Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 1 

Toluene Diisocyanate 

Benzene, 2,4,-diisocyanato-1-methyl- (2,4-TDI), CAS RN 584-84-9 

Benzene, 1,3,-diisocyanato-2-methyl- (2,6-TDI), CAS RN 91-08-7 

Benzene, 1,3,-diisocyanatomethyl- (TDI mixed isomers), CAS RN 26471-62-5 

Synopsis

The Ministers of the Environment and of Health have conducted a screening assessment 

of mixed isomers of toluene diisocyanate (TDI), Chemical Abstracts Service Registry 

Number (CAS RN) 26471-62-5; Benzene, 2,4-diisocyanato-1-methyl- (2,4-toluene 

diisocyanate = 2,4-TDI), CAS RN 584-84-9; and Benzene, 1,3-diisocyanato-2-methyl- 

(2,6 toluene diisocyanate = 2,6-TDI) CAS RN 91-08-7. These substances were identified 

in the categorization of the Domestic Substances List as high priorities for action under 

the Ministerial Challenge. They were considered to pose the greatest potential for 

exposure to individuals in Canada (GPE) in the case of CAS RN 26471-62-5, or an 

intermediate potential for exposure to individuals in Canada (IPE) in the case of CAS RN 

91-08-7 and CAS RN 584-84-9, and have been classified by other agencies on the basis 

of carcinogenicity. As these substances were determined not to meet the ecological 

categorization criteria for persistence, bioaccumulation potential, or inherently toxic to 

aquatic organisms, the focus of this screening assessment relates to human health aspects. 

The screening assessments for 2,4-TDI, 2,6-TDI and the mixed isomers have been 

combined because most toxicological data are available for the mixed isomers of TDI. 

The terms “TDI” and toluene diisocyanate in this assessment refer to either 2,4-TDI, 

2,6-TDI, or the mixed isomers of TDI. 

Toluene diisocyanate is an industrial chemical which was not manufactured by any 

company in Canada in a quantity above the reporting threshold of 100 kg in 2006, but 

which is imported into the country. In Canada, more than 85% of toluene diisocyanate 

was used in the manufacture of flexible polyurethane foam in 2006. 

Industrial releases of TDI in Canada are mainly to air and it is expected that most TDI 

released to air will remain in the vapour state and react chiefly with photolytically 

produced hydroxyl radicals, resulting in a half-life of less than two days. However, 

exposure to TDI may be elevated during use of consumer products containing the 

substance. 

Based principally on a weight of evidence for carcinogenicity in assessments by several 

international and national agencies, the available human epidemiological data and the 

experimental animal data are equivocal and thus inadequate to determine the 

carcinogenic risk to TDI in humans, via the inhalation route. TDI is considered to be 

carcinogenic, since oral dosing in animals was associated with appearance of tumours at 

multiple sites. Mixed results have been obtained for TDI in in vivo and in vitro 

genotoxicity assays. Therefore, although the mode of induction of tumours has not been 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 2 

fully elucidated, it cannot be precluded that the tumours observed in experimental 

animals resulted from direct interaction with genetic material. 

The upper-bounding estimate of exposure via inhalation to the general population or 

during use of consumer products containing TDI may approach or exceed the critical 

effect levels for non-cancer effects in the respiratory system, including respiratory 

hypersensitivity. Additionally, TDI has been classified as a dermal and respiratory 

sensitizer by the European Union. 

On the basis of the carcinogenicity of TDI mixed isomers, 2,4-TDI and 2,6-TDI, for 

which there may be a probability of harm at any level of exposure, as well as the potential 

inadequacy of the margins between estimated exposure to the general population or 

exposure from products and critical effect levels for non-cancer effects, it is concluded 

that they are substance that may be entering the environment in a quantity or 

concentration or under conditions that constitute or may constitute a danger in Canada to 

human life or health. 

On the basis of ecological hazard and reported releases of TDI mixed isomers, 2,4-TDI 

and 2,6-TDI, it is concluded that these substances are not entering the environment in a 

quantity or concentration or under conditions that have or may have an immediate or 

long-term harmful effect on the environment or its biological diversity, or that constitute 

or may constitute a danger to the environment on which life depends. Additionally, TDI 

mixed isomers, 2,4-TDI and 2,6-TDI do not meet criteria for persistence and 

bioaccumulation potential as set out in the Persistence and Bioaccumulation Regulations. 

These substances will be included in the Domestic Substances List inventory update 

initiative, to be launched in 2009. In addition and where relevant, research and 

monitoring will support verification of assumptions used during the screening assessment 

and, where appropriate, the performance of potential control measures identified during 

the risk management phase. 

Based on the information available, TDI mixed isomers, 2,4-TDI and 2,6-TDI meet one 

or more of the criteria set out in Section 64 of the Canadian Environmental Protection 

Act, 1999. 

Introduction 

The Canadian Environmental Protection Act, 1999 (CEPA 1999) (Canada 1999) requires 

the Minister of the Environment and the Minister of Health to conduct screening 

assessments of substances that have met the categorization criteria set out in the Act to 

determine whether these substances present or may present a risk to the environment or 

human health. Based on the results of a screening assessment, the Ministers can propose 

to take no further action with respect to the substance, to add the substance to the Priority 

Substances List (PSL) for further assessment, or to recommend that the substance be 

added to the List of Toxic Substances in Schedule 1 of the Act and, where applicable, the 

implementation of virtual elimination. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 3 

Based on the information obtained through the categorization process, the Ministers 

identified a number of substances as high priorities for action. These include substances 

that: 

• met all of the ecological categorization criteria, including persistence (P), 

bioaccumulation potential (B) and inherently toxic to aquatic organisms (iT), and 

were believed to be in commerce; and/or 

• met the categorization criteria for greatest potential for exposure (GPE) or 

presented an intermediate potential for exposure (IPE), and had been identified as 

posing a high hazard to human health based on classifications by other national or 

international agencies for carcinogenicity, genotoxicity, developmental toxicity or 

reproductive toxicity. 

 

The Ministers therefore published a notice of intent in the Canada Gazette, Part I, on 

December 9, 2006 (Canada 2006), that challenged industry and other interested 

stakeholders to submit, within specified timelines, specific information that may be used 

to inform risk assessment, and to develop and benchmark best practices for the risk 

management and product stewardship of those substances identified as the highest 

priorities. 

Isomers of toluene diisocyanate were identified as high priorities for assessment of 

human health risk because they were considered to present IPE or GPE and had been 

classified by other agencies on the basis of carcinogenicity. The Challenge for isomers of 

toluene diisocyanate was published in the Canada Gazette on February 3, 2007 (Canada 

2007a). A substance profile was released at the same time. The substance profile 

presented the technical information available prior to December 2005 that formed the 

basis for categorization of this substance. As a result of the Challenge, submissions of 

information were received. 

Although isomers of toluene diisocyanate were determined to be a high priority for 

assessment with respect to human health, they did not meet the criteria for potential for 

persistence, bioaccumulation or inherent toxicity for aquatic organisms. Therefore, this 

assessment focuses principally on information relevant to the evaluation of risks to 

human health. 

Under CEPA 1999, screening assessments focus on information critical to determining 

whether a substance meets the criteria for defining a chemical as toxic as set out in 

section 64 of the Act, where 

“64. [...] a substance is toxic if it is entering or may enter the environment in a quantity or 

concentration or under conditions that 

(a) have or may have an immediate or long-term harmful effect on the environment or its 

biological diversity; 

(b) constitute or may constitute a danger to the environment on which life depends; or 

(c) constitute or may constitute a danger in Canada to human life or health.” 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 4 

Screening assessments examine scientific information and develop conclusions by 

incorporating a weight of evidence approach and precaution. 

This screening assessment includes consideration of information on chemical properties, 

hazards, uses and exposure, including the additional information submitted under the 

Challenge. Data relevant to the screening assessment of this substance were identified in 

original literature, review and assessment documents, stakeholder research reports and 

from recent literature searches, up to September 2007. Key studies were critically 

evaluated; modelling results may have been used to reach conclusions. Evaluation of risk 

to human health involves consideration of data relevant to estimation of exposure (nonoccupational) of the general population, as well as information on health hazards (based 

principally on the weight of evidence assessments of other agencies that were used for 

prioritization the substance). Decisions for human health are based on the nature of the 

critical effect and/or margins between conservative effect levels and estimates of 

exposure, taking into account confidence in the completeness of the identified databases 

on both exposure and effects, within a screening context. The screening assessment does 

not represent an exhaustive or critical review of all available data. Rather, it presents a 

summary of the critical information upon which the conclusion is based. 

The screening assessments for 2,4-TDI, 2,6-TDI and the mixed isomers have been 

combined because most toxicological data are available for the mixed isomers of TDI. 

The term “TDI” in this assessment refers to either 2,4-TDI, 2,6-TDI, or the mixed 

isomers of TDI. 

This screening assessment was prepared by staff in the Existing Substances Programs at 

Health Canada and Environment Canada and incorporates input from other programs 

within these departments. This assessment has undergone external written peer 

review/consultation. Comments on the technical portions relevant to human health were 

received from Meridian Environmental Inc. and Starodub & Associates. While external 

comments were taken into consideration, the final content and outcome of the screening 

risk assessment remain the responsibility of Health Canada and Environment Canada.

Additionally, the draft of this screening assessment was subject to a 60-day public 

comment period. The critical information and considerations upon which the assessment 

is based are summarized below. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 5 

Substance Identity 

Table 1. Substance identity 

CAS RN and name CAS RN 584-84-9: benzene, 2,4,-diisocyanato-1-methyl- 

(2,4-TDI) 

CAS RN 91-08-7: benzene, 1,3,-diisocyanato-2-methyl- 

(2,6-TDI) 

CAS RN 26471-62-5: benzene, 1,3,-diisocyanatomethyl- 

(TDI mixed isomers) 

Synonyms 

CAS RN 584-84-9 

CAS RN 91-08-7 

CAS RN 26471-62-5 

1,3-Diisocyanato-4-methylbenzene; 2,4-Toluene 

diisocyanate (2,4-TDI); Isocyanic acid, 4-methyl-mphenylene ester 

1,3-Diisocyanato-2-methylbenzene; 2,6- Toluene 

diisocyanate (2,6-TDI); Isocyanic acid, 2-methyl-mphenylene ester 

Crude tolylene diisocyanate; 1,3-

Diisocyantomethylbenzene ; Toluene diisocyanate (80% 

2,4-TDI; 20% 2,6-TDI) 

Chemical formula C9H6N2O2

Chemical structure 

 

2,6- toluene diisocyanate 2,4- toluene diisocyanate 

SMILES Notation 91-08-7 O=C=Nc(c(c(N=C=O)cc1)C)c1 

584-84-9 O=C=Nc(c(ccc1N=C=O)C)c1 

Molecular mass 174.16 

TDI is most commonly sold as an 80:20 mixture of 2,4- and 2,6- isomers. A mixture 

that is 65:35 is also in commerce and a crude TDI mixture with an undefined isomer 

ratio is also sold commercially. Pure 2,4- TDI is used for some specialty purposes. Pure 

2,6-TDI has no industrial use. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 6 

Table 2. Physical and chemical properties 

Property Value Type Reference 

Melting point 

2,4-TDI 

2,6- TDI 

Mixed 2,4- and 2,6- 

isomers of TDI 

22oC 

7.2oC 

< 15oC (80:20 mix) 

< 8oC (65:35 mix) 

Exp 

Exp 

Exp 

Exp 

IARC 1986 

IARC 1986 

IARC 1986 

IARC 1986 

Boiling point 

2,4-TDI 

2,6- TDI 

Mixed 2,4- and 2,6- 

isomers of TDI 

252.5–254oC 

247–248.5oC 

252–254oC 

Exp at 1 atm 

Exp at .98 atm 

Exp at 1 atm 

IUCLID 2000 

IUCLID 2000 

IUCLID 2000 

Density 

 

1.22 g/cm3 Exp at 20oC IUCLID 2000 

Vapour pressure 

2,4-TDI 

2,6- TDI 

Mixed 2,4- and 2,6- 

isomers of TDI 

0.013–0.021 hPa 

0.016 hPa 

0.014–0.015 hPa 

Exp all at 20oC IUCLID 2000 

IUCLID 2000 

IUCLID 2000 

Henry’s Law constant 

(H) 

TDI reacts with water, 

therefore no estimation of H 

is made. 

Water solubility TDI reacts with water, and 

solubility in water cannot be 

determined. 

