1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS
      1.4.2 Other numbers
   1.5 Brand names/trade names
   1.6 Manufacturers and importers
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Relevant laboratory analyses/sample collection:
   2.4 First-aid measures and management principles
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/form
      3.3.3 Description
   3.4 Other characteristics
   4.1 Uses
      4.1.1 Uses
      4.1.2 Description
   4.2 High-risk circumstances of poisoning:
   4.3 Occupationally exposed populations
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eyes
   5.5 Parenteral
   5.6 Others
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion by route of exposure
   7.1 Mode of action
   7.2 Range of toxicity
      7.2.1 Human data Adults Children
      7.2.2 Animal data
      7.2.3 In vitro data
      7.2.4 Workplace standards
      7.2.5 Acceptable daily intake
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning:
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin contact
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systemic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological Central nervous system Peripheral nervous system Autonomic nervous system Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary Renal Others
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatologic
      9.4.9 Eyes, ears, nose, throat: local effects
      9.4.10 Hematological
      9.4.11 Immunological
      9.4.12 Metabolic Acid-base disturbances Fluid and electrolyte disturbances Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Others
   10.1 General principles
   10.2 Relevant laboratory analyses and other investigations.
      10.2.1 Sample collection
      10.2.2 Biomedical analysis
      10.2.3 Toxicological analysis
      10.2.4 Other investigations
   10.3 Life-supportive measures and symptomatic treatment
   10.4 Decontamination
   10.5 Elimination
   10.6 Antidote treatment
      10.6.1 Adults
      10.6.2 Children
   10.7 Management discussion
   11.1 Case reports from the literature
   11.2 Internally extracted data on cases
   11.3 Internal cases
   12.1 Availability of antidotes and antisera
   12.2 Specific Preventive Measures
                        Toluene diisocyanate

    1.  NAME

        1.1  Substance

             Toluene-2,4-diisocyanate (TDI)


        1.2  Group


        1.3  Synonyms

             2,4-diisocyanatotoluene benzene-2,4-diisocyanate-l-methyl
             isocyanic acid
             Di-isocyanate de 2,4-Tollylene (French)
             2,4-Toluylendiisocyanate (German)
             Toluen-diisocianato (Italian)
             Toluen-Diisocyanaat (Dutch)
             methyl-m-phenylene ester
             methyl-m-phenylene isocyanate (WHO, 1987)

        1.4  Identification numbers

             1.4.1  CAS


             1.4.2  Other numbers

                    Toluene-2,6-diisocyanate CAS number: 91-08-7
                    (NIOSH, 1985)

                    Crudell TDI (unidentified isomers) CAS number:
                    1321-38-6 (WHO,1987)

                    UN number: 2078 (UN, 1984)
                    HAZCHEM code: 2 XE (Hommel, 1986/1987)
                    RTECS access number: CZ 6300000 (2,4-TDI)
                                         CZ 6310000 (2.6-TDI)
                                         CZ 6200000 (80:20 mixture)

        1.5  Brand names/trade names

             Desmodur T 65
             Desmodur T 80
             Lupranat T 80
             Nacconate 100
             Hylene T
             Hylene TCPA
             Hylene TLC
             Hylene TM
             Hylene TM 65
             Hylene TRF
             Mondur TD
             Mondur TD 80
             Mondur TDS
             Niaz TDI
             Niaz TDI-P
             Rubinate TDI 80/20
             TDI 2,4, TDI 80
             (Hommel, 1986/87; NIOSH,  1985).

        1.6  Manufacturers and importers

             (to be completed by each centre)

    2.  SUMMARY

        2.1  Main risks and target organs

             Toluene-2-4-diisocyanate is highly volatile and is an
             irritant to the skin and mucous membranes. The most common
             and most serious effects occur in the lungs. Sudden acute
             bronchospasm attacks, pulmonary oedema, and respiratory
             distress may be life-threatening and may occur days, or even 
             months, after the first exposure.  Symptoms may also be
             delayed.  An additional risk is CNS-depression that can occur
             after exposure to high levels of toluene-2-4-diisocyanate.
             Toluene-2-4-diisocyanate can also irritate the skin, eyes,
             nose, and throat.

        2.2  Summary of clinical effects

             The first symptoms that occur after toluene-2-4-
             diisocyanate exposure are itching of the eyes, lacrimation,
             and irritation of the nose and pharynx.  Respiratory problems
             that include dry cough, chest pain, difficulty in breathing,
             wheezing dyspnea, and respiratory distress may occur later. 
             Symptoms may be delayed or may re-occur after the patient has
             been thought to recover.

             Central nervous system depression may occur together with
             skin problems.
             After low concentrations of exposure over a long time, the
             clinical effects consist of typical asthma with expiratory
             bradypnoea and eosinophilia in the spectorate.

        2.3  Relevant laboratory analyses/sample collection:

                    Blood gases (hypoxia)
                    Chest roentgenogram
                    TDI monitoring in the workplace.

        2.4  First-aid measures and management principles

             If inhaled:
             - Move patient to fresh air;
             - Maintain cardiorespiratory functions;
             - Administer oxygen;
             - Corticosteroids are used in both prevention and treatment
             of respiratory problems (by inhalation and intravenous
             - If bronchoconstriction occurs, use bronchodilators
             (theophylline or B2 receptor stimulants);
             - Observe exposed patients for symptoms of respiratory
             distress for at least 48 hours.
             If ingested:
             - Give water, activated charcoal, and supportive measures, as
             for corrosive ingestion.
             If eye contact:
             - Irrigate eyes with water for 15 minutes and consult
             If skin contamination:
             Wipe off TDI with a dry cloth, and then wash skin thoroughly
             with soap and water (isopropanol 30% may be used as a solvent
             if toluene-2-4-diisocyanate adheres to the skin).


