)   Comparative studies on the kinetics of cyanide formation from
         acetonitrile, as well as of conjugation to thiocyanate and its
         elimination, should be conducted.

    c)   The  in vitro sensitivity of cytochrome  c oxidase to cyanide
         in different species, including humans, should be investigated.


    No previous evaluations by international bodies are available.


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    1.  Propriétés, usages et méthodes d'analyse

         L'acétonitrile (CH3CN) est un sous-produit de la fabrication
    de l'acrylonitrile.  Il peut également se former lors de la
    combustion du bois et de la végétation.  C'est un liquide d'odeur
    éthérée.  L'acétonitrile est un solvant volatil, extrêmement
    polaire, que l'on utilise pour extraire les acides gras ainsi que
    les huiles animales et végétales.  On l'emploie également dans
    l'industrie pétrochimique pour la distillation extractive, du fait
    qu'il présente une miscibilité sélective aux composés organiques. 
    On l'utilise également comme solvant pour le filage des fibres
    synthétiques et dans le formage et le moulage des plastiques.  Au
    laboratoire, on l'utilise largement en chromatographie liquide à
    haute performance (CLHP) ainsi que comme solvant pour la synthèse de
    l'ADN et le séquençage des peptides.

         La technique d'analyse la plus largement utilisée pour
    l'acétonitrile est la chromatographie en phase gazeuse.

    2.  Concentrations dans l'environnement et sources
        d'exposition humaine

         On ne dispose que de très peu de données sur les concentrations
    d'acétonitrile dans l'environnement.  Dans l'ensemble du monde, on
    fait état de concentrations atmosphériques allant de 200 à
    42 000 ng/m3. Une étude donne des concentrations atmosphériques un
    peu plus élevées en milieu urbain qu'en milieu rural.  Une mesure
    effectuée avant et après la combustion de broussailles et de paille
    a montré que la concentration atmosphérique d'acétonitrile était
    multipliée par dix.

         On n'a pas décelé d'acétonitrile dans 72 échantillons d'eau au
    Japon, mais on en a trouvé dans 11 échantillons de sédiments
    aquatiques sur 60 à des concentrations allant de 0,02 à 0,54 mg/kg.
    On n'a pas trouvé d'acétonitrile dans les denrées alimentaires.

         La fumée de tabac contient de l'acétonitrile et la combustion
    de la mousse de polyuréthanne libère de l'acétonitrile et du cyanure

         C'est la production d'acrylonitrile qui présente les plus
    grands risques d'exposition mais elle s'effectue en enceinte fermée.
    L'utilisation pratique de l'acétonitrile peut conduire à une
    exposition plus importante.

    3.  Distribution et transformation dans l'environnement

         L'acétonitrile s'évapore à partir de l'eau et peut également le
    faire à partir de la surface du sol.  Il est facilement décomposé
    par plusieurs souches de bactéries communément présentes dans les

    boues d'égouts, les eaux naturelles et le sol.  L'acclimatation des
    bactéries à l'acétonitrile ou aux déchets de pétrole augmente la
    vitesse de décomposition.  La décomposition anaérobie paraît
    limitée, voire absente.

         L'hydrolyse de l'acrylonitrile est extrêmement lente.  Il n'y a
    pas de photodécomposition sensible dans l'eau ou l'atmosphère.  La
    réaction avec l'ozone est lente, de même qu'avec l'oxygène singulet. 
    Le principal mécanisme d'élimination de l'acétonitrile de la
    troposphère consiste dans sa réaction avec les radicaux hydroxyles;
    la durée estimative de séjour est de 20 à 200 jours.

         L'acétonitrile gagne la stratosphère où il se caractérise par
    son association aux amas d'ions positifs situés dans les régions

    4.  Effets sur l'environnement

         L'acétonitrile est peu toxique pour les microorganismes
    (bactéries, cyanobactéries, algues bleues et protozoaires) avec un
    seuil de toxicité de l'ordre de 500 mg/litre ou davantage.  Les
    valeurs de la CL50 dans le cas d'une intoxication aiguë sont de
    l'ordre de 700 mg/litre ou davantage pour les invertébrés et les
    poissons d'eau douce.  Des tests de toxicité aiguë ont été effectués
    dans des conditions statiques sans confirmation analytique des
    concentrations.  Les résultats analogues obtenus à l'issue de tests
    de 24 et 96 heures donnent à penser qu'il y a volatilisation de

    5.  Absorption, distribution, biotransformation et élimination

         L'absorption de l'acétonitrile s'effectue facilement par la
    voie digestive, percutanée et plumonaire.  Ces trois voies
    d'exposition entraînent toutes des effets généraux.

