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    INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY



    ENVIRONMENTAL HEALTH CRITERIA 75






    TOLUENE DIISOCYANATES







    This report contains the collective views of an international group of
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    policy of the United Nations Environment Programme, the International
    Labour Organisation, or the World Health Organization.

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    the United Nations Environment Programme,
    the International Labour Organisation,
    and the World Health Organization

    World Health Orgnization
    Geneva


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CONTENTS

ENVIRONMENTAL HEALTH CRITERIA FOR TOLUENE DIISOCYANATES

 1. SUMMARY AND CONCLUSIONS

     1.1. Summary
          1.1.1. Identity, properties, analytical methods
          1.1.2. Production, uses, and sources of exposure
          1.1.3. Kinetics, biotransformation, and elimination
          1.1.4. Effects on experimental animals
          1.1.5. Effects on human beings
          1.1.6. Effects on organisms in the environment
     1.2. Evaluation of hazards from long-term exposure to toluene 
          diisocyanates 
          1.2.1. Conclusions and recommendations

 2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

     2.1. Identity
     2.2. Physical and chemical properties
     2.3. Conversion factors
     2.4. Analytical methods

 3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

     3.1. Natural occurrence
     3.2. Man-made sources
          3.2.1. Production levels and processes
                 3.2.1.1  World production figures
                 3.2.1.2  Manufacturing processes: release into the 
                          environment 
          3.2.2. Uses

 4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

     4.1. Air
     4.2. Water
     4.3. Soil
     4.4. Biotransformation
     4.5. Bioaccumulation

 5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

     5.1. General population exposure
     5.2. Occupational exposure

 6. KINETICS AND METABOLISM

     6.1. Absorption
     6.2. Distribution
     6.3. Metabolic transformation and elimination
     6.4. Reaction with body components

 7. EFFECTS ON ORGANISMS IN THE ENVIRONMENT

 8. EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

     8.1. Single exposures
     8.2. Short-term exposures
          8.2.1. Inhalation
                 8.2.1.1  Guinea-pig
                 8.2.1.2  Mouse
                 8.2.1.3  Rat
                 8.2.1.4  Dog
          8.2.2. Dermal
                 8.2.2.1  Guinea-pig
                 8.2.2.2  Mouse
          8.2.3. Oral
     8.3. Long-term exposure
          8.3.1. Inhalation
                 8.3.1.1  Mouse
                 8.3.1.2  Dog
     8.4. Reproduction, embryotoxicity, and teratogenicity
     8.5. Mutagenicity and related end-points
          8.5.1. Bacterial mutagenicity
          8.5.2. Mammalian cell transformation
          8.5.3. Mammalian  in vivo study
     8.6. Carcinogenicity
          8.6.1. Oral
          8.6.2. Inhalation
     8.7. Special studies and mechanisms of toxicity

 9. EFFECTS ON MAN

     9.1. General population exposure - controlled human studies
          9.1.1. Single exposures
     9.2. Occupational exposure
          9.2.1. Acute toxicity
          9.2.2. Effects of short- and long-term occupational
                 exposure - epidemiological studies
                 9.2.2.1  Ocular
                 9.2.2.2  Dermal
                 9.2.2.3  Respiratory tract
                 9.2.2.4  Cancer epidemiology
                 9.2.2.5  Immunotoxicity
          9.2.3. Potential mechanisms of action

10. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

     10.1. Exposure to toluene diisocyanates
           10.1.1. Acute and short-term effects
           10.1.2. Health risks of long-term exposure to toluene 
                   diisocyanates 
     10.2. Evaluation of effects on the environment
     10.3. Conclusions and recommendations

11. PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

REFERENCES

WHO TASK GROUP ON TOLUENE DIISOCYANATES (TDIs)

 Members

Dr X. Baur, Pulmonary Section, Klinikum Grosshaden, University of 
   Munich, Munich, Federal Republic of Germany 

Dr L. Belin, Department of Medicine, Sahlgren's Hospital, Goteborg, 
   Sweden 

Ms Andrea Blaska, Office of Toxic Substances, US Environmental
   Protection Agency, Washington DC, USA  (Co-Rapporteur)

Dr M. Dieter, US National Institute for Environmental Health
   Sciences, Research Triangle Park, North Carolina, USA
    (Co-Rapporteur)

Dr M. Greenberg, Department of Health and Social Security, London, 
   United Kingdom. 

Dr I. Gut, Institute of Hygiene and Epidemiology, Prague, 
   Czechoslovakia  (Chairman) 

Dr M. Mann, Bayer AG, Leverkusen, Bayerwerk, Federal Republic of 
   Germany 

Dr C. Rosenburg, Institute of Occupational Health, Department of 
   Industrial Hygiene and Toxicology, Helsinki, Finland 

Professor H. Sakurai, School of Medicine, Keio University, Tokyo, 
   Japan 

 Secretariat

Dr G.C. Becking, International Programme on Chemical Safety,
   Interregional Research Unit, World Health Organization, Research 
   Triangle Park, North Carolina, USA  (Secretary) 

Mr A.C. Fletcher, International Agency for Research on Cancer, 
   Lyons, France 

NOTE TO READERS OF THE CRITERIA DOCUMENTS

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



                          *    *    *



    A detailed data profile and a legal file can be obtained from 
the International Register of Potentially Toxic Chemicals, Palais 
des Nations, 1211 Geneva 10, Switzerland (Telephone no. 988400 - 
985850). 

ENVIRONMENTAL HEALTH CRITERIA FOR TOLUENE DIISOCYANATES

    A WHO Task Group on Environmental Health Criteria for 
Diaminotoluenes met at the Monitoring and Assessment Research 
Centre, London, United Kingdom, from 20 to 25 October 1986. 
Professor P.J. Petersen welcomed the participants on behalf of 
the host Institution, and Dr G.C. Becking opened the meeting on 
behalf of the three co-sponsoring organizations of the IPCS 
(ILO/UNEP/WHO).  The Task Group reviewed and revised the draft 
criteria document and made an evaluation of the health risks of 
exposure to diaminotoluenes. 

    The efforts of DR M. DIETER, US NATIONAL INSTITUTE OF 
ENVIRONMENTAL HEALTH SCIENCES, Research Triangle Park, North 
Carolina, USA, in the preparation of the draft, and of all others 
who helped in the preparation and finalization of the document are 
gratefully acknowledged. 



                         * * *



    Partial financial support for the publication of this criteria 
document was kindly provided by the United States Department of 
Health and Human Services, through a contract from the National 
Institute of Environmental Health Sciences, Research Triangle Park, 
North Carolina, USA - a WHO Collaborating Centre for Environmental 
Health Effects.  The United Kingdom Department of Health and Social 
Security generously supported the cost of printing. 

1.  SUMMARY AND CONCLUSIONS

1.1.  Summary

1.1.1.  Identity, properties, analytical methods

    Toluene diisocyanates (TDIs) are synthetic organic chemicals of 
low relative molecular mass (174.17).  They are colourless to pale 
yellow liquids, at room temperature, with a distinct pungent odour 
detectable around 0.7 mg/m3, which is well above current exposure 
limits.  The different commercial grades solidify at between 4.7 C 
and 22 C and boil at 251 C at 760 mmHg.  Toluene diisocyanates 
react with water to form polyureas, carbon dioxide gas, and small 
amounts of diaminotoluenes, depending on the amount of water 
present.  They also react with basic chemicals, including proteins. 

    Adequate analytical methods have been developed to measure air 
levels of toluene diisocyanates in the work-place, for both area 
and personal monitoring.  The methods include:  (a) high-pressure 
liquid chromatography; (b) photometric methods; and (c) the use of 
direct-reading instruments in which a chemically impregnated paper 
tape changes colour on exposure to toluene diisocyanates.  The 
detection limits, ranging from 0.0001 to 0.07 mg/m3, depend on the 
sampling and analytical procedure. 

    Analytical methods have also been developed to measure toluene 
diisocyanates levels in environmental media and consumer products. 

1.1.2.  Production, uses, and sources of exposure

    Toluene diisocyanates are commercially available as > 99.5% 
pure 2,4-toluene diisocyanate (2,4-TDI), and 80:20 or 65:35 
mixtures of the 2,4- and 2,6-isomers.  "Crude"-TDI, with an 
unidentified isomer ratio, is also commercially available, but not 
widely used.  By far the most widely used compound is the 80:20 
isomer mixture. 

    Toluene diisocyanates are important industrial intermediates 
used in conjunction with polyether and polyester polyols as co-
reactants in the manufacture of polyurethane foams, paints, 
varnishes, elastomers, and coatings.  TDI-based polyurethane foams 
are widely used in the automotive and furniture industries, and in 
packaging and insulation. 

    Toluene diisocyanates released into the environment, will tend 
to partition into water and undergo rapid hydrolysis (half-life of 
0.5 seconds - 3 days in water, depending on pH and water turbidity) 
leading predominantly to the formation of relatively inert 
polymeric ureas.  Toluene diisocyanates would also be expected 
to undergo photolysis and hydroxy radical oxidation.  Therefore, 
transport and occurrence would be limited to the immediate vicinity 
of effluents or spills, and the resulting polyureas would probably 
be resistant to further biodegradation. 

    Consumer products, including single-pack paints and lacquers, 
may include traces of free toluene diisocyanates. 

    Exposure may occur in a wide variety of occupations, including 
the manufacture and use of chemicals, and work with polyurethane-
coating products.  It may also occur during transport, as a result 
of spills or leaks.  Excursions above safety limits are of 
particular concern for sprayers and their co-workers. 

1.1.3.  Kinetics, biotransformation, and elimination

    Toluene diisocyanates are highly reactive in body fluids with a 
reported half-life of less than 30 seconds in serum and < 20 min 
in stomach contents.  However, in oral administration studies using 
high doses, TDI forms insoluble polyurea-coated globules and 
persists much longer.  It is believed that TDIs react with the 
tissues they contact rather than being absorbed and distributed 
in the body in free form.  Isocyanates react with hydroxyl, amino, 
carboxyl, and sulfhydryl groups and can inactivate proteins by 
covalent bonding.  Animals, treated orally with 2,6-TDI, 
excreted mono- and di-acetylated diaminotoluene, indicating that 
diaminotoluene may be formed as a TDI metabolite.  Its immunogenic 
action may derive from relations with proteins or polyaccharides to 
form a hapten complex and new antigenic determinants. 

1.1.4.  Effects on experimental animals

    When inhaled, toluene diisocyanates are very toxic for animals.  
The 4-h LC50 ranges from 70 to 356 mg/m3.  Animals die of pulmonary 
oedema and haemorrhage.  TDIs, ingested orally or in contact with 
the skin, are relatively less toxic in terms of lethal dose.  The 
oral LD50 ranges from 3.06 to 4.13 g/kg body weight, and the dermal 
LD50 in rabbits is 10 g/kg body weight.  Liver, kidney, 
gastrointestinal, and skin damage occur via these routes. 

    Toluene diisocyanates are irritants for the mucous membranes of 
the respiratory tract, eyes, and skin and are sensitizers of the 
respiratory tract and skin. 

    Dermal application of toluene diisocyanates in one animal model 
resulted in sensitization, and subsequent bronchial challenge 
produced a hypersensitive response. 

    The mechanism of the sensitization reaction has been the 
subject of extensive research and is still under debate.  It has 
been suggested that sensitization, which may develop gradually or 
suddenly after exposure to toluene diisocyanates, may be due both 
to immunological factors, as evidenced by the production of 
TDI-specific antibodies, and to non-immunological factors, as 
evidenced by increased carbachol-induced contractibility. 

    TDI was positive in two bacterial mutagenicity tests.  
Toluene diisocyanates were negative for cell transformation 
in two mammalian  in vitro systems and one  in vivo system. 

    The results of 2-year, inhalation studies on mice and rats, 
using commercial grade 80:20 TDI at doses of 0.356 and 1.068 mg/m3, 
administered for 6 h/day, 5 days per week, for periods ranging from 
104 to 108 weeks, were negative for carcinogenicity.  In 2-year 
oral gavage studies with an 80:20 commercial grade mixture of 
TDI in corn oil (30 - 240 mg/kg), the incidences of a variety of 
tumours increased in both male and female rats and in female mice.  
The tumours consisted of subcutaneous fibromas/fibrosarcomas and 
pancreatic acinar cell adenomas in male rats, subcutaneous 
fibromas/fibrosarcomas, pancreatic islet cell adenomas, neoplastic 
nodules of the liver, and mammary gland fibroadenomas in female 
rats, and haemangiomas/haemangiosarcomas and hepatocullular 
adenomas in female, but not male, mice. 