IUCLID 2000 

Log Kow TDI reacts with water and 

with octanol, therefore no 

estimation of Kow is made. 

IUCLID 2000 

Log Koc TDI reacts with water and 

with octanol, therefore no 

estimation of Koc is made. 

Exp = experimental data 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 7 

Sources 

There are no known natural sources of TDI. 

Toluene diisocyanate is an industrial chemical which was not manufactured by any 

company in Canada in a quantity above the reporting threshold of 100 kg in 2006, but 

which is imported into the country. The industrial demand in Canada for TDI in 2006 was 

estimated to be 33.6 million kilograms (IAL Consultants 2007). From responses to a 

notice published under Section 71 of CEPA 1999, the quantity of TDI imported into 

Canada in 2006 was determined to be greater than10 million kilograms (Canada 2007a). 

This is the total for toluene diisocyanate isomers represented by the three CAS numbers 

identified in this report. It includes TDI imported in mixtures with other chemical 

substances and in consumer products if the quantity of TDI imported was equal to or 

greater than 100 kg in 2006. 

Toluene diisocyanate may be emitted to the environment from industrial processes that 

use TDI as a reactive intermediate. An example of this would be the manufacture of 

flexible polyurethane foam. Emissions from industrial activities are principally to air. 

Another potential source of TDI emissions to the environment is the incineration of 

polyurethane waste. Because TDI is a reactive chemical, long range transport of TDI is 

not expected to contribute significantly to human exposure in Canada. 

Toluene diisocyanate is present in some consumer products, which may emit TDI when 

used. Some examples of such products are specialty polyurethane-based paints, varnishes 

and coatings, polyurethane adhesives, sealants and mastic (IARC 1986; NTP 2005). It 

has been reported that mixtures of isocyanates, including TDI may be released when 

isocyanate-based paint, which is used extensively for the factory-applied primer coat on 

automobiles is heated during grinding or sanding of the surface (Karlsson et al. 2000). 

Potential sources of TDI in food arise from the use of polyurethanes in inks and 

adhesives applied to food packaging, and polyurethane elastomers in food handling 

equipment such as conveyor belts. If there is no functional barrier between inks or 

adhesives and food, the residual levels of TDI isomers and the potential migration of TDI 

into food are estimated based on professional judgement by Health Canada (as per e-mail 

from Food Directorate, Health Canada, May 2008, unreferenced). Polyurethane foam 

liners which may be made with TDI have been approved for restricted use as food contact 

material in Canada (Damant et al. 1995; Ellendt et al. 2003; CFIA 2007). 

Some products used in construction such as sealants, coatings, and adhesives which 

contain measurable amounts of free isocyanate are intended for use only by trained 

contractors. The degree to which untrained individuals may have access to such products 

is unknown. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 8 

Uses 

Mixtures of 2,4- and 2,6- toluene diisocyanate isomers dominate industrial use of TDI. 

Pure 2,4- isomer is used in some specialty elastomers applications. Pure 2,6- isomer is 

not a commercial industrial chemical (Allport et al. 2003). 

The use patterns reported in 2006 for TDI in Canada are shown in Tables 3 and 4. 

In Canada, about 86% of toluene diisocyanate was used in the manufacture of flexible 

polyurethane foam (PUF) in 2006. TDI is reacted with a polyol in the presence of a 

surfactant, catalyst, blowing agent and other process chemicals to form PUF. Flexible 

PUF is used extensively in household furniture and automotive upholstery, in mattresses, 

pillows, packaging and carpet underlay. Use of TDI to bond foam scrap to make carpet 

underlay consumes about one percent of all TDI in Canada (IAL Consultants 2007). This 

use of TDI is being phased out in other places in favour of the use of methylenediphenyl 

diisocyanate, MDI (Meeting with Isocyanates Panel, American Chemistry Council – 

ACC, Ottawa, 2007/08/08). Semi-flexible and semi-rigid PUF are used in automotive 

panels, padding and bumpers. Use of TDI to produce rigid PUF for insulation in 

applications such as refrigeration and foam-in-place caulking has largely been replaced 

by MDI (Meeting with Isocyanates Panel, ACC, Ottawa, 2007/08/08). 

The market demands for TDI used in coatings and adhesives in 2006 were about seven 

and five percent respectively of the total demand. TDI or a TDI derivative is used in 

polyurethane-modified alkyd paints and coatings including automotive and marine paint, 

wood varnish, floor treatment, wire and powder coating. TDI or a TDI derivative is used 

in sealants, adhesives and elastomers. Poly(urethane urea) cast elastomers based on TDI 

may be used in wheels, rollers, conveyors and similar products. TDI is used in the 

production of coatings for textiles for durability and waterproofing and in other textile 

applications (Ulrich 1996; IARC 1986; NTP 2005). TDI-based coatings are also used in 

paper production (Canada 2007a). Several biomedical applications of polyurethanes 

based on TDI have been reported elsewhere. In Canada, no products made with TDIbased polyurethane are licensed for use in biomedical applications. Two historical uses 

are the Today contraceptive sponge, made of polyurethane foam and the Même breast 

implant, no longer licensed for use in Canada, which consisted of a silicone core enclosed 

in a TDI-based polyurethane envelope (Benoit 1993). 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 9 

Table 3. TDI use patterns 

Canada 2006 – Demand for raw materials by product type 

Product type TDI 

(millions of kg) 

Flexible foam slabstock 19.64 

Flexible foam moulded 9.25 

Coatings 2.31 

Binders 0.36 

Elastomers 0.45 

Adhesives 1.59 

Total 33.6 

Adapted from 2006 End-Use Market Survey on the Polyurethane Industry in the US, Canada and Mexico, 

October 2007, by IAL Consultants for the Center for the Polyurethanes Industry 

Table 4. Canada 2006 – Demand for raw materials by end-use application 

End-use application TDI 

(millions of kg) 

Construction 2.90 

Transportation 12.11 

Furniture 9.53 

Foam Scrap 2.45 

Appliance 0.14 

Packaging 0.41 

Bedding 2.04 

Textiles and fibre 0.36 

Industrial 0.32 

Foundry - 

Marine 0.09 

Machinery 0.18 

Electronics - 

Wheels and tires - 

Footwear - 

Decorative - 

Other 3.13 

Total 33.6 

Adapted from 2006 End-Use Market Survey on the Polyurethane Industry in the US, Canada and Mexico, 

October 2007, by IAL Consultants for the Center for the Polyurethanes Industry 

Submissions made under Section 71 of CEPA 1999 indicate that in 2006, more than 

10 million kilograms of toluene diisocyanate isomers were imported into Canada (Canada 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 10 

2007a). No further detail on the quantity of TDI represented by each CAS number is 

given here because of confidentiality requirements. 

Releases to the Environment 

Industrial facilities in Canada that annually manufacture, process or otherwise use more 

than 10 tonnes of TDI, either as the mixture of isomers or as a specified isomer must 

report to the National Pollutant Release Inventory (NPRI) all releases to the environment 

and other transfers of the substance. The NPRI summary of releases of TDI from 

industrial facilities in Canada for 2002 to 2006 is shown in Table 5. No releases to 

surface waters or land were reported during that period; however, transfers to waste 

disposal facilities were reported (NPRI 2008). 

Table 5. National Pollutant Release Inventory data – Releases via stack or point 

source, fugitive emissions and other losses 

Year 2,4- TDI 

584-84-9 

2,6- TDI 

91-08-7 

Mixed 

isomers of 

TDI 

26471-62-5 

Total 

Releases 

of TDI 

isomers 

Tonnes 

2006 0.005 0.0 2.022 2.027 

2005 0.002 0.0 1.479 1.481 

2004 0.003 0.0 1.096 1.099 

2003 0.011 0.001 1.586 1.598 

2002 0.106 0.001 1.232 1.339 

Persistence and Bioaccumulation Potential 

Persistence 

In air, indirect photolytic degradation as a result of photogenerated hydroxyl radicals has 

been demonstrated to be a significant degradation pathway for TDI (Pemberton and Tury 

2004). Although TDI reacts rapidly with water, Tury et al. (2003) observed that reaction 

(i.e. hydrolysis) with atmospheric water was not significant. Tury et al. (2003) reported a 

half-life of 1.4 days for TDI based on experimental reaction rates, which compares well 

with the predicted and calculated values of 1.7 and 1.5 days (see Table 6). TDI is not 

expected to react with other photo-oxidative species in the atmosphere, such as ozone 

(Tury et al. 2003). Based on the evidence available, TDI is not considered persistent in 

air. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 11 

Table 6. Modelled data for persistence of TDI 

Medium Fate process Degradation 

value/range 

Degradation 

endpoint 

Reference 

Air Atm-oxidation 

by OH radicals* 

1.7 half-life (days) AOPWIN (2000) 

Air Atm-oxidation 

by OH radicals 

1.5 half-life (days) Atkinson (1989), 

calculated value 

Air Ozone reaction negligible half-life (days) AOPWIN (2000) 

Water/soil/ 

sediment 

Hydrolysis < 10 minutes half-life (days) HYDROWIN (2000) 

Water/soil/ 

sediment 

Biodegradation 15–60 half-life (days) BIOWIN (2000) 

Water/soil/ 

sediment 

Biodegradation 0.002–0.2186 Probability of 

rapid 

biodegradation 

BIOWIN (2000) 

TOPKAT (2004) 

Water/soil/ 

sediment 

Biodegradation 

(BOD) 

> 15 half-life (days) ASTER (1999) 

*Based on hydroxyl radical concentration of 1.5x 106 OH radicals/cm3 (12-h day) 

The Transport and Persistence Level III Model (TaPL3) (TaPL3 2000) is not considered 

appropriate in estimating characteristic travel distance (CTD) for TDI since the 

applicability domain of the model does not cover substances that react in water or soil. 

The CTD is defined as the maximum distance travelled in air by 63% of a substance; or 

the distance that 37% of the substance may travel beyond. Nevertheless, the three TDI 

substances are expected to have a CTD under 700 km based on two considerations. The 

first consideration is that a large number of non-reactive substances with water or soil 

modelled by TaPL3 have a CTD < 700 km if their atmospheric half lives are less than 2 

days, while the three TDI substances all have an atmospheric half life of less than 2 days 

(1.4 days reported by Tury et al., 2003; 1.5 days calculated according to Atkinson, 1989; 

and 1.7 days predicted by AOPWIN, 2000). The second consideration is that when a 

substance like TDI transforms into other forms in water and soil, the chance for the 

substance to re-enter the atmosphere from water and soil is reduced and this translates 

into a reduced potential for long-range transport. According to the criteria proposed by 

Beyer et al. (2000) for CTDs of > 2000 km as representing high long-range atmospheric 

transport potential (LRATP), 700-2000 km as moderate LRATP, and < 700 km as low 

LRATP, the long-range atmospheric transport potential of TDI is considered to be low 

(<700 km). This means that TDI is not expected to be able to reach areas far from its 

emission sources. 

In media where water is present (e.g., water, moist soils, sediment), TDI is considered 

transient, with a half-life of under a minute (Yakabe et al. 1999). The reaction of an 

amine with isocyanate is faster than the hydrolysis reaction of water with isocyanate, 

which, in the case of diisocyanates like TDI, leads primarily to reactions forming 

polyureas (Yakabe et al. 1999; Pemberton and Tury 2004). 

It is well documented in numerous studies that the aromatic diisocyanates will hydrolyze 

and react rapidly in both water and soil (Pemberton and Tury 2004; Heimbach et al. 

1996; Yakabe et al. 1999; Tury et al. 2003). 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 12 

The weight of evidence based on the above-described data indicates that TDI does not 

meet the persistence criteria for air (half-life in air ≥ 2 days) or water or soil (half-life in 

soil and water ≥ 182 days) or sediments (half-life in soil and water ≥ 365 days), as set out 

in the Persistence and Bioaccumulation Regulations (Canada 2000). 

Bioaccumulation

Modelled data suggest that TDI does not have the potential to bioaccumulate in the 

environment (see Table 7). Given the highly reactive properties of diisocyanates, TDI 

compounds are likely metabolized/degraded at rates fast enough to counter any potential 

for bioaccumulation or biomagnification. In addition, they are likely hydrolyzed in the 

gastrointestinal tract, thereby reducing the potential for uptake of the chemical from the 

gut (Yakabe et al. 1999; Pemberton and Tury 2004; IPCS 1987; IPCS1997). 