        3.1  Origin of the substance

             Toluene-2-4-diisocyanate is a synthetic organic
             chemical.  It is a natural derivative of primary amines with
             the general formula R-N=C=O.
             Toluene-2-4-diisocyanate does not occur naturally in the

        3.2  Chemical structure

             Molecular formula:        C9H6N202
             Molecular weight:         174.15
             Toluene di-isocyanates are produced as two isomers:  Toluene-
             2,4-diisocyanate (2,4-TDI) and Toluene-2,6-diisocyanate (2,6-
             TDI) which are commercially available in different
                    (i)    > 9.5% 2,4-TDI
                    (ii)   80% 2,4-TDI and 20% 2,6-TDI
                           (this ratio is the most common)
                    (iii)  65% 2,4-TDI and 35% 2,6-TDI.
                           "Crude toluene diisocyanate, with an
                           unidentified isomer ratio, is also commercially
                           available but is not generally used (WHO,

        3.3  Physical properties

             3.3.1  Colour

                    Colourless to yellow (but darkens on exposure
                    to sunlight) (WHO, 1987).

             3.3.2  State/form

                    Liquid (at room temperature) or crystal.

             3.3.3  Description

                    Boiling point: 251 C
                    Melting point: 19.5 to 2l.5 C
                    Autoignition temperature: 620 C
                    Flash point: open cup 135 C
                                 closed cup 127 C
                    (WHO, 1987).
                    Vapour density (air=1): 6
                    (WHO, 1987).
                    TDI is insoluble in water.  It is miscible with
                    alcohol, diglycol, monoethyl ether, ether, acetone,
                    carbon tetrachloride, benzene, chlorobenzene,
                    kerosene, and olive oil (Hommel, 1986/1987; Budavari,
                    It has a sharp pungent, sweet, fruity odour (Hommel,
                    1986/87; Budavari, 1996).
                    The odour threshold is 0.36 to 0.92 mg/m3.
                    (WHO, 1987).

        3.4  Other characteristics

             Toluene di-isocyanates may react violently with
             compounds containing active hydrogen atoms (such as alcohol)
             and generate enough heat to self-ignite and subsequently
             release toxic combustion products.  Other solvents that must
             not be mixed with toluene di-isocyanate include: water, acid,
             bases, and strong alkaline materials, such as sodium
             hydroxide and tertiary amines.
             Toluene di-isocyanate reacts with water and most acids to
             produce unstable carbonic acids, which subsequently
             decarboxylate (raising the pressure in closed containers) to
             yield relatively chemically inert and insoluble polymeric
             Toluene di-isocyanate also reacts with (-NH-) containing
             compounds to form ureides or ureas.
             Each reaction pathway is important in terms of the potential
             health hazards associated with toluene di-isocyanates, since
             both pathways are biologically, as well as commercially,
             significant, and occur at room temperature.

             Toluene di-isocyanates are manufactured in a closed system,
             and air emission is minimal; however, toluene di-isocyanate
             may be emitted into the atmosphere during the removal of
             phosgene and HCl from the first fractionating column.  They
             may be discharged in water effluents (WHO, 1987).


        4.1  Uses

             4.1.1  Uses

             4.1.2  Description

                    Toluene di-isocyanates are reactive ingredients
                    that are used in combination with polyether and
                    polyester polyols to produce polyurethane foams.  They
                    are mainly used in the production of:
                    -   flexible polyurethane foams,
                    -   polyurethane coatings,
                    -   elastomeric coating systems, adhesives, and

        4.2  High-risk circumstances of poisoning:

             Human beings can be exposed to toluene di-isocyanates in
             the environment:
             -   if they are close to areas where emissions occur,
             -   during indiscriminate use of household products, such as
                 polyurethane foam bits (concentrations of toluene di-
                 isocyanate in the air may reach 0.15 mg/m3 during
             -   during application of polyurethane varnishes,
             -   during combustion of polyurethanes, the general public
                 may be exposed to pyrolysis products of toluene di-
                 isocyanates (WHO, 1987),
             -   during transport, as a result of spills or leaks.
             Specific risk groups are people with complicating
             cardiopulmonary diseases, especially chronic bronchitis or
             asthma, and, possibly, smokers.

        4.3  Occupationally exposed populations

             Occupational exposure can occur in all phases of the
             manufacture and use of toluene di-isocyanate because of its

             During the production of polyurethane-coated wire, toluene
             di-isocyanate can be found in the work environment at
             concentrations ranging from 0.001 to 0.11 mg/m3.
             The highest levels of exposure occur during spraying with
             polyurethane foam, in a procedure that is usually conducted
             in confined spaces.
             Lacquer-spray workers and their assistants are exposed when
             using isocyanate lacquers (containing 0.2% to 1% monomeric
             toluene di-isocyanate).
             The jobs in which exposure may occur are: adhesive
             production, application of insulation and production of
             toluene di-isocyanate resins and lacquers, organic chemical
             synthesis, paint spraying, polyurethane foam production, work
             with rubber, shipbuilding, textile processing, and wire-
             coating (WHO, 1987).


        5.1  Oral

             Ingestion may occur accidentally or in attempted suicides.

        5.2  Inhalation

             Inhalation is the usual and most dangerous route of entry.

        5.3  Dermal

             Dermal contacts cause sensitization and chemical

        5.4  Eyes

             Irritation, corneal oedema, and conjunctivitis, among
             other ocular effects, have been reported, but the eyes are
             not an important route of entry.

        5.5  Parenteral

             Not reported.

        5.6  Others

             Not reported.

    6.  KINETICS

        6.1  Absorption by route of exposure

             In experiments in animals, high doses of oral toluene
             di-isocyanate were given. Toluene di-isocyanate formed
             insoluble polyurea-coated globules that persisted long after
             their formation.  It is thought that toluene di-isocyanates
             react with the tissues with which they come in contact,
             rather than being absorbed and distributed.
             Inhalation adversely affects the respiratory tract. These
             effects occur mainly after acute and chronic exposure,
             especially in workers.  After inhalation, toluene di-
             isocyanate also produces systemic effects and
             hypersensitivity reactions (WHO, 1987).
             There are no reports on the systemic absorption of toluene
             di-isocyanate after skin contact.  Studies in animals have
             shown that skin application of toluene di-isocyanate can
             cause pulmonary sensitization (WHO, 1987).

        6.2  Distribution by route of exposure

             No information is available.  It is likely that toluene
             di-isocyanates will react with the tissues with which they
             first came into contact and be transformed into various
             products (WHO, 1987).