1.1.5.  Effects on human beings

    Exposure to toluene diisocyanates can lead to adverse effects 
on the respiratory tract, skin, eyes, and gastrointestinal tract.  
A variety of respiratory illnesses have been induced in workers 
exposed occupationally to toluene diisocyanates, including 
irritation of the upper and lower respiratory tract, an asthma-
like sensitization response, and individual and group mean 
decreases in lung function.  These decreases have been noted, 
in some cases, after exposure to an estimated average TDI 
concentration of > 0.014 mg/m3 (for short-term as well as 
long-term occupational exposure). 

    Irritation of the eye, nose, and respiratory tract has been 
reported at levels of > 0.35 mg/m3.  The respiratory tract 
sensitization response, producing bronchial asthma in up to 10% 
of previously exposed individuals, may occur at a level of 0.036 
mg/m3. 

1.1.6.  Effects on organisms in the environment

    TDIs have been lethal for certain aquatic organisms at 
concentrations of between 10.5 and 508.3 mg/litre; the LD50 for two 
avian species was about 100 mg/kg body weight. 

1.2.  Evaluation of Hazards from Long-Term Exposure to Toluene 
Diisocyanates

    The risk of respiratory toxicity from repeated exposure can be 
summarized as follows: 

    (a)  chronic loss of ventilatory capacity, as measured by 
         forced expiratory volume and forced vital capacity; and

    (b)  immediate and/or delayed asthmatic responses.

    Estimates of past mean exposures to TDI have been made in 
many epidemiological studies in attempts to quantify dose-
response relationships for respiratory ill-health.  Because of 
inconsistencies in the hygiene sampling and measurements used in 
the past, it is difficult to be confident about the exact levels at 

which TDI causes the above-mentioned health effects.  It should be 
remembered that fluctuations in true individual exposure occur and, 
as the size and extent of the intermittent peaks is not known, 
their biological significance cannot be evaluated. 

    Once individuals are sensitized to toluene diisocyanates, low 
concentrations, much below current occupational exposure limits, 
can induce asthma.  Studies on experimental animals have shown that 
skin application of TDI can lead to pulmonary sensitization; thus, 
it is prudent to avoid repeated skin contact. 

    No data were available on the carcinogenic effects of toluene 
diisocyanates in human beings. 

    No carcinogenic effects of TDI were noted in an inhalation 
study on rats and mice.  However, gavage of the 80:20 mixture in 
corn oil produced dose-related carcinogenic effects in male and 
female rats and female mice.  It is considered that there is 
sufficient evidence for the carcinogenicity of TDI for experimental 
animals. 

    There is evidence of mutagenicity in two bacterial tests. 

    It is not possible, on the basis of available data, to evaluate 
the hazards for non-human targets from environmental levels of TDI. 

1.2.1.  Conclusions and recommendations

    1.  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. 

    2.  Additional animal carcinogenicity testing using the
        inhalation route should be carried out.

    3.  Morbidity and mortality studies are required on 
        occupational groups, for whom reliable exposure levels are 
        available, to address the question of cancer, and to 
        evaluate potential long-term human hazards under current 
        standards of good working practice. 

    4.  Because it is not possible to reach confident conclusions
        from data on the neurotoxicity of TDI, neurophysiological 
        and behavioural studies should be carried out on 
        asymptomatic workers exposed at current hygiene standards. 

    5.  For the foreseeable future, exposed workers require health
        monitoring by systematic symptom enquiry and by 
        standardized measurement of ventilatory function, with 
        subsequent analysis of trends in individual, and group 
        mean, values. 

    6.  Appropriate sampling strategies, together with existing
        analytical methods, have to be developed and used to obtain 
        better information about exposure.  Special attention 
        should be given to the detection and characterization of 
        peak values.  The results of these analyses should be 
        evaluated in parallel with careful health studies. 

    7.  Further metabolic studies of a qualitative and quantitative 
        nature are required with a view to developing methods of 
        measuring TDI uptake and monitoring exposure. 

    8.  Whether TDI produces sensitization in human beings by
        pharmacological or immune mechanisms needs to be elucidated 
        with a view to determining whether restrictions placed on 
        the employment of atopic subjects, in areas where TDI is 
        produced or used, are justified. 

    9.  Studies are required to determine whether TDI has embryo-
        toxic and teratogenic properties or induces adverse 
        reproductive effects at current exposure levels. 

   10.  Further environmental studies are required to monitor 
        general environmental levels of TDI in the neighborhood of 
        sources and to collect ecotoxicity data. 

2.  IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES, ANALYTICAL METHODS

2.1.  Identity

    Toluene diisocyanates (TDIs) are synthetic organic chemicals 
with a molecular formula of C9H6N2O2; a relative molecular mass of 
174.17; and the following chemical structure (R = -N=C=O): 

Chemical Structure

    Toluene diisocyanates are produced as 2 isomers (2,4-toluene 
diisocyanate (2,4-TDI) and 2,6-toluene diisocyanate (2,6-TDI)) 
and are commercially available in 3 isomer ratios:  (a)  > 99.5% 
2,4-TDI; (b) 80% 2,4-TDI/20% 2,6-TDI, which is the most common 
and referred to in this document as 80:20 mixture; and (c) 65% 
2,4-TDI/35% 2,6-TDI.  "Crude" toluene diisocyanate (Crude-TDI), 
with an unidentified isomer ratio, is also commercially available, 
but not widely used.  Various identification codes for the most 
commonly marketed toluene diisocyanates are listed in Table 1. 

Table 1.  Identification codes of commercial toluene diisocyanatesa
-------------------------------------------------------------------
Numeric index            2,4-TDI        2,6-TDI        Commercial
                                                       (80:20)
                                                       mixture
-------------------------------------------------------------------
CAS register number      584-84-9       91-08-7        26471-62-5

RTECS access number      CZ6300000      CZ6310000      CZ6200000

Wiswesser line notation  OCNR Bl ENCO   OCNR Bl CNCO   -

Shipping ID number       UN 2078        -              UN 2078

OHM TADS number          -              1-             7217313

Hazard substances data
bank number              0874           5272           6003
-------------------------------------------------------------------
a "Crude" toluene diisocyanate (unidentified isomers). CAS No. 1321-
   38-6 and chemical abstracts name benzene, diisocyanatomethyl-.

    The chemical, common, and trade names for toluene diisocyanates 
are listed in Table 2. 

Table 2.  Toluene diisocyanates:  Synonymous and Trade Names
--------------------------------------------------------------------
I.   Commercial mixtures: 2,4-, 2,6-isomers

Chemical abstracts name  benzene, 1,3-diisocyanatomethyl-

Other chemical names     diisocyanatotoluene; isocyanic acid; 
                         methyl- m-phenylene ester; methyl- m-
                         phenylene isocyanate; methylphenylene 
                         isocyanate; toluene diisocyanate; tolylene 
                         diisocyanate 

Common name              TDI

Trade names              Desmodur T65 (also-T80); Hylene T (also, 
                         -TCPA, -TLC, -TM, -TM65, -TRF); Isocyanic 
                         acid; Lupranat T80; Mondur TD (also, 
                         -TD80, -TDS); Nacconate 100; NCI-C50533; 
                         Niax TDI; Niax TDI-P; Rubinate TDI 80/20; 
                         TDI 80 

II.   2,4-TDI

Chemical abstracts name  benzene, 2,4-diisocyanato-1-methyl-

Other chemical names     di-iso-cyanatoluene; di-isocyanate de 
                         toluylene; diisocyanat-toluol; isocyanic 
                         acid; 4-methyl- m-phenylene ester; tolueen-
                         diisocyanaat; toluen-disocianato; toluene 
                         diisocyanate; toluene-2,4-diisocyanate; 
                         toluene, 2,4-diisocyanato-; 
                         toluilenodwuizocyjanian; toluylene-2,4-
                         diisocyanate; tolylene-2,4-diisocyanate; 
                         tolylene diisocyanate; 
                         tuluylendiisocyanat; 2,4-Dicyanato-1-
                         methyl-phenylene; 2,4-diisocyanato-1-
                         methylbenzene; 2,4-diisocyanatotoluene; 
                         2,4-toluene diisocyanate; 2,4-toluene 
                         diisocyanate; 4-methyl- m-phenylene 
                         diisocyanate; 4-methyl- m-phenylene 
                         isocyanate; 4-methyl-phenylene 
                         diisocyanate; 4-methyl-phenylene 
                         isocyanate 

Common names             TDI, 2,4-TDI

Trade names              Desmodur T65 (also-T80); Hylene T (also, 
                         -TCPA, -TLC, -TM, -TM65, -TRF); Isocyanic 
                         acid; Lupranat T80; Mondur TD (also, 
                         -TD80, -TDS); Nacconate 100; NCI-C50533; 
                         Niax TDI; Niax TDI-P; Rubinate TDI 80/20; 
                         TDI 80 
--------------------------------------------------------------------

Table 2.  (contd.)
--------------------------------------------------------------------
III.   2,6-TDI

Chemical abstracts name  benzene, 2,6-diisocyanato-1-methy-

Other chemical names     benzene, 1,3-diisocyanato-2-methyl-;
                         isocyanic acid; meta-tolylene diisocyanate;
                         2-methyl- m-phenylene isocyanate; 2,6-
                         toluene diisocyanates 

Common name              2,6-TDI

Trade names              not commercially available
--------------------------------------------------------------------

    The isomer or mixture studied is often not reported in the 
literature.  For the purposes of this document, in such cases, 
the chemical will be referred to as toluene diisocyanates.  When 
identified, the name of the particular isomer or mixture will be 
used. 

2.2.  Physical and Chemical Properties

    Toluene diisocyanates are colourless liquids or crystals, 
turning pale yellow on standing, and having a characteristic sharp 
pungent, sweet, fruity odour.  Some of the physical and chemical 
properties of toluene diisocyanates are listed in Table 3. 

    No properties of 2,6-TDI were found in the published 
literature, except for a boiling point of 129 - 133 C at 18 mmHg, 
and a specific gravity similar to that of 2,4-TDI (Pollock & 
Stevens, 1974). 

    Toluene diisocyanates are soluble in acetone, ethyl acetate, 
ether, benzene, carbon tetrachloride, chlorobenzene, kerosene, 
and various oils, e.g., corn oil.  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 such solvents that 
must not be mixed with toluene diisocyanates include water, acids, 
bases, and strong alkaline materials, such as sodium hydroxide and 
tertiary amines, etc. 

    Toluene diisocyanates react with water and most acids to 
produce unstable carbanic acids, which subsequently decarboxylate 
(raising the pressure in closed containers) to yield relatively 
chemically inert and insoluble polymeric urea (Hardy & Purnell, 
1978).  According to Holdren et al. (1984), reaction of TDI-vapour 
with water vapour does not take place in the gaseous phase.  They 
concluded that loss due to surface adsorption takes place first, 
since no diaminotoluenes or TDI-ureas could be detected in an 
environmental chamber.  Toluene diisocyanates also react with 
(-NH-)-containing compounds to form ureides or ureas.  Each 
reaction pathway is important in terms of the health hazard 

potential associated with toluene diisocyanates, since both 
pathways are biologically, as well as commercially, significant, 
and occur at room temperature (Chadwick & Cleveland, 1981). 

Table 3.  Physical and chemical properties of toluene diisocyanates
------------------------------------------------------------------------
Properties                   2,4-TDI            Commercial mixture
                                                (2,4-, 2,6-isomers)
------------------------------------------------------------------------
Freezing point ( C)         14 - 20a           11.5 - 13.5 (80:20 mix)
                             15c                11 - 14 (80:20 mix)
                                                3 - 5 (65:35 mix)b
                                                T80 = 12.5 - 13.5
                                                T65 = 4.7 - 6

Melting point ( C)          22b                12.5 - 13.5 (80:20 mix)
                                                4.7 - 6 (65:35 mix)

Boiling Point ( C)
 at 10 mmHg                  120b               121c
 at 760 mmHg                 251c               25l (both mixes)

Flash point ( C)
 open cup                    135a               132 (both mixes)
 closed cup                  127b               -

Explosive limits:
 Concentration (% v/v)
  lower                      0.9                0.9
  upper                      9.5                9.5

 Temperature ( C)
  lower                      -                  118
  upper                      -                  150

Fire temperature ( C)       -                  142

Autoignition temperature     620                620
( C)

Volatility; vapour pressure  1 mmHg (80 C)d    1.9 mmHg (94 C)a
                                                0.01 mmHg (20 C)

Vapour density (air = 1)     6d                 6e

Density (g/cm3)b,c           1.22 25/15         1.22 25/15 (both mixes)
                             1.2244 20/4c       -

Odour threshold              0.36 - 0.92 mg/m3
------------------------------------------------------------------------
a From:  Woolrich & Rye (1969).
b From:  Chadwick & Cleveland (1981).
c From:  Windholz (1983).
d From:  Hartung (1982).
e From:  NIOSH (1978).
f From:  Olin product literature.