         L'examen nécropsique de tissus provenant de personnes
    intoxiquées montre que l'acétonitrile se répartit dans l'ensemble de
    l'organisme.  Cette constatation est corroborée par l'étude sur
    l'animal qui montre également que la distribution de l'acétonitrile
    est relativement uniforme dans l'ensemble de l'organisme.  Rien
    n'indique que l'administration réitérée d'acétonitrile n'entraîne
    une accumulation dans les tissus chez l'animal.

         On possède une quantité substantielle de données selon
    lesquelles la majeure partie des effets toxiques généraux de
    l'acétonitrile seraient dus à sa métabolisation en cyanure,
    métabolisation qui est catalysée par le système des monooxygénases
    du cytochrome P-450.  La conjugaison du cyanure avec le thiosulfate
    conduit à la formation de thiocyanate qui est ensuite éliminé dans
    l'urine.  Les concentrations maximales de cyanure dans le sang de
    rats après administration de doses quasi-mortelles d'acétonitrile
    correspondent sensiblement à celles que l'on observe après

    l'administration d'une dose de cyanure de potassium correspondant à
    la DL50.  Toutefois, après administration d'acétonitrile, le pic
    de concentration du cyanure apparaît avec un retard pouvant
    atteindre plusieurs heures, par comparaison avec les autres
    nitriles.  En outre, la vitesse de formation plus élevée du cyanure
    chez la souris explique la sensibilité beaucoup plus forte de cette
    espèce aux effets toxiques de l'acétonitrile.  On a reconnu la
    présence de cyanure et de thiocyanate dans des tissus humains après
    exposition à l'acétonitrile.  Une partie de la dose d'acétonitrile
    est également éliminée telle quelle dans l'air expiré et dans les

    6.  Effets sur les mammifères de laboratoire

         L'acétonitrile produit des effets toxiques analogues à ceux que
    l'on observe en cas d'intoxication aiguë par le cyanure, encore que
    l'apparition des symptômes soit un peu plus tardive que dans le cas
    des cyanures minéraux ou d'autres nitriles saturés.  La CL50 par
    inhalation à 8 heures pour le rat mâle est de 13 740 mg/m3
    (7500 ppm).  La DL50 par voie orale chez le rat va de 1,7 à 8,5 g/kg
    selon les conditions de l'expérience.  Les souris et les cobayes se
    révèlent plus sensibles, avec une DL50 par voie orale de qui est
    de l'ordre de 0,2-0,4 g/kg.  Chez l'animal, les principaux symptômes
    consistent en une prostration suivie de crises convulsives.

         L'application cutanée d'acétonitrile entraîne une intoxication
    générale chez l'animal et on lui a attribué la mort d'un enfant. 
    Chez le lapin, la DL50 par voie percutanée est de 1,25 mg/kg.

         L'exposition subchronique d'animaux de laboratoire à
    l'acétonitrile produit des effets analogues à ceux que l'on observe
    après une intoxication aiguë.

         D'après les épreuves effectuées sur  Salmonella typhimurium,
    l'acétonitrile n'est pas mutagène, qu'il y ait ou non activation
    métabolique.  A très forte concentration, l'acétonitrile a provoqué
    une aneuploïdie chez une souche de levure diploïde.  Il n'a pas été
    fait état d'études sur l'animal qui concernent les effets chroniques
    ou cancérogènes de l'acétonitrile.

    7.  Effets sur l'homme

         On ne connaît pas les concentrations toxiques pour l'homme mais
    il est probable qu'elles sont supérieures à 840 mg/m3
    (500 ppm) d'air.  Les symptômes d'une intoxication aiguë par
    l'acétonitrile consistent en douleurs et sensation de constriction
    au niveau du thorax, nausées, vomissements, agitation, état
    semi-comateux et convulsions.  D'autres symptômes non spécifiques
    peuvent s'expliquer par l'effet irritant du composé.  Les effets
    généraux sont, semble-t-il, en grande partie attribuables à la
    transformation de l'acétonitrile en cyanure.  D'ailleurs, une

    intoxication aiguë provoque une élévation des taux sanguins de
    cyanure et de thiocyanate.  On a signalé deux accidents mortels dus
    à l'exposition à des vapeurs d'acétonitrile sur le lieu de travail
    ainsi que la mort d'un enfant qui avait avalé un produit cosmétique
    contenant de l'acétonitrile.  L'examen nécropsique de ces victimes a
    révélé la présence de fortes concentrations de cyanure dans les

         On ne dispose d'aucune étude épidémiologique sur l'incidence de
    cancers qui seraient liés à une exposition à l'acétonitrile.

