MONOGRAPH FOR UKPID
TOLUENE DIISOCYANATE
Mary-Jane Bennie
National Poisons Information Service (London Centre)
Medical Toxicology Unit
Guy's & St Thomas' Hospital Trust
Avonley Road
London
SE14 5ER
UK
This monograph has been produced by staff of a National Poisons
Information Service Centre in the United Kingdom. The work was
commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review group: Directors of the UK National Poisons Information
Service.
1 SUBSTANCE/PRODUCT NAME
1.1 Origin of substance
Toluene diisocyanates are not known to occur as natural products. They
are manufactured by the reaction of diaminotoluenes with phosgene.
1.2 Name
1.2.1 Compound
Toluene di-isocyanate
1.2.2 Generic names
Desmodur T100, Hylene-T, Mondur-TD, Mondur-TD-80, Nacconate-100, Niax
isocyanate TDI, Rubinate TDI
Rubinate TDI 80/20, T 100, TDI-80, TDI 80-20.
1.2.3 Synonyms
TDI, toluene diisocyanate, benzene 1,3 iisocyanatomethyl-, isocyanic
acid, methyl phenylene ester, isocyanic acid, methyl-m-phenylene
ester, methyl-meta-phenylene diisocyanate, methylphenylene isocyanate,
methyl-m-phenylene isocyanate, toluene-1,3-diisocyanate,
diisocyanates, diisocyanatotoluene, tolylene diisocyanate, tolylene
isocyanate.
1.2.4 Common names/street names
Toluene diisocyanates are produced as 2 isomers: 2,4 toluene
diisocyanate (2,4-TDI) and 2,6-toluene diisocyanate (2,6-TDI).
They are commercially available in 3 isomer ratios:
* > 99.5% 2,4-TDI
* 80% 2,4-TDI:20% 2,6-TDI, which is the most common and referred to
in this document as 80:20 mixture
* 65% 2,4-TDI:35% 2,6-TDI
'Crude' TDI, with an unidentified isomer ratio, is also commercially
available, but not widely used. By far the most widely used is the
80:20 isomer mixture.
Chemical name Common name
commercial mixture
2:4-, 2,6- isomers TDI
2,4-TDI TDI, 2,4-TDI
2,6 -TDI 2,6-TDI
1.3 Chemical group/family
Isocyanates.
1.4 Substance identifier and/or classification by use
1.5 Reference numbers
Number 2,4-TDI 2,6-TDI Commercial mixture
(80:20)
CAS 584-84-991-08-7 26471-62-5
RTECS CZ 6300000 CZ 6310000 CZ 6200000
EINECS 2095445 2020390 2477224
UN 2078
CEC 615-006-00-4
1.6 Manufacturer
Data not found.
1.7 Supplier/importer/agent/ licence holder
Data not found.
1.8 Presentation
1.8.1 Form
Colourless liquid or crystals with pungent odour; turn pale yellow on
exposure to air.
1.8.2 Formulation details
No data available.
1.8.3 Pack sizes available
No data available.
1.8.4 Packaging
No data available.
1.9 Physico-chemical properties
Chemical structure
TDIs are synthetic organic chemicals with a molecular formula of
C9H6N2O2 and the following chemical structure (R = -N=C=O).
Physical state
At room temperature liquid or crystals.
Colour
Colourless to pale yellow.
Odour
Distinct pungent, sweet, fruity, odour detectable around
0.7mg/m3.
Solubility in water and organic solvents
Soluble in acetone, alcohol, benzene, ethyl acetate, ether,
carbon tetrachloride, chlorobenzene, kerosene, and various oils,
e.g. corn oil. TDI reacts with water, releasing carbon dioxide
(Lewis, 1992).
Autoignition temperature
620°C
Important chemical interactions
They may react violently with compounds containing active
hydrogen, such as alcohols, with the generation of enough heat to
lead to self-ignition and subsequent release of toxic combustion
products. Other solvents that must not be mixed with toluene
diisocyanates include water, acids, bases, and strong alkaline
materials (Hardy and Purnell, 1978) such as sodium hydroxide and
tertiary amines. Toluene diisocyanates react with water and most
acids to produce polymeric urea.
Major products of combustion/pyrolysis
When heated to decomposition TDI emits toxic fumes of oxides of
nitrogen (Sax and Lewis, 1989).
Explosion limits
For 2,4 TDI
Concentration (% v/v)
lower 0.9%
upper 9.5%
Boiling point
At 760mmHg 251° C
At 10mmHg 120° C for 2,4-TDI
121° C for commercial mixture
Density (g/cm3)
2,4-TDI 1.22g/mL 25/15
Commercial mixture(2,4-,2,6-isomers) 1.22 g/mL 25/15 (both
mixes)
Vapour pressure
Pa at 20° C : 1.3
Relative vapour density
6.0
Flash point
open cup 135 (2,4-TDI)
132 (commercial mixture-2,4-, 2,6-isomers)
closed cup 127(2,4-TDI)
Reactivity
TDI forms potentially violent polymerisation reactions with bases
or acyl chlorides, reaction with water liberates carbon dioxide
(Lewis, 1992). TDI can react with alanine. The heat of this
reaction may be sufficient to ignite surrounding combustibles and
the material itself.
It reacts violently with amines, alcohols, bases, and warm water,
causing explosion hazards. Strong oxidizers, water, and acids
cause foam and splatter. TDI is combustible when exposed to heat
or flame. When heated to decomposition, TDI emits highly toxic
fumes of oxides of nitrogen (Lewis, 1992). TDI polymerizes in the
presence of alkali.
1.10 Hazard/risk classification
1.11 Uses
Toluene diisocyanates are reactive intermediates that are used in
combination with polyether and polyester polyols to produce
polyurethane products. The production of flexible polyurethane foams
represents the primary use of toluene diisocyanates (approximately 90%
of the toluene supply). The 80:20 mixture is used in their production
at an average of 30% by weight. Domestic consumption of flexible
polyurethane foam in the USA in 1981, estimated at 499 x 106 kg, can
be broken down into the following uses (in million kg): furniture
(208.7), transportation (99.8), bedding (63.5), carpet underlay (72.6)
and other uses (11.3). An estimated 27 x 106 kg of rigid polyurethane
foams, used in refrigeration equipment was produced with 'crude' TDI
in the USA in 1982 (US EPA 1984).
Polyurethane coatings represent the second largest market for toluene
diisocyanates. Toluene diisocyanates are also used in the production
of polyurethane elastomeric casting systems, adhesives, sealants and
other limited uses (Brandt, 1972; Granatek et al, 1975; Aragon et al,
1980).
TDI is one of the most common isocyanates employed in the manufacture
of polyurethane foams, elastomeres, and coating. Foams are used in
furniture, packaging, insulation and boat building. Flexible foams are
made of TDI, whereas the rigid foams have the less volatile MDI
(Finkle, 1983). Polyurethane coatings are used in leather, wire, tank
linings, masonary, paints, floors and wood finishes. Elastomers are
abrasion and solvent resistant, and are used in adhesives, coated
fabrics, films, linings, clay pipe seals, and in abrasive wheels, and
other mechanical items.
1.12 Toxicokinetics
1.12.1 Absorption
Absorption of toluene diisocyanates through the respiratory tract is
suggested by their high acute toxicity for animals via inhalation and
reports of systemic effects and antibody formation in individuals
exposed to toluene diisocyanates primarily via inhalation (Sharonova
and Kryzahanovskaya, 1976; Steinmetz et al, 1976; White et al, 1980).
1.12.2 Distribution
No information was found regarding the distribution of toluene
diisocyanates in mammalian systems. Because of the wide distribution
of water and other nucleophiles in tissues, it is likely that toluene
diisocyanates will react with the tissues they initially contact and
be transformed into various products.
1.12.3 Metabolism
Reaction of TDI with human serum albumin yields mono- or bisureido
protein derivatives (ITIC/USEPA 1981).
Hydrolysis of both isocyanate groups produce 2,4-toluene diamine, a
carcinogen (ITIC/USEPA 1981).
1.12.4 Elimination
No data available.
1.12.5 Half-life
No data available.
1.12.6 Special populations
No data available.
2 SUMMARY
3 EPIDEMIOLOGY OF POISONING
No data available.