    Toluene diisocyanates dimerize slowly at ambient temperatures 
and more rapidly at elevated temperatures.  Trimerization occurs at 
100 - 200 C and, above 175 C, carbodiimides form with the release 
of carbon dioxide (CO2) (Chadwick & Cleveland, 1981; Ulrich, 1983). 

2.3.  Conversion Factors

    At 25 C and 760 mmHg:
        1 mg/m3 = 0.14 ppm in air
        1 mg/litre = 140.5 ppm.

2.4.  Analytical Methods

    The sampling and determination of toluene diisocyanates in air 
has been the subject of several studies.  The method originally 
published by Marcali (1957) has been modified by several 
investigators (Grim & Linch, 1964; Meddle & Wood, 1970).  
Photometric methods are non-specific and most of them pool all the 
isocyanates.  Also, most procedures are severely hampered because 
other agents, particularly aromatic amines, interfere in a way that 
may result in falsely high readings.  In contrast, chromatographic 
techniques are specific and measure individual isocyanate species 
(Table 4). 

    Most recent analytical methods involve high-performance 
liquid chromatography (HPLC) using ultraviolet, fluorescence, or 
electrochemical detection (Dunlap et al., 1976; Sango & Zimerson, 
1980; Warwick et al., 1981).  Improved sampling techniques include 
the use of solid adsorbents (Tucker & Arnold, 1982).  The Marcali 
method has been evaluated for its response for the two isomers of 
toluene diisocyanate.  The simple modification involving changes in 
diazotization time and temperature eliminates the isomeric effect 
(Rando & Hammad, 1985).  An extension of the spectrophotometric 
method is the development of a tape method involving a chemically 
impregnated paper tape that changes colour on exposure to toluene 
diisocyanates (Reilly, 1968).  However, the presence of 
diaminotoluenes at concentrations similar to that of the toluene 
diisocyanates leads to significant negative interference with the 
colour-forming reaction (Walker & Pinches, 1981).  Also, at low 
humidity, the tape monitor tends to give falsely low readings 
(Mazur et al., 1986). 

    Levels of toluene diisocyanates in consumer products (lacquers) 
are usually determined, after appropriate extraction techniques, by 
gas chromatography and high-performance liquid chromatographic 
methods (McFadyen, 1976; Conte & Cossi, 1981). 

    In general, it should be understood that, with all analytical 
methods, reliable figures for isocyanate concentrations in air 
can be obtained only in the range of at least 5 - 10 times the 
detection limit. 


Table 4.  Analytical methods for the determination of toluene diisocyanates
---------------------------------------------------------------------------------------------------------
Purpose/method                                         Detection limit        Reference
---------------------------------------------------------------------------------------------------------
I. Detection of TDIs in work-place air

 1.  Spectrophotometry

    TDIs hydrolysed to the corresponding diamines,     0.07 mg 2,4-TDI/m3;    Marcali (1957)
    diazotized, coupled to  N-1-naphthyethylene-        field kit, 0.14 mg/m3
    diamine, and final colour measured at 550 nm;
     Note:  as the concentration of 2,6-TDI increases
    in the mixture, the total recovery of TDIs is
    reduced

    a modification of the Marcali method, in an                               Meddle & Wood (1970)
    attempt to circumvent interference by primary
    aromatic amines

    a further modification to eliminate the                                   Rando & Hammad (1985)
    difference in response for the two isomers

 2.  Gas chromatography

    2,4-TDI hydrolysed in dilute hydrochloric acid     0.06 - 0.23 mg/m3      De Pascale et al. (1983)
    and subsequent determination by gas-liquid 
    chromatography/mass fragmentography 2,4-DAT; 
    instrument detection limit is 500 pg

    gas liquid chromatography: TDIs hydrolysed to the  0.004 mg/m3            Audunsson & Mathiasson
    corresponding amines in dilute sulfuric acid;                             (1983)
    2,4- and 2,6-TDI detection limit depends on 
    sample volume

 3.  High-performance liquid chromatography

    TDI sampled in derivatizing absorber ( N-(4-nitro   14 g/m3               Dunlap et al. (1976)
    benzyl)propylamine) and subsequent determination
    of the urea derivative formed by UV detection;
    sample volume 20 litre at 1 - 2 litre/min
---------------------------------------------------------------------------------------------------------

Table 4.  (contd.)
---------------------------------------------------------------------------------------------------------
Purpose/method                                         Detection limit        Reference
---------------------------------------------------------------------------------------------------------
 3.  High-performance liquid chromatography (contd.)

    TDI derivatized during sampling with gamma-        0.0001 mg/m3           Sang & Zimerson (1980)
    ( N-methylaminomethyl)anthracene and analysis by
    fluorescence or UV detection; sample volume
    15 litre at 1 litre/min

    TDI sampled in absorbed solution containing        0.0002 mg/m3           Warwick et al. (1981)
    1-(2-methoxyphenyl) piperazine; the derivative
    formed is detected by electrochemical or UV
    detection; instrument detection limit 200 pg;
    sampling time 10 min at 1 litre/min

    TDI detected with electrochemical detection of     5 g/m3                Meyer & Tallman (1983)
    the derivative formed after treatment with
     p-aminophenol, instrument detection limit 100 pg;
    flow rate of 1 litre/min, for 10 min
     Note:  formation of multiple derivatives might
    lead to somewhat complex chromatograms

    TDIs determined as  N-(4-nitrobenzyl)propylamine    1 g/m3                Rosenberg (1984)
    derivatives with UV detection using a 10-litre
    sample

 4.  Direct read-out

    Tape-monitor using impregnated paper that yields   0.07 mg/m3             Reilly (1968)
    colour stain on exposure to isocyanate vapour

    TDIs absorbed on a piezoelectric quartz crystal    0.14 mg/m3             Alder & Isaac (1981a,b)
    coated with polyethylene glycol (PEG 400);         (portable kit);
    resulting change in weight of crystal is           0.043 mg/m3
    monitored by the associated change in the 
    oscillation frequency; PEG 400 minimizes the 
    effect of water vapour

    detection of TDIs with a coated quartz piezo-      0.07 mg/m3             Fielden et al. (1984)
    electric crystal                                   76 Hz cps SI
---------------------------------------------------------------------------------------------------------

Table 4.  (contd.)
---------------------------------------------------------------------------------------------------------
Purpose/method                                         Detection limit        Reference
---------------------------------------------------------------------------------------------------------
II.   Determination of free TDIs in flexible foam

 1.  Infrared spectroscopy

    based on the N=C=O stretching vibration; detects                          Conte & Cossi (1981)
    the presence of N=C=O groups independently of
    the molecular structure; extraction of unreacted
    TDIs in the foam with  o-dichlorobenzene and
    gas chromatographic determination using a flame
    ionization detector; free TDIs present at levels
    of about w/w foam in fresh foam (1 h after 
    production) disappear after 24 h, under all 
    storage conditions (both ambient and dry air)
---------------------------------------------------------------------------------------------------------
3.  SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE

3.1.  Natural Occurrence

    Toluene diisocyanates are not known to occur as natural 
products. 

3.2.  Man-Made Sources

3.2.1.  Production levels and processes

    Toluene diisocyanates are manufactured by the reaction of 
diaminotoluenes with phosgene.  The reaction temperature increases 
from ambient in the first reactor to about 200 C in the last 
reactor.  The isomer mixture is stripped of solvent and separated 
by distillation (NIOSH, 1978; IARC, 1979; Chadwick & Cleveland, 
1981). 

    The most widely marketed grade of toluene diisocyanate is the 
80:20 mixture of the 2,4- and 2,6-isomers.  A mixture of 65:35 
of 2,4-; 2,6-isomers is also available.  "Pure" 2,4-TDI is 
manufactured in small quantities and used for special applications.  
The residue product (i.e., "crude"-TDI) is sold as a speciality 
isocyanate (Chadwick & Cleveland, 1981; Ulrich, 1983). 

3.2.1.1.  World production figures

    The production of 80:20 mixture accounts for > 90% of 
the total toluene diisocyanates produced in USA.  In 1983, 
approximately 300 x 106 kg were produced in the USA; 29% of the 
1983 production was exported to Belgium, Canada, the Federal 
Republic of Germany, Japan, Korea, the Netherlands, and other 
countries (US ITC, 1985).  In the USA, it has been projected that 
the domestic demand for toluene diisocyanates will increase at the 
rate of 1 - 3% annually, until the year 1990 (Anon., 1983). 

    Production of toluene diisocyanates in Canada in 1975 amounted 
to 9 x 106 kg.  In 1982, the annual production capacity for toluene 
diisocyanates was 20 x 106 kg for Brazil and 12 x 106 kg for 
Mexico.  Western European nations (mainly Belgium, France, the 
Federal Republic of Germany, Italy, and Spain) reported a combined 
annual capacity for the production of toluene diisocyanates in 1982 
of > 326 x 106 kg.  Production capacity during 1982 within the 
Netherlands, Portugal, and the United Kingdom was not reported; 
however, production in 1976 in the United Kingdom was 25 x 106 kg. 
Seventy percent of the western European production was consumed 
nationally and 30% was exported, primarily to eastern Europe, the 
Middle East, and North Africa.  In eastern Europe, the German 
Democratic Republic and Yugoslavia had a combined production 
capacity of 47 x 106 kg toluene diisocyanates in 1982.  No figures 
were available for production within the USSR.  Japan reported an 
effective annual production capacity of 78 x 106 kg in 1982, and 
actual production reached 67 x 106 kg.  The global capacity for 
the production of toluene diisocyanates in 1982 was reported to 
be > 817 x 106 kg (Ulrich, 1983). 

3.2.1.2.  Manufacturing processes: release into the environment

    Toluene diisocyanates are manufactured in a closed system, and 
air emission is minimal.  However, toluene diisocyanates may be 
emitted into the atmosphere during the removal of phosgene and 
hydrogen chloride from the first fractionating column.  It is the 
belief of the Task Group that few of these products are emitted, 
because of improved manufacturing facilities.  After gas scrubbing, 
they may be discharged into the waste effluent (Dyson & Hermann, 
1971; Bagon & Hardy, 1978; Dharmarajan et al., 1978). 

    Levels of toluene diisocyanates ranging from 0.1 to 17.7 mg/m3 
have been monitored in stack gases from 3 plants manufacturing 
polyurethane foams (Grieveson & Reeve, 1983).  It was estimated 
that approximately 50  5 g toluene diisocyanates/tonne of TDI 
processed within the plant was emitted during the manufacture of 
soft-block foams (Grieveson & Reeve, 1983). 

3.2.2.  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 (~ 90% of 
the total 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). 

4.  ENVIRONMENTAL TRANSPORT, DISTRIBUTION, AND TRANSFORMATION

    There are very few studies on the overall environmental fate 
of toluene diisocyanates in the published literature.  Available 
studies have been summarized by Duff (1983).  On the basis of this 
review and available information on the physical and chemical 
properties, the following statements can be supported. 

4.1.  Air

    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 comparable 
concentrations of an aliphatic amine were simultaneously present in 
the chamber.  Again, no hydrolysis products of TDI could be 
detected. 

4.2.  Water

    In most industrial situations, toluene diisocyanates are 
hydrolysed by water to give the corresponding polymeric ureas and 
carbon dioxide (Chadwick & Cleveland, 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 & Grieveson, 1984). 

4.3.  Soil

    A computerized 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. 

