Di-isocyanate de 2,4-Tollylene (French)
methyl-m-phenylene isocyanate (WHO, 1987)
1.4 Identification numbers
1.4.2 Other numbers
Toluene-2,6-diisocyanate CAS number: 91-08-7
Crudell TDI (unidentified isomers) CAS number:
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
Hylene TM 65
Mondur TD 80
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)
2.1 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
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)
TDI monitoring in the workplace.
2.4 First-aid measures and management principles
- 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.
- 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. PHYSICO-CHEMICAL PROPERTIES
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
Colourless to yellow (but darkens on exposure
to sunlight) (WHO, 1987).
Liquid (at room temperature) or crystal.
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
Vapour density (air=1): 6
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.
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. USES/HIGH RISK CIRCUMSTANCES OF POISONING
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
- 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
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. ROUTES OF ENTRY
Ingestion may occur accidentally or in attempted suicides.
Inhalation is the usual and most dangerous route of entry.
Dermal contacts cause sensitization and chemical
Irritation, corneal oedema, and conjunctivitis, among
other ocular effects, have been reported, but the eyes are
not an important route of entry.
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
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
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
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
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.
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).
No data available.
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).
No data available.
8. TOXICOLOGY AND OTHER ANALYSES
9. CLINICAL EFFECTS
9.1 Acute poisoning
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
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).
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.
No reports available.
9.2 Chronic poisoning:
No reports available.
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
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.
No data available.
9.3 Course, prognosis, cause of death
Long-time exposure results in a significant decrease in
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,
Neurological symptoms and even coma may occur after acute
inhalation of high concentrations.
The course of the illness may be complicated by secondary
Death can occur from pulmonary oedema or severe respiratory
9.4 Systemic description of clinical effects
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.
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.,.
220.127.116.11 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
18.104.22.168 Peripheral nervous system
22.214.171.124 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).
126.96.36.199 Skeletal and smooth muscle
No data available.
After acute toluene di-isocyanate inhalation,
nausea, vomiting, and abdominal pain may occur (see
references in section 9.1.2).
9.4.7 Endocrine and reproductive systems
No data available.
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 &
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
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
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
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).
188.8.131.52 Acid-base disturbances
No data available.
184.108.40.206 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
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
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
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
- 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
- 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
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).
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,
No data available
10.6 Antidote treatment
10.7 Management discussion
See relevant sections.
11. ILLUSTRATIVES CASES
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 (39.7°C) .
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
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. ADDITIONAL INFORMATION
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
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
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Author:Dr Per Kulling
Swedish Poison Information Centre Karolinska Hospital
Date: February 1986
Reviewer: Dr Jenny Pronczuk
Hospital de Clinicas
Av Italia s/n
Telex: BINAME LTY 6991
Peer Review: Hamilton, May 1989
London, March 1990
Finalised: IPCS, April 1997