        6.3  Biological half-life by route of exposure

             Toluene di-isocyanates are highly reactive in body
             fluids.  They have a reported half-life of less than 30
             seconds in serum and less than 20 min in stomach contents
             (WHO, 1987).

        6.4  Metabolism

             TDIs as all isocyanates, react easily with moist mucous
             membranes, forming primary amines, which further react with
             TDI forming a urea derivative (see section 7.1).
             Some reports on toluene-2,6- diisocyanate in rats showed that
             most of the compound formed polymers in the gastrointestinal
             tract, and that most toluene-2,6-diisocyanate derived
             material was eliminated in the faeces and urine, mainly in
             the form of 2,6-bis-acetylaminotoluene.  The lower dosages of
             toluene-2,6-diisocyanate given to the rats seemed to allow it
             to hydrolyse to monomeric 2,6-diaminotoluene, rather than
             form polymers.  The 2,6-diaminotoluenes could then be
             absorbed, acetylated, and excreted in the urine (NTP,

             Rosenberg and Savolainen (1986) studied workers who were
             occupationally exposed to the 80:20 toluene di-isocyanate
             isomer mixture.They reported that concentrations of tolune
             diamine (TDA) found in the urine after hydrolytic treatment
             were linearly related to the estimated toluene di-isocyanate
             dose.  A possible pathway in the metabolism of toluene di-
             isocyanate would involve the formation of TDA, its
             conjugation, and excretion (but it is not known).

        6.5  Elimination and excretion by route of exposure

             Very little data are available (see Section 6.4).


        7.1  Mode of action

             Like other isocyanates, toluene di-isocyanate is a
             highly reactive compound.  The toxicological properties of
             isocyanates are attributed to the -N=C=O group.  It reacts
             vigorously and exothermically with water forming  an unstable
             carbamic acid that immediately dissociates to form a primary
             amine with liberation of C02. The primary amine so produced
             will react further with excess toluene di-isocyanate
             generating a urea derivative (NIOSH, 1973;  Dodson,1975).
             Isocyanates also react readily with all organic compounds
             that contain reactive hydrogen atoms, especially if the
             hydrogen atom is attached to oxygen, nitrogen, or sulfur as
             in -OH, -NH, -NH2, and -SH groups (e.g. , in carbohydrates,
             lipids, proteins, and their complexes).  For example, toluene
             di-isocyanate will react and combine with a variety of sites
             on the protein molecule to form additional compounds, which
             themselves react to form further additional compounds and to
             polymerize.  Such reactions can denature proteins, form
             abnormal cross-linkages, and generally disorganize the
             protein thus altering its normal function.  This reactivity
             with proteins can account for its potency as a sensitizing
             agent in human beings (NIOSH, 1973; Woolrich, 1973).  Thus,
             more than one reaction may occur in a system at a given
             The toxic effects of toluene di-isocyanate are attributed to
             two different toxic actions:
             a)  A primary irritant action on the mucous membranes of the
             eyes, and the gastrointestinal and respiratory tracts (Fuchs
             & Valade, 1951; Reinl, 1953; Swensson et al.,. , 1955;
             Upjohn, 1970; NIOSH, 1973; Bernstein, 1982; Fish, 1982; 
             Swensson & Andersson, 1985).

             b)  Bronchospasm  due to either a pharmacological or an
             immunological reaction.
             The pharmacological reaction is attributed to altered Beta-
             adrenergic function (NIOSH, 1973; Adams, 1975; van Ert &
             Battigelli, 1975; Butcher et al., 1976; Butcher et al., 1977;
             Chailleux et al., 1982; Swensson & Andersson, 1985), i.e. ,
             blockade of the S adrenergic system by diminishing the
             formation of cyclic adenosine monophosphate (c-AMP) after
             catecholamine stimulation (Adams, 1975; Ert & Battigelli,
             1975; Chailleux et al., 1982; Swensson & Andersson, 1985) .
             It may also be attributed to local histamine release (Fuchs &
             Valade, 1951; Dernehl, 1966; Williamson, 1965; Dodson, 1971;
             NIOSH, 1973; Hansson, 1976; Swensson & Andersson, 1985).
             Toluene di-isocyanate may react with naturally occurring
             proteins or polysaccharides to form immunohapten complexes
             (WHO, 1987) (see also sections 9.1.2 and 9.2.2).
             The immunological reaction is a true allergic reaction that
             includes antigen reactions and the formation of antibodies,
             especiall4y of the IgE type, but also of the IgG type (Konzen
             et al.,., 1966; Taylor, 1970; Weill et al., 1975; Butcher et
             al., 1976; Belin et al., 1981; Swensson & Andersson,

        7.2  Range of toxicity

             7.2.1  Human data


    Table 1: Human exposure to TDI in the air (Swensson & Andersson 1985):

    mg/m3        PPM          Effects
    3.6          0.5          Eye and nose irritation in all exposed
                              (Henschler et al., 1962)
    0.7          0.1          Nose irritation in 1 of 6 exposed people
                              (Henschler et al., 1962)
    0.36         0.05         Eye irritation in 3 of 6 exposed people
                              (Hensler et al., 1962)
    0.2-0.5      0.03-0.07    Mild respiratory tract symptoms in all
                              exposed people (Hama, 1957)

    Table 1 (cont'd)

    mg/m3        PPM          Effects
    0.07-0.21    0.01-0.03    No subjective symptoms
                              (Hama, 1957)
    0.007        0.001        Subjective symptoms only in sensitized
                              people (Vandervort & Shama, 1973).
                             After (acute) exposure to levels above 0.035
                             to 0.70 mg/m3, the symptoms are: eye and
                             nose irritation, burning sensation of the
                             nose and throat, and a choking sensation. 
                             Above 0.70 to 3.5 mg/m3, the respiratory
                             symptoms are irritation, cough, and chest 
                             discomfort. At higher levels, chemical
                             pneumonitis may occur  (WHO, 1987).
                             TCLO = 0.5 PPM (irritation) (NIOSH, 1985).
                             Serious toxic effects occur in human beings
                             at 5 ppm (Ganz & Mager, 1954; Friebel &
                             Luchtrath, 1955; Ehrlicher, 1961; Brugsch &
                             Elkins, 1963; Dernehl, 1966; Butcher,


                             No data available.