4.4.  Biotransformation

    Studies were conducted under laboratory or environmental 
conditions to evaluate the potential degradation of soft 
polyurethane foams, with either a polyester or a polyether base, 
both prepared with an isomeric mixture of 2,4 and 2,6-diisocyanates 
(Martens & Domsch, 1981).  Polyurethane-ether foams were highly 
resistant to chemical and microbial degradation.  Polyurethane-
ester foams were quite susceptible to degradation, especially at 
elevated temperatures (50 C), yielding 0.25% 2,4-toluenediamine 
and 0.38% 2,6-toluenediamine in acidic (pH 1) water extracts of 
leachate after 3 months incubation in the laboratory.  The 
incubation mixture contained 1 g of finely chopped soft 
polyurethane foam of a polyester base prepared with the isomeric 
mixture of 2,4- and 2,6-diisocyanates, in 100 ml of leachate (pH 
7.5) from a refuse tip near Braunschweig, Federal Republic of 

Germany.  An experimental study conducted near this site 
corroborated the laboratory results.  Soft polyurethane foam cubes 
were checked for weight loss after 13 months incubation in the 
refuse tip, where they were found in the refuse layer of a 25:10:1 
(weight) mixture of municipal refuse, sewage sludge, and caustic 
lime.  The polyurethane-ester foam cubes lost 17 - 31% of their 
initial weight in the stratified filling, and, if the layers of 
fill were mixed, weight loss ranged between 35 and 86%.  The 
polyurethane-ether foam cubes did not degrade under these 
conditions.  It was concluded that soft polyurethane foams prepared 
with toluene diisocyanate isomers are susceptible to chemical 
hydrolysis under extreme environmental conditions, and that under 
these circumstances, an accumulation of aromatic amines can occur, 
if their microbial degradation is impeded. 

4.5.  Bioaccumulation

    There are no data on the bioaccumulation of TDIs. 

5.  ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE

    No data were found on levels of toluene diisocyanates in the 
general environment. 

5.1.  General Population Exposure

    Human beings and animals would be exposed to toluene 
diisocyanates in environmental media only in the immediate vicinity 
of effluents, factories, or areas of spillage (sections 3.2.1.2 and 
4).  Consumers may also be exposed to toluene diisocyanates through 
the indiscriminate use of several commercially available household 
products, such as polyurethane foam kits (US EPA, 1984).  For 
example, Peters & Murphy (1971) tested 5 "instant" polyurethane 
foam products and found that concentrations of toluene 
diisocyanates in the air ranged from 0 to 0.15 mg/m3 during 
applications.  They also noted that labels on the cans were 
inadequate regarding contents, precautions, and toxicity warnings.  
Consumers may also be exposed to toluene diisocyanates during the 
application of polyurethane varnishes (US EPA, 1984). 

    Beall & Ulsamer (1981) suggested that toluene diisocyanates 
might be an indoor air pollutant.  During pyrolysis of 
polyurethanes, the general public could be exposed to the pyrolytic 
products of toluene diisocyanates.  No monitoring levels were 
given. 

5.2.  Occupational Exposure

    Because of the volatility of toluene diisocyanates, exposure 
can occur in all phases of their manufacture and use (Sittig, 
1979).  Monitoring data for toluene diisocyanates in the work-
place is extensive with levels found between 0.014 and 1.050 mg/m3 
(NIOSH, 1978; Hosein & Farkas, 1981; Belin et al., 1983).  During 
the production of polyurethane-coated wire, toluene diisocyanates 
may be found in the work-place, during the different stages of the 
coating process, at concentrations ranging between < 0.001 and 
0.11 mg/m3 (Rosenberg, 1984).  The highest levels have occurred 
during spraying with polyurethane foam, a procedure that is usually 
conducted in confined spaces (Hosein & Farkas, 1981).  Isocyanate 
lacquers contain 0.2 - 1% monomeric toluene diisocyanates (Tu & 
Fetsch, 1980), and short-term excursions above safe limits are of 
a particular concern for spray workers and their assistants. 

    Sittig (1979) estimated that approximately 40 000 workers in 
the USA were potentially exposed to toluene diisocyanates in such 
jobs as adhesive production, insulation, application and production 
of toluene diisocyanate resins and lacquers; organic chemical 
synthesis, paint spraying, polyurethane foam production, working 
with rubber, shipbuilding, textile processing, and wire-coating.  
Consumer use of products containing TDI could result in many more 
cases of exposure. 

6. KINETICS AND METABOLISM

6.1.  Absorption

    Absorption of toluene diisocyanates through the respiratory 
tract is suggested by:  (a) their high acute toxicity for animals 
via inhalation (section 8.1); and (b) reports on systemic effects 
and antibody formation in individuals exposed to toluene 
diisocyanates primarily via inhalation (Sharonova & Kryzhanovskya, 
1976; Steinmetz et al., 1976; White et al., 1980; Sharonova et al., 
1982). 

6.2.  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, rather 
than that they will be absorbed and distributed throughout the body 
as toluene diisocyanates. 

6.3.  Metabolic Transformation and Elimination

    No published studies on the biotransformation of toluene 
diisocyanates were found.  However, one report (NTP, 1985) on the 
disposition of 2,6-TDI in Fischer 344 rats was available to the 
Task Group.  The apparent half-life of 2,6-TDI was dependent on 
the vehicle in which it was administered, its concentration in the 
solvent, and the rate of mixing as the compound was added.  In an 
aqueous suspension of stomach contents, the half-life of 2,6-TDI 
was < 2 min, whereas in serum, the half-life was < 30 seconds. 

    When [C14]-2,6-TDI was given orally to rats in corn oil, most 
of the compound formed polymers in the gastrointestinal tract.  At 
doses of 900 mg/kg body weight, the insoluble polyureas usually 
lined the stomach, slowing down or preventing the migration of 
stomach contents into the intestine.  At a 60 mg/kg dose level, 
these results were not observed (NTP, 1985).  Most 2,6-TDI-derived 
materials were eliminated in the faeces or were found in the 
gastrointestinal tract 72 h after dosing.  Approximately 12% of 
the low dose (60 mg/kg body weight) and only 5% of the high dose 
(900 mg/kg) were excreted in the urine (24-h after treatment), 
mainly in the form of 2,6-bis(acetylamino) toluene (54%).  Increased 
urinary excretion of 2,6-TDI metabolites with decreasing dosage was 
consistent with the lower concentration of the compound in the 
stomach permitting increasing amounts of the 2,6-TDI to be 
hydrolysed completely to monomeric 2,6-diaminotoluene rather than 
forming polymers.  The 2,6-diaminotoluene could then be absorbed, 
acetylated, and excreted in the urine.  Materials derived from 
2,6-TDI were not concentrated in any tissue (NTP, 1985).  In rats 
exposed dermally to 2,4-TDI, no unreacted isocyanate was detected 
in the urine, but 2,4-TDA was detected after hydrolysis of the 
urine (Rosenberg & Savolainen, 1985).  The same authors studied 
workers occupationally exposed to the 80:20 TDI isomer mixture, and 

reported that concentrations of TDA in the urine after hydrolytic 
treatment were linearly related to the estimated TDI dose 
(Rosenberg & Savolainen, 1986).  A possible biochemical pathway 
would involve the formation of TDA, its conjugation and excretion, 
but it was not known if this had taken place. 

6.4.  Reaction with Body Components

    Toluene diisocyanates are highly reactive towards a large 
number of active hydrogen and basic nitrogen compounds (Ozawa, 
1967; Alarie, 1973; Brown & Wold, 1973; Brown et al., 1982).  Thus, 
more than one reaction may occur in a system at a given time.  The 
results of an  in vitro study reported by the NTP (1985) showed that 
2,6-TDI would react with both rat serum and stomach contents at 
37 C.  The 2,6-TDI appeared to form a polymeric film, which 
encapsulated globules of 2,6-TDI, thus limiting the availability of 
the compound in the interior of the globules for further reaction. 

    Mixtures of TDI isomers, such as 80:20, may behave in a 
different manner to single 2,6- or 2,4-TDI isomers. 

    Isocyanates react with carboxyl groups and form amines, acid 
anhydrides, and ureas (Fry, 1953).  Ozawa (1967) and Brown & Wold 
(1973) demonstrated that diisocyanates were active-site-specific 
reagents towards the hydroxyl groups of serine in proteases.  Such 
reactions can result in the irreversible inactivation of enzymes, 
such as adenylate cyclase, serine proteases, alcohol dehydrogenase, 
and cholinestrase (Brown & Wold, 1973; Twe & Wold, 1973; Butcher et 
al., 1979; Dewair et al., 1983). Isocyanates react with amino 
groups to form ureas, which are also highly stable and unlikely to 
dissociate under biological conditions. 

    Isocyanates form thiolic acid and esters when reacting with 
sulfhydryl groups in proteins.  However, this reaction takes place 
at low pH only, whereas the products are unstable at pH 7 or higher 
(Twe & Wold, 1973). 

    Toluene diisocyanates may react with naturally occurring 
proteins or polysaccharides and form immuno hapten complexes.  The 
results of an  in vitro study by Ted Tse & Pesce (1979) showed that 
toluene diisocyanates will react with human serum-albumin via one, 
or both, of the isocyanate groups to form mono- or bisureido 
protein derivatives.  Such derivatives may be immunogenic and may 
possibly lead to allergenic responses, as well as new antigenic 
determinants (Baur, 1983). 

7.  EFFECTS ON ORGANISMS IN THE ENVIRONMENT

    Lethality data for some avian and aquatic species are listed in 
Table 5. 

    Although practically insoluble in water, dispersed TDI can form 
droplets and cause toxicity in aquatic systems. 

    Curtis et al. (1979) reported that 2,4-toluene diisocyanates 
appeared to be toxic for fathead minnows only in the unreacted 
form, and most lethality occurred during the first 12 h of 
the test.  The LC50 for aquatic species ranged from 10.5 to 
508.3 mg/litre in static tests.  The oral LD50 for avian species 
was > 100 mg/kg body weight (Schafer et al., 1983). 


Table 5.  Lethality of toluene diisocyanates for aquatic and avian species
---------------------------------------------------------------------------------------------------------
Species                Dose/concen-   Condition           Lethality             Reference
                       tration
                       (mg/litre)
---------------------------------------------------------------------------------------------------------
 Freshwater

Fathead Minnow         194a           static              24-h LC50             Curtis et al. (1979)
 (Pimephales promelas)  172.1          static              48-h LC50             
                       164.5          static              96-h LC50
                                      reconstituted
                                      softwater (20 C)

 Saltwater

Grass shrimp           508.3a         salinity 25 parts/  mortality less than   Curtis et al.
 (Palaemonetes pugio)                  thousand; 22 C;    65% below this level  (1979)
                                      static              within 96 h

Harpacticoid copepod   11.8b          salinity 7 parts/   96-h LC50             Bengtsson & Tarkpea
( Nitocra spinipes      (10.5 - 13.2)  thousand; static                          (1983)
Boeck) Crustacea

 Avian

Redwinged blackbird    100 mg/kgc     oral                LD50                  Schafer et al. (1983)
 (Agelaius phoeniceus)

Starling               > 100 mg/kgc  oral                LD50                   Schafer et al. (1983)
 (Sturnus vulgaris)
---------------------------------------------------------------------------------------------------------
a 2,4-isomer.
b Authors did not state the units; mg/litre were assumed on the basis of previous publication of Lindn 
  et al. (1979).
c 2,6-isomer.
8.  EFFECTS ON EXPERIMENTAL ANIMALS AND  IN VITRO TEST SYSTEMS

8.1.  Single Exposures

    Application of drops of toluene diisocyanates in the eyes of 
rabbits caused immediate reaction suggestive of pain, lachrymation, 
swelling of the eyelids, a conjunctival reaction, and mild damage 
to the cornea (Zapp, 1957; Grant, 1974; Duprat et al., 1976; 
Woolrich, 1982). 

    Intratracheal administration of 0.3 ml toluene diisocyanates in 
guinea-pigs resulted in coagulation of proteins in the respiratory 
tract and rapid death from respiratory distress (Friebel & 
Lchtralh, 1955).  The acute toxicity of toluene diisocyanates via 
various routes of exposure is summarized in Table 6. 

