TOLUENE DIISOCYANATES

Data were last reviewed in IARC (1986) and the compounds were classified in IARC

Monographs Supplement 7 (1987).

1. Exposure Data

1.1 Chemical and physical data

1.1.1 Nomenclature

Commercial toluene diisocyanate mixtures

Chem. Abstr. Serv. Reg. No.: 26471-62-5

Chem. Abstr. Name: 1,3-Diisocyanatomethylbenzene

IUPAC Systematic Name: Isocyanic acid, methyl-meta-phenylene ester

Synonyms: Diisocyanatotoluene; TDI; toluene diisocyanate

2,4-Toluene diisocyanate 

Chem. Abstr. Serv. Reg. No.: 584-84-9

Chem. Abstr. Name: 2,4-Diisocyanato-1-methylbenzene

IUPAC Systematic Name: Isocyanic acid, 4-methyl-meta-phenylene ester

Synonyms: 2,4-Diisocyanatotoluene; 2,4-TDI; 2,4-toluene diisocyanate 

2,6-Toluene diisocyanate

Chem. Abstr. Serv. Reg. No: 91-08-7

Chem. Abstr. Name: 1,3-Diisocyanato-2-methylbenzene

IUPAC Systematic Name: Isocyanic acid, 2-methyl-meta-phenylene ester

Synonyms: 2,6-Diisocyanatotoluene; 2,6-TDI; 2,6-toluene diisocyanate 

1.1.2 Structural and molecular formulae and relative molecular mass

C9H6N2O2 Relative molecular mass: 174.16 

–865–

CH3

O C N NCO

2,6-Toluene diisocyanate

CH3

N C O

NCO

2,4-Toluene diisocyanate
1.1.3 Chemical and physical properties of the pure substances

(a) Description: Colourless to pale yellow liquid with pungent odour (United States

National Library of Medicine, 1997)

(b) Boiling-point: 251°C (2,4-isomer) (Lide, 1997)

(c) Melting-point: 20°C (2,4-isomer); 18°C (2,6-isomer) (Lide, 1997)

(d) Solubility: 2,4- and 2,6-Toluene diisocyanates decompose in water and are very

soluble in acetone and benzene (Lide, 1997)

(e) Vapour pressure: 1.3 Pa at 20°C (2,4-isomer) (Lewis, 1993)

(f) Flash point: 132°C (2,4-isomer) (Lewis, 1993)

(g) Conversion factor: mg/m3 = 7.1 × ppm

1.2 Production and use

Worldwide production capacities for toluene diisocyanates in 1987 were reported as

(thousand tonnes): western hemisphere, 356; eastern Europe, 46; western Europe, 380;

and Japan and the Far East, 88 (Ulrich, 1989). Worldwide production capacities in 1993

were reported as (thousand tonnes): North America, 485; Europe, 530; Pacific region,

308; and Latin America, 102.5 (Anon., 1995).

Toluene diisocyanate is commonly produced as a mixture of the 2,4- and 2,6-isomers, that is used as a monomer in the preparation of polyurethane foams, elastomers and

coatings, as a cross-linking agent for nylon-6, and as a hardener in polyurethane

adhesives and finishes. Polyurethane elastomers made from toluene diisocyanates are

used in coated fabrics and clay-pipe seals. Polyurethane coatings made from toluene

diisocyanates are used in floor finishes, wood finishes and sealers, and in coatings for

aircraft, tank trucks, truck trailers and truck fleets (United States National Library of

Medicine, 1997).

1.3 Occurrence

1.3.1 Occupational exposure

According to the 1981–83 National Occupational Exposure Survey (NOES, 1997),

approximately 40 000 workers in the United States were potentially exposed to toluene

diisocyanates (see General Remarks). Occupational exposures to toluene diisocyanates

may occur during their production and in the production of polyurethane foams, elastomers, coatings, adhesives and finishes. Exposure may also occur in the use of some

polyurethane products. Data on occupational exposure levels have been presented in a

previous monograph (IARC, 1986). More recent exposure levels have been reported in

connection with epidemiological (Section 2) and toxicological (Section 4) studies.

1.3.2 Environmental occurrence

Toluene diisocyanates may be released to the environment as fugitive emissions and

from stack exhaust during the production, transport and use of toluene diisocyanate in the

manufacture of polyurethane foam products and coatings. They have been detected at

low levels in wastewater samples (United States National Library of Medicine, 1997).