Table 7. Modelled data for bioaccumulation of TDI 

Test organism Endpoint Value wet weight 

(L/kg) 

Reference 

Fish BAF 380 Gobas BAF T2MTL (Arnot and 

Gobas 2003) 

Fish BCF 151–1183 Gobas BCF T2LTL (Arnot and 

Gobas 2003); OASIS Forecast 

(2005); 

BCFWIN (2000) 

For toluene diamine, a product of hydrolysis, experimental bioconcentration factors 

(BCFs) for 2,4-toluene diamine of < 5 to < 50 (MITI 1992) suggest they are also not 

likely to accumulate in organisms.

The weight of evidence indicates that TDI does not meet the bioaccumulation criterion 

(BCF, BAF ≥ 5000) as set out in the Persistence and Bioaccumulation Regulations

(Canada 2000). 

Environmental Fate 

Industrial releases of TDI are expected to be mainly to air, where photolytic degradation 

is expected to yield a half-life of less than 2 days (see above). TDI has a transient 

existence in water, moist soils and sediments due to rapid hydrolysis. Environmental fate 

modelling to estimate partitioning into environmental compartments is therefore not 

considered relevant for TDI. 

Potential to Cause Ecological Harm 

As indicated above, TDI does not meet the persistence or bioaccumulation criteria as set 

out in the Persistence and Bioaccumulation Regulations (Canada 2000). 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 13 

Due to the anticipated transient existence of TDI in aqueous media, including moist soils, 

it is unlikely that ecological effects will be elicited by the parent TDI compounds. 

Experimental ecotoxicological data for TDI and its degradation products (LC50’s and 

EC50 for water flea, fish, shrimp and algae > 1 mg/L; Tadokoro et al 1997; Curtis et al 

1978; Danish EPA 1998; MITI 1992) indicate low to moderate toxicity to aquatic 

organisms. Other toxicity data suggest low likelihood of effects to terrestrial biota such 

as plants, earthworms (NOEC’s, EC50 and LC50 >1000 mg/L; Van der Hoeven et al. 

1992a,b) and birds (oral LC50’s of ≥100 mg/kg body weight for Agelaius phoenicens

exposed to 2,4-TDI and 2,6-TDI; as cited in IUCLID 2000).

The National Pollutant Release Inventory reported 2 200 kg of the isomer mixture was 

released (92% to air, 8% media unspecified) in 2006 (NPRI 2008). Given the dispersive 

nature of these releases, they are unlikely to result in significant exposure of organisms in 

the environment. 

Based on the information available, TDI is unlikely to cause ecological harm in Canada. 

Potential to Cause Harm to Human Health

Exposure Assessment 

Environmental Media and Diet 

Measured concentrations of toluene diisocyanate in environmental media and dietary 

sources in Canada were not located. Reports of the concentration of TDI in air outside a 

manufacturing facility in North Carolina, USA that was subsequently closed (Levine et 

al. 2001) were not considered representative of exposures in Canada. 

The partitioning of TDI into environmental media was not estimated by modelling, but an 

estimate of the maximum concentration of TDI in air downwind of a manufacturing plant 

in Canada was made. The International Isocyanate Institute has estimated that in the 

European industry, 25 grams of TDI are released to the atmosphere per tonne of TDI used 

in producing flexible polyurethane foam (Chapman 1994). Modelling the ambient air 

concentration at 100 metres from a low building with no stack using a model within 

EUSES (European Union System for the Evaluation of Substances) gave the prediction of 

an annual air concentration of 6.7 E-3 μg/m3

 for a plant with a continuous release of TDI 

of 8.8 kg/yr (Tury et al. 2003). A Canadian plant reported a release of 1,400 kg of mixed 

isomers of TDI to air in 2006 (NPRI 2008). Extrapolating from the result by Tury et al., 

the estimated annual average concentration of TDI in air at 100 metres from the plant is 

1.06 μg/m3. It is expected that short-term air concentrations will vary from this average 

because of production cycles, plant stack height, wind, local topography and other 

factors. Furthermore, this concentration of TDI in air is a conservative estimate 

applicable only to the population in the vicinity of the plant. Industrial releases of TDI in 

Canada are mainly to air and it is expected that most TDI released to air will remain in 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 14 

the vapour state and react chiefly with photolytically produced hydroxyl radicals, 

resulting in a half-life of less than two days (Tury et al. 2003; Atkinson 1989). 

The upper-bounding estimate of exposure to TDI via environmental media ranged from 

0.21 μg/kg-bw (kilogram of body weight) per day for persons aged 60 years and more to 

0.64 μg/kg-bw per day for children aged 6 months to four years (see Appendix 1). 

Consumer Products 

The use of consumer products may contribute to the exposure of individuals to TDI. Free 

isocyanate has been detected on the surface of cured polyurethane foam aged 1-30 years 

using a solvent-coated colour indicating pad, but this test was not specific for TDI. 

Samples of PUF were shredded, extracted with solvent, and the extract was analysed. 

Both TDI and total reactive isocyanate groups were quantified in the extracts (Krone et 

al. 2003). In another experiment, the 2,4- and 2,6- isomers of TDI were extracted by 

solvent from polyurethane foam and positively identified and measured at levels of 

nanograms per gram of foam (Gagné et al. 2003). The amines 2,4- and 2,6- toluene 

diamine, which may be present as the result of hydrolysis of 2,4- and 2,6- toluene 

diisocyanate have also been extracted from polyurethane foam (Marand et al. 2004). 

These experiments indicate that TDI and the corresponding amines may migrate from 

foam in consumer products and thus be available for dermal or oral uptake. The degree 

to which the use of solvents may be responsible for enhancing extraction of TDI from 

PUF is unquantifiable. 

An experiment in which humidified air was drawn through pieces of foam loaded with 1 

ppm of TDI and aged for three days showed that 99.9% of the TDI was retained in the 

foam (Hugo et al. 2000). There is further experimental evidence that TDI which is 

present in polyurethane foam is not volatilized in measurable quantities after an initial 

curing period of several days (Kelly et al. 1999; Katsuyama et al. 2003). Kelly et al. 

(1999) investigated a number of polyurethane consumer products that are made with TDI 

including carpet padding, furniture cushions, sheet foam, varnishes and sealants and 

found no detectable emissions of isocyanates at an emission rate higher than 0.96 

μg/m2

/hour for coatings applied to surfaces or for polyurethane foam. Kelly et al. (1999) 

further estimated an equilibrium concentration in household air based on the detection 

limit of the experimental method in this study and concluded that the highest steady-state 

residential air concentration would be not more than 0.19 μg/m3

 for application of a 

polyurethane coating. 

In a study by Katsuyama et al. (2003) of consumer products, no emissions of TDI above 

the detection limits were measured when urethane adhesive, paint and varnish were 

tested, but TDI was found when rigid polyurethane foam was placed in an atmosphere 

with acetone vapour. The investigators estimated a flux rate of TDI and, based on average 

Japanese home size and ventilation rate, calculated an equilibrium concentration of 2,4-

TDI of 4.28 x 10-2 ppb (305 μg/m3

 ) in Japanese houses. Rigid polyurethane foam slab is 

not a building material typically used in Canadian residential construction and the 

concentration of acetone in air used in the experiment does not represent normal 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 15 

residential conditions; therefore, the exposure described by Katsuyama et al. (2003) is not 

considered pertinent. 

It has been shown experimentally that isocyanate-based paints for concrete floors and 

deck sealer emit measurable concentrations of 2,6-TDI to air following application of the 

coating (Kelly et al. 1999; Jarand et al. 2002). Although the concentrations of TDI in air 

that were measured in these experiments in small environmental chambers cannot be 

extrapolated to residential exposures, the concentration of TDI in coatings and the 

percentage of TDI released to air can be used to model exposure. 

Using data from Jarand et al. (2002) to estimate the maximum concentration of 2,6-TDI 

in a room during and five hours after painting a concrete floor with a two part 

polyurethane sealer, an estimate of the concentration of TDI in air of 24 μg/m3

 was 

obtained. The dose received by an adult doing light work for an hour was estimated to be 

0.44 μg/kg-bw per day. A second scenario using data on 2,6-TDI emissions from a 

concrete sealer measured by Kelly et al. (1999) yielded a much higher estimate of daily 

intake over a one hour period; however, the authors stated that the product tested by 

Kelly et al. (1999) was sold for application solely by licensed contractors. Given 

uncertainties regarding availability of this TDI-based sealer to Canadian retail consumers, 

only the scenario based on the findings by Jarand et al. (2002) was retained. It was 

determined that the product that was tested by Jarand et al. (2002) is available at the retail 

level in Canada in 2008. The dermal exposure that might arise from use of concrete 

sealer was not estimated in these scenarios. Dermal exposure would be an additional 

contribution to exposure. 

It should be noted that the estimate of dose is for a one hour exposure. It should be 

further noted that use of such a concrete sealer is a relatively infrequent activity, probably 

less than once every 3 to 5 years. 

Elaboration of a scenario for exposure to infants mouthing polyurethane foam from 

pillows or other objects made of polyurethane foam using the figure of 7.8 ng TDI 

released/g foam (Gagné et al. 2003) resulted in an estimated intake of 0.1 ng/kg-bw per 

day. This is an overestimate of the exposure because the extraction conditions in 

mouthing are much milder than those used by Gagné et al. (2003). Note that this estimate 

of exposure does not account for the reactivity of TDI with saliva. It is anticipated that a 

much smaller quantity of TDI will be available for ingestion than the 0.1 ng/kg-bw per 

day estimated for this scenario. The estimated intake of 0.1 ng/kg-bw per day from the 

foam mouthing scenario is less than 0.1% of the estimated intake from ambient and 

indoor air for the age group 6 months to 4 years and is therefore considered to be 

negligible. 

Exposure scenarios are presented in Appendix 2. 

The confidence in the exposure database is considered to be very low. No data on the 

concentration of toluene diisocyanate in any environmental medium used to estimate 

human exposure were located. Confidence in the estimate of exposure from the use of 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 16 

consumer products is low because of uncertainty about consumer access to urethane 

surface coatings containing TDI. 

Health Effects Assessment 

Appendix 3 contains a summary of the available health effects information for toluene 

diisocyanate. The majority of the available data for TDI is on the mixture of isomers. 

The International Agency for Research on Cancer (IARC) classified toluene diisocyanate 

as “possibly carcinogenic to humans” (Carcinogenicity Group 2B), based on inadequate 

evidence for the carcinogenicity of toluene diisocyanates in humans and sufficient 

evidence for the carcinogenicity of toluene diisocyanates in experimental animals (IARC 

1986; IARC 1999). TDI has also been classified by the European Commission (EC) as 

Category 3 for carcinogenicity (“causes concerns for humans owing to possible 

carcinogenic effects”) (European Commission 1997, 2004; ESIS v.4.50 2006); and by the 

United States National Toxicology Program (NTP) as “reasonably anticipated to be a 

human carcinogen” (NTP 2005). These classifications were based on significantly 

increased tumour incidences at multiple sites in mice and rats exposed orally by gavage 

for 2 years. Female mice exposed orally to 60 or 120 mg/kg-bw/day TDI had 

significantly increased hepatocellular adenomas and combined hemangiomas (spleen, 

subcutaneous) and hemangiosarcomas (liver, ovaries, peritoneum) (NTP 1983). Female 

rats exposed orally to 60 or 120 mg/kg-bw/day TDI had significantly increased mammary 

gland fibroadenomas and pancreatic islet cell adenomas; male rats exposed to 30 or 60 

mg/kg-bw/day TDI had increased subcutaneous fibromas and fibrosarcomas (significant 

when combined), and pancreatic acinar cell adenomas (significant at the high dose) (NTP 

1983). In each study, the increased tumours were observed at the lowest exposure level 

tested. Male mice exposed to up to 240 mg/kg-bw/day TDI did not develop exposurerelated tumours (NTP 1983). 