Table 6.  Lethality of toluene diisocyanates
------------------------------------------------------------------------
Route/species  Concentration  Duration  Lethality  Reference
                              (h)
------------------------------------------------------------------------
 Inhalation

Rat            56.96 mg/m3    1         LC50       Harton & Rawl (1976)

Rat            98.96  8.6    4         LC50       Duncan et al. (1962)
               mg/m3

Rat (male)     348.88 mg/m3   4         LC50       Bunge et al. (1977)
    (female)   356 mg/m3      4         LC50

Mouse          69.1  9.96    4         LC50       Duncan et al. (1962)
               mg/m3

Rabbit         78.32 mg/m3    4         LC50       Duncan et al. (1962)

Guinea-pig     90.4  19.2    4         LC50       Duncan et al. (1962)
               mg/m3

 Oral

Rat            3060 mg/kg     -         LD50       Harton & Rawl (1976)
               body weight

Mouse (male)   4130 mg/kg     -         LD50       Woolrich (1982)
               body weight

 Dermal

Rabbit         10 000 mg/kg   -         LD50       Harton & Rawl (1976)
------------------------------------------------------------------------

    The toxicity of toluene diisocyanates, administered orally, is 
low, but they are very toxic after inhalation exposure.  Animals 
reportedly died of acute pulmonary congestion, oedema, and 
haemorrhage.  Duncan et al. (1962) reported that during inhalation 

exposures, all animals (Table 6) exhibited irritation.  Tracheitis 
and bronchitis, with sloughing of superficial epithelium, occurred 
after exposure to 14.2 mg/m3 for 4 h.  Rapid coagulation and 
necrosis of the epithelium was evident following exposure to 
35.8 mg/m3, suggesting direct chemical injury. 

8.2.  Short-Term Exposures

8.2.1.  Inhalation

8.2.1.1.  Guinea-pig

    Exposure of guinea-pigs to 1200 mg toluene diisocyanates/m3, 
as an aerosol, or 250 - 550 mg/m3, as a vapour, for 10 - 20 min at 
irregular intervals, for one month, caused asthmatic reactions 
after the first few inhalations, changing into continuous dyspnoea 
in the course of the study (Friebel & Lchtralh, 1955).  Attainment 
of these concentrations could only be achieved with both aerosol 
and vapours.  Bronchiolitis obliterans, pneumonia, and emphysema 
occurred with little healing.  Guinea-pigs sensitized to chicken 
albumin responded in the same manner as untreated animals, 
indicating the predominance of a primary toxic effect.  However, 
a possible role of allergic type reactions could not be excluded 
completely. 

    Immunological sensitization and pulmonary hypersensitivity to 
an 80:20 mixture were evaluated in the guinea-pig.  Five days after 
exposure to 1.78 mg/m3 (3 h/day for 5 days), 3 out of 16 exposed 
guinea-pigs had developed antibody against TDI-guinea-pig serum-
albumin antigen, as demonstrated by immuno-diffusion, compared with 
0/16 before exposure (Karol et al., 1980).  Three additional 
animals showed antibody responses with the more sensitive passive 
cutaneous anaphylaxis assay (PCA).  That is, a total of 6/16 
exposed animals were antibody positive.  No consistent increases 
indicative of a pulmonary hypersensitive reaction were observed. 

    Concentration-dependent immunological responses to toluene 
diisocyanates were measured following exposures that mimicked 
industrial exposures and might lead to allergic reactions in 
exposed workers (Karol, 1983).  Guinea-pigs were exposed to 0.85 - 
71.2 mg 80:20 mixture/m3, 3 h/day, for 5 days.  On day 22, assays 
for TDI-specific antibody, skin sensitivity, and pulmonary 
sensitivity to toluene diisocyanates were performed.  No antibody 
to toluene diisocyanates was detected in animals exposed to a 
concentration of 0.85 mg/m3, whereas 55% of the animals exposed 
to > 2.56 mg 80:20 mixture/m3 displayed TDI-specific antibody in a 
dose-related fashion.  Pulmonary sensitivity to TDI-protein antigen 
was observed at concentrations exceeding 2.6 mg/m3.  Doses higher 
than 14.2 mg/m3 resulted in pneumotoxicity and fewer pulmonary 
hypersensitivity reactions.  Exposure of a group of 24 guinea-pigs 
to 0.14 mg 80:20 mixture/m3 (6 h/day, 5 days/week, for 70 days) in 
whole-body exposure chambers, did not elicit these reactions 
(Karol, 1983). 

8.2.1.2.  Mouse

    The effects of single and repeated exposures to 2,4-TDI (99.7% 
pure) vapour at concentrations ranging from 0.05 to 14.2 mg/m3 were 
investigated in male Swiss-Webster mice, to detect the level of 
sensory irritation caused by this chemical (Sangha & Alarie, 1979).  
The results obtained demonstrated that the level of response not 
only depended on the concentration, but also on the duration of 
exposure; recovery rates also depended on the duration of exposure.  
The RD50 (respiratory rate decrease of 50%) values decreased
significantly between 10 and 180 min and the levels of response 
were exactly the same at 180 and 240 min of exposure.  The RD50 
found at 180 or 240 min of exposure was 1.42 mg/m3.  Repeated 
exposures to 2,4-TDI concentrations of or above 0.14 mg/m3 resulted 
in cumulative effects, because of incomplete recovery prior to a 
repeat exposure. 

    Weyel et al. (1982) measured the sensory irritation of 2,6-TDI 
vapour at 0.37 - 7.6 mg/m3 in male Swiss-Webster mice.  After a 3-h 
exposure, a decrease in respiratory rate occurred with a pattern 
indicative of sensory irritation of the upper respiratory tract, 
which was similar to that noted by Sangha & Alarie (1979) with 
exposure to 2,4-TDI at levels of > 0.14 mg/m3.  An inverse linear 
relationship (respiratory rate decrease versus log concentration of 
2,6-TDI) was obtained that was identical to the slope and 
relationship obtained in the earlier study on 2,4-TDI.  From the 
concentration-response (sensory irritation) relationship for 
2,6-TDI, the RD50 was determined to be 1.85 mg/m3. 

    Lesions in the nasal cavity with a distinct anterior-posterior 
severity gradient developed in mice after exposure to toluene 
diisocyanates at 2.84 mg/m3, for 6 h/day, over 5 days (Buckley et 
al., 1984).  The lesions ranged from slight epithelial hypertrophy 
or hyperplasia to epithelial erosion, ulceration, and necrosis with 
variable inflamation of the subepithelial tissues.  There was also 
an associated loss of the olfactory nerves in the lamina prioria in 
exposed animals. 

8.2.1.3.  Rat

    Studies by Henschler et al. (1962) on the inhalation toxicity 
of toluene diisocyanates are summarized in Table 7. 

    At exposure levels of 35.6 and 71.2 mg toluene 
diisocyanates/m3, death was due to mechanical blocking of the 
respiratory passages by mucosal tissue detached from bronchi and 
trachea.  At lower exposure levels, the fatal sequelae also 
included heavy peribronchitis and spreading bronchopneumonia.  
After cessation of exposure, partial reversal of pulmonary changes 
occurred after several months in the 7.12 mg/m3 exposure group, and 
complete remission occurred in the 3.56 mg/m3 exposure group.  
After 40 exposures at 0.712 mg/m3, there were no definitive changes 
in the respiratory tract, the only toxicological response being a 
depression in body weight (Henschler et al., 1962). 

Table 7.  Inhalation toxicity of toluene diisocyanatesa
-------------------------------------------------------------------
Number of exposures     Concentration   Lethality
(schedule)              (mg/m3)
-------------------------------------------------------------------
24                      3.56            45% fatality of animals
(6 h/day, 6 days/week,                  with initial body weight
twice, miss 4 weeks,                    of 91 - 124 g; 0% fatality
repeat second 12                        of animals with initial
exposures)                              body weight of 140 - 180 g

10                      7.12            75% fatality

4                       35.6            65% fatality

2                       71.2            lethal for most animals;
                                        2,4-isomer more toxic than
                                        2,6-isomer

3 or 5                  71.2            lethal for all
                                        exposed animals
-------------------------------------------------------------------
a The 71.2 level mg/m3 was for 2,4- or 2,6-isomer or a 65:35 
  mixture of isomers. The 35.6, 7.12, and 3.56 mg/m3 levels were 
  for the 80:20 mixture.  From:  Henschler et al. (1962).

8.2.1.4.  Dog

    Four male dogs were exposed to concentrations of toluene 
diisocyanates averaging 10.68 mg/m3, 35 - 37 times, for various 
lengths of exposure (30 - 120 min), over a period of 4 months.  
The dogs showed lachrymation, coughing, restlessness, and 
expectoration of white frothy material.  When killed after the last 
exposure, all dogs showed mild congestion and inflammation of the 
trachea and large bronchi.  A conspicuous feature was the presence 
of thick mucous plugs in some of the bronchial branches (Zapp, 
1957). 

8.2.2.  Dermal

    Toluene diisocyanates were described as a "medium" irritant for 
rabbits and guinea-pigs, capable of producing cutaneous sensitivity 
similar to contact allergy.  The allergenic capacity was long-
lasting and depended on the allergen concentration (Zapp, 1957; 
Duprat et al., 1976). 

8.2.2.1.  Guinea-pig

    Dermal contact with toluene diisocyanates in the animal model 
resulted in "rare" cases of sensitization (Peschel, 1970) and in 
subsequent respiratory tract hypersensitivity (Karol et al., 1981).  
Dermal contact sensitivity developed by the 7th day, following 
applications of 1 - 100% solutions of 80:20 mixture (diluted with 
olive oil) to the dorsal skin of the guinea-pig.  After 14 days, 
animals were evaluated for toluene diisocyanates sensitivity by 

serological analysis and by bronchial provocation challenge.  
Bronchial challenge with 0.03 mg toluene diisocyanates/m3, or 
aerosols of TDI-protein conjugates, or  p-tolyl isocyanate resulted 
in respiratory hypersensitivity (Karol et al., 1981).  These 
responses were immediate; the respiratory rate increases were 3 
times those in non-sensitive guinea-pigs.  In challenges using 
isocyanate conjugates, TDI-specific pulmonary reactions were 
elicited more effectively when the hapten-protein conjugates rather 
than the toluene diisocyanates vapour served as the challenging 
agent. 

    Koschier et  al. (1983) evaluated the dose-dependent eliciting 
of dermal sensitization in young adult guinea-pigs treated with 
2,4-TDI (2,6-isomer was < 2.5%).  Induction was by cutaneous 
application (25 l) of 8 - 40% 2,4-TDI in  n-butyl ether on 2 
separate uncovered dorsal sites.  Five days later, animals were 
challenged with 0 - 0.4% 2,4-TDI (25 l per site).  All challenge 
applications from 0.025% (6.25 g) elicited a positive response in 
75 - 100% of the animals.  The results demonstrated that 2,4-TDI 
induced sensitization and that the severity of the dermal response 
was correlated with the concentration used at induction and 
challenge.  In a second study, in the group induced with 4% 2,4-
TDI, no effects were elicited after a dermal challenge application 
of 3 g, and a minimum effect was seen with 6.25 g 2,4-TDI 
(Koschier et al., 1983). 

8.2.2.2.  Mouse

    In a dose-response study (Tanaka, 1979), a 100% increase in 
ear-swelling in C3H/He mice, 24 h after challenge with 0.5 ml of 5% 
TDI, was reduced to 50% after 72 h.  In a second trial, 81% ear-
swelling resulted from a 5% challenge with TDI; there was a 6.5% 
ear-swelling response to a 1% TDI challenge, compared with 2.4% in 
vehicle controls.  There was a cross-reactivity between TDI and 
monodiisocyanate (MDI), so that sensitization with either 
diisocyanate resulted in equal ear-swelling responses to challenge 
with the opposite diisocyanate.  The degree of response in cross-
reactivity was 4-times that in controls and about 35% of a 
challenge response by the same diisocyanate used for sensitization.  
Thymectomy did not change the ear-swelling responses to TDI.  In a 
subsequent study, Tanaka et al. (1984) reported that TDI induced a 
delayed-type hypersensitivity reaction in the ear skin of male ICR 
mice, and that 7-week-old mice sensitized with 1 - 5% (100 l/dose) 
TDI solutions showed ear-swelling with a challenge of 1% (2 l) TDI 
solution.  The responses in 5-, 7-, and 13-week-old mice were the 
same but were very slight in 16-week-old mice.  Seven-week-old 
BalB/C mice showed similar responses to ICR mice, but reactions in 
ddY mice were much weaker. 