866 IARC MONOGRAPHS VOLUME 71
1.4 Regulations and guidelines

The American Conference of Governmental Industrial Hygienists (ACGIH) (1997)

has recommended 0.036 mg/m3 as the 8-h time-weighted average threshold limit value

for occupational exposures to 2,4-toluene diisocyanate in workplace air. Similar values

have been used as standards or guidelines for 2,4- or 2,6-toluene diisocyanates in several

countries. In some other countries, values ranging from 0.04 to 0.14 mg/m3 for mixed

isomers have been used (International Labour Office, 1991).

No international guideline for toluene diisocyanates in drinking-water has been established (WHO, 1993).

2. Studies of Cancer in Humans

2.1 Cohort studies

Sorahan and Pope (1993) studied 5824 men and 2465 women who had been

employed for at least six months during 1958–79 at 11 factories in England and Wales

which made polyurethane foams. Exposures to isocyanates were classified by an

occupational hygienist on the basis of recorded job titles. The highest-exposure category

comprised jobs in which either the 8-h time-weighted average exposure during 1978–86

was greater than 4 ppb [28.4 μg/m3] or peak exposures exceeded 10 ppb [71 μg/m3] on

most days. Cohort members were followed up through National Health Service records,

and their mortality during 1958–88 and cancer incidence during 1971–86 were compared

with national rates by the person–years method. In addition, internal comparisons of risk

according to exposure were carried out by Poisson regression analysis, and through a

nested case–control study. Overall mortality in the cohort was close to expectation (816

deaths; standardized mortality ratio (SMR), 0.97), as was total mortality from cancer

(221 deaths; SMR, 0.9). In men, no notable elevation of mortality was recorded for any

specific cancer. In women, significant excesses of deaths were observed for cancers of

the pancreas (6 versus 2.2 expected; SMR, 2.7; 95% confidence interval (CI), 1.0–6.0)

and lung (16 versus 9.1 expected; SMR, 1.8; 95% CI, 1.0–2.9). However, there was no

significant elevation of mortality from these tumours in both sexes combined (pancreas,

14 deaths versus 10.3 expected; lung, 81 deaths versus 81.3 expected), and in the internal

analyses, risk was not related to isocyanate exposure. Mortality from rectal cancer was

low (5 deaths versus 10.2 expected in men and women combined). In female workers,

high rates of pancreatic (standard rate ratio (SRR), 3.2) and lung cancer (SRR, 2.3) were

seen, as well as increased incidence of cancers of the larynx (3 cases versus 0.3 expected)

and kidney (4 versus 0.9), but all of the cases were classified as having minimal or zero

exposure to isocyanates. An earlier survey in the industry had indicated a high prevalence of smoking among female employees, and the authors concluded that this may

have contributed to the increased frequency of some cancers in women.

In Sweden, a cohort study was carried out at nine factories manufacturing polyurethane foam that incorporated toluene diisocyanates or methylenediphenyl diisoTOLUENE DIISOCYANATES 867
cyanate (see this volume) (Hagmar et al., 1993a). Exposures to airborne isocyanates had

been monitored at all of the plants since 1965. Time-weighted average concentrations of

toluene diisocyanates had generally been below 100 μg/m3, and those of

methylenediphenyl diisocyanate below 10 μg/m3, but with peaks up to 3 mg/m3 and

0.35 mg/m3, respectively. Other potential exposures included freons, silicone oils and

waxes, amine accelerators, ethanolamine, methylene-bis-(2-chloroaniline) (MOCA) (see

IARC, 1993), triethylamine, triethylene diamine, styrene (see IARC, 1994) and various

other organic solvents. The cohort comprised 4154 workers who were employed during

1958–87 at a time when personnel records were complete, and who had worked for at

least one year by 1987. The vital status of all subjects at 31 December 1987 was ascertained, and information about those who had died and about incident cancers was

obtained from Statistics Sweden and the National Tumour Registry. Rates of death and

cancer incidence were compared with those in the national population by the

person–years method. There were fewer deaths in total than expected (130 deaths; SMR,

0.8; 95% CI, 0.7–0.9); mortality from cancer (33 deaths; SMR, 0.8; 95% CI, 0.5–1.1) and

overall cancer incidence (72 cases; standardized incidence ratio (SIR), 0.8; 95% CI,

0.6–1.0) were also below expectation. Among the subset of subjects classified as exposed

to toluene diisocyanates or methylenediphenyl diisocyanate, there were 39 incident

cancers (45.8 expected) including five cases of rectal cancer (1.8 expected) and no cases

of lung cancer (4.0 expected). With allowance for a minimum latency of 10 years, the

SIR for rectal cancer was 3.2 (3 cases).