4 MECHANISM OF ACTION/TOXICITY
4.1 Mechanism
TDI exposure tends to have a cumulative effect in man. There are two
classes of reaction to TDI :
1. primary irritation or pharmacodynamic action to which all exposed
persons are susceptible to some degree and
2. sensitisation reaction or allergic response in those persons who
have become sensitised to TDI during earlier exposure (Butcher et al,
1977)
TDI is a severe irritant to all living tissues with which it comes in
contact in liquid or vapour form, especially the mucous membranes of
the eyes, gastrointestinal and respiratory tract. It also has a marked
inflammatory reaction on direct skin contact (Hathaway et al, 1988).
Respiratory sensitisation occurs in susceptible persons after repeated
exposure to TDI at levels of 0.002ppm and below (Elkins, 1962). A
chronic syndrome consisting of coughing, wheezing, tightness or
congestion in the chest and shortness of breath has been characterised
with repeated exposures at such low concentrations (NIOSH, 1973).
A sensitised individual in addition to the aforementioned instant
reactions may be afflicted with marked tissue eosinophilia and acute
pneumonitis with inflammatory oedema of the lungs (Fabbri, 1985;
Fabbri, 1987; Zocca et al, 1990 ).
Some individuals who have been reported to have an allergic response
have been demonstrated to have circulating antibodies to TDI or to
TDI-animal protein conjugates (Butcher et al, 1977; Fabbri, 1987;
Finkel, 1983; Karol, 1980; Karol, 1981).
Further evidence is the demonstration of lymphocyte transformation in
TDI sensitised workers induced by TDI-conjugated proteins.
TDI-induced late asthmatic reactions have been attributed to increased
bronchovascular permeability caused by leukotriene B4 levels which
also promote granulocyte adherence and leukocyte migration into
tissues (Zocca et al, 1990).
Because one micromole of TDI can stimulate methacholine-induced
tracheal ring contractions, the pharmacological effect of TDI is
believed to be due to an autonomic imbalance between cholinergic and
beta-adrenergic neural control (Borm et al, 1989).
Epithelial damage, thickening of basement membrane, and mild to
moderate inflammatory reaction in the submucosa were demonstrated in
TDI-sensitised patients who have ceased work within 4 to 40 months
prior to bronchial biopsy (Paggiaro, 1990).
4.2 Toxic dose
In the UK and many other countries, a maximum permissible
concentration of TDI in the atmosphere to which operatives may be
exposed continuously has been laid down, the ceiling threshold limit
value TLV(C), and it is 0.02 parts per million (0.01ppm in Sweden),
but exposure to even lower concentrations than this may produce
asthmatic symptoms of varying intensity in sensitised persons. Ceiling
Threshold Limit Value TLV(C), is defined as the maximum concentration
of material in the atmosphere that can be tolerated throughout a 7 to
8 hour working day, or a 40 hour working week. The TLV(C) is expressed
in ppm (i.e. parts of vapour per million parts of contaminated air by
volume at 25° C and 760mmHg pressure) and in mg/m3 (i.e. milligrams
per cubic metre of air). It is important to note that on contact with
water, TDI is converted to toluene diamine which is carcinogenic to
both mice and rats (National Cancer Institute, 1979). Each
diisocyanate on hydrolysis might produce breakdown products with
different carcinogenic properties.
Exposure to higher concentrations may cause symptoms in individuals
who have not become allergic. In mild cases the affected individual
usually experiences slight irritation of the eyes, nose and throat.
There may be cough, particularly troublesome at night, and sense of
tightening in the chest. In more severe cases the individual
experiences acute bronchial irritation and difficulty in breathing.
Detection of TDI by smell is an unreliable procedure since the minimum
concentration of isocyanate vapour that can be detected by most people
in this manner exceeds 0.1ppm. However with reasonable care
concentrations can be kept below the permissible limit of 0.02ppm.
TDI levels of 0.3 to 0.7 ppm was associated with a high incidence of
illness but no cases were observed from concentrations below 0.03 ppm
(Hama, 1947). The maximum incidence of illnesses occurred when the
average concentration of vapour was 0.1 ppm and very little trouble
was reported at 0.01 ppm (Walworth and Virchow, 1959).
No respiratory symptoms or changes in pulmonary function were noted
among workers pouring and moulding polyurethane foam and breathing as
much as 0.001 to 0.002 ppm TDI (Roper and Cromer, 1975). Occasional
exposures to TDI beyond 0.02 ppm caused no significant deterioration
in lung function (Erlicher and Brochhagen, 1976).
A dose-response relationship was demonstrated between acute pulmonary
function changes and exposure of 112 workers to 0.0035 to 0.06
milligram TDI/cubic meter (IARC, 1979). Exposure of volunteers have
shown that 0.05 to 0.1ppm TDI in the air can cause eye and nose
irritation (Grant and Schuman 1993 ). A normal age- and smoking-
related rate of decline forced expiratory volume in 1 second (FEV1)
was demonstrated in subjects exposed to 0.001 to 0.0015 ppm TDI thus
negating any effects of TDI at these levels (Musk et al, 1985).
Permissible Exposure levels
The threshold Limits Committee of the American Conference of
Governmental Industrial Hygienists (ACGIH) adopted 0.1ppm as a
tentative exposure limit in 1956. In 1959 this was changed from a
tentative to a recommended value. In 1961 the recommended maximum
allowable concentration of TDI was changed to 0.02ppm. A concentration
of 0.01ppm was recommended in 1962 at the ACGIH Annual meeting and in
1968 the ACGIH recommended a ceiling of 0.02ppm for TDI. In 1973 the
national institute for occupational safety and health recommended that
TDI be controlled so that no workers be exposed to a time-weighted
average (TWA) concentration of TDI more than 0.005ppm for any 8 hour
work day or for any 20-minute period to more than 0.02ppm (NIOSH,
1973).
In 1978 it was recommended that the period of the TWA was extended to
a 10-hour day (or 40-hour week) and that the ceiling level be 0.02ppm
for any 10-minute period (NIOSH, 1978). The recommendations of the
ACGIH in 1980 were for 0.005ppm as an 8-hour TWA with excursions to a
ceiling of 0.02ppm for four 15-minute periods a day.
5 FEATURES OF POISONING
5.1 Acute
Toluene diisocyanate are irritant to skin, lungs, the mucous membranes
of the conjunctiva and the gastrointestinal tract. They may also cause
euphoria, ataxia and mental aberrations. The signs and symptoms of
acute exposure are non-specific and include, complaints of irritation
of the nose and throat, shortness of breath, choking, coughing,
retrosternal discomfort or pain, and gastrointestinal stress (e.g.
nausea, vomiting and abdominal pain). The onset of signs and symptoms
may be delayed following exposure, and may persist for several days,
months, or years following exposure, and may persist for several days,
months, or years following removal from the contaminated environment
(Walworth and Virchow 1959; Munn 1960; NIOSH 1978).
5.1.1 Ingestion
There have been no reports of human ingestion. Necropsy of rats
revealed corrosive action on stomach as well as possible toxic effects
on the liver (ACGIH 1986).
5.1.2 Inhalation
This is the commonest route of exposure. TDI is a strong irritant of
the eyes, mucous membranes, and skin. It is a potent sensitizer of the
respiratory tract. A common respiratory system response to inhaled TDI
is both acute and chronic diminution of ventilatory capacity, measured
by a decrease in FEV1 even in the absence of other overt symptoms
(Adams, 1970; Adams, 1975; Moller et al, 1986; Venables, 1985; Weill
et al, 1981). Exposure of humans to sufficient concentrations causes
irritation of the eyes, nose and throat, a choking sensation, and a
productive cough of the paroxysmal type, often with retrosternal
soreness and chest pain (NIOSH, 1973; Elkins et al, 1962). If the
breathing zone concentration reaches 0.5 ppm, the possibility of
respiratory response is imminent (Rye, 1973). Depending on the length
of exposure and the level of concentration above 0.5 ppm, respiratory
symptoms will develop with a latent period of 4 to 8 hours (Rye,
1973). Higher concentrations produce a sensation of oppression or
constriction of the chest. There may be bronchitis, severe
bronchospasm or pulmonary oedema. Nausea and vomiting and abdominal
pain may complicate the presenting symptoms. Upon the subject's
removal from exposure, the symptoms may persist for 3-7 days (Rye,
1973).