    Allergic dermatitis developed in mice by sensitization to 
toluene diisocyanates, followed by inhalation exposure to the test 
compound to determine if a delayed type allergy plays a role in 
lung disorders caused by toluene diisocyanates.  At a concentration 
of 4.27 mg/m3, inhaled for 2 h, allergic dermatitis did develop, 
but without noticeable pathological changes in the respiratory 
organs (Ohsawa, 1983). 

8.2.3.  Oral

    Oral gavage of 1500 mg/kg per day resulted in the death of 50% 
of rats within a total of 10 treatments.  Pathological examination 
revealed injury to the gastrointestinal tract and liver (Zapp, 
1957).  No other toxic effects were reported from these studies. 

8.3.  Long-Term Exposure

8.3.1.  Inhalation

8.3.1.1.  Mouse

    A dose-related increase in the incidence and severity of either 
chronic or necrotic rhinitis occurred in mice exposed through 
inhalation to the 80:20 mixture of toluene diisocyanates at 0.36 or 
1.07 mg/m3, for 6 h/day, 5 days/week, over 2 years.  In addition, 
lesions of variable incidence and severity were seen in the lower 
respiratory tract (interstitial pneumonitis, catarrhal bronchitis) 
and eyes (keratitis) of some mice, with a higher incidence in the 
1.07 mg/m3 group.  Morbidity and mortality due to rhinitis occurred 
in both treated groups (Loeser, 1983). 

8.3.1.2.  Dog

    Patterson et al. (1983) immunized 3 dogs (by endotracheal tube) 
with an aerosol of toluene diisocyanates at 1 mg/kg body weight, 
every 2 weeks, for 4 months (2 - 3 times the maximal TLV for 
occupational exposure).  Thereafter, 2 dogs were dosed with 1 mg/kg 
body weight every 4 weeks for 6 months (stated to be the cumulative 
dose analagous to long-term exposure to 0.14 mg/m3).  Systemic 
immune responses to TDI-dog serum-albumin, including elevated 
specific antibody titers of IgG, IgA, IgM, and development of 
specific lymphocyte reactivity, were seen in all animals.  Elevated 
IgG and IgA titers were persistent.  Although increased, the lower 
titer of IgM antibody was of short duration.  The antibody IgE was 
detected, but levels fluctuated and became negative, even with 
continued exposure to toluene diisocyanates.  Airway responses 
that occurred immediately after exposure to the aerosol included 
abnormalities of selected pulmonary function parameters.  They were 
clearly not immunologically mediated, because they occurred with 
initial exposure.  However, other immediate airway responses 
occurred that qualitatively simulated IgE-mediated, antigen-induced 
airway responses in dogs.  There was a statistically-significant 
correlation between the latter airway responses and immediate skin 
reactions (Patterson et al., 1983). 

8.4.  Reproduction, Embryotoxicity and Teratogenicity

    No published data were found on the effects of toluene 
diisocyanates on reproduction, or on the embryotoxicity or 
teratogenicity of these compounds. 

8.5.  Mutagenicity and Related End-Points

8.5.1.  Bacterial mutagenicity

    There are conflicting reports about the mutagenicity of toluene 
diisocyanates.  Anderson & Styles (1978) reported that toluene 
diisocyanate of unknown purity was non-mutagenic in a study of 120 
chemicals tested by Purchase et al. (1978), but the fact that 
several known mutagens failed to give positive results means that 
the original report was suspect.  Andersen et al. (1980) later 
optimized the procedures to test the reactive isocyanates and 
showed that a mixture of 2,4- and 2,6-toluene diisocyanates caused 
a dose-dependent mutagenic response, using S-9 activation, in 
 S. typhimurium strains TA 98, TA 100, 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. 

8.5.2.  Mammalian cell transformation

    Toluene diisocyanates were negative in two  in vitro cell 
transformation assays using human lung and hamster kidney cells 
(Styles, 1978). 

8.5.3.  Mammalian  in vivo study

    Studies by Loeser (1983) failed to show a dose- or treatment-
related percentage increase in micronucleated erythrocytes from the 
bone marrow of rats and mice exposed through inhalation to 80:20 
mixture at 0.35 or 1.06 mg/m3, for 6 h/day, 5 days/week, over 4 
weeks. 

8.6.  Carcinogenicity

8.6.1.  Oral

    Long-term oral (gavage) administration of the 80:20 mixture 
of 2,4-, 2,6-TDI in corn oil resulted in increased incidences of 
various types of tumours in Fischer 344/N rats and B6C3F1 mice 
(NTP, 1986).  Female rats and mice were dosed with 60 or 120 mg/kg 
body weight; male rats received 30 or 60 mg/kg body weight; and 
male mice were dosed with 120 or 240 mg/kg body weight, for 5 days 
per week, over 2 years.  However, it is worth noting that the 
reaction of toluene diisocyanates with the moisture in the corn oil 
resulted in unknown reaction products and in doses qualitatively 
and quantitatively different from those reported, possibly as much 
as 23% below the target dose.  Long-term treatment, by gavage, with 
the TDI-corn oil mixture caused dose-related reductions in body 
weight gain.  A dose-dependent pattern of cumulative toxicity began 

at weeks 70 - 75, culminating at 103 weeks in the following 
percentage mortality in control, low-, and high-dose groups, 
respectively:  male rats: 28%, 72%, and 84%; female rats: 28%, 62%, 
and 88%; male mice:  8%, 20%, and 48%; and female mice: 32%, 14%, 
and 34%. 

    Significant increases were noted in the incidence of 
subcutaneous fibromas and fibrosarcomas (combined) in male and 
female rats; pancreatic acinar-cell adenomas in male rats; 
pancreatic islet-cell adenomas, neoplastic nodules of the liver, 
and mammary gland fibroadenomas in female rats; haemangiomas and 
haemangiosarcomas (combined), and hepatocellular adenomas in 
female mice (NTP, 1986).  It was concluded that the 80:20 mixture 
of 2,4-, 2,6-TDI in corn oil was carcinogenic for male and female 
rats and female mice, when administered orally by gavage.  The 1986 
NTP report was reviewed during its preparation by Rampy et al. 
(1983). 

8.6.2.  Inhalation

    In a long-term inhalation study, Sprague Dawley CD rats and 
CD-1 mice were exposed to the 80:20 isomer mixture at nominal 
levels of 0.356 mg/m3 (0.05 ppm) or 1.068 mg/m3 (0.15 ppm), for 
6 h/day, 5 days per week, for 108 weeks (female rats), 110 weeks 
(male rats), or 104 weeks (male and female mice) (Loeser, 1983).  
The type and incidence of tumours and the number of tumour-bearing 
animals of either species did not indicate any carcinogenic effect.  
The main pathological changes in mice occurred in the nasal cavity 
and included dose-related incidences of epithelial atrophy, mucuous 
and squamous metaplasia, inflammation, and focal destructive 
rhinitis with debris. 

    In this study, there was an unexplained high mortality in both 
the control and treated rats and mice.  In the high-exposure groups 
(1.068 mg/m3), significantly lower weight gains were noted 
throughout the study in mice and during the first 12 weeks in rats.  
Haematological indices, clinical chemistry, and urinalyses were not 
affected by the doses of 80:20 mixture used, nor were there dose-
related changes in organ weights.  It was tentatively concluded 
that, under these experimental conditions, the 80:20 mixture at 
0.356 or 1.068 mg/m3 did not lead to a carcinogenic response or to 
other adverse clinical responses.  Although some reductions in 
weight gain were noted, the doses used were probably below maximal 
tolerated doses.  In addition, the high mortality rate reported 
reduced the sensitivity of this bioassay. 

8.7.  Special Studies and Mechanisms of Toxicity

    On the basis of the possible reactions to toluene diisocyanates 
(section 7.5), it is most likely that covalent binding and slow 
recovery could follow reaction of toluene diisocyanates with 
hydroxyl and amino groups of receptor proteins in the nasal 
mucosa.  Under the conditions proposed by Brown & Wold (1971), it 
is possible that only the first "reversible noncovalent" complex 
may have been formed after short durations of exposure to toluene 

diisocyanates, since recovery was rapid (Sangha & Alarie, 1979) 
(section 8.2.1.2).  With longer exposure, the slow recovery would 
be due to the formation of the covalent irreversible complex (Brown 
& Wold, 1971). 

    In a subsequent study, McKay & Brooks (1984) reported a 
significant difference in carbachol-stimulated tracheal smooth 
muscle strips from guinea-pigs exposed to toluene diisocyanates 
(0.02 mg/m3, 5 h/day, for 20 days) compared with controls.  The 
observed increase in maximal tension and the shift of the dose-
effect curve for exposed animals suggested a direct effect of 
toluene diisocyanates on tracheal smooth muscle.  The toluene 
diisocyanate tested had an isomer content of 97.8% 2,4-TDI and 2.2% 
2,6-TDI. 

    Kido et al. (1983a) measured histamine release from the 
leukocytes of guinea-pigs exposed to a toluene diisocyanate level 
of less than 7 mg/m3 (1 ppm), to study the mechanism of induction 
of asthma by toluene diisocyanates.  In guinea-pigs with IgE 
antibody, histamine release was > 20% with an average peak value 
(apv) of 40% compared with < 20% and an apv of 8.8% in controls, 
and a histamine release of approximately 20% with an apv of 24.1% 
in guinea-pigs without elevated IgE antibody levels. 

    The authors hypothesized that, after exposure to toluene 
diisocyanates, the IgE antibody, which is homocytotropic to 
basophils, resulted in histamine release  in vitro by the TDI-human 
serum-albumin (TDI-HSA) conjugated antigen, and that it is possible 
that an immediate-type allergic reaction by the IgE antibody is 
involved in the mechanism of induction of TDI-asthma. 

    Studies by Chen & Bernstein (1982) have shown the presence of 
hapten-specific IgE antibodies in the sera of guinea-pigs immunized 
with either toluene-diisocyanate-human serum-albumin or 
hexamethylene diisocyanate-human serum-albumin or hexamethylene 
diisocyanate-human serum-albumin and subsequently challenged with 
conjugates of the respective ligands coupled to transferrin.  In 
these studies, both homocytotropic (IgG and IgE), and precipitating 
antibodies were produced under appropriate conditions of parenteral 
immunization.  The authors postulated that the complex nature of 
the immune response generated by diisocyanate compounds in guinea-
pigs might also serve as an appropriate model for isocyanate-
induced human sensitivity reactions, which are known to involve 
diverse immunological and nonimmunological mechanisms. 

    Tanaka et al. (1984) induced nasal allergy in guinea-pigs by 
painting a 10% solution of toluene diisocyanates in ethyl acetate 
on the bilateral nasal vestibules, once a day, for 5 days.  After 
waiting 3 weeks, the animals were challenged in a similar manner 
with a 5% toluene diisocyanates solution; the process was repeated 
2 times per week, for 3 months.  Sneezing and rhinorrhea occurred 
in guinea-pigs, either with or without dyspnoea, and many 
eosinophils were found in nasal smears.  Histopathology indicated 
enhanced secretory function, eosinophil infiltration, and probable 
degranulation of mast cells in the nasal mucosa.  A significant 

release of histamine from the nasal mucosa in TDI-sensitized 
guinea-pigs was noted, when stimulated  in vitro by TDI-guinea-pig 
serum-albumin. 

9.  EFFECTS ON MAN

9.1.  General Population Exposure - Controlled Human Studies

9.1.1.  Single exposures

    In human volunteers, eye and nose irritation began at acute 
concentrations of 0.35 - 0.92 mg/m3, while skin irritation 
generally occurred at higher levels (Brugsch & Elkins, 1963; 
Bruckner et al., 1968; Sittig, 1981; Woolrich, 1982).  The odour 
threshold for aerosols of toluene diisocyanates was tested in human 
volunteers by several investigators (Munn, 1960; Henschler et al., 
1962; Brugsch & Elkins, 1963).  The responses were not uniform, 
probably because of differences in chemical purity, protocol, etc.  
Ehrlicher's group reported the following: slight odour = 0.92 mg/m3 
(0.13 ppm); odour without irritation = 4.28 mg/m3 (0.60 ppm); 
burning eyes and nose = 13.57 mg/m3 (1.9 ppm); and severe 
irritation of eyes and respiratory tract = 27.8 mg/m3 (3.9 ppm).  
Henschler et al. (1962) reported values that were about 10 times 
lower for the irritation effects of TDI in human exposure.  In a 
30-min exposure of 6 persons, levels of 0.07 and 0.14 mg/m3 (0.01 
and 0.02 ppm) were not perceived, a level of 0.35 mg/m3 (0.05 ppm) 
was recognized by everyone, slight irritation of the eye, nose, and 
throat occurred at concentrations of between 0.35 and 0.7 mg/m3 
(0.05 and 0.1 ppm), secretions in the eye and nose occurred in most 
persons at 0.7 mg/m3 (0.1 ppm) and always at 3.5 mg/m3 (0.5 ppm), 
and, overall, the irritative effect was greater in response to 2,6-
than to 2,4-TDI.  The difference in threshold response can perhaps 
be attributed to more accurate analytical procedures used by 
Henschler et al. (1962). 