A nested case–control study was carried out in an expanded cohort of 7023 men and

women from the same factories (Hagmar et al., 1993b). The subjects had worked during

1958–87, but unlike in the cohort study, no minimum period of employment was

specified. Each of 119 subjects with a cancer registered during 1959–87 was matched

with three controls of the same sex and age (to within six years), who were under followup at the time the cancer occurred. Because of missing information, the final analysis was

based on 114 cases and 313 referents. Exposures were rated by an occupational hygienist

who was unaware of subjects’ disease status, and risks were estimated by conditional

logistic regression. No association was found between exposure to isocyanates and overall cancer incidence (odds ratio, 0.9; 90% CI, 0.6–1.3). Nor was there any association

with rectal cancer. Among subjects with high exposure there was a non-significant

increase in prostate cancer (4 cases; odds ratio, 2.7; 95% CI, 0.4–18.1).

Schnorr et al. (1996) studied 2717 male and 1893 female employees from four polyurethane foam plants in the United States, all of whom had worked for at least three

months during 1958–84 in a department or job in which exposure to toluene diisocyanates occurred. Airborne concentrations of toluene diisocyanates had been greater

than 0.2 mg/m3 at one of the plants during 1965–69, but personal monitoring in 1984–85

at the three plants which were still then operating indicated 4-h time-weighted average

exposures below 0.04 mg/m3. Other potential exposures included dichloromethane (see

this volume) , aliphatic amines, nitrogen dioxide, acrolein (see IARC, 1995) and acrylonitrile (see this volume). The cohort was followed through the National Death Index,

868 IARC MONOGRAPHS VOLUME 71
social security and internal revenue records, and state bureaux of motor vehicles; vital

status was determined for 96.9% of subjects at 31 December 1993. Their mortality was

compared with that of the national population by the person–years method, with

adjustment for sex, race, age and calendar period. Mortality from all causes was close to

expectation (316 deaths; SMR, 0.95; 95% CI, 0.85–1.1) as was mortality from all

cancers (71 deaths; SMR, 1.0; 95% CI, 0.8–1.3) and from lung cancer (20 deaths; SMR,

1.0; 95% CI, 0.6–1.6). There were small excesses of deaths from rectal cancer (3 versus

1.1 expected) and Hodgkin’s disease (2 versus 0.9), but these were not significant, and

there was no tendency for risk of cancer mortality to rise with increasing duration of

exposure.

2.2 Case–control study

In the Montreal case–control study carried out by Siemiatycki (1991) (see monograph on dichloromethane in this volume), the investigators estimated the associations

between 293 workplace substances and several types of cancer. Isocyanates were one of

the substances, and it was stated that the most common form in this study was toluene

diisocyanates. The main occupations to which isocyanate exposure was attributed in this

study were motor vehicle refinishers, motor vehicle mechanics and foundry workers.

Only 0.8% of the study subjects had ever been exposed to isocyanates. For most types

of cancer examined (oesophagus, stomach, colon, rectum, pancreas, prostate, bladder,

kidney, skin melanoma, lymphoma), there was no indication of an excess risk due to

isocyanates. For lung cancer, in the population subgroup of French Canadians (the

majority ethnic group in this region), based on 10 cases exposed at any level, the odds

ratio was 2.2 (90% CI, 0.9–5.3). [The interpretation of the null results has to take into

account the small numbers and presumably low exposure levels. Workers had multiple

exposures.]

3. Studies of Cancer in Experimental Animals

Commercial mixtures of 2,4- and 2,6-toluene diisocyanates administered by gavage

induced a dose-related increase in the incidence of subcutaneous fibromas and fibrosarcomas (combined) in male rats, together with an increase in the incidence of pancreatic acinar-cell adenomas in male rats and of pancreatic islet-cell adenomas, neoplastic nodules of the liver and mammary gland fibroadenomas in female rats. In female

mice, dose-related increases in the combined incidence of haemangiomas and haemangiosarcomas and of hepatocellular adenomas were observed after gavage administration.