             7.2.2  Animal data

                    Toluene di-isocyanate is very toxic for animals
                    when inhaled. Contact with the skin or by ingestion
                    are relatively less toxic (table 2).

    Table 2: Toxicity data of toluene di-isocyanate in animals
                 LD50          LC50 inhalation    LD50 dermal 4 hours
                 (mg/kg)       (PPM)              (mg/kg)
    Rat          4100-5800     2-8                -
    Mouse        4100-5600     1.4-10             -
    Rabbit       3060-4130       -                10.000
    Guinea-pig        -        1.8-13             -
    (Zapp, 1957: Duncan et al., 1962; Woolrich, 1973; NIOSH, 1985; WHO,
                    Animals die of pulmonary oedema and haemorrhage.

             7.2.3  In vitro data

                    The results of an  in vitro study by NTP
                    (1985) showed that toluene-2,6- diisocyanate reacts
                    with both rat serum and stomach contents at 37 C. It
                    appeared to form a polymeric film which encapsulated
                    globules of toluene-2,6- diisocyanate, thus limiting
                    the availability of the compound for further
                    An  in vitro study with human serum albumin
                    demonstrated that toluene di-isocyanate can form mono-
                    or bisureido-protein derivatives.  Such derivatives
                    may be immunogenic and may cause allergic responses,
                    as well as new antigenic determinants (Baur,
                    A significant decrease in erythrocyte cholinesterase
                    activity was found in human erythrocytes exposed to
                    toluene di-isocyanate (Dewair et al., 1983).

             7.2.4  Workplace standards

                    TLV/TWA    0.005 ppm    OSHA
                    STEL       0.02 ppm     OSHA
                    TLV        0.005 ppm    ACGIH
                    STEL       0.02 ppm     ACGIH
                    Irritation of the respiratory tract can occur at
                    levels ranging between 0.712 mg/m3 and 3.560 mg/m3
                    (Henschler et al., 1962).

                    The asthma-like response, evident in up to 10% of
                    previously exposed workers may occur at levels of
                    0.0356 mg/m3 (Bernstein, 1982) . The explanation for
                    this response is still not known, but there is
                    evidence supporting either immunological or
                    pharmacological mechanisms or both (WHO, 1987) (see
                    section 7.1).
                    A variety of respiratory illnesses have occurred in
                    workers occupationally exposed to toluene di-
                    isocyanate.  They include irritation of the upper and
                    lower respiratory tracts, an asthma-like sensitization
                    response, and individual and group mean decreases in
                    lung function.  These decreases have been noted after
                    exposure to 0.014 mg/m3 (short-term and long-term
                    occupational exposure) (see also section

             7.2.5  Acceptable daily intake

                    No data available.

        7.3  Carcinogenicity

             Toluene di-isocyanate is an animal carcinogen when
             administered by gavage. Tumours consist of: subcutaneous
             fibromas, fibrosarcomas, pancreatic acina cell adenomas (in
             male rats); subcutaneous fibromas, fibrosarcomas, pancreatic
             islet-cell adenomas, neoplastic nodules of the liver, and
             mammary gland fibro-adenomas (in female rats); and
             hemangiomas, hemangiosarcomas, and hepatocellular adenomas
             (in female mice) (WHO, 1987).
             According to some reports, there is no evidence of its
             carcinogenic effects in human beings (NIOSH, 1973; Swensson &
             Andersson, 1985).  Turchetto- Mortillaro & Schiavon (1982)
             reported a case of adenocarcinoma in a 47-year-old non-
             smoking spray-painter who had been exposed to isocyanates for
             15 years. However, no epidemiological studies of
             mortality or cancer incidence among exposed workers are
             available (WHO, 1987; IARC, 1986).

        7.4  Teratogenicity

             No data available.

        7.5  Mutagenicity

             There are conflicting reports about the mutagenicity of
             toluene di-isocyanate on bacterial tests (WHO, 1987).
             There is no evidence of mutagenic effects in human beings
             (NIOSH, 1973; Swensson & Andersson, 1985).
             There is one report on chromosomal effects in human
             lymphocytes (Maki-Paakanen and Norppa, 1987).

        7.6  Interactions

             No data available.



        9.1  Acute poisoning

             9.1.1  Ingestion

                    There are no reports of isolated toluene di-
                    isocyanate ingestion in human beings.  Studies in
                    animals have shown that there are corrosive effects on
                    the gastric mucosa after toluene di-isocyanate
                    ingestion (Zapp, 1975; Woolrich, 1982; Swensson
                    Andersson, 1985).
                    Ingestion of a diisocyanate dissolved in methylene
                    chloride resulted in intense abdominal pain, vomiting
                    and diarrhoea in two patients.  Mucosal material was
                    found in the vomitus from one of the patients.  No
                    sequelae were noted (Bernoulli et al.,. 1978; Swensson
                    & Andersson 1985).

             9.1.2  Inhalation

                    Inhalation of toluene di-isocyanate has a
                    primary irritant effect on all parts of the
                    respiratory tract: nose, nasopharynx, larynx,
                    bronchial tree, and bronchiolar system.  The symptoms
                    are: burning irritation of nose and throat,
                    laryngitis, cough, which may be paroxysmal and may or
                    may not produce sputum, retrosternal soreness, chest
                    pain, severe bronchospasm, rales, rhonchi and wheezes,
                    and oppression or constriction of the chest.  In
                    severe cases, even pulmonary oedema may ensue, usually
                    after a recovery period of several hours (12 to 48
                    hours). Superimposed infections and other
                    complications of the respiratory tract may also occur