Although the acute effects may be severe, their importance is
overshadowed by respiratory sensitisation in susceptible persons, this
has occurred after repeated exposure to levels of 0.02 ppm TDI and
below (Elkins 1962). This will be further discussed in the chronic
exposure section.
5.1.3 Dermal
Dermal absorption is low but irritation and inflammation are common.
5.1.4 Ocular
Eye contact with toluene diisocyanates (vapour, aerosols, or liquids)
causes mild irritation, characterised by itching and lacrimation,
which may progress to conjunctivitis and keratoconjunctivitis (Brugsh
and Elkins, 1963; Luckenbach and Kieler, 1980). Oculorhinitis may also
occur and be delayed by a few hours (Paggiaro et al, 1985).
Severe conjunctival irritation and lacrimation may occur following
exposure of liquid or high vapour concentration (Axford et al, 1976).
Burning or prickling sensations from lower concentrations have been
reported (Grant and Schuman, 1993).
Iridocyclitis and secondary glaucoma were noted in a workman who
accidentally splashed TDI in one eye (Grant and Schuman 1993).
5.1.5 Other routes
No data available.
5.2 Chronic toxicity
5.2.1 Ingestion
No data available.
5.2.2 Inhalation
The onset of symptoms of sensitisation may be insidious, becoming
progressively more pronounced with continued exposure over a period of
days to months. Initial symptoms are nocturnal dyspnoea and/or
nocturnal cough with progression to asthmatic bronchitis (NIOSH 1973).
Immediate, late and dual patterns of bronchospastic response to
laboratory exposure to TDI in sensitised individuals have been
observed, confirming the clinical findings of nocturnal symptoms in
some exposed workers. The time from initial employment to the
development of symptoms suggestive of asthma has been reported to vary
from 6 months to 20 years.
5.2.3 Dermal
Skin sensitisation on repeated exposure to toluene diisocyanates may
occur. Urticaria, dermatitis, and allergic contact dermatitis have
been reported in workers exposed to toluene diisocyanates-based
photopolymerised resins (Brugsch and Elkins, 1963; Calas et al, 1977).
The dermatological symptoms included skin lesions of an eczematous,
and also, of an irritant, pruriginous and erythematous nature. Studies
on experimental animals have shown that skin application of TDI can
lead to pulmonary sensitisation thus, it is prudent to avoid repeated
skin contact.
5.2.4 Ocular
Evidence of microcystic corneal oedema and conjuctival infection in
both eyes in a polyurethane foam worker has been reported (Luckenbach
and Kieler, 1980).
5.2.5 Other routes
Data not available.
5.3 Systematic description of clinical effects
5.3.1 Cardiovascular
Data not available.
5.3.2 Respiration
Peters and Murphy (1970) identified four general patterns of airway
response to TDI in man :
1. chemical bronchitis (following high doses)
2. isocyanate asthma (in "sensitised" subjects)
3. acute asymptomatic deterioration in airway function during a long
shift and
4. chronic deterioration in airway function with prolonged low levels
of exposure.
Later, a fifth pattern of airway response was observed:
5. failure of asthma to clear in sensitised subjects whose exposure to
isocyanates has ceased (Paggiaro et al, 1984; Peters and Wegman,
1975).
In high enough concentrations isocyanates have a primary irritant
effect on the respiratory tract producing complaints of dry throat and
cough. In addition they may give rise to acute pulmonary oedema some
hours after exposure which may be fatal. An asthmatic attack may
result at these levels as well as at levels devoid of an immediate
irritant effect. When asthmatic attacks occur immediately on exposure
and cease shortly after exposure ceases, cause and effect are readily
associated. Asthmatic attacks may occur at an interval of hours after
cessation of exposure, presenting as nocturnal cough and dyspnoea,
when the association may be less obvious. The natural history of
continued exposure in the latter presentation may be the development
of symptoms during, as well as after cessation of exposure.
Even if the affected worker transfers from isocyanate work, recovery
may be protracted. Cough may be the dominant feature.
Characteristically it is dry, only producing a small amount of sputum
after a severe protracted bout of coughing. Dyspnoea may dominate and
vary from gross acute airway obstruction with cyanosis and distress to
dyspnoea only on effort. Sensitised workers may develop asthma at
atmospheric levels of isocyanate below the control limit. Interstitial
pulmonary fibrosis has been reported as a long term hazard.
Burning or irritation of nose and throat, choking sensation, cough
which may or may not produce blood-streaked sputum, laryngitis,
retrosternal soreness and chest pain have been reported (Elkins et al,
1962; NIOSH, 1973).
Depending upon the length of exposure and level of concentration above
0.5ppm, respiratory symptoms will develop with a latent period of 4 to
8 hours (Rye, 1973) and based on the onset of symptoms, asthmatic
reactions to isocyanate challenge have been classified as immediate,
late or dual (Fabbri, 1990). At the end of a few days to two months of
exposure, lacrimation and irritation of the conjunctivae and pharynx
occur and are later coupled with dry nocturnal cough and sternal pain.
The symptoms worsen in the evening and disappear in the morning with
minimal mucus production. Symptoms diminish after a few days rest but
recur upon return to work. The characteristic substernal pain may be
due to the paroxysmal or persistent cough often associated with
inhalation. Asthmatic syndrome, chronic bronchitis, emphysema and cor
pulmonale have been noted with high exposures (Axford et al, 1976).
The onset of symptoms experienced by the TDI sensitised individual may
be insidious, becoming progressively more pronounced with continued
exposure over days to months. The initial symptoms of dyspnoea and
cough can progress to severe asthma and bronchitis (ACGIH, 1986;
Bruckner et al, 1968; Porter et al, 1975; Weill et al, 1981;
Williamson, 1965).
Workers exposed to low TDI levels may also experience sudden acute and
severe asthmatic reactions (Banks et al, 1986). Late asthmatic
reactions have been documented in sensitised workers in association
with early elevations of the neutrophils, eosinophils, leukotrienes
B4, and albumin in bronchoalveolar lavage fluid (Fabbri 1990; Fabbri
et al, 1985; Fabbri et al, 1987; Zocca et al, 1990).
Susceptibility to TDI-induced asthma does not require a prior history
of atopy or allergic conditions, and sensitisation may not be
especially common in atopics (Bernstein 1982). Given sufficient
exposure, it appears that virtually any person may become sensitised.
The proportion of individuals with TDI asthma in working populations
has varied from 4.3% to 25% (ACGIH 1986). There is some evidence that
this percentage has decreased with decreasing air concentrations.
Exposure to spills of TDI appears to increase the risks of
sensitisation. The pathophysiology of TDI-induced asthma is unknown.
Both immunological and non-immunological pharmacological mechanisms
have been postulated. Amines may play a causative role in TDI-induced
asthma (Berlin et al, 1983). It is clear however, that TDI-induced
asthma is not solely mediated by a type I hypersensitivity response
associated with IgE antibody (Bernstein, 1982).
Several studies have provided evidence of cross-shift and progressive
annual declines in FEV1 of 25% to 75% among asymptomatic workers
without evidence of TDI asthma when exposed to low levels of TDI
(below 0.02ppm and as low as 0.003ppm). The annual declines were
two-to threefold greater than expected, appeared dose related, and
correlated with observed cross-shift declines. Workers, in general,
exhibited no acute or chronic symptoms or pulmonary function
decrements related to these exposures (Diem et al, 1982; Wegman et al,
1982).
The diagnosis of TDI-induced asthma relies primarily on the clinical
history in a worker with known exposure, recognising that symptoms
such as wheezing, dyspnoea and cough develop at night long after the
end of the shift. Serial measurement of peak flow rates by the worker
may help one to make the diagnosis (Burge et al, 1979). Non-specific
bronchial hyperreactivity to histamine or methacholine is frequently,
but not invariably present in patients with TDI-induced asthma. Its
absence may indicate that the asthma is quiescent owing to no recent
exposure, and re-exposure may lead to hyperreactivity. Failure to
demonstrate non-specific hyperreactivity on a single test does not
exclude the diagnosis of TDI-induced asthma (Burge et al, 1982). RAST
testing for IgE antibodies against p-tolyl monoisocyanate antigens
probably is not useful because of the occurrence of false positive (in
exposed but asymptomatic workers) and false negative results (Butcher
et al, 1983).
Specific bronchoprovocation challenge with TDI is a definitive way to
make the diagnosis, but often is not practical because of the need for
prolonged observation for late reactions and the risk of severe
reactions.