No treatment-related tumour was observed after exposure of mice or rats to commercial

toluene diisocyanates by inhalation, although the results of the study with rats have not

been reported fully (IARC, 1986).

TOLUENE DIISOCYANATES 869
4. Other Data Relevant to an Evaluation of Carcinogenicity 

and its Mechanisms

4.1 Absorption, distribution, metabolism and excretion

Toluene diisocyanates are reactive molecules that combine readily with nucleophiles,

and as such have a propensity to react with proteins at the site of application to animals,

in other tissues and with plasma (Kennedy et al., 1994). They are hydrolysed in aqueous

media to the corresponding diamines, which can react with unchanged toluene

diisocyanates to form polymeric ureas (Chadwick & Cleveland, 1981; Ulrich, 1983).

The major metabolites of toluene diisocyanates in both animals and humans are

toluene diamines and their acetylated products (Rosenberg & Savolainen, 1985; Bartels

et al., 1993; Lind et al., 1996).

4.1.1 Humans

The toxicokinetics of 2,4- and 2,6-toluenediisocyanates in 11 chronically exposed

workers at two flexible foam polyurethane production plants have been reported. The

toluene diisocyanate concentrations in air varied between 0.4 and 4 μg/m3 in one plant

and in the other between 10 and 120 μg/m3. In one of the plants, the plasma 2,4-toluene

diamine levels were 0.4–1 ng/mL before a 4–5-week holiday and 0.2–0.5 ng/mL

afterwards. The corresponding plasma levels of 2,6-toluene diamine were 2–6 and 0.5–2

ng/mL, respectively. In the other plant, the plasma 2,4-toluene diamine concentrations

were 2–23 ng/mL before the holiday and 0.5–6 ng/mL afterwards and those of 2,6-

toluene diamine were 7–24 ng/mL before and 3–6 ng/mL afterwards. The plasma

concentrations of 2,4-toluene diamine were 2–24 ng/mL before a 12-day holiday, and

1–14 ng/mL afterwards. The corresponding values for plasma 2,6-toluene diamine were

12–29 and 8–17 ng/mL, respectively. The urinary elimination rates for 2,4-toluene

diamine before the holiday were 0.04–0.54 and 0.02–0.18 μg/h afterwards. The

corresponding values for 2,6-toluene diamine were 0.18–0.76 μg/h before and 0.09–

0.27 μg/h after the holiday. The half-life in urine ranged from 5.8 to 11 days for 2,4- and

2,6-toluene diamines. The differences in exposure were reflected by the plasma toluene

diamine concentrations. The mean half-life in plasma was 21 (range, 14–34) days for 2,4-

toluene diamine and 21 (16–26) days for 2,6-toluene diamine. The study showed that the

half-life in plasma of chronically exposed workers for 2,4- and 2,6-toluene diamine was

twice as long as for volunteers with short-term exposure. An indication of a two-phase

elimination pattern in urine was found. The first phase was related to the more recent

exposure and the second, much slower one was probably related to release of toluene

diamines in urine from toluene diisocyanate adducts in the body (Lind et al., 1996).

The average air concentration of toluene diisocyanates at a toluene diisocyanate

flexible foam plant was 29.8 μg/m3 (12.5–19.9; n = 12). The highest exposure measured

was approximately 3 mg/m3 toluene diisocyanates. 2,4- and 2,6-Toluene diamine levels

in urine and in plasma from four exposed workers and one volunteer were determined

870 IARC MONOGRAPHS VOLUME 71
after strong acid hydrolysis. The plasma toluene diamine concentrations among the

workers were 1–38 g/L and 7–24 μg/L for 2,4- and 2,6-toluene diamine, respectively.

The individual plasma levels among the workers over the three-day periods varied from

7 to 73%. For a volunteer, plasma concentration reached a maximum about 24 hours after

the last exposure. The half-time of plasma toluene diamines for the volunteer was about

10 days. The urine levels varied greatly with time and exposure. High levels were found

during or shortly after the exposure (Tinnerberg et al., 1997).

4.1.2 Experimental systems

Timchalk et al. (1994) examined the route-dependent metabolism of [14C]toluene 2,4-

diisocyanate and [14C]toluene 2,4-diamine in Fischer 344 rats. Forty-eight hours after an

oral dose of 60 mg [14C]toluene 2,4-diisocyanate/kg bw, 81%, 8% and 4% of the

radioactivity was found in the faeces, urine and tissue/carcass/gastrointestinal tract

contents, respectively. Markedly different results were obtained following inhalation

exposure of rats to 2 ppm [14.2 mg/m3] [14C]toluene 2,4-diisocyanate for 2 h. Forty-eight

hours after exposure, 47%, 15% and 34% of the recovered radioactivity was in the faeces,

urine and tissue/carcass/gastrointestinal tract contents, respectively.