                    (Ganz & Mager, 1954; Hama, 1957; Henschler et al.,
                    1962; Brugsch & Elkins, 1963; Elkins et al.,., 1962;
                    Glass & Thom, 1964; McKerrow et al.,., 1970;
                    Lineweaver, 1972; NIOSH, 1973; Schmidt-Nowara et al.,
                    1973; Gervais et al., 1973; Axford et al., 1976;
                    Butcher et al., 1977a,b; Bernstein, 1982; Butcher,
                    1982b; Paggiaro et al., 1984; Swensson & Andersson,
                    Neurological symptoms such as headache, insomnia,
                    euphoria, ataxia, neurosis with depression and
                    paranoid tendencies, dizziness, and unconsciousness
                    have been noted after acute inhalation of toluene di-
                    isocyanate vapour (Mastromatteo, 1965; McKerrow et
                    al., 1970; Lineweaver, 1972; NIOSH, 1973; Danger,
                    1973; LeQuesne et al.,., 1976; Swensson & Andersson,
                    1985). These symptoms may persist for weeks and even
                    months after exposure (LeQuesne et al., 1976). Nausea,
                    vomiting, and abdominal pain may also occur after
                    acute TDI vapour inhalation (Fuchs & Valade, 1951;
                    Schurmann, 1955; NIOSH, 1973).
                    Severe cases lead to pulmonary oedema that may occur
                    after a few hours or be delayed, appearing even after
                    recovery (12 to 48 hours post exposure).
                    Impotence may also occur (Barlow & Sullivan, 1982;
                    Swensson & Andersson, 1985).
                    Apart from the direct irritant effects, an acute
                    allergic -like reaction may occur after a delay of
                    several hours (oculorhinitis, asthmatic syndrome) and
                    also after exposure to low concentrations, even when
                    there have been no initial symptoms.  This delayed
                    acute reaction is more likely to occur after repeated
                    exposure to toluene di-isocyanate (Elkins et al.,
                    1962; Brugsch & Elkins, 1963; Longley, 1964; Dernehl,
                    1966; Belin et al., 1981; Paggiaro et al., 1985;
                    Swensson & Andersson, 1985).

             9.1.3  Skin exposure

                    Liquid toluene di-isocyanate produces a marked
                    transient inflammatory reaction with redness,
                    irritation, and dermatitis. No serious skin lesions
                    have been reported. Toluene di-isocyanate vapour and
                    aerosol may also cause skin irritation that occurs
                    only at levels higher than those that cause
                    respiratory effects (Fahy, 1958; Munn, 1960; Fisher,
                    1967; NIOSH, 1973; Schmidt-Nowara et al.,. , 1973;
                    Woolrich, 1982, Swensson & Andersson, 1985) . Skin
                    sensitization may also occur but is rare, and there is
                    no relationship between skin sensitivity and

                    respiratory sensitivity to toluene di-isocyanate
                    (Dernehl, 1966; Sweet, 1968; Peschel, 1970; NIOSH,
                    1973; Rothe, 1976; Emmett, 1976; Liden, 1980; Swensson
                    & Andersson, 1985).
                    There are no reports of skin absorption of toluene di-

             9.1.4  Eye contact

                    Transient smarting, burning, or prickling
                    sensation and lacrimation may occur after exposure to
                    lower concentrations, especially in chronic exposure
                    (Henschler et al., 1962; NIOSH, 1973).
                    Severe lacrimation, blepharospasm, conjunctivitis,
                    keratitis, corneal oedema, or photophobia, are seen
                    after exposure to liquid or high-vapour concentrations
                    (Brugsch & Elkins, 1963; NIOSH, 1973; Schmidt-Nowara
                    et al.,., 1973; Grant, 1986; Kolmodin-Hedman et al.,
                    1980; Luckenbach & Kielar, 1980; Alexandersson et al.,
                    1984).  Severe iridocyclitis and secondary glaucoma
                    have also been reported (Grant, 1986).  No permanent
                    eye damage has been reported.  Delayed oculorhinitis
                    may occur (Paggiaro et al., 1985).

             9.1.5  Parenteral exposure

                    No reports available.

             9.1.6  Other

                    No reports available.

        9.2  Chronic poisoning:

             9.2.1  Ingestion

                    No reports available.

             9.2.2  Inhalation

                    Apart from the acute or delayed symptoms that
                    occur after acute exposure to toluene di-isocyanate
                    vapour, repeated low-level exposure to toluene di-
                    isocyanate may lead to hypersensitivity reactions due
                    to a progressive sensitizing process (see section -
                    toxic mechanisms).  This may lead to acute and severe
                    asthmatic attacks immediately or within a few hours
                    after repeated toluene di-isocyanate exposure, or to
                    recurrent episodes of influenza-like illness,
                    associated with pneumonitis or active interstitial
                    lung disease, often associated with eosinophilia and

                    antibody formation (Fuchs & Valade, 1951; Holmqvist et
                    al.,., 1953; Ganz & Mager, 1954; Friebel & Luchtratch,
                    1955; Ehrlicher, 1961; Brugsch & Elkins, 1963; Scheel
                    et al.,. , 1964; Konzen et al.,. , 1966; Dernehl,
                    1966; Peters et al.,. , 1968; Avery et al.,., 1969;
                    Taylor, 1970; Fristedt & Haeger-Aronsen, 1972; NIOSH,
                    1973; Peters & Wegman, 1975; Weill et al.,. , 1975;
                    Adams, 1975; Charles et al.,. , 1976; Butcher et al.,.
                    , 1976; Butcher et al.,. , 1977; Chester et al.,. ,
                    1979; White et al.,., 1980; Kolmodin-Hedman et al.,.,
                    1980; Butcher, 1982a; Butcher, 1982b; Baur et al.,.
                    1982; Paggiaro et al.,., 1984; Levy & Fink, 1985;
                    Paggiaro et al.,. , 1985; Peters & Wegman, 1975; 
                    Swensson & Andersson, 1985).
                    Risk of respiratory toxicity from repeated exposure
                    can be summarized in:
                          i)  chronic loss of ventilatory capacity as
                          measured by forced expiratory volume and forced
                          vital capacity.
                          ii) immediate and/or delayed asthmatic
                          responses (WHO, 1987).
                    However, one report suggests that toluene di-
                    isocyanate exposure at the levels of 0.001 ppm may not
                    induce adverse pulmonary effects when the workers are
                    not hyper-sensitized to toluene di-isocyanate (Omae,
                    1984).  It refers to a 2-year observation of

             9.2.3  Skin contact

                    Skin sensitization on repeated exposure to
                    toluene di-isocyanate may occur, but systemic
                    poisoning has not been reported through skin
                    Skin lesions may be eczematous, irritant, pruritic,
                    and erythematous (WHO, 1987).
                    Studies in animals have shown that skin application of
                    toluene di-isocyanate can cause pulmonary
                    sensitization, and it is recommended that repeated
                    skin contact should be avoided (WHO, 1987).