 

Exposure-related tumours were not observed in mice and rats exposed via inhalation to 

0.36 and 1.07 mg/m3 TDI for 2 years (Loeser 1983). The International Programme on 

Chemical Safety (IPCS 1987) noted that the animals in this study were probably not 

given the maximum tolerated dose and therefore the highest dose may not have been 

sufficient to detect a response. However, this was based on body weight changes, not on 

other effects. There was also an unexplained high mortality rate in control and treated 

animals, reducing the sensitivity of the bioassay. Although Loeser (1983) reported a 

significant increase in mortality of female mice at both doses, the United States 

Environmental Protection Agency (US EPA 1995) concluded that there were no 

exposure-related effects observed on mortality, organ weights or clinical chemistry 

parameters in rats or mice. Histopathological findings from the rat nasal passages from 

this study were reported by Owen (1984). The lowest-observed-adverse-effect 

concentration (LOAEC) was 0.36 mg/m3

 in rats based on a dose-related increase in the 

incidence and severity of chronic and necrotic rhinitis in female rats. Similar effects were 

reported in mice but there was insufficient detail to establish effect levels. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 17 

IARC (1999) concluded that in humans, there was no strong association or consistent 

pattern regarding the carcinogenicity of inhalation exposure to TDI from three industrial 

cohort studies and a population-based case-control study (Hagmar et al 1993a and 1993b; 

Sorahan and Pope 1993; Schnorr et al. 1996). These studies may be of limited value due 

to the small sample sizes, relatively short follow-up, young cohorts and lack of 

consideration of smoking (Bolognesi et al 2001). In the review by Bolognesi et al 

(2001), it was concluded that “...the available human evidence and the experimental data 

are inadequate to evaluate the carcinogenic risk of TDI for humans." 

Although more recent epidemiological studies are available (Kerr et al. 2000; Mikoczy et 

al. 2004; Sorahan and Nichols 2002; Clark et al 2003), no international assessments are 

yet available on these updated data and full weight of evidence analyses of the overall 

epidemiological data are not practicable within the context of this screening assessment. 

Based on the oral carcinogenicity study in male rats outlined above (NTP 1983, 1986), 

the California EPA has calculated an oral cancer slope factor for TDI, and a related 

inhalation cancer unit risk factor for TDI using cross-route extrapolation and California 

EPA’s Expedited Proposition 65 methodology (California EPA 1999). 

Mixed results have been obtained for TDI in in vivo and in vitro genotoxicity assays 

(Appendix 3). In vivo, TDI induced sex-linked mutations in Drosophila (oral exposure) 

but did not induce micronuclei in mouse or rat erythrocytes (inhalation exposure). In one 

study of human exposure, workers exposed to a mixture of TDI isomers in air had a 

statistically significant increase in structural chromosome aberrations, sister chromatid 

exchange, and micronuclei in peripheral blood lymphocytes relative to controls (Bilban 

2004). However, this study had a small sample size, subjects may have been 

occupationally exposed to numerous chemicals in addition to TDI, and there was no 

consideration for smoking. Studies with smaller sample sizes indicated negative results 

for DNA strand breaks in human lymphocytes of workers (Marczynski et al. 2003, 2005). 

In vitro, TDI induced mutations, DNA damage, chromosomal aberrations and sister 

chromatid exchanges in some studies but not in others. Bolognesi et al. (2001) indicated 

that the stability of the applied diisocyanate was not studied in the in vitro studies, and 

that the reacting species may not be the same between the in vitro and in vivo studies. 

However, the authors concluded that TDI was “probably genotoxic” due to TDI’s 

potential to react with DNA. 

The primary target organs for non-neoplastic effects of exposure to TDI by the inhalation, 

dermal, and oral routes were the lung and respiratory tract. Inhalation and dermal 

exposure to TDI lead to respiratory hypersensitivity. In a review on dermal exposure to 

isocyanates, it is concluded that multiple lines of evidence from animal, human, and 

biomarker studies indicate that in certain exposure settings, human skin is likely an 

important route of isocyanate exposure and can contribute to the development of 

isocyanate asthma (Bello et al 2007).. TDI has been classified for dermal and inhalation 

sensitization (“may cause sensitization by inhalation or skin contact”) by the European 

Union (European Commission 1997, 2004; ESIS 2006). Exact exposure conditions and 

concentrations leading to sensitization have not been determined. However, in 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 18 

experimental animals, single challenge exposures at levels as low as 0.03 mg/m3 induced 

respiratory hypersensitivity in previously sensitized guinea pigs (Karol et al. 1981), and 

in humans, challenge at 1 ppb (0.007 mg/m3

) induced an asthmatic response in previously 

sensitized humans (Lemière et al. 2002; Ott et al. 2003). This was observed in humans 

who had previously been exposed occupationally to TDI, whereas in humans with nonoccupational asthma, sensitization to TDI in controlled experiments occurred as low as 

10 ppb (0.07 mg/m3) (Ott et al. 2003). Thus, based on both human and experimental 

animal data, values in the range of 0.007 to 0.07 mg/m3 are considered to be the critical 

effect levels for acute exposure in this assessment. 

Note that occupational asthma has been reported from excessive exposure to 

diisocyanates in polyurethane production facilities (Cragg 2001). Also, there is evidence 

to show that asthmatic symptoms may continue in one-half of patients with TDI-asthma 

who avoided occupational exposure for more than 2 yr and had received anti-asthma 

medications (Krone and Klingner 2005). 

The lowest-observed-effect concentration (LOEC) for repeated inhalation exposure to 

TDI was 1.9 ppb (0.014 mg/m3

 Human Equivalent Concentration derived by the US EPA 

(1995)) based on significantly decreased lung function in humans in a 5-year prospective 

occupational study (Diem et al. 1982). This was the critical study used for determination 

of the chronic inhalation reference concentration (RfC) by the US EPA (1995). The value 

of 0.014 mg/m3

 is considered to be a critical effect level for chronic exposure in this 

assessment. Several other long-term epidemiological studies were reviewed by the US 

EPA. However, the study by Diem et al (1982) was selected as the only study from which 

a no-observed-effect concentration (NOEC) (0.006 mg/m3) and a LOEC could be 

determined. The EPA noted difficulties and uncertainties associated with quantitation of 

TDI exposure in epidemiological studies. Effects on the respiratory system were also 

observed in experimental animals exposed via inhalation to TDI levels 5- to 26-fold 

higher than 0.014 mg/m3 (LOAEC = 0.36 mg/m3 in chronic rat study; LOEC = 

0.07 mg/m3

 in 5-day guinea pig study). 

The lowest-observed-effect level (LOEL) for oral exposure to TDI was 30 mg/kg-bw/day 

based on bronchopneumonia, decreased body weight gain and mortality in rats exposed 

by gavage for 2 years (NTP 1986). Microscopic changes in the lungs and trachea were 

also observed at this exposure level in a 28-day rat study (Japanese MHLW 2005). 

The confidence in the toxicity database is moderate as data for acute toxicity, repeated 

dose toxicity, carcinogenicity, genetic toxicity and reproductive and developmental 

toxicity are available, although limited in nature. 

Although a thorough analysis of the mode of action of TDI is beyond the scope of this 

screening level assessment, it is recognized that the route of exposure to TDI may 

influence tumourigenesis. By oral exposure, TDI undergoes hydrolysis in the stomach to 

form toluene diamine (TDA). By inhalation exposure, TDI is absorbed in the upper 

respiratory tract and results in the formation of acid-labile conjugates with little diamine 

formed. The differential formation of TDA via the two routes of exposure may contribute 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 19 

to the mechanism by which TDI was carcinogenic in mice and rats by oral but not 

inhalation exposure (Doe and Hoffman 1995; IARC 1999; Collins 2002). However, the 

potential occurrence of neoplasms from inhalation exposure cannot be discounted, as it is 

uncertain whether maximum tolerable doses were attained in the chronic inhalation 

studies. 

Characterization of Risk to Human Health 

Based principally on weight of evidence based assessments by several international and 

national agencies (IARC, EU and US NTP), as well as an independent review by a 

multinational group of experts (Bolognesi et al, 2001), the available human 

epidemiological data and the experimental inhalation animal data are equivocal and thus 

inadequate to determine the carcinogenic risk of inhalation exposure to TDI in humans. 

Applying a precautionary approach, TDI is considered to be carcinogenic, since oral 

dosing in animals was associated with appearance of tumours at multiple sites. Mixed 

results have been obtained for TDI in in vivo and in vitro genotoxicity assays. Therefore, 

although the mode of induction of tumours has not been fully elucidated, it cannot be 

precluded that the tumours observed in experimental animals resulted from direct 

interaction with genetic material. Note that a similar approach was taken by the 

California EPA in its assessment in that they extrapolated the oral rat carcinogenicity 

study data to calculate a TDI inhalation cancer unit risk factor (California EPA 1999).

For non-cancer effects, TDI has been classified as a dermal and respiratory sensitizer by 

the European Union. With respect to non-cancer effects, comparison of the critical effect 

level for chronic non-neoplastic effects via inhalation in humans (i.e. 14 μg/m3

) and the 

conservative upper-bounding exposure estimate via inhalation for TDI (1.06 μg/m3

), in 

the vicinity of a plant using TDI, results in a margin of exposure of approximately 13. 

In this assessment, values in the range of 0.007 to 0.07 mg/m3 are considered to be the 

critical effect levels for acute exposure. Also, the lowest LOEC determined for shortterm to subchronic non-neoplastic effects is 0.07-0.14 mg/m3 based effects on the 

respiratory system in a 5-day guinea pig, a 6-month rat, and a 10-month dog study, 

respectively. This range of 0.07-0.14 mg/m3 will be used for the general human 

population. Note that these levels are 2.5-150 fold below the concentrations used in the 

long term inhalation studies in rats and mice (0.36 and 1.07 mg/m3

). 

Comparison of the critical effect levels for acute non-neoplastic effects via inhalation in 

sensitized humans (i.e. 7-70 μg/m3

 ) and the conservative upper-bounding exposure 

estimate via inhalation for TDI from consumer products (i.e. 24 μg/m3 ) results in 

margins of exposure of <1 to 2.9. 

Comparison of the critical effect levels for short term to subchronic non-neoplastic 

effects via inhalation in the general population (i.e. 70-140 μg/m3

 ) and the conservative 

upper-bounding exposure estimate via inhalation for TDI from consumer products (i.e. 24 

μg/m3 ) results in margins of exposure of 2.9-5.8. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 20 

Thus, the margins of exposure for non-neoplastic effects and exposure via inhalation to 

the general population and for consumer product exposure scenarios (although 

conservative in nature), are not adequate to account for uncertainties in the databases on 

exposure and effects 

Uncertainties in Evaluation of Risk to Human Health 

The estimate of human exposure to isomers of toluene diisocyanate is highly uncertain. 

No data on the concentration of TDI in environmental media representative of daily 

exposure were located for Canada or elsewhere. Modelling of environmental partitioning 

of TDI in Canada was not estimated because of the high degree of reactivity of the 

substance in water, sediments and moist soils; results of fugacity modelling would not be 

meaningful. Modelling of the concentration of TDI 100 metres from a plant producing 

polyurethane foam was used to give an upper-bounding estimate of the concentration of 

TDI in both ambient and indoor air for an exposed sub-population. The concentration of 

TDI in indoor air may be less than in ambient air in these circumstances. These 

simplifications may overestimate daily exposure. 

Estimates of exposure arising from the use of consumer products are uncertain. The 

concentration of TDI in a range of consumer products is not known with certainty, but 

availability to Canadian consumers of a surface coating containing up to 3% TDI was 

established. 

The scope of this screening assessment does not take into consideration a full analysis of 

the mechanism of action of TDI. There is uncertainty surrounding the mechanism of 

tumourigenesis of TDI following exposure. With regards to effects reported for 

previously sensitized humans, they may occur at a lower level of exposure than the 

effects reported for non-sensitized humans. However, effects do occur in short-term 

studies of non-sensitized experimental animals at exposures only one order of magnitude 

higher than those reported for sensitized humans. 

Conclusion 

Based on the available information, it is concluded that TDI is not entering the 

environment in a quantity or concentration or under conditions that have or may have an 

immediate or long-term harmful effect on the environment or its biological diversity, or 

that constitute or may constitute a danger to the environment on which life depends. 

On the basis of the carcinogenicity of TDI, for which there may be a probability of harm 

at any level of exposure, as well as the potential inadequacy of the margins between 

estimated exposure to the general population or exposure from products and critical effect 

levels for non-cancer effects, it is concluded that TDI be considered as a substance that 

may be entering the environment in a quantity or concentration or under conditions that 

constitute or may constitute a danger in Canada to human life or health. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 21 

. 

It is therefore proposed that TDI does not meet the criteria in Paragraphs 64(a) and 64(b) 

of CEPA 1999, but it does meet the criteria in Paragraph 64(c) of CEPA 1999. 

Additionally, TDI does not meet criteria for persistence and bioaccumulation potential as 

set out in the Persistence and Bioaccumulation Regulations. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 22 

References 

ACC (American Chemistry Council), Diisocyanates Panel. 2005. An Assessment of 

Persistence, Bioaccumulation and Inherent Ecotoxicity of Aromatic Diisocyanate 

Substances on the Canadian Domestic Substances List (DSL). In cooperation with: 

Gilbert International, Ltd. Arlington, VA. Jan. 10 2005. 