In comparative studies, [14C]toluene 2,4-diamine, the hydrolysis product of [14C]-

toluene 2,4-diisocyanate, was administered to rats at doses of 3 mg/kg bw (orally or

intravenously) and 60 mg/kg bw orally. After 48 h, the distribution of radioactivity was

similar in all cases (urine, 64–72%; faeces, 20–31%; and tissue/carcass/gastrointestinal

tract, 2–5%). Comparison of the toluene 2,4-diisocyanate inhalation group with the oral

toluene 2,4-diisocyanate and toluene 2,4-diamine treatment groups indicated that a

larger percentage of the inhaled radioactivity was in the tissues/carcass and that

excretion of radioactivity into the urine was slower following toluene 2,4-diisocyanate

inhalation.

Following inhalation or oral exposure to [14C]toluene 2,4-diisocyanate, about 90%

and 65% of the quantitated urinary metabolites were acid-labile conjugates. In contrast,

only 16–39% of the urinary metabolites were conjugated following oral administration

of [14C]toluene 2,4-diamine.

Inhalation exposure to toluene 2,4-diisocyanate results primarily in the formation of

acid-labile conjugates, with little or no toluene 2,4-diamine being formed. This suggests

that the disposition of inhaled toluene 2,4-diisocyanate is quite different from that of

orally administered toluene 2,4-diisocyanate or of intravenously or orally administered

toluene 2,4-diamine.

4.2 Toxic effects

The toxicity of toluene diisocyanates has been reviewed (WHO, 1987).

4.2.1 Humans

Toluene diisocyanates are potent respiratory irritants and sensitizers, even at low airborne concentrations. Chronic bronchitis, chronic restrictive pulmonary disease and

TOLUENE DIISOCYANATES 871
hypersensitivity pneumonitis have also been described among toluene diisocyanateexposed people (IARC, 1986).

A follow-up study (Pisati et al., 1993) of patients with toluene diisocyanate-induced

asthma suggested that a short period of exposure and a short duration of symptoms before

diagnosis, followed by complete cessation of exposure, are likely to lead to improvement

of the symptoms and lung function. A decrease only of the exposure led to deterioration

of lung function, and long exposure and duration of symptoms were unfavourable

prognostically.

No deterioration of lung function, but an increased frequency of respiratory symptoms were observed in a follow-up study among non-sensitized workers with a mean

exposure to toluene diisocyanates of 3 ppb [21.3 μg/m3] (Omae et al., 1992a). This study

also suggested that among workers with a mean exposure of 8 ppb [57 μg/m3], peak

exposures to 30 ppb [213 μg/m3] and above were associated with a loss of ventilatory

function among employees not sensitized to toluene diisocyanates (Omae et al., 1992b).

4.2.2 Experimental systems

Inhalation exposure to toluene diisocyanates is irritating to the eyes and respiratory

tract, and induced chronic rhinitis, interstitial pneumonia and catarrhal bronchitis after

long-term exposure. Respiratory sensitization to toluene diisocyanate developed in

guinea-pigs after inhalation but also after dermal exposure (IARC, 1986).

Toluene diisocyanates induced respiratory epithelial inflammation, metaplasia and

necrosis in mice at the lowest concentration tested (0.71 mg/m3) after the shortest

exposure period studied (6 h per day for four days). The reaction became more severe

when the exposure period was extended to 9 or 14 days. No effects were observed in the

olfactory epithelium, trachea or lungs (Zissu, 1995) 

In-vitro tracheal hyperreactivity to carbachol was induced in mice by cutaneous

application of toluene diisocyanates (isomeric composition not indicated), followed by

nasal toluene diisocyanate challenge; this was not accompanied by an elevation of

toluene diisocyanate-specific IgE. The reaction could be transferred to naive recipient

mice by transfusion of lymphoid cells from sensitized mice (Scheerens et al., 1996).

Inhalation exposure of guinea-pigs to toluene diisocyanates (3 h per day on five

consecutive days) led to sensitization (antibody formation, pulmonary reactiveness to

toluene diisocyanate-albumin conjugate), at exposure levels ≥ 0.14 mg/m3 (Huang et al.,

1993).