         L'acétonitrile peut provoquer de graves brûlures oculaires.  Il
    convient d'éviter tout contact de la peau avec le composé.  Dans de
    nombreux pays, il est recommandé que l'exposition des travailleurs
    ne dépasse pas 70 mg/m3 d'air (40 ppm) en moyenne pondérée par
    rapport au temps au cours d'un poste de travail de 8 heures.


    1.  Propiedades, usos y métodos analíticos

         El acetonitrilo (CH3CN) es un subproducto de la fabricación
    del acrilonitrilo.  También puede formarse por combustión de madera
    y de vegetación.  Es un líquido de olor semejante al del éter.  El
    acetonitrilo es un disolvente volátil de alta polaridad utilizado
    para la extracción de ácidos grasos y de aceites animales y
    vegetales.  Se emplea en la industria petroquímica en la destilación
    extractiva debido a su miscibilidad selectiva con compuestos
    orgánicos.  Se utiliza como disolvente para el hilado de fibras
    sintéticas y en la fusión y el moldeado de plásticos.  Está muy
    difundido su empleo en laboratorio en los análisis por cromatografía
    líquida de alto rendimiento (HPLC) y como disolvente para la
    síntesis de ADN y la secuenciación de péptidos.

         La técnica analítica más ampliamente utilizada para el
    acetonitrilo es la cromatografía de gases.

    2.  Niveles ambientales y fuentes de exposición humana

         Hay muy pocos datos disponibles sobre los niveles de
    acetonitrilo en el medio ambiente.  A escala mundial se han
    notificado concentraciones de acetonitrilo en el aire que oscilaban
    entre 200 y 42 000 ng/m3.  En un estudio se detectaron en el aire
    de zonas urbanas valores algo más elevados que en el de zonas
    rurales.  Mediciones separadas efectuadas antes y después de la
    quema de arbustos y paja mostraron una decuplicación de la
    concentración de acetonitrilo en el aire.

         No se ha detectado la presencia de acetonitrilo en 72 muestras
    de agua del Japón, pero sí en 11 de 60 muestras de sedimentos
    acuáticos, en concentraciones que oscilaban entre 0,02 y 0,54 mg/kg. 
    Tampoco se ha encontrado acetonitrilo en los alimentos.

         El humo de tabaco contiene acetonitrilo y la espuma de
    poliuretano al quemarse libera acetonitrilo y cianuro de hidrógeno.

         Si bien la producción de acrilonitrilo conlleva el máximo
    riesgo de exposición, ésta se efectúa en un sistema cerrado.  Los
    usos prácticos del acetonitrilo entrañan una exposición mayor.

    3.  Distribución y transformación en el medio ambiente

         El acetonitrilo presente en el agua se volatiliza, como también
    se volatilizaría el que se hallase presente en la capa superficial
    del suelo.  Se biodegrada fácilmente por acción de varias cepas de
    bacterias comunes en el fango de alcantarillas, en las aguas
    naturales y en el suelo.  La aclimatación de las bacterias al

    acetonitrilo o a los desechos de petróleo incrementa la tasa de
    degradación.  La degradación anaeróbica parece ser limitada o

         La hidrólisis del acrilonitrilo en el agua es extremadamente
    lenta.  No hay fotodegradación significativa en el agua ni en la
    atmósfera.  La reacción con el ozono es lenta, como también lo es la
    reacción con el oxígeno singlete.  El principal mecanismo para
    eliminar el acetonitrilo de la troposfera es la reacción con
    radicales hidroxilo; los tiempos de residencia se han estimado entre
    20 y 200 días.

         El acetonitrilo llega hasta la estratosfera, en cuyas regiones
    superiores está asociado característicamente en aglomerados de iones

    4.  Efectos ambientales

         El acetonitrilo es poco tóxico para los microorganismos
    (bacterias, cianobacterias, algas verdes y protozoarios) con
    umbrales de 500 mg/litre o más.  Las CL50 agudas para
    invertebrados y peces de agua dulce son de 700 mg/litre o más.  Se
    han hecho pruebas de toxicidad aguda en condiciones estáticas sin
    confirmación analítica de las concentraciones.  Algunos resultados
    semejantes de otras pruebas, obtenidos después de 24 y 96 horas,
    parecen indicar una volatilización del acetonitrilo.

    5.  Absorción, distribución, biotransformación y eliminación

         El acetonitrilo se absorbe fácilmente en el tracto
    gastrointestinal y a través de la piel y de los pulmones.  Se ha
    informado de que la exposición por estas tres vías tiene efectos

         El examen de tejidos en la autopsia de personas envenenadas ha
    mostrado que el acetonitrilo se distribuye por todo el cuerpo.  Esta
    observación está corroborada por estudios realizados en animales, en
    los cuales se ha encontrado que el acetonitrilo se distribuye
    bastante uniformemente en todo el cuerpo.  No hay indicaciones de
    acumulación en los tejidos animales después de administraciones
    repetidas de acetonitrilo.