Following removal from exposure, some patients have had resolution of
symptoms and findings suggestive of asthma.
Long term respiratory symptoms with slightly impaired ventilatory
function have been reported and in some, irreversible damage has been
documented (Adams, 1970; Adams, 1975; Banks et al, 1990; Innocenti et
al, 1981; Luo et al, 1990; Mapp et al, 1988; Moller et al, 1986;
Paggiaro et al, 1984; Venables et al, 1985; Weill et al, 1981).
Lozewicz et al (1987) reported that 82% of 50 patients followed up,
continued to have respiratory symptoms four or more years after
avoidance of exposures, and nearly one half of these patients required
treatment at least once per week.
A 43 year old male with a 6 year history of TDI induced asthma
developed a fatal asthma attack while mixing 2 components of a
polyurethane paint. Despite advice to change jobs he continued to work
while taking anti-asthmatic drugs at home and work to control his
symptoms of asthma (Fabbri et al, 1988).
Haemorrhagic pneumonia was diagnosed in a 34 year old spray painter
who presented with haemoptysis, dyspnoea, bilateral pulmonary
opacities, respiratory failure and high levels of IgG and IgE
antibodies against HDI-HSA (hexamethylene diisocyanate human serum
albumin) and TDI-HSA (Patterson et al, 1990). He was declared normal
after 2 days of assisted ventilation and 11 days of steroids.
Hypersensitivity pneumonitis was confirmed by biopsy in a 41 year old
automobile paint sprayer who presented with dyspnoea, cyanosis, fever,
crepitant rales, reticulonodular radiographic infiltrates, restrictive
pulmonary function, and elevated TDI-specific IgG (Yoshizawa et al,
1989). He improved markedly with prednisolone and oxygen.
A 53 year old steel plant maintenance worker who occasionally glued
pipes together presented with cough, fever, malaise interstitial
pneumonitis, eosinophilia, and elevated IgG antibody levels specific
for diphenylmethane diisocyanate (MDI) (Walker et al, 1989).
5.3.3 Neurological
Firefighters exposed to TDI and possibly other substances experienced
neurological complaints of euphoria, loss of co-ordination and loss of
consciousness. Long-lasting symptoms of personality change,
irritability, depression, and loss of memory (confirmed by
psychometric testing) were also reported (Le Quesne et al, 1976;
McKerrow et al, 1970; O'Donoghue 1985). Whether these complications
are a result of neurotoxic or hypoxaemic effects of diisocyanates is
not known.
5.3.4 Gastrointestinal
Inhalation of vapour or aerosol may produce vomiting and abdominal
pain (Axford et al, 1976). Epigastric and substernal pain may be
secondary to the paroxysmal or persistent cough associated with
inhalation.
5.3.5 Hepatic
No data available.
5.3.6 Urinary
No data available.
5.3.7 Endocrine and reproductive system
Possible impotence. Fire-fighters exposed to TDI and possibly other
substances suffered from impotence for some time after exposure. This
was thought to be due to an indirect neurological effect rather than
to direct toxicity to the male genitalia (Le Quesne et al, 1976).
5.3.8 Dermatological
Skin sensitisation on repeated exposure to toluene diisocyanates may
occur. Urticaria, dermatitis, and allergic contact dermatitis have
been reported in workers exposed to toluene diisocyanates-based
photopolymerised resins (Brugsch and Elkins, 1963; Calas et al, 1977).
The dermatological symptoms included skin lesions of an eczematous,
and also, of an irritant, pruriginous and erythematous nature. A 21
year old female developed a rash following direct skin contact with
toluene diisocyanates. The urticaria or maculopapular lesions occurred
primarily over exposed areas, but occasionally spread to covered areas
and lasted for up to 10 days after exposure. Titres of specific Ig E
antibodies gradually declined over the period of observation from a
high level after occupational exposure ceased. The low level
corresponded to those found in non-sensitised toluene diisocyanates
workers (Karol et al, 1978).
5.3.9 Eye, ears, nose and throat
Burning and irritation of the nose and throat and laryngitis have been
reported. Severe conjunctival irritation and lacrimation from liquid
or high vapour concentrations is likely. Lower concentrations may
produce a burning or prickling sensation. Glaucoma and iridocyclitis
have been reported with a splash incident.
5.3.10 Haematological
No data available.
5.3.11 Immunological
Elevated specific IgE and IgG antibodies have been noted among
sensitised and exposed workers. Positive skin test reactions to
TDI-conjugates with human serum albumin and positive TDI-specific IgE
and IgG antibodies have been reported but the exact mechanism involved
is still unknown (Butcher et al, 1977; Cartier et al, 1989; Finkel,
1983; Karol et al, 1979; Karol, 1980; Keskinen et al, 1988; Wass and
Berlin, 1989).
Serum chemotaxis factor - Release of a serum chemo-attracting factor
for normal neutrophils and activation of asthmatic were demonstrated
among workers with late asthmatic reaction to TDI (Valentino et al,
1988).
HDI-specific Ig G antibodies were elevated in a car painter who had 3
episodes of hypersensitivity pneumonitis-like disease after exposure
to acrylic lacquers with hexamethylene diisocyanate (HDI) as the
curing agent (Selden et al, 1989).
5.3.12 Metabolic
5.3.12.1 Acid-base disturbances
No data available.
5.3.12.2 Fluid and electrolyte disturbances
No data available.
5.3.12.3 Other
5.3.13 Allergic reactions
5.3.14 Other clinical effects
5.4 At risk groups
5.4.1 Elderly
No data available.
5.4.2 Pregnancy
No data available.
5.4.3 Children
No data available.
5.4.4 Enzyme deficiencies
No data available.
5.4.5 Enzyme induced
No data available.
5.4.6 Occupations
In the USA, it is estimated that 40,000 workers are involved in the
manufacture or processing of toluene diisocyanate. As far as the
general population is concerned, intake of toluene diisocyanates,
apart from their use in the form of polyurethane lacquers and paints,
is of a very low order, because of the short persistence of TDI.
5.4.7 Others
6 MANAGEMENT
6.1 Decontamination
Ingestion
No applicable.
Inhalation exposure
Monitor patient for respiratory distress. If a cough or difficulty in
breathing develops, evaluate for respiratory tract irritation,
bronchitis and pneumonia. Sensitised individuals should be cautioned
to avoid further exposure as serious allergic reactions may result.
Move patient to fresh air. Monitor for respiratory distress. If cough
or difficulty in breathing develops, evaluate for respiratory tract
irritation, bronchitis, or pneumonitis. Administer 100% humidified
supplemental oxygen with assisted ventilation as required.
Eye exposure
Exposed eyes should be irrigated with copious amounts of tepid water
for at least 15 minutes. If irritation, pain, swelling, lacrimation,
or photophobia persist, the patient should be seen by an
ophthalmologist.
Dermal exposure
Wash exposed areas thoroughly with soap and water. A physician may
need to examine the area if irritation or pain persists.
6.2 Supportive care
Monitor patient for respiratory distress. Bronchodilators and oxygen
may be resorted to in an acute attack. If necessary consider
endotracheal intubation and ventilation.
6.3 Monitoring
Monitor patients for respiratory distress and bronchospasm.
6.4 Antidotes
None available.
6.5 Elimination techniques
No data available.
6.6 Investigations
Perform respiratory function tests to assess degree of bronchospasm
induced by inhalation of TDI. In acute exposure arterial blood gases
should also be performed if the patient exhibits respiratory distress.
6.7 Management controversies
Several placebo-controlled randomized double-blind crossover studies
have been conducted to investigate the efficacy of varying
bronchodilators. Theophylline (6.5mg/kg twice a day) has only partial
effect (Mapp et al, 1987). Prednisolone and aerosolised beclomethasone
(1mg twice daily) have been shown to prevent late asthmatic reactions
or increased airway responsiveness in TDI-sensitized patients (De
Marzo et al, 1988, Fabbri et al, 1985).
7 CASE DATA
Case 1 - Neurological complications after a single severe
exposure.