Allport DC, Gilbert DS, Outterside SM, editors. 2003. MDI and TDI: Safety, health and 

the environment: a source book and practical guide. Chichester (GB). 

Andersen M, Binderup M-L, Kiel P, Larsen H, Maxild J. 1980. Mutagenic action of 

isocyanates used in the production of polyurethanes. Scand J Work Environ Health 

6:221-226 

.Anderson D, Styles JA. 1978. The bacterial mutation test. Six tests for carcinogenicity. 

Br J Cancer 37(6):924-930. 

[AOPWIN] Atmospheric Oxidation Program for Windows [Estimation Model]. 2000. 

Version 1.91. Washington (DC): U.S. Environmental Protection Agency, Office of 

Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. 

Available from: www.epa.gov/oppt/exposure/pubs/episuite.html 

Arnot JA, Gobas FAPC. 2003. A generic QSAR for assessing the bioaccumulation 

potential of organic chemicals in aquatic food webs. QSAR Comb Sci 22(3):337-345. 

[ASTER] Assessment Tools for the Evaluation of Risk. 1999. Duluth (MN): US 

Environmental Protection Agency, Mid-Continent Ecology Division. Available from: 

http://www.epa.gov/med/Prods_Pubs/aster.htm. Restricted access. 

Atkinson, R. 1989. Kinetics and mechanisms of the gas-phase reactions of the hydroxyl 

radical with organic compounds. J Phys Chem Ref Data Monograph No 1. 

Ban M, Morel G, Longonne I, Huguet N, Pepin E, Binet S. 2006. TDI can induce 

respiratory allergy with Th2-dominated response in mice. Toxicology 218: 39-47. 

[BCFWIN] BioConcentration Factor Program for Windows [Estimation Model]. 2000. 

Version 4.02. Washington (DC): U.S. Environmental Protection Agency, Office of 

Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. 

Available from: www.epa.gov/oppt/exposure/pubs/episuite.htm. 

Benoit, F. 2004. Degradation of polyurethane foams used in the Même breast implant. J 

Biomedical Materials Res 27:1341-1348. 

Bello D, Herrick CA, Smith TH, Woskie SR, Streichner RP, Cullen MR, Liu YL, Redlich 

CA. 2006. Skin exposure to isocyanates: Reasons for concern. Environmental Health 

Perspectives 115: 328-335. 

Beyer A, Mackay D, Matthies M, Wania, F, Webster, E. 2000. Assessing long-range 

transport potential of persistent organic pollutants. Environ Sci Technol 34(4): 699-703. 

Bilban M. 2004. Mutagenic testing of workers exposed to toluene-diisocyanates during 

plastics production process. Am J Ind Med 45(5):468-474. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 23 

[BIOWIN] Biodegradation Probability Program for Windows [Estimation Model]. 2000. 

Version 4.02. Washington (DC): U.S. Environmental Protection Agency, Office of 

Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. 

Available from: www.epa.gov/oppt/exposure/pubs/episuite.htm 

Bolognesi C, Baur X, Marczynski B, Norppa H, Sepai O, Sabbioni G. 2001. 

Carcinogenic risk of toluene diisocyanate and 4,4'-methylenediphenyl diisocyanate: 

epidemiological and experimental evidence. Crit Rev Toxicol 31: 737-772. 

Canada, Dept. of the Environment, Dept. of Health. 2007a. Canadian Environmental 

Protection Act, 1999: Notice with respect to certain substances on the Domestic 

Substances List (DSL). Canada Gazette. Part I. Vol. 141, p. 162-177. Ottawa: Queen’s 

Printer. Available from : http://canadagazette.gc.ca/partI/2007/20070203/pdf/g1-

14105.pdf. 

Canada, Dept. of the Environment, Dept. of Health. 2007b. Substance profiles for The 

Challenge: toluene diisocyanates; CAS RN 91-08-7, 2,6-diisocyanato-1-methyl-benzene 

(2,6 toluene diisocyanate); CAS RN 584-84-9, 2,4-diisocyanato-1-methyl-benzene (2,4-

toluene diisocyanate); CAS RN 26471-62-5, 1,3-diisocyanatomethyl-benzene (mixed 

isomers of toluene diisocyanate). Available from: 

http://www.ec.gc.ca/substances/ese/eng/challenge/batch1_TDI.cfm. 

Canada, Dept. of the Environment, Dept. of Health. 2006. Canadian Environmental 

Protection Act, 1999: Notice of intent to develop and implement measures to assess and 

manage the risks posed by certain substances to the health of Canadians and their 

environment. Canada Gazette, Part I, vol. 140, no. 49, p. 4109 – 4117. Ottawa: Queen’s 

Printer. Available from: http://canadagazette.gc.ca/partI/2006/20061209/pdf/g1-

14049.pdf. 

Canada. 2000. Canadian Environmental Protection Act: Persistence and 

Bioaccumulation Regulations, P.C. 2000-348, 23 March, 2000, SOR/2000-107, Canada 

Gazette. Part II, vol. 134, no. 7, p. 607−612. Ottawa: Queen’s Printer. Available from: 

http://canadagazette.gc.ca/partII/2000/20000329/pdf/g2-13407.pdf. 

Canada. 1999. Canadian Environmental Protection Act, 1999 = Loi canadienne sur la 

protection de l’environnement, 1999. Statutes of Canada = Statuts du Canada, Chapter 

33, part III. Canada Gazette. Part III. Vol. 22, no. 3. Ottawa: Queen’s Printer. Available 

from : http://canadagazette.gc.ca/partIII/1999/g3-02203.pdf. 

[CalEPA] California Environmental Protection Agency. 1999. Air Toxics Hot Spots 

Program Risk Assessment Guidelines: Part II. Technical Support Document for 

Describing Available Cancer Potency Factors. Berkley (CA): Office of Environmental 

Health Hazard Assessment. 

[CFIA] Canadian Food Inspection Agency. 2007. Reference listing of accepted 

construction materials, packaging materials and non-food chemical products. Accessed 

July 2007. Available from: 

http://active.inspection.gc.ca/scripts/fssa/reference/compresults.asp?lang=e&cmp=A307. 

Chapman JF. 1994. European Emissions Project, Phase 1(A) – Gas Emissions Study – A 

rationale. Manchester (GB): Gilbert International Isocyanates. Report No.: 11157 (cited 

in Tury et al. 2003). 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 24 

Clark RL, Bugler J, Paddle GM, Chamberlain JD, Allport DC. 2003. A 17-year 

epidemiological study on changes in lung function in toluene diisocyanate foam workers. 

Int Arch Occup Environ Health 76: 295-301. 

Collins MA. 2002. Toxicology of toluene diisocyanate. Appl Occup Envir Hyg 17: 846-

855. 

Cragg, ST. 2001. Polyurethanes, miscellaneous organic polymers, and silicones. In Allan, 

RE et al, editors & contributors. Patty’s industrial hygiene and toxicology [book on the 

internet]. John Wiley and Sons. 

Curtis, M.W., Copeland, T.L. and C.H. Ward. 1978. Aquatic toxicity of substances 

proposed for spill prevention regulation. In: Proc. Natl. Conf. Control of Hazardous 

Material Spills, Miami Beach, FL: 99-103. 

Damant AP, Jickells SM, Castle L. 1995. Liquid chromatographic determination of 

residual isocyanate monomers in plastics intended for food contact use. J of AOAC Int 

78(3): 711-719. 

Danish Environmental Protection Agency. 1998. Immobilization test of aniline 

compounds with the crustacean Daphnia magna. Project no. 303587, Danish EPA, 

Copenhagen, Denmark. [Cited in ACC 2005]. 

Descotes, J. 1988. Identification of contact allergens: the mouse ear sensitization assay. J 

Toxicol-Cut Ocular Toxicol 7:263-272. 

Diem JE, Jones RN, Hendrick DJ, Glindmeyer HW, Dharmarajan V, Butcher BT, 

Salvaggio JE, Weill H. 1982. Five-year longitudinal study of workers employed in a new 

toluene diisocyanate manufacturing plant. Am Rev Respir Dis 126(3):420-428. 

Doe JE, Hoffman HD. 1995. Toluene diisocyanate: An assessment of carcinogenic risk 

following oral and inhalation exposure. Toxicol Ind Health 11:13-32. 

Duff PB. 1983. The fate of TDI in the environment. Proceedings of the Society of the 

Plastic Industry's 6th International Technical Conference, San Diego, California. New 

York (NY): Society of Plastics Industry. pp. 408-412. 

Ebino K, Ueda H, Kawakatsu H, Shutoh Y, Kosaka T, Nagayoshi E, Lemus R, Karol 

MH. 2001. Isolated airway exposure to toluene diisocyanate results in skin sensitization. 

Toxicol Lett 121: 79-85. 

[ECB] European Chemicals Bureau. 2004. Risk assessment report for Toluene-2,4-

diamine (CAS #95-80-7). Ispra (IT): European Chemicals Bureau. Available from: 

http://ecb.jrc.it/existing-chemicals/. 

Ellendt K, Gutsche B, Steiner G. 2003. Analysis of Laminates – Determination of 

Isocyanate Residues and Primary Aromatic Amine Migration. Deutsches LebensmittelRundschau 99(4):131-136. 

Environ Corporation International. 2003. VCCEP Report - Tier 1 Assessment of the 

potential health risks to children associated with exposure to the commercial 

pentabromodiphenyl ether product: prepared for Great Lakes Chemical, USA. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 25 

[ESIS] European Chemical Substances Information System [database on the Internet]. 

2006. CAS No. 91-08-7; 2-methyl-m-phenylene diisocyanate. CAS No. 584-84-9; 4-

methyl-m-phenylene diisocyanate. CAS No. 26471-62-5; M-tolylidene diisocyanate. 

Version 4.50. European Chemical Bureau (ECB). Available from: http://ecb.jrc.it/esis. 

Estlander T, Keskinen H, Jolanki R, Kanerva L. 1992. Occupational dermatitis from 

exposure to polyurethane chemicals. Am J Contact Dermat 27:161-165. 

European Commission. 1997. Summary Record - Toluene di-isocyanates. Commission 

Working Group on the Classification and Labelling of Dangerous Substances. Meeting at 

ECB Ispra, 15-21 October 1997. Report No.:ECBI/51/97 - Rev. 3. 

European Commission. 2004. 2-methyl-m-phenylene diisocyanate. 4-methyl-m-phenylene 

diisocyanate. M-tolylidene diisocyanate. Commission Directive 2004/73/EC of April 29, 

2004. Annex 1A. Official Journal of the European Union. 16.6.2004. L 216/49. European 

Commission. 29th ATP. 

Foureman P, Mason JM, Valencia R, Zimmering S. 1994. Chemical mutagenesis testing 

in Drosophila. X. Results of 70 coded chemicals tested for the National Toxicology 

Program. Environ Mol Mutagen 23(3):208-227. 

Gad,SC, Dunn BJ, Dobbs DW, Reilly C, Walsh RD. 1986. Development and validation 

of an alternative dermal sensitization test: the mouse ear swelling test (MEST). Toxic 

appl Pharmac 84:93-114. 

Gagnaire F, Ban M, Cour C, Micillino JC, Bonnet P, Hettich D. 1997. Role of 

tachykinins and neutral endopeptidase in toluene diisocyanate-induced bronchial 

hyperresponsiveness in guinea pigs. Toxicology 116(1-3):17-26. 

Gagné S, Lesage J, Ostiguy C, Van T H. 2003. Determination of unreacted 2,4-toluene 

diisocyanate (2,4TDI) and 2,6-toluene diisocyanate (2,6TDI) in foams at ultratrace level 

by using HPLC-CIS-MS-MS. Analyst 128:1447-51. 

Goossens A, Detienne T, Bruze M. 2002. Occupational allergic contact dermatitis caused 

by isocyanates. Am J Contact Dermat 47:304-308. 

Gulati DK, Witt K, Anderson B, Zeiger E, Shelby MD. 1989. Chromosome aberration 

and sister chromatid exchange tests in Chinese hamster ovary cells in vitro. III. Results 

with 27 chemicals. Environ Mol Mutagen 13(2):133-193. 

Hagmar L, Welinder H, Mikoczy Z. 1993a. Cancer incidence and mortality in the 

Swedish polyurethane foam manufacturing industry. Br J Ind Med 50(6):537-543. 