         Hay datos sustanciales que hacen pensar que el acetonitrilo
    tiene efectos tóxicos sistémicos a través de su transformación
    metabólica en cianuro, catalizada por el sistema de la
    citocromo-P-450-monooxigenasa.  El cianuro se conjuga posteriormente
    con el tiosulfato para formar tiocianato, que se elimina por la
    orina.  Las concentraciones máximas de cianuro en la sangre de ratas
    después de la administración de dosis casi letales de acetonitrilo
    se aproximan a las concentraciones observadas después de la
    administración de una DL50 de cianuro de potasio.  Sin embargo, la
    concentración máxima de cianuro después de la administración de

    acetonitrilo se alcanza con un retraso de hasta varias horas en
    comparación con otros nitrilos.  Por otra parte, la mayor rapidez
    con la cual se produce el cianuro en el ratón parece explicar la
    sensibilidad mucho mayor de esta especie a los efectos tóxicos del
    acetonitrilo.  Se ha detectado la presencia de cianuro y de
    tiocianato en tejidos humanos después de la exposición al
    acetonitrilo.  Parte de la dosis de acetonitrilo también se elimina
    sin modificaciones a través del aire que se exhala y de la orina.

    6.  Efectos en mamíferos de laboratorio

         El acetonitrilo produce efectos tóxicos similares a los
    observados en el envenenamiento agudo con cianuro, aunque los
    síntomas comienzan a manifestarse con algún retraso en comparación
    con los producidos por cianuros inorgánicos u otros nitrilos
    saturados.  La CL50 en machos de rata sometidos a inhalación
    durante 8 horas es de 13 740 mg/m3 (7500 ppm).  La DL50 por vía
    oral en la rata oscila entre 1,7 y 8,5 g/kg, según las condiciones
    del experimento.  Los ratones y los cobayos parecen ser más
    sensibles, con una DL50 por vía oral de 0,2 a 0,4 g/kg.  Los
    síntomas principales en los animales parecen ser la postración
    seguida de convulsiones.

         La aplicación dérmica de acetonitrilo tiene efectos tóxicos
    sistémicos en animales y ha sido un factor causal de defunción en un
    niño.  La DL50 percutánea en conejos es de 1,25 ml/kg.

         La exposición subcrónica de animales al acetonitrilo produce
    efectos similares a los observados después de la exposición aguda.

         El acetonitrilo no ha tenido efectos mutagénicos en ensayos
    realizados con  Salmonella typhimurium, con y sin activación
    metabólica.  En concentraciones muy altas produce aneuploidía en una
    estirpe diploide de levaduras.  No se tiene noticia de estudios
    sobre los efectos crónicos o carcinogénicos del acetonitrilo en

    7.  Efectos en el hombre

         Se desconocen los niveles tóxicos en el hombre, pero
    probablemente rebasen los 840 mg/m3 (500 ppm) en el aire.  Los
    síntomas y signos de la intoxicación aguda con acetonitrilo
    comprenden dolor torácico, sensación de opresión en el pecho,
    náuseas, vómitos, taquicardia, hipotensión, respiración corta y poco
    profunda, dolor de cabeza, agitación, semiinconsciencia y
    convulsiones.  Otros síntomas no específicos tal vez obedezcan a los
    efectos irritantes del compuesto.  Los efectos sistémicos parecen
    atribuibles en gran medida a la conversión del acetonitrilo en
    cianuro.  Los niveles de cianuro y de tiocianato en la sangre son
    elevados durante la intoxicación aguda.  Se han comunicado dos
    defunciones posteriores a la exposición a vapores de acetonitrilo en

    el lugar de trabajo y la defunción de un niño que había ingerido un
    cosmético que contenía acetonitrilo.  Se encontraron concentraciones
    elevadas de cianuro en la autopsia de esas personas.

         No se han notificado estudios epidemiológicos sobre la
    incidencia de cáncer relacionada con la exposición al acetonitrilo.

         El acetonitrilo puede causar quemaduras graves en los ojos. 
    Debe evitarse el contacto de la piel con el acetonitrilo líquido. 
    En muchos países se ha recomendado que la exposición de los
    empleados al acetonitrilo en un turno de 8 horas no rebase un
    promedio, ponderado en función del tiempo, de 70 mg/m3 de aire
    (40 ppm).

    See Also:
       Toxicological Abbreviations
       Acetonitrile (ICSC)