Le Quesne et al, (1976) reported on a group of fireman who were
heavily exposed to toluene di-isocyanate while fighting a fire in a
factory where polyurethane foam was manufactured. During the course of
the fire a total of 4500 litres of TDI leaked from 2 storage tanks and
the men were exposed intermittently over 8 hours to TDI in the air and
some of them by direct contact with TDI which soaked their clothing
and equipment. Other chemicals were also used at the plant but with
the massive leakage of TDI it was felt that their symptoms were most
likely to be due to that chemical. During and after the fire 31 out of
35 men complained of respiratory symptoms and 16 out of 35 men of
gastrointestinal symptoms. In 23 cases, the men complained of
neurological symptoms such as difficulty in concentrating, poor
memory, headache, irritability or depression. In the 5 of these cases
there had been acute onset of euphoria, ataxia, and loss of
consciousness. Amongst the various neurological abnormalities observed
up to 3 weeks after a fire, there were 2 complaints of impotence for 2
weeks. One of the cases was one of the 5 men who suffered from loss of
consciousness during the fire and he still shows signs of ataxia and
had an abnormal EEG at 3 weeks with persistent neurological symptoms
including prominent depression up to 4 years after a fire. In the
other case, there was confusion in the first three weeks and ataxia
and abnormal EEG at 3 weeks with persistent memory difficulties up to
4 years after the fire. Of the 23 complaining of neurological effects,
18 were re-examined 4 years after the fire and 13 were found to be
still clinically affected with difficulty in concentration,
irritability and depression. Psychometric testing also confirmed a
selective memory deficit in long term recall in those still affected.
Thus, from the spectrum of effects observed it seems likely that the
reported temporary impotence in 2 of the exposed individuals was
probably secondary to neurological impairment following heavy exposure
to TDI.
Case 2
A 43 year old male with a 6 year history of TDI-induced asthma
developed a fatal asthma attack while mixing 2 components of a
polyurethane paint. Despite advice to change jobs he continued to work
while taking anti-asthmatic drugs at home and work to control his
symptoms of asthma (Fabbri et al, 1988)
Case 3
Haemorrhagic pneumonia was diagnosed in a 34 year old spray painter
who presented with haemoptysis, dyspnoea, bilateral pulmonary
opacities, respiratory failure and high levels of IgG and IgE
antibodies against HDI-HSA (hexamethylene diisocyanate human serum
albumin) and TDI-HSA (Patterson et al, 1990). He was declared normal
after 2 days of assisted ventilation and 11 days of steroids..
Case 4
Hypersensitivity pneumonitis was confirmed by biopsy in a 41year old
automobile paint sprayer who presented with dyspnoea, cyanosis, fever,
crepitant rales, reticulonodular radiographic infiltrates, restrictive
pulmonary function, and elevated TDI-specific IgG (Yoshizawa et al,
1989). He improved markedly with prednisolone and oxygen.
Case 5
A 53 year old steel plant maintenance worker who occasionally glued
pipes together presented with cough, fever, malaise, interstitial
pneumonitis, eosinophilia and elevated IgG antibody levels specific
for diphenylmethane diisocyanate (MDI) (Walker et al, 1989).
8 ANALYSIS
8.1 Agent/toxin/metabolite
No data available.
8.2 Sample containers to be used
No data available.
8.3 Optimum storage conditions
Storage of toluene diisocyanate in polyethylene containers is
hazardous due to absorption of water through the plastic (Lewis,
1992). Containers should remain closed as much as possible (OHM/TADS
1993). Inside storage should be in a dry, fire-resistant,
well-ventilated storage room (OHM/TADS 1993). If stored in tanks, it
should be blanketed with inert gas, such as nitrogen, or with dry air
(HSBD, 1993). Storage Temperature - 75 to 100 degrees F (HSDB 1993).
Store separate from amines, alcohols, bases and acids (HSDB, 1993).
8.4 Transport of samples
No data available.
8.5 Interpretation of data
No data available.
8.6 Conversion factors
At 25°C and 750mmHg :
1mg/m3 = 0.14 ppm in air
1mg/litre = 140.5 ppm
8.7 Other recommendations
There is sufficient knowledge about TDI to classify it as a very toxic
compound, when inhaled, and it should be treated as a potential human
carcinogen and as a known animal carcinogen. Consequently, the
greatest priority should be given to safe methods of use, and the
education, training, and supervision of operatives, together with
state enforcement of legislation by an effective inspectorate. Special
attention should be paid to the prevention and adequate treatment of
unscheduled releases and spills.
Normal protective equipment should be provided for all workers and a
stock of decontaminants always available. Containers should be kept
closed to prevent escape of vapour and entry of moisture. TDI must
always be handled in a properly ventilated area. Machines should be
equipped with enclosed ventilation hoods and benchwork done only in
properly designed fume cupboards. The efficacy of the ventilation must
be such that concentrations greater than the TLV do not arise in the
general working area. Whenever products containing TDI are handled in
inadequately ventilated areas, breathing apparatus must also be worn.
Workers exposed to airborne isocyanate merit:
1. pre-employment examination
2. periodic examination routinely
3. re-examination on return to work following sickness absence
4. instruction in the first-aid treatment of accidental exposures and
contamination
Pre-employment examination
The aim is to identify and to establish base line of fitness.
Examination should include a history taking based on the MRC
respiratory questionnaire (1976), spirometry (minimally FEV1 and FVC)
and physical examination of the respiratory system.
Where appropriate, a chest X ray may be included. By extrapolation
from analogous conditions, it was earlier believed that atopic
subjects might be hypersusceptible to sensitisation, so skin testing
with common allergens was used for their identification. This
hypotheses has not been substantiated.
Workers suffering from hayfever, recurrent acute bronchitis,
interstitial pulmonary fibrosis, occupational chest disease and
impaired lung function should not risk exposure to isocyanates and
prepolymers. Where there is the potential for exposure to a
significant skin hazard, workers identified as being at special risk
from existing conditions should be informed and provision made for
their protection.
Periodic examination
In the absence of significant sickness the questionnaire should be
repeated annually. It is believed at present that a significant
proportion of subjects who become sensitised do so in the first two
months. Tests of ventilatory capacity should be carried out two weeks,
six weeks and six months after engagement and subsequently six
monthly. Significant departures from normal should lead to suspicion
and reconsideration of environmental hygiene.
After absence with respiratory disease lasting two weeks or more, or
after repeated lesser absences at short intervals, it would be prudent
for the doctor to re-examine the worker by questioning, examination
and spirometry to determine if there has been significant departure
from previous values and the relation to occupational exposure.
Medical surveillance
The available evidence presented indicates that serial measurements of
the FEV1 is a useful means of identifying acute and long term effects
of isocyanates in a workforce. The results of lung function tests may
complement exposure measurements in indicating the presence of a
problem in an industry. A change in FEV1 in an individual during the
course of a workshift or over a longer period of time would be
suggestive of an adverse effect, as would "asthma" (with or without
"sensitisation") or progressive chronic impairment of lung function.
An annual decrement in FEV1 of 0.02 litres in an adult non-smoker
would be anticipated from ageing alone. The frequency of lung function
testing of exposed subjects is arbitrary but it is suggested that all
subjects should have preemployment measurements and subsequent
measurements at least annually or more often if symptoms arise. It is
difficult to be certain what work of workshift or annual loss of FEV1
in an individual should signal the need for action. However, workshift
decrements of 0.3 litres or greater and annual decrements of 5% or 0.2
litres should be cause for evaluation and more frequent testing since
the evidence presented suggests that these decrements may be
associated with eventual chronic airflow obstruction or may be
representative of asthma which may become intractable.
For the foreseeable future, exposed workers require health monitoring
by systemic symptom enquiry and by standardised measurement of
ventilatory function, with subsequent analysis of trends in
individual, and group mean, values.
9 OTHER TOXICOLOGICAL DATA
9.1 Carcinogenicity
IARC (1979) evaluated the data on the carcinogenicity of TDI and found
insufficient experimental animal or human data on which to base an
evaluation. An evaluation of additional data by IARC (1986) led to the
conclusion that there is sufficient evidence for the carcinogenicity
of TDI for experimental animals.
In the absence of adequate case reports or epidemiological studies,
there is insufficient data to assess the carcinogenicity of TDI for
human beings (IARC, 1986). No epidemiological studies of mortality or
cancer incidence among workers exposed to toluene diisocyanate were
available.
One case report of adenocarcinoma in a 47 year old non-smoking spray
painter has been published. The subject had been exposed to toluene
diisocyanate and 4,4-methylene diisocyanate for 15 years. The level of
exposure to isocyanates were not reported and neither were other
chemicals to which the subject may have been exposed (Mortillaro and
Schiaron, 1982).