    Brugsch & Elkins (1963) reported that the minimum concentration 
of toluene diisocyanates for irritation was 0.35 - 0.7 mg/m3 (0.05 - 
0.1 ppm) and that all subjects were irritated at 3.5 mg/m3 (0.5 
ppm). 

    Odour threshold values varied from 0.35 to 0.92 mg/m3 (0.05 to 
0.13 ppm) in these studies. 

9.2.  Occupational Exposure

9.2.1.  Acute toxicity

    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 removal from the contaminated environment 
(Ehrlicher & Pilz, 1956; Walworth & Virchow, 1959; Munn, 1960, 
1968; NIOSH, 1978). 

    Eye contact with toluene diisocyanates (vapour, aerosols, or 
liquids) causes mild irritation, characterized by itching and 
lachrymation, which may progress to conjunctivitis and 
keratoconjunctivitis (Brugsch & Elkins, 1963; Luckenbach & Kieler, 
1980).  Oculorhinitis may also occur and be delayed by a few hours 
(Paggiaro et al., 1985). 

    Systemic symptoms, which developed after acute occupational 
exposure to toluene diisocyanates, have been reported by Axford et 
al. (1976) and Le Quesne et al. (1976).  These two reports describe 
the findings from one accident in which the victims were firemen 
involved in both fire-fighting and clean-up operations at a 
polyurethane foam factory, where a large quantity of toluene 
diisocyanates (4500 litres) had leaked. 

    Exposed firemen experienced symptoms during and/or after the 
fire.  Symptomatology included 15 cases of gastrointestinal 
distress, 4 of which, though asymptomatic during the fire, 
developed gastrointestinal symptoms the following day, 3 
experiencing abdominal pain with diarrhoea, while the other 
complained of nausea and vomiting.  All symptoms eased within 2 
days without any apparent long-term effects (following 4 years of 
monitoring). 

    In addition to gastrointestinal symptoms, 23 firemen complained 
of neurological symptoms.  Five firemen experienced symptoms (i.e., 
euphoria, ataxia, intermittent shaking of the limbs, dizziness, and 
loss of consciousness) immediately on exposure.  Symptoms such as 
headaches, difficulty in concentrating, poor memory, and confusion 
persisted for 3 weeks in 14 of the firemen.  After 4 years, poor 
memory was the most common complaint, followed by personality 
change, irritability, or depression, in a total of 13 firemen 
(Le Quesne et al., 1976).  Interpretation of these findings is 
complicated by simultaneous exposure to other toxic components 
released during these types of fires. 

    In an earlier investigation, Hama (1957) reported cold-like 
symptoms and nocturnal sweating, without fever, in addition to the 
gastrointestinal and neurological symptoms described above. 

9.2.2.  Effects of short- and long-term  occupational exposure - 
epidemiological studies

9.2.2.1.  Ocular

    Luckenbach & Kieler (1980) reported evidence of microcystic 
corneal oedema and conjuctival infection in both eyes in a 
polyurethane foam worker (40-year-old female).  Clouded vision, 
decreased visual acuity, and loss of light perception developed 
within one week of employment.  Both corneas and conjunctivae 
returned to normal after 3 days without exposure to the 
occupational chemicals.  Similar visual effects have been 
attributed to some amine catalysts (Belin et al., 1983). 

9.2.2.2.  Dermal

    Skin sensitization on repeated exposure to toluene 
diisocyanates may occur.  Urticaria, dermatitis, and allergic 
contact dermatitis have been reported in workers exposed to toluene 
diisocyanates-based photopolymerized resins (Brugsch & Elkins, 
1963; Calas et al., 1977).  The dermatological symptoms included 
skin lesions of an eczematous, and also, of an irritant, 
pruriginous and erythaematous 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.  Titers of specific IgE antibodies gradually declined 
over the period of observation from a high level of 1050 net cpm 
[by radioallergosorbent test (RAST)] to 270 net cpm after 
occupational exposure ceased.  The lower level corresponds to those 
found in non-sensitized toluene diisocyanates workers (Karol et 
al., 1978). 

9.2.2.3.  Respiratory tract 

    Occupational exposure to toluene diisocyanates has produced a 
variety of respiratory effects in workers including irritation of 
the upper and lower respiratory tract, an asthma-like sensitization 
response, dyspnoea, cyanosis, and pulmonitis and decreases in lung 
function (Swensson et al., 1955; Brugsch & Elkins, 1963; Gandevia, 
1963; Peters et al., 1968, 1969; Peters, 1970; Gaffuri & Brugnone, 
1971; Charles et al., 1976; Wegmen et al., 1977; Burge et al., 
1979; Burge, 1982).  Short-term, as well as long-term exposures to 
toluene diisocyanates, in some instances at levels < 0.007 mg/m3, 
have been reported to result in significant decreases in lung 
function (NIOSH, 1978).  However, the results of more recent 
studies by Musk et al. (1982) failed to support such effects at 
levels of isocyanates of the order of 0.007 mg/m3 (0.001 ppm).  
Sensitization after a single exposure was not demonstrated by Pepys 
(1980).  Irritation of the respiratory tract can occur at levels 
ranging between 0.712 and 3.560 mg/m3 (Henschler et al., 1962).  
The asthmatic response, evident in up to 10% of previously exposed 
individuals, may occur at levels of toluene diisocyanates > 0.0356 
mg/m3 (Bernstein, 1982).  The basis for this response is still 
uncertain, but there is evidence supporting either immunological or 
pharmacological mechanisms, or a combination of both (Scheel et 
al., 1964; Weill et al., 1975; Butcher et al., 1977, 1980; 
Cockcroft & Mink, 1979; Chadwick & Cleveland, 1981; NIOSH, 1981; 
Bernstein, 1982; Karol, 1983). 

    Toluene diisocyanate-induced asthma may not be evident until 
after many years of exposure (Salvaggio, 1979).  However, TDI may 
cause immediate, delayed, or biphasic asthmatic reactions (Baur et 
al., 1983; NIOSH, 1981).  The immediate reaction reaches a peak 
within minutes.  Late reactions occur from 2 to 8 h after exposure 
and may show a recurring pattern.  Most affected people have non-
specific bronchial hyperreactivity, as measured by mechanical 

intratracheal challenge tests.  This reaction may continue for 
several years after cessation of exposure implying persisting 
asthmatic symptoms.  Immunologically sensitized workers can be 
identified by means of RAST and skin testing. 

    A 43-year-old non-smoking molder (female) first exhibited 
throat irritation and a non-productive cough after 4 months of 
exposure to toluene diisocyanates.  Dyspnoea was noted, which 
worsened during work-days, resulting finally in an episode that 
required emergency treatment.  One month later, after cessation of 
exposure, the patient was without symptoms, and pulmonary function 
had returned to normal.  Subsequent symptomatic episodes were 
successfully treated with isoproterenol (Smith et al., 1980).  
Other symptoms, such as faintness, nausea, vomiting of "foamy" 
materials, anxiety, rapid pulse rate, elevated blood pressure, 
fever, and cyanosis, were reported by Brugsch & Elkins (1963).  
The patient, who was a 62-year-old spray painter, was coating the 
inside of a large tank for 7 days without respiratory protection.  
An ECG showed hypertrophy of the left ventrical, and a chest 
roentgenogram showed prominent bronchovesicular markings and an 
enlarged cardiac silhouette.  The patient improved and was 
discharged after 4 days. 

    Epidemiological studies of health effects from occupational 
exposure to toluene diisocyanates are summarized in Table 8. 

9.2.2.4.  Cancer epidemiology

    No epidemiological studies of mortality or cancer incidence 
among workers exposed to toluene diisocyanates were available to 
the Task Group. 

    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 levels of exposure to isocyanates were not reported and neither 
were other chemicals to which the subject may have been exposed 
(Mortillaro & Schiavon, 1982). 

9.2.2.5.  Immunotoxicity

    Several investigators have detected toluene diisocyanates 
sensitization with the lymphocyte transformation test and other 
immunoassays, but have been unable to consistently demonstrate 
elevated antibody titers (Bruckner et al., 1968; Avery et al., 
1969; Danks et al., 1981; Game, 1982).  Studies on the immune 
response following exposure to toluene diisocyanates are 
summarized in Table 9. 


Table 8.  Epidemiological studies of health effects from occupational exposure to toluene diisocyanates
---------------------------------------------------------------------------------------------------------
Concentration (mg/m3)    Effects                                                Reference
---------------------------------------------------------------------------------------------------------
< 0.213 (0.03 ppm);      38 workers at a polyurethane foam factory; after 1     Peters et al. (1968)
mostly < 0.142           day exposure (Monday), statistically significant
(0.02 ppm)               decreases in FVC, FEV1 peak-flow rate, and FEF25-50%;
                         after 5 days' exposure (Friday), in 34 workers, the
                         FVC returned to baseline, the FEV1 was still 
                         depressed, and the respiratory flow rates were more 
                         depressed; diurnal variation could not account for 
                         these changes; workers with respiratory symptoms 
                         showed greater decreases in FEV1

0.014 - 0.093            111 workers at a polyurethane foam factory; changes    Wegman et al. (1974);
(0.002 - 0.013 ppm)      measured in FEV1 between Monday AM and PM of work      Peters & Wegman (1975)
                         day; 51 workers (0.014 mg/m3 exposure): 78 ml
                         decrease; 43 workers (0.028 mg/m3 exposure): 106 to
                         112 ml decrease; 17 workers (0.064 - 0.093 mg/m3 
                         exposure): 180 ml decrease

0.072 (0.001 ppm)        107 workers from 2 polyurethane manufacturing plants;  Musk et al. (1982)
(time-weighted average)  5-year change in FEV did not exceed that expected for
                         aging; no significant change in FEV was noted between
                         Monday AM and PM of work day

0.356 - 0.712            287 workers in 2 TDI plants; lung function (FEV1 and   Adams (1975)
                         FVC) measured annually for 8 years; 180 workers with 
                         no respiratory symptoms: FEV1 and FVC normal; 46
                         workers with respiratory symptoms and still employed:
                         only questioned and reported more respiratory effects
                         than controls; 61 workers with respiratory symptoms
                         no longer at plant: FEV1 averaged 271 ml and FVC
                         averaged 269 ml lower than predicted from 608 controls

< 0.01 - > 0.025        57 workers at toluene diisocyanates plant; a dose-    Wegman et al. (1977)
(< 0.0015 - > 0.0035     response relationship observed; exposure to < 0.01
ppm)                     mg/m3 did not affect FEV1; exposure to > 0.025 mg/m3
                         resulted in decrease in FEV1 of 103 ml/year, which 
                         exceeded expected value by 3 - 4 times; workers
                         exposed to < 0.01 mg/m3 showed normal 2-year decline
                         (-12 ml in 2 years); differences in FEV1 not explained 
                         by age, time employed, smoking habits, or lung size
---------------------------------------------------------------------------------------------------------                         

Table 8.  (contd.)
---------------------------------------------------------------------------------------------------------
Concentration            Effects                                                Reference
(mg/m3)
---------------------------------------------------------------------------------------------------------
0.0007 - 0.178           223 workers at a new TDI plant; measured for           Diem et al. (1982)
(0.0001 - 0.025 ppm)     pulmonary function, with 3 or more data points to
(TWA)                    calculate slope of annual response (during 5-year
                         exposure); low and high cumulative exposure groups
                         exposed for 2% and 15% of time, respectively, toluene
                         diisocyanates exceeding 0.036 mg/m3; significant 
                         effects of smoking on spirometric tests and lung
                         volumes; after adjustment for pack-years smoking,
                         the FEV1, %FEV, and FEF25-75% declined more in
                         "high" exposure group (74 workers) than in "low"
                         exposure group (149 workers); in non-smokers,
                         average FEV1 decline was 38 ml/year greater in
                         high- compared with low-exposure groups; a 24 ml/year
                         excess average decline attributed to longer exposure
                         to levels above 0.014 mg/m3

0.007 - > 0.014          145 workers at TDI plant surveyed for lung function    Omae (1984)
(0.007 - > 0.002 ppm)    1980 and workers re-examined in 1982; short-term
                         exposure to > 0.014 mg/m3 occurred in 9.3% of samples
                         in 1980, and 1.9% in 1982; no dose response in loss of
                         pulmonary function; 0.007 mg/m3 was not associated
                         with acute or chronic effects on pulmonary function
---------------------------------------------------------------------------------------------------------
Note: Diem et al. (1982) clarified that the toluene diisocyanates workers were compared according to 
       cumulative exposure, not concentration categories, and that the low-exposure group's 8-h TWA was
       spent at < 0.036 mg TDI/m3 and the high-exposure at > 0.036 mg TDI/m3.  There was a mean increase 
       in FEV1 of 1 ml/year for the low-exposure category and a mean decrease in FEV1 of 1 ml/year for 
       the high-exposure category.  They indicated that, because of variations in daily exposure to 
       toluene diisocyanates, an average 8-h TLV < 0.036 mg/m3 might be necessary to achieve compliance.