             9.2.4  Eye contact

                    Toluene di-isocyanate is an ocular irritant. No
                    chronic poisonings from eye exposure are

             9.2.5  Parenteral exposure

                    No data available.

             9.2.6  Other

                    No data available.

        9.3  Course, prognosis, cause of death

             Long-time exposure results in a significant decrease in
             lung function.
             Low concentrations of toluene di-isocyanate (much below
             current occupational exposure) can cause asthma in sensitized
             individuals (WHO, 1987).
             Usually, at the end of a toluene di-isocyanate exposure that
             ranges from a few days to 2 months, symptoms include
             irritation of the conjunctiva, nose, and pharynx.  Later,
             there are respiratory problems: cough in the evening, and
             chest pain and dyspnea that become worse during the night. 
             After a few days, rest, these symptoms may be alleviated, but
             a return to work is generally accompanied by a recurrence of
             the cough, chest pains, wheezing dyspnea, and respiratory
             distress.  Chest roentgenogram and blood tests are usually
             negative and the patient can recover without sequelae when
             kept out of the polluted atmosphere.  Some people may also
             have cutaneous problems, mostly eczematous (ILO, 1983).
             The asthmatic reaction may be immediate (reaching a peak
             within minutes), retarded (2 to 8 h after exposure) and may
             be biphasic or recurrent (Baur et al.,. 1982).  Exposures to
             very low concentrations over > 1 to several years may result
             in typical asthma with  eosinophilia in the sputum (ILO,
             1983) .
             Neurological symptoms and even coma may occur after acute 
             inhalation of high concentrations.
             The course of the illness may be complicated by secondary
             lung infection.
             Death can occur from pulmonary oedema or severe respiratory

        9.4  Systemic description of clinical effects

             9.4.1  Cardiovascular

                    There is no definite evidence that toluene di-
                    isocyanate has cardiovascular toxicity. Brugsch and
                    Elkins (1963) reported the case of a 62-year-old spray
                    painter who, after a 7-day exposure to toluene di-
                    isocyanate, had an EKG which showed hypertrophy of the
                    left ventricle, a chest x-ray with prominent
                    bronchovascular markings and an enlarged cardiac
                    silhouette.  The patient improved and was discharged
                    after 4 days.

             9.4.2  Respiratory

                    The main effects of toluene di-isocyanate are
                    on the entire respiratory system.
                    Acute exposure causes throat irritation, a choking
                    sensation, cough, chest pain, wheezing dyspnea, and at
                    high levels, chemical pneumonitis.  Pulmonary oedema
                    can occur even hours or days after apparent
                    Long-term exposure causes: (i) immediate or delayed
                    asthmatic responses (with the typical wheezing dyspnea
                    and eosinophilic sputum); or (ii) chronic loss of
                    ventilatory capacity (measured by forced expiratory
                    volume and forced vital capacity). The asthmatic
                    response is evident in up to 10% of previously exposed
                    patients and may occur at toluene di-isocyanate levels
                    of 0.0356 mg/m3 (Bernstein, 1982) . The asthmatic
                    reaction may be immediate (reaching a peak within
                    minutes), retarded (2 to 8 hours after exposure) and
                    may be biphasic or recurrent (Baur et al.,.

             9.4.3  Neurological

            Central nervous system

                             Headache, insomnia, euphoria,
                             ataxia, neurosis with depression and paranoid
                             tendencies have been reported.  Dizziness and
                             even unconsciousness may occur after acute
                             inhalation of toluene di-isocyanate vapour
                             (see references in section 9.1.2) . Central
                             nervous system (CNS) symptoms may persist for
                             weeks or months after exposure (LeQuesne et
                             al.,., 1976).

            Peripheral nervous system

                             No reports.

            Autonomic nervous system

                             It has been suggested that abnormal
                             cholinergic receptor activity or adrenergic
                             blockage may increase the bronchial airway
                             hyperreactivity to toluene di-isocyanate
                             (WHO, 1987) (see section 7.1.b)  Impotence  
                             may occur (Barlow & Sullivan, 1982; Swensson
                             & Andersson, 1985).

            Skeletal and smooth muscle

                             No data available.

             9.4.4  Gastrointestinal

                    After acute toluene di-isocyanate inhalation,
                    nausea, vomiting, and abdominal pain may occur (see
                    references in section 9.1.2).

             9.4.5  Hepatic

                    No reports.

             9.4.6  Urinary


                             No reports.


                             No reports.

             9.4.7  Endocrine and reproductive systems

                    No data available.

             9.4.8  Dermatologic

                    Skin sensitization may occur after repeated
                    exposure to toluene di-isocyanate.  Urticaria,
                    dermatitis, and allergic contact dermatitis are
                    reported in workers exposed to toluene di-isocyanate
                    based photopolymerized resins (Brugsch & Elkins,

                    Dermatological symptoms include eczematous, irritant,
                    pruritic, or erythematous skin lesions.  Lesions occur
                    on exposed areas but may spread to covered areas (WHO,

             9.4.9  Eyes, ears, nose, throat: local effects

                    - odour imperceptible (in 30 min exposure) at
                    < 0.07 to 0.14 mg/m3 (0.01 to 0.02 ppm);
                    - recognized odour = 0.35 mg/m3 (0.05 ppm)
                    - slight irritation of eyes, nose, throat = 0.35 to
                    0.70 mg/m3 (0.05 to 0.1 ppm) (Henschler et al.,.,
                    - lacrimination and rhinitis = 0.7 to 3.5 mg/m3 (0.1
                    to 0.5 ppm)
                    The irritative effect was greater in response to
                    toluene-2,6-diisocyanate than to toluene-2,4-
                    Eye contact with toluene di-isocyanate (vapour,
                    aerosols,or liquid) causes mild irritation, with
                    itching and lacrimation, which may progress to
                    conjunctivitis (Brugsch & Elkins, 1963; Luckenbach &
                    Kielar, 1980).
                    Microcystic corneal oedema in both eyes have been
                    reported in a 40-year-old female polyurethane foam
                    worker (Luckenbach & Kielar, 1980).
                    Clouded vision, decreased visual acuity, and loss of
                    light perception developed within 1 week of employment
                    and returned to normal after 3 days without exposure
                    (Belin et al., 1983).
                    Oculorhinitis may be delayed a few hours (Paggiaro et
                    al., 1985).