When guinea-pigs were sensitized to toluene diisocyanates by daily instillations for

one week on the nasal mucosa and further exposed nasally once a week for four weeks,

pulmonary alveolitis, characterized by infiltration of mononuclear cells and eosinophils,

was observed. Vasculitis was not found, and fibrosis was negligible, but small nonnecrotizing granulomas, containing epithelioid histiocytes, multinucleated giant cells,

lymphocytes and eosinophils were also observed. The histological picture was thus

reminiscent of the hypersensitivity pneumonitis described in humans after exposure to

toluene diisocyanates (Yamada et al., 1995). 

872 IARC MONOGRAPHS VOLUME 71
4.3 Reproductive and developmental effects

4.3.1 Humans

No data were available to the Working Group.

4.3.2 Experimental systems

When female Wistar rats were exposed by inhalation to toluene diisocyanates

(nominal concentrations 1, 3 or 9 mg/m3, 6 h per day) on days 6 through 15 of gestation,

a slight increase of asymmetric sternebrae was observed at the highest dose, but no

adverse effect on maternal weight gain, number of corpora lutea, implantation sites, preand postimplantation loss, fetal or placental weight, gross and visceral anomalies or

degree of ossification was detected (Buschmann et al., 1996).

4.4 Genetic and related effects 

4.4.1 Humans

No data were available to the Working Group.

4.4.2 Experimental systems (see Table 1 for references)

Unless otherwise indicated, studies were carried out with an 80/20 mixture of

2,4/2,6-toluene diisocyanates. In one of two studies, toluene diisocyanate induced mutations in Salmonella typhimurium strains TA100, TA1538, and TA98 in the presence of an

exogenous metabolic activation system only. It induced sex-linked recessive lethal mutations in Drosophila in a single study.

Toluene diisocyanate did not induce unscheduled DNA synthesis in rat primary

hepatocytes. 2,4-Toluene diisocyanate induced mutations in mouse lymphoma L5178Y

cells at the tk locus in the presence of exogenous metabolic activation and increased the

frequency of sister chromatid exchanges but not chromosomal aberrations in Chinese

hamster ovary cells. 2,6-Toluene diisocyanate induced gene mutations in L5178Y cells

in the presence of an exogenous metabolic activation system and induced sister chromatid exchanges and chromosomal aberrations in Chinese hamster ovary cell cultures.

In human lymphocyte cultures prepared from a male donor, toluene diisocyanate

induced DNA single-strand breaks and chromosomal aberrations, but not sister chromatid exchanges.

Micronuclei were not induced in erythrocytes of mice or rats exposed to atmospheric

concentrations of 1.1 mg/m3 toluene diisocyanate for 6 h per day on five days per week

for four weeks.

5. Summary of Data Reported and Evaluation

5.1 Exposure data

Toluene diisocyanates are industrial chemicals produced in large volumes. Exposure

to toluene diisocyanates may occur during their production and in the processing and

handling of polyurethane foams.

TOLUENE DIISOCYANATES 873
Table 1. Genetic and related effects of toluene diisocyanates Test system Resultsa Doseb (LED or HID) Reference Without exogenous metabolic activation With exogenous metabolic activation SA0, Salmonella typhimurium TA100, reverse mutation

–

+ NG Andersen et al. (

SA0, Salmonella typhimurium TA100, reverse mutation NT

– 1250 Anderson & Sty

SA5, Salmonella typhimurium TA1535, reverse mutation NT

– 1250 Anderson & Sty

SA7, Salmonella typhimurium TA1537, reverse mutation

–

– NG Andersen et al. (

SA8, Salmonella typhimurium TA1538, reverse mutation

–

+ NG Andersen et al. (

SA8, Salmonella typhimurium TA1538, reverse mutation NT

– 1250 Anderson & Sty

SA9, Salmonella typhimurium TA98, reverse mutation

–

+ NG Andersen et al. (

SA9, Salmonella typhimurium TA98, reverse mutation NT

– 1250 Anderson & Sty

DMX, Drosophila melanogaster, sex-linked recessive lethal

mutations

+ 15000 ppm feed Foureman et al. 

URP, Unscheduled DNA synthesis, rat primary hepatocytes,

in vitro

– NT 50 Shaddock et al. (

G5T, Gene mutation, mouse lymphoma L5178Y cells, tk locus

in vitroc

? + 75 McGregor et al. 