Inhalation experiments with TDI cited in one study (Laskin et al,
1972) did not result in tumour production. However the evidence
concerning the possible respiratory carcinogenicity of polyurethane
foam dust appears to be conflicting (Laskin et al, 1972; Stemmer et
al, 1975; Thyssen et al, 1978). Commercial grade TDI administered by
gavage to mice has produced haemangiomas in the spleen and
subcutaneous tissues, haemangiosarcomas in the liver, ovaries and
peritoneum, and hepatocellular adenomas in female mice. All of these
tumours showed a dose-response relationship (National Toxicology
Program, 1986).
9.2 Genotoxicity
No data available.
9.3 Mutagenicity
There are conflicting reports about the mutagenicity of TDI. Anderson
and Styles (1978) reported that TDI of unknown purity was
non-mutagenic in a study of 120 chemicals tested but the fact that
several known mutagens failed to give positive results means that the
original report was suspect. Anderson et al (1980) later optimised the
procedures to test the reactive isocyanates and showed that a mixture
of 2,4- and 2,6-toluene diisocyanate caused a dose-dependent mutagenic
response, using S-9 activation, in S. typhimurium strains TA 98,
TA100, and TA 1538. The positive control for these mutagen tests was
the hydrolysis product of 2,4-TDI, 2,4-diaminotoluene, reported by
Ames et al (1975) to be mutagenic. The NTP has also tested toluene
diisocyanates using the Salmonella test system and found that both
2,6-TDI and a mixture of 2,4- and 2,6-TDI (80:20) were mutagenic in
S. typhimurium strains TA 98 and TA 100 in the presence (but not the
absence) of Aroclor 1254-induced male Sprague Dawley or Syrian hamster
liver S9. Neither sample was mutagenic in S. typhimurium strains TA
1535 or TA 1537, with or without metabolic activation.
9.4 Reprotoxicity
No published data were found on the effects of toluene diisocyanates
on reproduction, or on the embryotoxicity or teratogenicity of these
compounds. No relevant studies were found except for a report of
transient impotence in two grossly exposed men.
9.5 Teratogenicity
Data not available.
9.6 ADI acceptable daily intake
9.7 MRL
9.8 AOEL
9.9 TLV
9.10 Relevant animal data
No relevant data found.
9.11 Relevant in vitro data
Toluene diisocyanates were negative in two in-vitro cell
transformation assays using human and hamster kidney cells (Styles
1978).
10 ENVIRONMENTAL DATA
10.1 Ecotoxicological data
No data found.
10.2 Behaviour
Adsorption onto soil
If spilled on wet land TDI is rapidly degraded. In one experiment
simulating a spill, 5.5% of the original material remained after 24
hours, and in a field situation, the concentration of toluene
diisocyanate had declined to the ppm levels in 12 weeks (HSDB 1993)
10.3 Biodegradation
Environmental fate
There are very few studies on the overall environmental fate of
toluene diisocyanates in the published literature. It has been
demonstrated in environmental chambers that in the gaseous phase, TDI
vapour and water vapour do not react to form diaminotoluenes, since
not even trace amounts of these compounds were detected (Holdren et
al, 1984). A rate of loss of about 20% of TDI-vapour per hour could be
explained by surface adsorption. This rate of loss was much higher and
more rapid when simultaneously present in the chamber. Again, no
hydrolysis products of TDI could be detected.
In most industrial situations, toluene diisocyanates are hydrolysed by
water to give the corresponding polymeric ureas and carbon dioxide
(Chadwick et al, 1981). However, when toluene diisocyanates come into
contact with water without agitation, as in spills, a hard crystalline
crust of polymeric ureas forms slowing down further degradation of the
toluene diisocyanates, unless the crust is mechanically broken. The
solid reaction products are insoluble and biologically inert
(Brochhagen and Grieveson, 1984).
A computerised partitioning model proposed by Mackay (1979) indicated
that toluene diisocyanates released into the environment will tend to
partition into water. However, in making this prediction, the
reactivity of the compounds was not taken into consideration.
Photolysis
In the atmosphere TDI reacts with photochemically produced hydroxyl
radicals and is also removed by dry deposition (HSDB, 1993).
Half-life in water, soil and vegetation
The half life for toluene diisocyanate in the atmosphere is 3.3 hours
by reaction with photochemically produced hydroxyl radicals (HSDB,
1993).
10.4 Environmentally important metabolites
No information on the environmental toxicity of TDI was found in
available references at the time of this review. TDI may be released
to the environment as fugitive emissions and from stack exhaust during
the production, transport, and use of toluene diisocyanate in the
manufacture of polyurethane foam products and coatings, as well as
from spills (HSDB, 1993). If released into water, a crust forms around
the liquid toluene diisocyanate and less than 0.5% of the original
material remains after 35 days. Low concentrations of toluene
diisocyanate disappears from the aqueous environment in approximately
a day (HSDB, 1993).
10.5 Hazard warnings
An evaluation of the hazards for non-human targets from environmental
levels of TDI is not possible on the basis of available data.
10.5.1 Aquatic life
Data not available.
10.5.2 Bees
Data not available.
10.5.3 Birds
Data not available.
10.5.4 Mammals
Data not available.
10.5.5 Plants
Data not available.
10.5.6 Protected species
Data not available.
10.6 Waste disposal data
At the time of this review, criteria for land treatment or burial
(sanitary landfill) disposal practices are subject to significant
revision. Prior to implementing land disposal of waste residue
(including waste sludge), consult with environmental regulatory
agencies for guidance with environmental regulatory agencies for
guidance on acceptable disposal practices (HSDB 1993). Toluene
diisocyanate is a waste chemical stream constituent which may be
subjected to ultimate disposal by controlled incineration. Oxides of
nitrogen are removed from the effluent gas by scrubbers and/or thermal
devices (HSDB 1993). Toluene diisocyanate is a potential candidate for
liquid injection incineration, rotary kiln incineration, and fluidized
bed incineration (HSDB 1993).
This compound should be susceptible to removal from waste water by air
stripping (HSDB 1993).
The re-use and the disposal of uncleaned empty drums and containers is
not permissible because of the hazards associated with isocyanate
remaining on the walls of the drums. As a matter of principle all
residues of isocyanates in containers must be decontaminated in an
appropriate way.
There are three basic methods for disposal of isocyanate wastes, the
choice will depend in part on the scale on the scale of operation i.e.
amount of waste to be treated and in part on the availability of the
'neutralising' agent
1. Reaction with waste polyol
React with excess waste polyol to make a low quality foam which may be
incinerated, tipped or otherwise disposed of in an authorised waste
disposal area.
2. Reaction with liquid decontaminant
React with excess liquid decontaminant by adding the isocyanate slowly
and with stirring to liquid decontaminant in a fully opening drum.
Leave for 48 hours, close the drum and dispose of by tipping or
otherwise.
3. Incineration
Incineration should be done in properly supervised equipment specially
designed for the disposal of noxious chemical wastes.
Author
Mary-Jane Bennie
National Poisons Information Service (London Centre)
Medical Toxicology Unit
Guy's & St Thomas' Hospital Trust
Avonley Road
London
SE14 5ER
UK
This monograph was produced by the staff of the London Centre of the
National Poisons Information Service in the United Kingdom. The work
was commissioned and funded by the UK Departments of Health, and was
designed as a source of detailed information for use by poisons
information centres.
Peer review was undertaken by the Directors of the UK National
Poisons Information Service.
REFERENCES
AAR. 1987
Emergency handling of hazardous material in surface transportation.
Hazardous materials systems (BOE). Association of American Railroads,
Washington
ACGIH. 1986
Documentation of the threshold limit values and biological exposure
indices, 5th ed, pp580-585
Am Conference of Govt Ind Hyg, Inc, Cincinnati
Adams WGF. 1975
Long-term effects on the health of men engaged in the manufacture of
tolylene diisocyanate (TDI).
Br J Ind Med 32-72
Adams WGF. 1970
Lung function of men engaged in the manufacture of tolylene
diisocyanate (TDI).
Proc Roy Soc Med 63:378.
Ames BN, Kammen HO, Yamasaki E. 1975
Hair dyes are mutagenic: Identification of a variety of mutagenic
ingredients.
Proc Natl Acad Sci (USA) 72: 2423-2327
Anderson D, Styles JA. 1978
Appendix II. The bacterial mutation test.