             9.4.10 Hematological

                    There have been no reports on effects on blood
                    or blood-forming organs except for leukcocytosis and
                    eosinophilia in sensitized persons (see sections 9.1.2
                    and 9.2.2).

             9.4.11 Immunological

                    Exposure to low toluene di-isocyanate
                    concentrations (0.14 mg/m3) cause hypersensitivity
                    in a variable percentage of people at risk.  It may
                    occur immediately, or after months or even years of
                    exposure.  Hypersensitivity to toluene di-isocyanate
                    may be evaluated with RAST (Radio Allergo-Sorbent
                    Test) assays but neither the antibody responses to
                    this specific antigen, nor the level of IgE antibody,
                    were consistently elevated in people with
                    hypersensitivity or asthmatic responses (Baur, 1983;
                    Belin et al., 1981).
                    Asthma caused by from toluene di-isocyanate exposure
                    appears to be a complex syndrome resulting from
                    several mechanisms, including IgE in some people (WHO,
                    Present immunoassay techniques will not detect all
                    susceptible individuals.
                    Mono- and bisureido derivatives of toluene di-
                    isocyanate  in vitro reaction with human serum
                    albumin may be immunogenic and may possibly lead to
                    allergenic responses as well as to new antigenic
                    determinants (Baur, 1983).

             9.4.12 Metabolic

           Acid-base disturbances

                             No data available.

           Fluid and electrolyte disturbances

                             No data available.


                             No data available.

             9.4.13 Allergic reactions

                    Skin rashes, asthma, hypersensitivity,
                    pneumonitis, and other toluene di-isocyanate induced
                    effects raised a controversy, that has yet to be
                    resolved, over the relative importance of immune-
                    controlled responses versus pharmacologically mediated
                    response in sensitized workers (WHO, 1987) (see
                    section 9.4.11).

             9.4.14 Other clinical effects

                    No data available.

             9.4.15 Special risks

                    People with cardiopulmonary diseases,
                    especially chronic bronchitis and asthma, are at
                    greater risk of developing clinical effects.
                    Pregnancy: No data available
                    Breast feeding: No data available
                    Enzyme deficiencies: No data available

        9.5  Others

             No data available.


        10.1 General principles

             After inhalation the patient should be kept from
             further contact with toluene di-isocyanate and, if
             symptomatic, be given oxygen, bronchodilators, and
             corticosteroids.  Clinical treatment and observation should
             be prolonged because there is a risk of delayed respiratory
             After eye contact: thorough irrigation for a few minutes and
             ophthalmologic consultation.
             After skin exposure: wash with plenty of water and then with
             soap and water.

        10.2 Relevant laboratory analyses and other investigations.

             10.2.1 Sample collection

                    - Blood and urine (routine and other
                    biomedical analysis)

                    - Sputum for detection of eosinophilia (or secondary
                    - Sampling of toluene di-isocyanate in the

             10.2.2 Biomedical analysis

                    - Blood and urine routine analysis (or other
                    according to patient's clinical condition
                    - Blood gases (for evaluation of hypoxia).
                    - Chest X-ray
                    - Electrocardiogram
                    - After acute episodes: measurements of ventilatory

             10.2.3 Toxicological analysis

                    Monitoring of toluene di-isocyanate in the air
                    (no practical methods are available for in human

             10.2.4 Other investigations

                    In preparation

        10.3 Life-supportive measures and symptomatic treatment

             Toluene di-isocyanate Inhalation
             If there are acute symptoms:
             - Complete bed rest, if possible in semi-recumbent position,
             even if acute symptoms have subsided.
             - Administer oxygen.
             - Optimal symptomatic treatment including bronchodilators
             (theophylline, Beta2-receptor stimulants) and assisted
             - Corticosteroid therapy has been successful in preventing
             and treating toxic pulmonary damage (Lorin & Kulling, 1986) :
             Inhalation of betamethasone spray and systemic corticosteroid
             treatment may be useful:
             (a)  after moderate exposure:
             give betamethasone (or an equivalent corticosteroid
             preparation), 4 to 8 mg iv as a single dose; repeat if
             (b)  after severe exposure with or without toxic pulmonary
             oedema: give betamethasone (or an equivalent corticosteroid
             8 to 16 mg iv 3 to 4 times daily.

             - If there are delayed symptoms: treat delayed symptoms with
             supportive therapy and corticosteroids.
             Toluene di-isocyanate Ingestion
             General supportive measures as for mild corrosive ingestion
             (see section 10.4).

        10.4 Decontamination

             If TDI is ingested:
             - Give water to dilute toluene di-isocyanate.
             - Emesis is contraindicated because of TDI's corrosive
             - Careful gastric lavage may be indicated if larger amounts
             have been ingested.
             - Give activated charcoal.
             - General supportive measures as for corrosive ingestion.
             Eye contact with toluene di-isocyanate:
             Irrigate eyes water for at least 15 minutes if eyes have been
             splashed with liquid toluene di-isocyanate or exposed to high
             vapour concentrations.  Consult an ophthalmologist.
             If there is irritation or pain after eyes have been exposed
             to low vapour concentrations, irrigate eyes with water for 15
             minutes, if irritation or pain persists, consult an
             Skin contact with toluene di-isocyanate
             Wipe off toluene di-isocyanate with a dry cloth.
             Irrigate skin with plenty of water and wash thoroughly with
             soap and water.
             If toluene di-isocyanate still adheres to the skin, 30% 
             isopropanol could be used as a solvent as toluene di-
             isocyanate is soluble in alcohols (Hommel, 1986/87; Budavari,

        10.5 Elimination

             No data available

        10.6 Antidote treatment

             10.6.1 Adults

                    None available.

             10.6.2 Children

                    None available.

        10.7 Management discussion

             See relevant sections.