Hagmar L, Stromberg U, Welinder H, Mikoczy Z. 1993b. Incidence of cancer and 

exposure to toluene diisocyanate and methylene diphenyldiisocyanate: a cohort based 

case-referent study in the polyurethane foam manufacturing industry. Br J Ind Med 

50(11):1003-1007. 

Harton EE Jr, Rawl RR. 1976. Toxicological and skin corrosion testing of selected 

hazardous materials. Springfield (VA): US Department of Commerce. 

Health Canada. 1998. Exposure factors for assessing total daily intake of priority 

substances by the general population of Canada. Unpublished report. Ottawa (ON): 

Health Canada, Environmental Health Directorate. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 26 

Heimbach F, Jaeger K, Sporenberg W. 1996. Fate and Biological Effects of Polymeric 

MDI (4,4-diphenylmethane diisocyanate and homologues) in small artificial ponds. 

Ecotox Environ Safety 33:143-153. 

Henschler D, Assmann W, Meyer K-O. 1962. Toxicology of toluene diisocyanate. Arch 

Toxikol 19:364-387. 

Holdren MW, Spicer CW, Riggin RM. 1984. Gas Phase Reaction of Toluene 

Diisocyanate with Water Vapour. Am Ind Hyg Assoc J 45(9):626-633 

Holness DL, Nethercott JR. 1997. Results of patch testing with a specialized collection of 

plastic and glue allergens. Am J Contact Derm 8:121-124. 

Huang J, Wang XP, Ueda A, Aoyama K, Chen BM, Matsushita T. 1991. Allergologic 

evaluation for workers exposed to toluene diisocyanate. Ind Hlth 29:85-92. 

Hugo JM, Spence MW, Lickly TD. 2000. The Determination of the Ability of 

Polyurethane Foam to Release Toluene Diisocyanate into Air. Appl. Occ Env Hygiene 

15(6): 512-519. 

[HYDROWIN] Hydrolysis Rates Program for Microsoft Windows [Estimation Model]. 

2000. Version 1.67. Washington (DC): U.S. Environmental Protection Agency, Office of 

Pollution Prevention and Toxics; Syracuse (NY): Syracuse Research Corporation. 

Available from: www.epa.gov/oppt/exposure/pubs/episuite.htm 

IAL Consultants. 2007. End-use market survey on the polyurethane industry in the US, 

Canada and Mexico. Center for the Polyurethanes Industry. 

[IARC] Working Group on the Evaluation of Carcinogenic Risks to Humans. 1986. Some 

Chemicals Used in Plastics and Elastomers. IARC Monogr Eval Carcinog Risks Hum. 

39: 287-332. 

[IARC] Working Group on the Evaluation of Carcinogenic Risks to Humans. 1999. Reevaluation of some organic chemicals, hydrazine and hydrogen peroxide. IARC Monogr 

Eval Carcinog Risks Hum. 71 Pt 2: 865-879. 

[IPCS] International Programme on Chemical Safety. 1987. Toluene Diisocyanates. 

Geneva (CH): World Health Organization. (Environmental Health Criteria 75). Jointly 

sponsered by the United Nations Environment Programme, the International Labour 

Organization, and the World Health Organization. 

[IPCS] International Programme on Chemical Safety. 1997. Poison Information 

Monograph: Toluene-2,4-diisocyanate. Available from: 

http://www.inchem.org/documents/pims/chemical/pim534.htm. 

[IUCLID] International Uniform Chemical Information Database. 2000. CAS RN. 

26471-62-5. m-tolyidene diisocyanate. European Commission. European Chemicals 

Bureau.. Creation date: 2000 February 18. 

Jarand CW, Akapo SO, Swenson LJ, Kelman BJ. 2002. Diisocyanate emission from a 

paint product: a preliminary analysis. Appl Occup Environ Hyg 17(7):491-494. 

Jeong YC, Kim DH, Kim BR, Park M. 1998. In vitro and in vivo reactions of 2,4-toluene 

diisocyanate with DNA and blood proteins. J Toxicol Sci 23 Suppl 4:660-661. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 27 

Kanerva L, Jolanki R, Alanko K, Estlander T. 1999. Patch-test reactions to plastic and 

glue allergens. Acta derm.-vener Stockh 79:296-300. 

Kanerva L, Estlander T, Jolanki R, Keskinen H. 2001. Asthma from diisocyanates is not 

mediated through a Type IV, patch-test-positive mechanism. Am J Contact Dermat 

44:247-248. 

Karlsson D, Spanne N, Dalene M, Skarping G. 2000. Airborne thermal degradation 

products of polyurethane coatings in car repair shops. J Environ Monit 2:462-469. 

Karol MH, Hauth BA, Riley EJ, Magreni CM. 1981. Dermal contact with toluene 

diisocyanate (TDI) produces respiratory tract hypersensitivity in guinea-pigs. Toxicol 

appl Pharmacol 58: 221-230 [cited in IPCS 1987]. 

Katsuyama Y, Shinohara N, Kumagai K, Fujii M, Yanagisawa Y. 2003. Emission of 

diisocyanates in indoor air. Proceedings of ISIAQ 7th International Conference, 

December 2003. 

Kelly TJ, Myers JD, Holdren MW. 1999. Testing of household products and materials for 

emission of toluene diisocyanate. Indoor Air 9:117–124. 

Kerr MA, Nascav PC, Mundt KA, Michalek AM, Baptiste, Mahoney MC. 2000. Parental 

occupational exposures and risk of neuroblastoma: a case-control study (United States). 

Cancer Causes Control 11:635-643. 

Krone CA, Ely JTA, Klingner T, Rando RJ. 2003. Isocyanates in flexible polyurethane 

foams. Bull Environ Contam Toxicol 70(2):328-335. 

Krone CA, Klingner T. 2005. Isocyanates, polyurethane and childhood asthma (review 

article). Pediatr Allergy Immunol 16: 368-379. 

Le Coz, C-J, El Aboubi S, Ball C. 1999. Active sensitization to toluene di-isocyanate. 

Contact Dermatitis 41:104-105. 

Lemière C, Romeo P, Chaboillez S, Tremblay C, Malo JL 2002. Airway inflammation 

and functional changes after exposure to different concentrations of isocyanates. J 

Allergy Clin Immunol. 110(4):641-646. 

Levine SP, Redinger CF, Robert WP. 2001. Community exposure assessment and 

intervention effectiveness at Trinity American Corporation, Glenola, North Carolina. 

Amer Ind Hyg Assoc J 62: 649-657. 

Loeser E. 1983. Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluenediisocyanate (80/20) in rats and mice. Toxicol Lett 15(1):71-81. 

Maestrelli P, Del Prete GF, De Carli M, D'Elios MM, Saetta M, Di Stefano A, Mapp CE, 

Romagnani S, Fabbri LM. 1994. CD8 T-cell clones producing interleukin-5 and 

interferon-gamma in bronchial mucosa of patients with asthma induced by toluene 

diisocyanate. Scand J Work Envir Hlth. 20:376-381. 

Maki-Paakkanen J, Norppa H. 1987. Chromosome aberrations and sister-chromatid 

exchanges induced by technical grade toluene diisocyanate and methylenediphenyl 

diisocyanate in cultured human lymphocytes. Toxicol Lett 36(1):37-43. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 28 

Marand Å, Karlsson D, Dalene M, Skarping G. 2004. Extractable organic compounds in 

polyurethane foam with special reference to aromatic amines and derivatives thereof. 

Anal Chim Acta 510(1):109-119. 

Marczynski B, Czuppon AB, Marek W, Baur X. 1992. Indication of DNA strand breaks 

in human white blood cells after in vitro exposure to toluene diisocyanate (TDI). Toxicol 

Ind Health 8(3):157-69. 

Marczynski B, Merget R, Teschner B, Korn M, Rabstein S Bruning T. 2003. Changes in 

low molecular weight DNA fragmentation in white blood cells after diisocyanate 

exposure of workers. Archs Toxicol 77: 470-476. 

Marczynski B, Merget R, Mensing T, Rabstein S, Kappler M, Bracht A, Haufs MG, 

Kafferlein HU, Bruning T. 2005. DNA strand breaks in the lymphocytes of workers 

exposed to diisocyanates: indications of individual differences in susceptibility after lowdose and short-term exposure. Archs Toxicol 79:355-362. 

Marek W, Potthast J, Marczynski B, Mensing T, Baur X. 1999. Subchronic exposure to 

diisocyanates increases guinea pig tracheal smooth muscle responses to acetylcholine. 

Respiration 66(2):156-161. 

McGregor DB, Brown AG, Howgate S, McBride D, Riach C, Caspary WJ. 1991. 

Responses of the L5178Y mouse Lymphoma cell forward mutation assay. V: 27 coded 

chemicals. Environ Mol Mutagen 17(3):196-219. 

Meredith SK, Bugler J, Clark RL. 2000. Isocyanate exposure and occupational asthma: a 

case-referent study. Occup envir Med 57:830-836. 

Mikoczy Z, Welinder H, Tinnerberg H, Hagmar L. 2004. Cancer incidence and mortality 

of isocyanate exposed workers from the Swedish polyurethane foam industry: updated 

findings 1959-98. Occup envir Med 61:432-437. 

Militello G, Sasseville D, Ditre C, Brod BA. 2004. Allergic contact dermatitis from 

isocyanates among sculptors. Dermatitis 15:150-153. 

[MHLW] Ministry of Health Labour and Welfare (JP). 2005. Safety examination of 

existing chemicals and safety programmes in Japan (in Japanese with English summary). 

[MITI] Ministry of International Trade & Industry (Jpn). 1992. Biodegradation and 

bioaccumulation: data of existing chemicals based on the CSCL Japan. Edited by 

Chemicals Inspection & Testing Institute (JP): The Ministry, Chemical Products Safety 

Division Basic Industries Bureau.. 

Moscato G, A. Dellabianca A, Corsico G, Biscaldi G, Gherson, Vinci G. 1993. Bronchial 

responsiveness to ultrasonic fog in occupational asthma due to toluene diisocyanate. 

Chest 104:1127-1132. 

[NPRI] National Pollutant Release Inventory [database on the Internet]. 2008. Gatineau 

(QC): Environment Canada. [cited 2007]. Available from: 

http://www.ec.gc.ca/pdb/querysite/query_e.cfm. 

[NTP] National Toxicology Program. 1983. NTP technical report on the toxicology and 

carcinogenesis studies of commercial grade 2,4 (80%)- and 2,6 (20%)-toluene 

diisocyanate (CAS No. 26471) in F344/N rats and B6C3F1 mice (gavage studies). 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 29 

Technical Report No. 251 (draft). 

[NTP] National Toxicology Program. 1986. NTP technical report on the toxicology and 

carcinogenesis studies of commercial grade 2,4 (80%)- and 2,6 (20%)-toluene 

diisocyanate (CAS No. 26471) in F344/N rats and B6C3F1 mice (gavage studies). 

Technical Report No. 251. 

[NTP] National Toxicology Program. 2005. 11th report on carcinogens. Substance 

profile: toluene diisocyanate. 

[OASIS Forecast] Optimized Approach based on Structural Indices Set [Internet] 2005. 

Version 1.20. Bourgas, Bulgaria: Laboratory of Mathematical Chemistry. Available 

from: http://oasis-lmc.org/?section=software. 

Ott MG, Diller WF, Jolly AT. 2003, Respiratory effects of toluene diisocyanate in the 

workplace: A discussion of exposure-response relationships. Critical Reviews in 

Toxicology 33:1–59. 

Owen PE. 1984. The toxicity and carcinogenicity of toluene isocyanate vapour 

administered by inhalation for a period of 113 weeks. Addendum Report: Volume 2. 

Hazelton Laboratories Europe [cited in US EPA 1995]. 

Paggiaro, PL, Vagaggini B, Dente FL, Bacci E, Bancalari L, Carrara M, Di Franco A, 

Giannini D, Giuntini C. 1993. Bronchial hyperresponsiveness and toluene diisocyanate. 

Long-term change in sensitized asthmatic subjects. Chest 103:123-1128. 

Park H.-S, Kim HY, Nahm DH, Son JW, Kim YY. 1999. Specific IgG, but not specific 

IgE, antibodies to toluene diisocyanate-human serum albumin conjugate are associated 

with toluene diisocyanate bronchoprovocation test results. J Allergy clin Immun 104:847-

851. 

Patterson R, Zeiss CR, Harris KE. 1983. Immunologic and respiratory responses to 

airway challenges of dogs with toluene diisocyanate. J Allergy Clin Immunol 71(6):604-

611. 

Peel M, Marczynski B, Baur X. 1997. Comparison of the binding potential of various 

diisocyanates on DNA in vitro. J Toxicol Environ Health 52(6):517-526. 