Br J Cancer 37: 924-930.
Aragon JJ, Feliu JE, Frenkel RA, and Sols A. 1980
Permeabilization of animal cells for kinetic studies of intracellular
enzymes : in situ behaviour of the glycolytic enzymes of erythrocytes.
Proc Natl Acad Sci (USA) 77 (11): 6324-6328
Axford AT, Mc Kerrow CB, Jones AP et al,: 1976
Accidental exposure to isocyanate fumes in a group of fireman.
Br J Ind Med 33:65-71.
Banks DE, Rando RJ, Barkman HW Jr. 1986
Isocyanate-induced respiratory disease.
Ann Allergy 57:389-396
Banks DE, Rando RJ, Barkman HW Jr. 1990
Persistence of toluene diisocyanate-induced asthma despite negligible
workplace exposure.
Chest 97:121-125
Belin L et al,. 1983
Amines: Possible causative agents in the development of bronchial
hyperreactivity in workers manufacturing polyurethanes from
isocyanates.
Br J Ind Med 40:251-257
Berstein I. 1982
Isocyanate-induced pulmonary diseases: A current perspective.
J Allergy Clin Immunol 70:24-31
Borm PJA, Bast A and Zuiderveld OP. 1989
In vitro effect of toluene diisocyanate on beta adrenergic and
muscarinic receptor function in lung tissue of the rat.
Br J Ind Med 46:56-59
Brandt GH. 1972
Soil stabilisers. In : Goring C, AI and Hamaker JW ed.
Organic chemicals in the soil environment.
New York, Marcel Dekker, pp 692-693, 719-720
Brochhagen FK, Grieveson BM. 1983
Environmental aspects of isocyanates in water and soil.
Cell Polym 3:11-17
Bruckner HC, Avery SB, Stetson DM et al,. 1968
Clinical and immunological appraisal of workers exposed to
diisocyanate.
Arch Environ Health 16:619-625
Brugsch HG, Elkins HB. 1963
Toluene diisocyanate (TDI) toxicity.
N Engl J Med 268 (7) : 353-357
Burge P, O'Brien I, Harries M. 1979
Peak flow rate record in the diagnosis of occupational asthma due to
isocyanates.
Thorax 34:317
Burge P. 1982
Nonspecific bronchial hyperreactivity in workers exposed to toluene
diisocyanate, diphenylmethane diisocyanate and colophony.
Eur J Resp Dis 63 (suppl 1230):91-96
Butcher BT, Jones RN, O'Neill CE et al,. 1977
Longitudinal studies of workers employed in the manufacture of toluene
diisocyanate.
Am Rev Respir Dis 116:411-421
Calas E, Castelain PY, Lapointe HR, Ducos P, Cavelier C, Duprat P,
Poitou P. 1977
Allergic contact dermatitis to a photopolymerizable resin used in
printing.
Contact Dermat 3(4): 186-194
Cartier A, Grammer L, Malo Jl et al,. 1989
Specific serum antibodies against isocyanates: association with
occupational asthma.
J Allergy Clin Immunol 84:507-514
Chadwick DH, Cleveland TH. 1981
Isocyanates, organic. In:Kirk Othmer encyclopedia of chemical
technology, 3rd ed.
New York, John Wiley and Sons, Vol 13, pp 789-818
De Marzo N, Fabbri LM, Crescioli S et al,. 1988
Dose-dependent inhibitory effect of inhaled beclomethasone on late
asthmatic reactions and increased airway responsiveness to
methacholine induced by toluene diisocyanate in sensitized patients.
Pul Pharm 1:15-20
Diem JE et al,. 1982
Five year longitudinal study of workers employed in a new toluene
diisocyanate manufacturing plant.
Am Rev Resp Dis 126:420-428
Elkins HB, McCarl GW, Brugsch HG et al,. 1962
Massachusetts experience with toluene diisocyanate.
Am Ind Hyg Assoc J 23: 265-272
Erlicher H, Brochhagen FK. 1976
Urethane in the Environments.
Proceedings of the Plastic and Rubber Institute Conference, September
21-22
Fabbri LM. 1990
Airway inflammation and late asthmatic reactions.
Eur Respir J 3:367-368
Fabbri LM, Boschetto P, Zocca E et al,. 1987
Bronchoalveolar neutrophilia during late asthmatic reactions induced
by toluene diisocyanate.
Am Rev Respir Dis 136:36-42
Fabbri LM, Chiesura-Corona P, Dal Vecchio L et al,. 1985
Prednisolone inhibits late asthmatic reactions and the associated
increase in airway responsiveness by toluene diisocyanate in
sensitized subjects.
Am Rev Respir Dis 132: 1010-1014
Fabbri LM, Danieli D, Crescioli P et al,. 1988
Fatal asthma in a subject sensitised to toluene diisocyanate.
Am Rev Respir Dis 137: 1494-1498
Finkel AJ (Ed). 1983
Hamilton and Hardy's Industrial Toxicology 4th ed.
John Wright, PSG Inc, Boston, MA
Granatek CH, Corry PM, and Golkin EM. 1975
Use of fluorescent X-Ray spectroscopy to quantitate binding of
anti-embryonic antibody to humam tumour cells.
AACR Abstr 16:47
Grant WM and Schuman JS. 1993
Toxicology of the Eye, 4th Ed.
Charles C Thomas, Springfield
Hama GM. 1947
Arch Ind Health 16:232.
as cited in ACGIH: Documentation of the threshold limit values and
biological exposure indices, 5th ed.
Am Conference Govt Ind Hyg, Inc, Cincinnati, OH, 1986.
Hardy HL and Purnell CJ. 1978
Use of foam for the emergency suppression of vapour emissions from
organic isocyanate liquid surfaces.
Ann Occup Hyg 21: 95-98
Hathaway GJ, Proctor NH, Hughes JP and Fischman ML (eds)
Proctor and Hughes' Chemical hazards of the workplace 3rd ed.
Van Nostrand Reinhold, New York
Holdren MW, Spicer CW, Riggin RM. 1984
Gas phase reaction of toluene diisocyanate with water vapor.
Am Ind Hyg Assoc J 45(9):626-633.
HSDB : Hazardous substances data bank. National library of medicine,
Bethesda, MD (CD-ROM Version). Micromedex, Inc, Englewood, Co, 1993.
IARC. 1986
Toluene diisocyanate. In Some chemicals used in plastics and
elastomeres, Lyons, International Agency for Research on Cancer, pp
287-323
Monographs on the evaluation of the carcinogenic risk of chemicals to
humans, Vol 39
IARC: Monographs on the Evaluation of the Carcinogenic Risk of
Chemicals to Man.
World Health Organisation, International Agency for Research on
Cancer, geneva, 1979.
Innocenti A, Franzinelli A, Sartorelli E. 1981
Long-term study of workers with asthma caused by polyurethane resins.
Med Lavoro 19813:231
ITIC/USEPA 1981
Information Review No 231 Toluene Diisocyanates
Karol MH, Ioset HH, Alarie YC. 1978
Tolyl-specific IgE antibodies in workers with hypersensitivity to
toluene diisocyanate.
Am Ind Hyg Assoc J 39:454-458
Karol Mh, Sandberg T, Riley EJ et al,. 1979
Longitudinal study of tolyl-reactive IgE antibodies in workers
hypersensitive to TDI.
J Occup Med 21:354-358
Karol MH. 1980
Study of guinea pig and human antibodies to toluene diisocyanate.
Am Rev Respir Dis 122:965-970
Karol MH. 1981
Survey of industrial workers for antibodies to toluene diisocyanate.
J Occup Med 23:741-747
Keskinen H, Tupasela O, Tiikainen U et al,. 1988
Experiences of specific IgE in asthma due to diisocyanates.
Clin Allergy 18:597-604
Laskin S, Drew RT, Vapiello VP, Kuschner M. 1972
Inhalation studies with freshly generated polyurethane dust.
Third International Conference on Environmental Toxicology.
Springfield, VA : NTIS Publications (US Department Commerce)
Le Quesne PM, Axford AT, Mc Kerrow CB et al,. 1976
Neurologic complications after a single severe exposure to toluene
diisocyanate.
Br J Ind Med 33:72-78
Lewis RJ. 1992
Sax's Dangerous Properties of industrial materials 8th ed.