        11.1 Case reports from the literature

             A 62-year-old male spray-painted the inside of a tank
             for 7 days without respiratory protection.  His symptoms were
             faintness, nausea, vomiting of foaming material, anxiety,
             rapid pulse rate, high blood pressure, fever, and cyanosis. 
             The ECG showed left ventricular hypertrophy and the chest
             roentgenogram an enlarged cardiac silhouette.  The patient
             improved and was discharged after 4 days (Brugsch & Elkins,
             A group of firemen involved in both firefighting and clean-up
             at a polyurethane foam factory where 4,500 litres of toluene
             di-isocyanate had leaked, had symptoms during and/or after
             the incident.  Gastrointestinal distress was reported in 15
             patients, 4 of whom had it again the following day. It
             consisted of: abdominal pain, diarrhoea, nausea, and
             vomiting. (All gastrointestinal symptoms ceased within 2
             days).  Neurological symptoms were reported in 25 firemen,
             and were either immediate (5 patients), or delayed.  Acute
             symptoms were euphoria, ataxia, intermittent shaking of the
             limbs, dizziness, and loss of consciousness.  In 14 firemen,
             other symptoms such as headaches, difficulty in
             concentration, poor memory and confusion persisted for 3
             weeks.  In 13 firemen after 4 years, poor memory was the most
             common symptom, followed by personality change, irritability,
             or depression (LeQuesne et al., 1976; Axford et al., 1976).
             Simultaneous exposure to other pyrolysis products complicates
             interpretation of the data.
             Cold-like symptoms, nocturnal sweating, and gastrointestinal
             and neurological symptoms in exposed workers have been
             reported (Hama, 1957).

             A 43-year-old non-smoking moulder (female) had throat
             irritation and cough after 4 months of exposure to toluene
             di-isocyanate.  Dyspnoea became worse during workdays and
             caused an acute episode that required emergency treatment. 
             One month later, after exposure was stopped, the patient was
             asymptomatic and her pulmonary function returned to normal. 
             Subsequent symptomatic episodes were successfully treated
             with isoproterenol (Smith et al., 1980).
             Thirty-eight workers who were exposed to toluene di-
             isocyanate at a polyurethane foam factory for 1 day (Monday)
             showed statistically significant decreases in forced vital
             capacity (FVC), forced expiratory volume (FEV), peak-flow
             rate, and an forced expiatory flow (FEF) of 25 to 50%.  After
             5-day exposure (Friday) in 34 workers, the FVC returned to
             baseline, the FEV was still depressed, and the respiratory
             flow rates were more depressed.  Diurnal variation could not
             account for these changes.  Workers who already had
             respiratory symptoms showed greater decreases in FEV (Peters
             et al.,. 1968).

        11.2 Internally extracted data on cases

             (Swedish Poison Information Centre)
             A 17-year-old male inhaled toluene di-isocyanate after an
             explosion of a toluene di-isocyanate tank. On admission to
             hospital, he presented with the following symptoms:
             respiratory distress, rhinitis, flushed skin, increased 
             muscular tone, shivering, vertigo, sweating, restlessness,
             fatigue, confusion, and vomiting.
             Most symptoms subsided within 6 hours, except for vomiting
             and fatigue that subsided within 24 hours. The patient fully
             recovered after another 24 hours. Initial treatment included
             oxygen, theophylline, and corticosteroids.
             A 40-year-old man's skin and eyes were splashed with toluene
             di-isocyanate during unloading work at a plant.  His skin and
             eyes were immediately irrigated with water.  He had slight
             transient respiratory distress, but no skin symptoms. 
             Chemosis occurred in one eye together with slight corneal
             opacification.  Prolonged eye irrigation was performed and
             his symptoms subsided within 48 hours.
             A 37-year-old male was admitted to hospital with headache,
             malaise, shivering, slight transient respiratory distress,
             "aching all over", tachycardia, and hyperthermia (39.7C) .
             He had been spray-painting while wearing a protective face
             mask that was not working.  His symptoms subsided
             spontaneously within 12 hours. The patient had presented with
             similar symptoms on two previous occasions.

             A 53-year-old male was splashed in the face with toluene di-
             isocyanate at a plant.  Irrigation with water only was
             started immediately. on admission to hospital, he presented
             with obstructive pulmonary symptoms.  An X-ray showed mild
             infiltrations on one lung that disappeared 2 days later.  An
             "asthma infusion", including corticosteroids, was
             administered for 24 hours and his symptoms subsided during
             this time.  The patient was observed for another 24 hours and
             then discharged.
             A 46-year-old male was splashed in the face with toluene di-
             isocyanate.  Irrigation with water was started immediately. 
             On admission to hospital the patient presented with no
             symptoms except for a slight transient irritation of the
             eyes.  A single dose of corticosteroids was given

        11.3 Internal cases

             Added by PC using monograph.


        12.1 Availability of antidotes and antisera


        12.2 Specific Preventive Measures

             A preemployment medical examination must include a
             questionnaire and a physical so that people with allergic
             cutaneous or respiratory problems will not be placed in
             hazardous jobs.
             Exposed workers must be kept under routine observation.
             Working clothes, gloves, goggles, and protective materials
             must be cleaned regularly.
             Respiratory protection must be provided with masks that have
             a prefilter.  However, if the toluene di-isocyanate
             concentration is high, the best form of protection is an air-
             supplied breathing apparatus.
             Industrial waste must not be destroyed by burning.  In fires
             involving isocyanates, carbon dioxide or powder extinguishers
             must be used and firemen must wear self-contained breathing
             Ref: ILO, 1983.


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    14. AUTHOR(S)/DATE

        Author:Dr Per Kulling
                    Swedish Poison Information Centre Karolinska Hospital
                    Box 60500
                    10401 Stockholm
                    Tel: 46-8-338765
                    Fax: 46-8-327584
        Date:       February 1986

        Reviewer:   Dr Jenny Pronczuk
                    CIAT 70
                    Hospital de Clinicas
                    Av Italia s/n
                    Tel: 598-2-470300
                    Fax: 598-2-470300
                    Telex: BINAME LTY 6991
        Peer Review:         Hamilton, May 1989
                             London, March 1990
        Editor:              M.Ruse
        Finalised:           IPCS,  April 1997

    See Also:
       Toxicological Abbreviations