FVC = forced vital capacity.
FEV1 = forced expiratory volume in 1 second.
FEV1/FVC% = ratio of FEV1/FVC x 100.
FEF25-50% and FEF25-75% = forced expiratory flow between 25% and 50% or 25% and 75% of FVE, respectively.


                            
Table 9.  Immune response in workers exposed to toluene diisocyanates
---------------------------------------------------------------------------------------------------------
Level (mg/m3)       Sample number              Immune response                    References

---------------------------------------------------------------------------------------------------------
0.028 - 0.142       32 workers                 hypersensitive responses           Porter et al. (1975)
                                               correlated with TDI levels
                                               > 0.35 mg/m3; IgG antibodies
                                               present and broncho-constriction
                                               occurred

frequently > 0.14   166 workers; increased     pulmonary function normal;        Butcher et al. (1977)
                    incidence of TDI-specific  positive skin test and broncho-
                    IgE antibodies             constriction noted

0.142 challenge     23 workers (4 sensitive    specific IgE antibodies in 3 out   Karol et al. (1978)
                    to TDI)                    of 4 sensitive workers;

                                               19 non-sensitized workers had
                                               antibody titers comparable with
                                               controls; high levels to specific
                                               IgE antibodies not correlated 
                                               with serum-IgE levels

< 0.175             87 workers                 respiratory symptoms with         Kido et al. (1983b)
                                               reduction in FEV1; tolyl-specific
                                               IgE detected in 2 workers only;
                                               RAST indicated generally low
                                               levels in all sensitized workers
                                               

0.119 - 0.147       39 workers                 Significant elevation of serum-    Hobara et al. (1984)
                                               IgE levels in only 4 out of 10
                                               workers exposed for less than 1 
                                               year, all having obstructive
                                               impairment of liver function
---------------------------------------------------------------------------------------------------------                       

    The results of these studies indicated that exposure to
low concentrations of toluene diisocyanates (> 0.14 mg/m3)
induced hypersensitivity in a variable and unknown percentage
of the individuals at risk.  The duration of exposure to
toluene diisocyanates necessary to induce hypersensitivity was
also highly variable, sometimes occurring immediately or
requiring months or even years of exposure.  There has been
some success in evaluating the hypersensitivity to toluene
diisocyanates with RAST assays using the TDI-HSA antigen, but
neither the antibody responses to this specific antigen, nor
the level of IgE antibody were consistently elevated in
individuals with hypersensitivity and asthmatic responses
(Baur, 1983; Belin et al., 1983; Barkman et al., 1984).
Present immunoassay techniques will not detect all susceptible
individuals.

9.2.3.  Potential mechanisms of action

    Irritation and toxic effects are presumed to stem from the 
reactivity of the isocyanate groups (i.e., -NCO) on toluene 
diisocyanates and their quasipolymers (Brugsch & Elkins, 1963).  
Wegman et al. (1974) demonstrated a dose-response relationship for 
these symptoms.  Irritation will stimulate mucous-secreting goblet 
cells, with a proportional decrease in ciliated epithelial cells.  
Impaired clearance and mucal stagnation may result, followed by 
epithelial desquamation, submucosal glandular hypertrophy, and 
basement membrane thickening as in chronic tracheo-bronchitis 
(Braman & Teplitz, 1978). 

    The mechanisms concerned (immunological or pharmacological) in 
the production of asthma and hypersensitivity pneumonitis through 
occupational exposure to toluene diisocyanates are still the 
subject of debate.  The controversy stems from the paradoxical 
nature of the sensitivity reactions.  Karol et al. (1978) reported 
specific IgE antibodies in sera from workers sensitive to toluene 
diisocyanates, suggesting an IgE-mediated mechanism for sensitivity 
to the compound.  It was reported by Thurman et al (1978) that 
toluene diisocyanates induced lymphocytes to undergo blastogenesis, 
suggesting antigenic stimulation.  In many instances, no specific 
IgE antibodies against TDI-HSA conjugates were demonstrated 
(Gaffuri & Brugnone, 1971; Butcher et al., 1977, 1980).  Positive 
results were observed in 14 - 19% of toluene diisocyanates 
reactors, depending on the method of evaluation (Butcher et al., 
1980; Baur et al., 1983).  Smith et al. (1980) also found a worker 
sensitized to toluene diisocyanates, but with no IgE antibodies, 
leukocyte inhibition factor for isocyanate antigen, or even 
bronchial hyperreactivity to methacholine, an important component 
of bronchial asthma.  Asthma resulting from toluene diisocyanates 
exposure appears to be a complex syndrome with several possible 
mechanisms of causation, including an IgE mechanism in some 
individuals. 

    Salvaggio (1979) suggests that preexisting asthmatic 
conditions, together with partial andrenergic blockage or abnormal 
cholinergic receptor activity, may increase bronchial airway 
hyperreactivity to irritants, such as toluene diisocyanates.  A 
significant decrease in erythrocyte-cholinestrase activity was 
found in  in vitro studies in 70% of a group of 30 workers exposed 
to toluene diisocyanates (Brown et al. 1982; Dewair et al., 1983; 
Manno & Lotti, 1976). 

    The results of several  in vitro studies showed evidence of 
inhibition of elevated levels of intracellular cyclic AMP 
production by TDI at doses as low as 6.7 x 10-7 mol (Butcher et 
al., 1977; Davies et al., 1977).  The explanation for these 
responses is unclear. 

    The controversy over immune-controlled versus pharmaco-
logically mediated response to toluene diisocyanates in sensitized 
workers has yet to be resolved. 

10.  EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT

10.1.  Exposure to Toluene Diisocyanates

    In the USA, it has been estimated that approximately 40 000 
workers are involved in the manufacture or processing of toluene 
diisocyanates.  Occupational exposure levels have been reported to 
range from 0.001 to 1 mg/m3. 

    Figures are not available on the total discharge of unreacted 
TDI into the environment.  However, releases into the air ranging 
from 0.1 to 17.7 mg/m3 have been measured in stack gases emitted 
from a plant manufacturing polyurethane foams.  It has been 
reported that approximately 50 g of TDI are released per tonne 
of processed TDI in the manufacture of polyurethane foams, the 
manufacture of which consumes about 90% of TDI produced. 

    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. 

10.1.1.  Acute and short-term effects

    The odour threshold for toluene diisocyanates in human beings 
is estimated to range between 0.35 and 0.92 mg/m3 (0.05 and 0.13 
ppm). 

    The lowest levels of TDI associated with acute effects were 
reported to be:  0.035 - 0.70 mg/m3, eye and nose irritation, 
burning nose and throat, and a choking sensation; 0.70 - 3.5 mg/m3, 
a respiratory response of irritation, cough, and chest discomfort.  
At higher levels, chemical pneumonitis may be expected. 

10.1.2.  Health risks of long-term exposure to toluene diisocyanates

    Risk of respiratory toxicity from repeated exposure can be 
summarized as follows:  (a) chronic loss of ventilatory capacity as 
measured by forced expiratory volume and forced vital capacity; (b) 
immediate and/or delayed asthmatic responses. 

    In many epidemiological studies, past mean exposures to TDI 
have been estimated in an attempt to quantify dose-response 
relationships for respiratory ill health.  Because of the 
uncertainties in the sampling procedures and analytical 
measurements used in past industrial health surveys, it is 
difficult to be confident about the exact levels at which TDI 
causes the above-mentioned health effects.  It should be remembered 
that fluctuations in the true individual exposure occur and, as 
both the size and extent of the intermittent peaks are unknown, 
their biological significance cannot be evaluated. 

    Once individuals are sensitized to toluene diisocyanates, low 
concentrations, much below current occupational exposure limits, 
can induce asthma.  Studies on experimental animal have shown that 
skin application of TDI can lead to pulmonary sensitization; thus, 
it is prudent to avoid repeated skin contact. 

    No data were available on the carcinogenic effects of toluene 
diisocyanates in human beings. 

    No carcinogenic effects of TDI were noted in an inhalation 
study on rats and mice.  However, the 80:20 mixture in corn oil, 
administered by gavage, was carcinogenic for male and female rats 
and female mice in a dose-related manner.  It is considered that 
there is sufficient evidence for the carcinogenicity of TDI for 
experimental animals. 

    There is evidence of mutagenicity in two bacterial tests. 

10.2.  Evaluation of Effects on the Environment

    An evaluation of the hazards for non-human targets from 
environmental levels of TDI is not possible on the basis of 
available data. 

10.3.  Conclusions and Recommendations

 1.  There is sufficient knowledge about TDI to classify it as a 
     very toxic compound by inhalation, and TDI 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, the education, training, and 
     supervision of operatives, and state enforcement of 
     legislation by an effective inspectorate.  Special attention 
     should be paid to the prevention and adequate treatment of 
     unscheduled releases and spills. 

 2.  Additional animal carcinogenicity testing by the inhalation 
     route should be carried out. 

 3.  Morbidity and mortality studies are required on occupational 
     groups for whom reliable exposure data are available, to 
     address the question of cancer and to evaluate the potential 
     of toluene diisocyanates to cause long-term human health 
     hazards under current standards of good working practice. 

 4.  Because it is not possible to reach confident conclusions from 
     the data on the neurotoxicity of TDI, neurophysiological and 
     behavioural studies should be carried out on asymptomatic 
     workers, exposed at current hygiene standards. 

 5.  For the foreseeable future, exposed workers require health
     monitoring by systematic symptom enquiry and by standardized 
     measurement of ventilatory function, with subsequent analysis 
     of trends for individuals and for group mean values. 

 6.  Appropriate sampling strategies together with existing
     analytical methods have to be developed and used to obtain 
     better information about exposure, with special reference to 
     the detection and characterization of peak values.  The 
     results of these analyses need to be evaluated in special 
     studies in parallel with careful health studies. 

 7.  Further metabolic studies of a qualitative and quantitative 
     nature should be carried out with a view to developing methods 
     of measuring TDI uptake and monitoring exposure. 

 8.  Whether TDI produces sensitization in human beings by
     pharmacological or immune mechanisms needs to be elucidated 
     with a view to determining whether restrictions placed on the 
     employment of atopic subjects, in areas where TDI is produced 
     or used, are justified. 

 9.  Studies are required to determine whether TDI has embryo-toxic 
     and teratogenic properties or has adverse reproductive effects 
     at current exposure levels. 

10.  Further environmental studies are required to monitor general 
     environmental levels of TDI in the neighbourhood of sources 
     and to collect ecotoxicity data. 

11.  PREVIOUS EVALUATIONS BY INTERNATIONAL BODIES

    IARC (1979) evaluated the data on the carcinogenicity of 
toluene diisocyanates 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 toluene 
diisocyanates for experimental animals. 

    In the absence of adequate case reports or epidemiological 
studies, there is insufficient data to assess the carcinogenicity 
of toluene diisocyanates for human beings (IARC 1986). 

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    See Also:
       Toxicological Abbreviations
       Toluene Diisocyanates (IARC Summary & Evaluation, Volume 71, 1999)