Van Nostrand Reinhold Company, New York, NY, 1992, pp3312-3313
Lozewicz S, Assoufi BK, Hawkins R et al,. 1987
Outcome of asthma induced by isocyanates.
Br J Dis Chest 81:14-22
Luckenbach M, Kieler. 1980
Toxic corneal epithelial oedoma from exposure to high atmospheric
concentration of toluene diisocyanates. Am J Opthalmol 90: 682-686
Luo JCJ, Nelsen KG, Fischbein A. 1990
Persistent reactive airway dysfunction after exposure to toluene
diisocyanate.
Br J Ind Med 47:239-241.
Mackay D. 1979
Finding fungacity feasible.
Environ Sci Technol 13(10):1218-1223
Mapp CE, Corona PC, DeMarzo N et al,. 1988
Persistant asthma due to isocyanates, a follow up study of subjects
with occupational asthma due to toluene diisocyanate (TDI).
Am Rev Respir Dis 137:1326-1329
Mapp CE, Boschetto P, Dal Vecchio L et al,. 1987
Protective effect of antiasthma drugs on late asthmatic reaction and
increased responsiveness induced by toluene diisocyanate in sensitized
subjects.
Am Rev Respir Dis 136:1403-1407
McKerrow CT, Davies HJ, Jones PA. 1970
Symptoms and lung function following acute and chronic exposure to
tolylene diisocyanate.
Proc Roy Soc Med 63:376-378
Moller DR, Brooks SM, Mc Kay RT et al,. 1986
Chronic asthma due to toluene diisocyanate.
Chest 90:494-499
Mortillaro PT, Schiavon M. 1982
[One case of lung cancer that developed in the course of a
bronchopulmonary disease due to isocyanates].
Med Lav 3: 207-209 (in Italian)
Munn A. 1960
Experiences with diisocyanates.
Trans Assoc Ind Med Off 9:134-138
Musk AW, Peters JM, Bernstein L. 1985
Absence of respiratory effects in subjects exposed to low
concentrations of TDI and MDI : a re-evaluation.
J Occup Med 27:917-920.
National Cancer Institute. 1979
Bioassay of 2,4 Diaminotoluene for possible Carcinogenic
carcinogenesis technical report series #162.
DHEW Pub (NIH) 79-1718. Washington. DHEW(NIH)
National Toxicology Program. 1986
Toxicology and carcinogenesis studies of commercial grade TDI (80%)
and 2,6 (20%) Toluene diisocyanate. NIH Publication #86-2507.
Washington DHHS (NIH)
NIOSH. 1978
Criteria for a recommended standard occupational exposure to
diisocyanates, Rockville, Maryland, US National Institute for
Occupational Safety and Health (NIOSH 78-215; PB 81-226615)
NIOSH. 1973
Criteria for a recommended standard - Occupational exposure to toluene
diisocyanate.
DHEW Pub No (HSM) 73-11022
O'Donoghue JL (ed). 1985
Neurotoxicology of industrial and commercial chemicals.
CRC Press, Inc, Boca Raton, Florida 1985:Volume I:p136, Volume II:p34.
OHM/TADS. 1993
Oil and Hazardous Materials Technical Assistance Data System. US
Environmental Protection Agency, Washington, DC (CD-ROM Version).
Micromedex, Inc, Englewood
Paggiaro PL, Bacci E, Paoletti P et al,. 1990
Bronchoalveolar lavage and morphology of the airways after cessation
of exposure in asthmatic subjects sensitized to toluene diisocyanate.
Chest 98: 536-542
Paggiaro PL, Loi AM, Rossi O et al,. 1984
Follow-up study of patient with respiratory disease due to toluene
diisocyanate (TDI).
Clin Allergy 14:463-469
Paggiaro PL, Rossi O, Lastrucci L, Pardi F, Pezzini A, Buschieri L.
1985
TDI-induced oculorhinitis and bronchial asthma.
J Occup Med 27: 51-52
Patterson R, Nugent KM, Harris KE et al,. 1990
Immunologic hemorrhagic pneumonia caused by isocyanates.
Am Rev Respir Dis 14:226-230
Peters JM, Murphy RLH. 1970
Pulmonary toxicity of isocyanates.
Ann Intern Med 73: 654-655
Peters JM, Wegman DH. 1975
Epidemiology of toluene diisocyanate (TDI)-induced respiratory
disease.
Environ Health Perspect 11: 97-100
Porter CV, Higgins RL, Scheel LD. 1988
A retrospective study of clinical, physiologic, and immunologic
changes in workers exposed to toluene diisocyanate.
Am Ind Hyg Assoc J 36: 159-168
Roper CP Jr, Cromer JW Jr. 1975
Health Hazard evaluation determination report 74-118-218.
HEW, PHS, CDC, NIOSH
Rye WA. 1973
Human responses to isocyanate exposure.
J Occup Med 15 : 306-307
Sax NI, Lewis RJ. 1989
Dangerous properties of industrial materials, 7th ed.
Van Nostrand Reinhold Co, New York
Selden AI, Belin L, Wass U. 1989
Isocyanate exposure and hypersensitivity pneumonitis - a report of
probable case and prevalence of specific immunoglobulin g antibodies
among exposed individuals.
Scand J Work Environ Health 15;234-237
Sharonova ZV and Kryzhanovskaya NA (1976) [Toluene diisocyanate
induced occupational liver pathology] Gig Tr Prof Zabol. 11 : 27-31
(in Russian)
Steinmetz PR, Al-Awqati Q and Lawton WJ. 1976
Speciality rounds. Nephrology rounds. University of Iowa Hospitals :
renal tubular acidosis.
Am J Med Sci 271(1) : 40-54
Stemmer KL, Bingham E, Barkley W. 1975
Pulmonary response to polyurethane dust.
Environ Health Perspect 11:109
Styles JA. 1978
Mammalian cell transformation in vitro.
Br J Cancer 37: 931-936.
Thyssen J, Kimmerle G, Dickhaus S, Emminger E, Mohr U. 1978
Inhalation studies with polyurethane dust in relation to respiratory
tract carcinogenesis.
J Environ Pathol Toxicol 1:501
US EPA. 1984
Toluene diisocyanates (TDI) 584-84-9; 91-08-7: 26471-62-5; 1321-38-6,
Washington DC, US Environmental protection agency
Valentino M, Governa M, Fiorini R. 1988
Increased neutrophil leukocyte chemotaxis induced by release of a
serum factor in toluene-diisocyanate (TDI) asthma.
Lung 166:317-325.
Venables KM, Dally MB, Burge PS et al,. 1985
Occupational asthma in a steel coating plant.
Br J Ind Med 42:517-524
Venables KM, Dally MB, Burge PS et al,. 1985
Occupational asthma in a steel coating plant.
Br J Ind Med 42:517-524
Walker CL, Grammer LC, Shaughnessy MA et al,. 1989
Diphenylmethane diisocyanate hypersensitivity pneumonitis: a
serological evaluation.
J Occup Med 31:315-319
Walworth HT, Virchow WE. 1959
Am Ind Hyg Assoc J 20:205. As cited in ACGIH: Documentation of the
Threshold Limit Values and Biological Exposure Indices, 5th ed. Am
Conference of Govt Ind Hyg, Inc, Cincinnati, OH 1986
Wass U, Belin L. 1989
Immunologic specificity of isocyanate-induced IgE antibodies in serum
from 10 sensitized workers.
J Allergy Clin Immunol 83: 126-135
Wegman D et al,. 1982
Accelerated loss of FEV1 in polyurethane production workers: A four
year prospective study.
Am J Ind Med 3:209-215
Weill H, Butcher B, Dharmarajan V et al,. 1981
NIOSH Contract No 210-75-0006
White WG, Morris MJ, Sugden E and Zapata E. 1980
Isocyanate induced asthma in a car factory.
Lancet 1 (8171) : 756-760
Williamson KS. 1965
Studies in diisocyanate workers.
Trans Assoc Ind Med Off 15: 29-35
Yoshizawa Y, Ohtsuka M, Noguchi K et al,. 1989
Hypersensitivity pneumonitis induced by toluene diisocyanate: sequelae
of continuous exposure.
Ann Int Med 110: 31-34
Zocca E, Fabbri LM, Boschetto P et al,. 1990
Leukotriene B4 and late asthmatic reactions induced by toluene
diisocyanate.
J Appl Physiol 68:1576-1580