GST, Gene mutation, mouse lymphama L5178Y cells, tk locus

in vitrod

–

+ 25 McGregor et al. 

SIC, Sister chromatid exchange, Chinese hamster ovary CHO cells

in vitroc

+

– 300 Gulati et al. (198

SIC, Sister chromatid exchange, Chinese hamster ovary CHO cells

in vitrod

+

– 50 Gulati et al. (198

CIC, Chromosomal aberrations, Chinese hamster ovary CHO cells

in vitroc

–

– 1000 Gulati et al. (198

CIC, Chromosomal aberrations, Chinese hamster ovary CHO cells

in vitrod

+

– 600 Gulati et al. (198
Table 1 (contd)Test system Resultsa Doseb

(LED or HID)

Reference

Withoutexogenousmetabolicactivation

Withexogenousmetabolicactivation

DIH, DNA single-strand breaks, human lymphocytes in vitroe + NT 2400 Marczynski 

(1992)

SHL, Sister chromatid exchange, human lymphocytes in vitroe – – 90 Mäki-Paakka

Norppa (198

CHL, Chromosomal aberrations, human lymphocytes in vitroe (+) + 45 Mäki-Paakka

Norppa (198

MVM, Micronucleus test, CD-1 mouse erythrocytes in vivo – 1.1 mg/m3 inh

6 h/d, 5 d/wk, 4 wk

Loeser (1983

MVR, Micronucleus test, Sprague-Dawley CD rat erythrocytes

in vivo

– 1.1 mg/m3 inh 6 h/d,

5 d/wk, 4 wk

Loeser (1983

a +, positive; (+), weakly positive; –, negative; ?, inconclusive; NT, not testedb LED, lowest effective dose; HID, highest ineffective dose; in-vitro tests, μg/mL; NG, not given; inh, inhalation. All data are from tesan 80:20 mixture of 2,4-toluene diisocyanate:2,6-toluene diisocyanate unless otherwise indicated.c Test using 2,4-toluene diisocyanated Test using 2,6-toluene diisocyanatee Results are from cultures of peripheral blood lymphocytes obtained from one donor for each study.
5.2 Human carcinogenicity data

The risk of cancer associated with occupational exposure to isocyanates has been

examined in three industrial cohort studies and in a population-based case–control study

of several types of cancer. No strong association or consistent pattern has emerged.

5.3 Experimental data

Commercial mixtures of 2,4- and 2,6-toluene diisocyanates were tested for carcinogenicity in mice and rats by gavage and by inhalation exposure. Administration by

gavage induced a dose-related increase in the incidence of subcutaneous fibromas and

fibrosarcomas (combined) in male rats, together with an increase in the incidence of

pancreatic acinar-cell adenomas in male rats and in pancreatic islet-cell adenomas, neoplastic nodules of the liver and mammary gland fibroadenomas in female rats. In female

mice, dose-related increases in the combined incidence of haemangiomas and haemangiosarcomas and of hepatocellular adenomas were observed; no treatment-related tumour

was seen in male mice, possibly due to poor survival. No treatment-related tumour was

observed after exposure of mice or rats to commercial toluene diisocyanate by inhalation,

although the results of the study with rats have not been reported fully.

5.4 Other relevant data

Toluene diisocyanates are metabolized to toluene diamines in humans and rats.

Toluene diisocyanates are irritants and respiratory sensitizers in humans and rats.

Toluene diisocyanate did not induce micronuclei in mammalian erythrocytes in vivo.

It induced DNA damage and chromosomal aberrations but not sister chromatid

exchanges in human lymphocytes in vitro. It induced gene mutation and sister chromatid

exchanges but not DNA damage or chromosomal aberrations in rodent cells in vitro. It

induced sex-linked mutations in Drosophila and in some experiments was mutagenic in

bacteria. The presence of an exogenous metabolic activation system led to inconsistent

results, sometimes enhancing and at other times eliminating the genotoxic effects of

toluene diisocyanate.

5.5 Evaluation

There is inadequate evidence for the carcinogenicity of toluene diisocyanates in

humans.

There is sufficient evidence for the carcinogenicity of toluene diisocyanates in

experimental animals.

Overall evaluation

Toluene diisocyanates are possibly carcinogenic to humans (Group 2B).

876 IARC MONOGRAPHS VOLUME 71
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