Pemberton D, Tury, B. 2004. TDI industry risk assessment: sections on physico-chemical 

properties, environmental exposures, and environmental effects. Report 2004/E. 

Manchester (UK): Gilbert International Ltd. 

Pisati F, Baruffini A, Zedda S. 1993. Toluene diisocyanate induced asthma: outcome 

according to persistence or cessation of exposure. Br J ind Med 50:60–64. 

Schnorr TM, Steenland K, Egeland GM, Boeniger M, Egilman D. 1996. Mortality of 

workers exposed to toluene diisocyanate in the polyurethane foam industry. Occup 

Environ Med 53(10):703-707. 

Seel K, Walber U, Herbold B, Kopp R. 1999. Chemical behaviour of seven aromatic 

diisocyanates (toluenediisocyanates and diphenylmethanediisocyanates) under in vitro 

conditions in relationship to their results in the Salmonella/microsome test. Mutat Res 

438(2):109-123. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 30 

Shaddock JG, Robinson BY, Casciano DA. 1990. Effect of pretreatment with hepatic 

mixed-function oxidase inducers on the genotoxicity of four rat carcinogens in the 

hepatocyte/DNA repair assay. Mutagenesis 5(4):387-391. 

Shiotsuka RN, Warren DL, Halliburton AT, Sturdivant DW. 2000. A comparative 

respiratory sensitization study of 2,4- and 2,6-toluene diisocyanate using guinea pigs. 

Inhal Toxicol 12: 605-615. 

Sorahan T, Pope D. 1993. Mortality and cancer morbidity of production workers in the 

United Kingdom flexible polyurethane foam industry. Br J Ind Med 50(6):528-536. 

Tadokora H, et al. 1997. Ecotoxicities of TDI and TDA to fish, algae and aquatic 

invertebrates. IN: Chemicals Inspection and Research Institute, Japan. III Report No. 

11217 

[TaPL3] Long Range Transport and Persistence Level III model [Internet]. 2000. Version 

2.10. Peterborough (ON): Trent University, Canadian Environmental Modelling Centre. 

Available from: http://www.trentu.ca/academic/aminss/envmodel/models/TaPL3.html 

Thorne, PS, Hillebrand JA, Lewis GR, Karol MH. 1987. Contact sensitivity by 

diisocyanates: potencies and cross-reactivities. Toxic Appl Pharmac 87:155-165. 

[TOPKAT] Toxicity Prediction Program [Internet]. 2004. Version 6.2. San Diego (CA): 

Accelrys Software Inc. Available from: 

http://www.accelrys.com/products/topkat/index.html 

Tury B, Pemberton D, Bailey RE. 2003. Fate and potential environmental effects of 

methylenediphenyl diisocyanate and toluene diisocyanate released into the atmosphere. J 

Air Waste Manage Assoc 53:61-66. 

Tyl RW. 1988. Developmental toxicity study of inhaled toluene diisocyanate vapor in CD 

(Sprague-Dawley) rats. Union Carbide, Bushy Run Research Center. Revised Project No. 

50-592. 

Tyl RW, Fisher LC, Dodd DE, Pritts IM, Kubena MF, Losco PE , Troup CM, Lyon JP, 

Landry TD. 1999a. Developmental toxicity evaluation of inhaled toluene diisocyanate 

vapor in CD rats. Toxicol Sci 52(2):248-257. 

Tyl RW, Neeper-Bradley TL. 1989. Two-generation reproductive study of inhaled 

toluene diisocyanate in CD (Sprague-Dawley) rats. Union Carbide, Bushy Run Research 

Center. Project No. 86-33-90704. 

Tyl RW, Neeper-Bradley TL, Fisher LC, Dodd DE, Pritts IM, Losco PE, Lyon JP, 

Landry TD. 1999b. Two-generation reproductive toxicity study of inhaled toluene 

diisocyanate vapor in CD rats. Toxicol Sci 52(2):258-268. 

Ulrich H. 1996. Chemistry and Technology of Isocyanates. Chichester (GB): John Wiley 

& Sons, Ltd. 

[US EPA] US Environmental Protection Agency. 1995. 2,4-/2,6-Toluene Diisocyanate 

mixture (TDI). Washington (DC): US Environmental Protection Agency, Integrated Risk 

Information System (IRIS). 

[US EPA] US Environmental Protection Agency. 2002. Child-specific exposure factors 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 31 

handbook. Interim report. Washington (DC): US Environmental Protection Agency, 

National Center for Environmental Assessment, Office of Research and Development. 

Vandenplas O, Cartier A, Ghezzo H, Cloutier Y, Malo JL. 1993. Response to 

isocyanates: Effect of concentration, duration of exposure, and dose. Am Rev resp Dis 

147:1287-1290. 

Van der Hoeven N, Roza P, Henzen L. 1992a. Determination of the effect of TDI, TDA, 

MDI, and MDA on the emergence and growth of the plant species Avena sativa and 

Lactuca sativa according to OECD Guideline no. 208. TNO. III Report no. 11024. [Cited 

in Pemberton and Tury 2004]. 

Van der Hoeven N, Roza P, Henzen L. 1992b. Determination of the LC50 (14 days) of 

TDI, TDA, MDI, and MDA to the earthworm Eisenia fetida according to OECD 

guideline no. 207. TNO. III Report no. 11025. [Cited in Pemberton and Tury 2004]. 

Vanoirbeek, JA, Tarkowski JM, Ceuppens JL, Verbeken EK, Nemery B, Hoet PH. 2004. 

Respiratory response to toluene diisocyanate depends on prior frequency and 

concentration of dermal sensitization in mice. Toxic Sci 80:310-321. 

Yakabe Y, Henderson KM, Thompson WC, Pemberton D, Tury B, Bailey RE. 1999. Fate 

of methylenediphenyl diisocyanate and toluene diisocyanate in the aquatic environment. 

Environ Sci Technol 33(15):2579-2583. 

Zapp JA Jr. 1957. Hazards of isocyanates in polyurethane foam plastic production. Arch 

Ind Hlth 15(4):324-330. 

Zissu D, Binet S, Limasset JC. 1998. Cutaneous sensitization to some polyisocyanate 

prepolymers in guinea pigs. Contact Dermatitis 39:248-251. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 32 

Appendix 1. Upper-bounding estimates of daily intake of 2,4- toluene diisocyanate 

and 2,6- toluene diisocyanate by the general population in Canada 

Estimated intake (μg/kg-bw per day) of TDI by various age groups 

0–6 months1

Route of 

exposure 

formula 

fed2

not formula 

fed 

0.5–4 

years3

5–11 

years4

12–19 

years5

20–59 

years6

60+ 

years7

Air8 0.30 0.64 0.50 0.28 0.24 0.21 

Drinking 

water9

_ _ _ _ _ _ 

Food and 

beverages10

_ _ _ _ _ _ _ 

Soil11 _ _ _ _ _ _ 

Total intake 0.30 0.30 0.64 0.50 0.28 0.24 0.21 

 

1 Assumed to weigh 7.5 kg, to breathe 2.1 m3 of air per day, to drink 0.8 L of water per day (formula 

fed) or 0.3 L/day (not formula fed) and to ingest 30 mg of soil per day (Health Canada 1998). 

2 For formula-fed infants, intake from water is synonymous with intake from food. No data on 

concentrations of TDI in formula were identified for Canada. 

3 Assumed to weigh 15.5 kg, to breathe 9.3 m3

 of air per day, to drink 0.7 L of water per day and to 

ingest 100 mg of soil per day (Health Canada 1998). 

4 Assumed to weigh 31.0 kg, to breathe 14.5 m3

 of air per day, to drink 1.1 L of water per day and to 

ingest 65 mg of soil per day (Health Canada 1998). 

5 Assumed to weigh 59.4 kg, to breathe 15.8 m3 of air per day, to drink 1.2 L of water per day and to 

ingest 30 mg of soil per day (Health Canada 1998). 

6 Assumed to weigh 70.9 kg, to breathe 16.2 m3

 of air per day, to drink 1.5 L of water per day and to 

ingest 30 mg of soil per day (Health Canada 1998). 

7 Assumed to weigh 72.0 kg, to breathe 14.3 m3

 of air per day, to drink 1.6 L of water per day and to 

ingest 30 mg of soil per day (Health Canada 1998). 

8 An annual average concentration 100 metres from a polyurethane foam plant was calculated to be 

1.06 μg/m3 (see Exposure Assessment, this report). Ambient air was assumed to be representative of 

exposure to indoor air, although use of certain consumer products may give rise to the release of 

toluene diisocyanate in indoor air. 

9 No reports of measurement of toluene diisocyanate in drinking water were located. The half-life of 

toluene diisocyanate in water with a moderate degree of mixing is estimated to be 1–3 hours (Yakabe 

et al. 1999). It is therefore assumed that toluene diisocyanate is not present in drinking water. 

10 No reports of measurement of toluene diisocyanate in food or beverages were located. Reports of the 

migration of toluene diisocyanate from food packaging were located, but they are not indicative of the 

concentration of TDI in food and beverages. 

11 No reports of measurement of toluene diisocyanate in soil were located. The half-life of toluene 

diisocyanate in moist soil has been experimentally determined to be less than one hour (Duff, 1983). 

TDI is not considered to be persistent and except at the site of an industrial spill, is not expected to be 

present on soil. 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 33 

Appendix 2. Exposure estimates from the use of consumer products 

Consumer 

product 

scenario

Assumptions Estimated 

daily intake 

 (μg/kg-bw 

per day)

Concrete 

sealer 

Version 1

From Jarand et al. (2002), a commercially available two-part concrete deck sealer tested 

in an environmental chamber released 0.38 μg of 2,6-TDI per gram of sealer applied per 

hour over a five-hour period. 

Coverage of sealer is 100 sq. ft./US gal 

Room area 20 m2

, approx. 215 sq. ft. 

Room volume = 50 m3 

Estimate 2 gallons weigh about 9.5 kg and the time to apply 1coat is 1 hour. 

Total emission for one coat of sealer on concrete floor over a one hour period is 

0.38 E-6 g TDI/g sealer hr -1x 9500 g sealer/coat x 1 coat x 1 hour = 3.6 E-3 g TDI. 

Assuming 50% of TDI released to air is adsorbed to walls (Holdren et al. 1984) and the 

room ventilation is 0.5 hr-1, the concentration of TDI in air would be 

3.6E-3 g TDI x 10 E+6 μg x 0.5 = 24 μg/m3

. 

 50 m3 g x 1.5 

Assuming one hour of light work by an adult weighing 70.9 kg, breathing 1.3 m3

/hour, 

the estimated dose is 

24 μg/m3

 x 1.3 m3/hour x 1 hour = 0.44 μg/kg-bw per day. 

 70.9 kg-bw 

Using an averaging period of 365 days, the dose is 1.2 ng/kg-bw per day. 

 

 0.44

Mouthing 

foam 

cushion 

Assume three different pieces of foam are mouthed during one day and each piece 

weighs 5 grams. 

The concentration of TDI in aged foam was determined by Gagné et al. (2003) to be 

 7.8 ng/g foam. Assume that 1% of the total can be extracted by saliva (extraction factor 

=0.01). 

The average time spent daily by 6–18 month old infants mouthing “other” objects is 9 

minutes. (Environ Corporation International 2003) The mean body weight of 1 year old 

infants is 11.4 kg (US EPA 2002). 

The estimated daily intake is: 

3 events/day x 5 g foam/event x 7.8 ng TDI/ g foam x 0.01 extraction factor

 11.4 kg-bw 

= 0.1 ng TDI /kg-bw per day. 

1 E-4 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 34 

Appendix 3. Summary of health effects information for toluene diisocyanates* 

* Data is for the mixture of isomers unless otherwise stated. 

Endpoint Lowest effect levels1/Results

Laboratory animals and in vitro

Acute toxicity Lowest oral LD50 (rat): 3060 mg/kg (Harton and Rawl 1976, cited in IPCS 1987) 

Additional studies: Woolrich 1982, cited in IPCS 1987 

Lowest inhalation LC50 (rat) = 57 mg/m3

 (Harton and Rawl 1976, cited in IPCS 1987) 

Additional studies: Duncan et al 1962, Bunge et al 1977, both cited in IPCS 1987. 

Lowest dermal LD50 (rabbit) = 10 000 mg/kg (Harton and Rawl 1976, cited in IPCS 

1987) 

Short-term repeateddose toxicity Lowest oral LOEL (rat, 28 days): 30 mg/kg-bw/day based on microscopic changes in the 

lungs and trachea (Japanese MHLW 2005 –study summary only). 

Additional studies: Zapp 1957, cited in IPCS 1987; NTP 1986. 

Lowest inhalation LOEC (guinea pig, 5 days): 0.07 mg/m3

 based on increased 

responsiveness of tracheal smooth muscle (Marek et al. 1999) 

Numerous additional studies 

Subchronic toxicity Lowest oral LOEL (rat, mouse, 13 weeks): 120 mg/kg-bw/day based on 

bronchopneumonia and decreased body weight in rat; liver inflammation and necrosis in 

mouse (NTP 1986) 

Lowest inhalation LOEC (rat, 27 weeks; dog, 10 months): 0.14 mg/m3 based on 

histological changes in nasal cavity and upper respiratory tract of F1 generation rats (Tyl 

and Neeper-Bradley 1989, cited in US EPA 1995; published as Tyl et al. 1999b); elevated 

antibody titres, decreased pulmonary function and immediate skin reaction in dogs 

(Patterson et al 1983, cited in IPCS 1987) 

Additional studies: Gagnaire et al. 1997; Henschler et al. 1962, cited in IPCS 1987; 

Friebel 1955, cited in IPCS 1987; Zapp 1957, cited in IPCS 1987 

Chronic toxicity/ 

carcinogenicity 

Oral cancer bioassay in rats: 

Fischer rats were dosed by gavage 5 days/week for 106 weeks. Females were dosed at 0, 

60, or 120 mg/kg-bw/day, males at 0, 30, or 60 mg/kg-bw/day. In males, there was a 

significant increase in combined subcutaneous fibromas and fibrosarcomas (3/50, 6/50, 

12/50 in the control, low and high dose respectively), and an increase in pancreatic acinar 

cell adenomas (1/47, 3/47, 7/49 in the control, low and high dose respectively – significant 

in high group only). In females there was an increase in mammary gland fibroadenomas 

(15/50, 21/50, 18/50 in the control, low and high dose respectively – not significant using 

Fisher exact test but significant by incidental or life-table analysis), and in pancreatic islet 

cell adenomas at terminal sacrifice (0/36, 3/19, 2/6 in the control, low and high dose 

respectively – significant using test for incidental tumours comparing each dose group to 

controls). There was also one islet cell carcinoma in a low-dose female and an increase in 

liver neoplastic nodules in females (no incidences stated in IARC) (NTP 1983, cited in 

IARC 1986). 

Oral cancer bioassay in mice: 

B6C3F1 mice were dosed by gavage 5 days/week for 105 weeks. Females were dosed at 

0, 60, or 120 mg/kg-bw/day, males at 0, 120, or 240 mg/kg-bw/day. No treatment-related 

tumours were observed in males. In females, there was a significant increase in combined 

hemangiomas (spleen, subcutaneous) and hemangiosarcomas (liver, ovaries, peritoneum) 

(0/50, 1/50, 5/50 in the control, low and high dose respectively); and in hepatocellular 

adenomas: (2/50, 3/50, 12/50 in the control, low and high dose respectively) (NTP 1983, 

cited in IARC 1986). 

Inhalation cancer bioassay in mice and rats: 

Male and female mice were exposed for 6 hours/day, 5 days/week for 104 weeks, at 0, 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 35 

Endpoint Lowest effect levels1/Results

0.36 or 1.07 mg/m3. There was no significant difference in tumour incidences and types 

between dosed and control groups. (Loeser 1983, cited in IARC 1986). There was a doserelated increase in the incidence and severity of either chronic or necrotic rhinitis but 

details were insufficient to establish effect levels. Although Loesser (1983) reported a 

significant increase in mortality of female mice at both doses, the US EPA (1995) 

concluded that there were no exposure-related effects observed on mortality, organ 

weights, haematological parameters, blood chemistry or urinalysis parameters. 

Rats were exposed for 6 hours/day, 5 days/week for 104 weeks, at 0, 0.36 or 1.07 mg/m3

for 108 weeks (males) or 110 weeks (females). There was no significant difference in 

tumour incidences and types between dosed and control groups (Loeser 1983, cited in 

IARC 1986). There were dose-related increases in the incidence and severity of chronic 

and necrotic rhinitis in female rats. 

Lowest non-neoplastic oral (gavage) LOEL (rat, 105–106 weeks): 30 mg/kg-bw/day 

(lowest dose tested) based on acute bronchopneumonia, decreased body weight gain and 

mortality (NTP 1986, cited in IPCS 1987). 

Additional studies: NTP 1986, cited in IPCS 1987 (mouse). 

Lowest non-neoplastic inhalation LOAEC: 0.36 mg/m3 based on significantly increased 

chronic and necrotic rhinitis in female rats. 

Developmental 

toxicity 

Lowest inhalation LOEC: 0.5 ppm (3.57 mg/m3) based on a single skeletal variation, 

which was noted to be a common variation and possibly not significant relative to 

historical controls. In this study, pregnant rats were exposed to TDI vapour for 6 h/day 

during gestation days 6–15. (Tyl 1988, cited in US EPA 1995; published as Tyl et al. 

1999a) 

Reproductive 

toxicity 

Lowest inhalation NOEC: No effect of exposure on any reproductive organs or 

parameters at the highest dose level of 0.3 ppm (2.14 mg/m3

). In this study, male and 

female rats were exposed to TDI vapour for 6 h/day, 5 days/wk, then 7 days/wk during a 

3-wk mating period, gestation and lactation in both generations of a 2-generation 

reproduction study (Tyl and Neeper-Bradley 1989, cited in US EPA 1995; published as 

Tyl et al. 1999b). 

Genotoxicity and 

related endpoints: in 

vivo

Sex-linked recessive lethal assay:

Positive: Drosophila melanogaster. Oral – 15 000 ppm in feed (mixed isomers) 

(Foureman et al. 1994, cited in IARC 1999) 

Micronucleus assay

Negative: Mouse, rat (bone marrow). Inhalation – 1.1 mg/m3

 for 6 hours/day, 5 

days/week for 4 weeks (mixed isomers) (Loeser 1983, cited in IARC 1986, 1999). 

Genotoxicity and 

related endpoints: in 

vitro

Mutagenicity in Salmonella typhimurium: 

Positive: TA100, TA1538, TA98 with activation (mixed isomers) (Andersen et al. 1980, 

cited in IARC 1986, 1999). TA100, TA1537, TA98 with activation (2,4- and 2,6-TDI and 

mixed isomers) (Seel et al. 1999). 

Negative: TA100, TA1535, TA1538, TA98 with activation (mixed isomers) (Anderson 

and Styles 1978, cited in IARC 1986, 1999). TA1537 with activation; TA100, TA1537, 

TA1538, TA98 without activation (mixed isomers) (Andersen et al. 1980, cited in IARC 

1986, 1999). TA1535 with activation; TA100, TA1535, TA1537, TA98 without activation 

(2,4- and 2.6-TDI and mixed isomers) (Seel et al. 1999). 

Mutagenicity in rodent cell lines: 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 36 

Endpoint Lowest effect levels1/Results

Positive: mouse lymphoma cells (L5178Y); mutations at tk locus with activation (2,4- and 

2,6-TDI) (McGregor et al. 1991, cited in IARC 1999). 

Chromosomal aberrations: 

Positive: Chinese hamster ovary cells without activation (2,6-TDI) (Gulati et al. 1989, 

cited in IARC 1999). Human lymphocytes with and without activation (mixed isomers) 

(Maki-Paakkanen and Norppa 1987, cited in IARC 1999). 

Negative: Chinese hamster ovary cells without activation (2,4-TDI); Chinese hamster 

ovary cells with activation (2,4 and 2,6-TDI) (Gulati et al. 1989, cited in IARC 1999). 

Unscheduled DNA synthesis: 

Negative: rat primary hepatocytes without activation (mixed isomers) (Shaddock et al. 

1990, cited in IARC 1999) 

Sister chromatid exchange: 

Positive: Chinese hamster ovary cells without activation (2,4- and 2,6-TDI) (Gulati et al.

1989, cited in IARC 1999) 

Negative: Chinese hamster ovary cells with activation (2,4- and 2,6-TDI) (Gulati et al. 

1989, cited in IARC 1999). Human lymphocytes with and without activation (mixed 

isomers) (Maki-Paakkanen and Norppa 1987, cited in IARC 1999) 

DNA strand breaks: 

Positive: Human lymphocytes without activation (mixed isomers) (Marczynski et al. 

1992, cited in IARC 1999) 

DNA binding 

Positive: calf thymus DNA – crosslinking (2,4- and 2,6-TDI) (Jeong et al. 1998); calf 

thymus DNA – conformational changes, strand breaks (mixed isomers) (Peel et al. 1997)

Sensitization Numerous qualitative studies (e.g., patch tests in humans, Buehler tests in guinea pigs, 

ear-swelling tests in mice) indicate that TDI is a dermal sensitizer. In addition, dermal 

exposure to TDI can induce respiratory sensitivity (Ban et al 2006; Descotes 1988; 

Estlander et al. 1992; Gad et al. 1986; Goossens et al. 2002; Holness and Nethercott 1997; 

Huang et al. 1991; Kanerva et al. 1999, 2001; Le Coz et al. 1999; Maestrelli et al. 1994; 

Mandervelt et al. 1997; Meredith et al. 2000; Militello et al. 2004; Moscato et al. 1993; 

Paggiaro et al. 1993; Park et al. 1999; Pisati et al. 1993; Shiotsuka et al. 2000; Thorne et 

al. 1987; Vandenplas et al. 1993; Vanoirbeek et al. 2004; Zissu et al. 1998). One study 

suggests that inhalation exposure may also result in skin sensitization (Ebino et al 2001). 

A single exposure may also cause an immediate or delayed asthmatic reaction in 

previously exposed individuals. Single challenge exposures at levels as low as 0.03 mg/m3

induced respiratory hypersensitivity in previously sensitized guinea pigs (Karol et al. 

1981).

Epidemiological studies 

Chronic toxicity/ 

carcinogenicity 

In humans, no strong association or consistent pattern (cancer) from 3 industrial cohort 

studies and a population-based case-control study (Sorahan and Pope 1993, Hagmar et al. 

1993(a and b), Schnorr et al. 1996; all cited in IARC 1999). 

LOEC – non-neoplastic inhalation (human, 5 years): 1.9 ppb (0.014 mg/m3

) based on 

decreased lung function in a prospective occupational study (Diem et al. 1982, cited in US 

EPA 1995). The decreased lung function was expressed as significant annual declines in 

forced expiratory volume over one second (FEV1) and forced expiratory flow at 25–75% 

(FEF 25-75). 
Screening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) 

July 2008 

 37 

Endpoint Lowest effect levels1/Results

Additional studies: numerous epidemiological studies (Hagmar et al. 1993a, 1993b; Kerr 

et al. 2000; Clark et al 2003; Mikoczy et al. 2004; Schnorr et al. 1996; Sorahan and 

Nichols 2002; Sorahan and Pope 1993) . 

Occupational epidemiology studies 

Positive: Structural chromosome aberrations, sister chromatid exchange and micronuclei 

in peripheral blood lymphocytes of 26 workers in a plastics factory exposed to air 

concentrations of 0.007 to 0.016 mg/m3 over an average exposure period of 11.7 years [21 

controls]. Possible confounding effects of smoking were not taken into account (Bilban 

2004). Studies with smaller sample sizes indicated negative results for DNA strand breaks 

in human lymphocytes of workers challenged with 2 or 5 hr of exposure to TDI 

(Marczynski et al. 2003, 2005). 

Sensitization studies 

Ott et al (2003) reviewed respiratory sensitization in non-occupationally exposed humans 

and concluded that individuals “...with increasingly severe BHR [bronchial 

hyperresponsiveness] or nonoccupational asthma may experience symptoms at TDI 

concentrations in the range of 10- to 20 ppb.” (subjects exposed to consecutive 1 h 

exposures at 10 and 20 ppb TDI) and “Some individuals with TDI-induced (occupational) 

asthma respond to TDI concentrations as low as 1 ppb.” (subjects exposed to 30 min 

exposures). Challenge at 1 ppb (0.007 mg/m3

) induced an asthmatic response in 

previously sensitized humans (Lemière et al. 2002; 4 subjects exposed up to 2 hr 

exposures; they had not been exposed to isocyanates for an average of 4.8 ± 5.0 yrs). 

1. LD50 = lethal dose; LOEL = lowest-observed-effect level.