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-met hyl- (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 H ealth have conducted a screening assessment of mixed isomers of toluene diisocyanate (T DI), Chemical Abstracts Service Registry Number (CAS RN) 26471-62-5; Benzene, 2,4-diisocyanato-1-m ethyl- (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 Substan ces List as high priori ties for action under the Ministerial Challenge. They were cons idered 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 individu als in Canada (IPE) in the case of CAS RN 91-08-7 and CAS RN 584-84-9, a nd 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, bio accumulation 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 ar e 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 ch emical 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 ha lf-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 fo r carcinogenicity in assessments by several international and national agencies, the avai lable human epidemiological data and the experimental animal data are equivocal and thus inadequate to determine the carcinogenic risk to TDI in humans, via the i nhalation 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 inductio n of tumours has not beenScreening 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 th at the tumours observed in experimental
animals resulted from direct inte raction with genetic material.

The upper-bounding estimate of exposure via in halation to the general population or during use of consumer products containing TD I may approach or exceed the critical
effect levels for non-cancer effects in th e 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 TD I 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 leve ls for non-cancer eff ects, it is concluded that they are substance that may be en tering 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 repor ted 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 fo r 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 a ddition and where rele vant, research and monitoring will support verificati on of assumptions used during the screening assessment and, where appropriate, the performance of po tential control measures identified during the risk management phase.

Based on the information available, TDI mi xed isomers, 2,4-TDI and 2,6-TDI meet one
or more of the criteria se t 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 scr eening assessment, the Ministers can propose
to take no further action with re spect 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 Sc hedule 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 th e categorization pro cess, the Ministers
identified a number of substa nces as high priorities for act ion. These include substances
that:

• met all of the ecological categorizati on 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 grea test potential for exposure (GPE) or presented an intermediate potential for exposure (IPE), and had been identified as posing a high hazard to human health base d on classifications by other national or international agencies for carcinogenicity, genotoxicity, developm ental toxicity or reproductive toxicity.

The Ministers therefore publishe d a notice of intent in the Canada Gazette , Part I, on December 9, 2006 (Canada 2006), that cha llenged industry and other interested stakeholders to submit, within specified time lines, 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 thos e substances identified as the highest priorities.

Isomers of toluene diisocyanate were identi fied as high prioriti es for assessment of human health risk because they were consid ered 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 toxici ty 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 de fining 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-ter m 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 evid ence approach and precaution.

This screening assessment includes considera tion 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, stak eholder research reports and from recent literature searches, up to Sept ember 2007. Key studies were critically evaluated; modelling results may have been us ed to reach conclusions. Evaluation of risk
to human health involves consideration of da ta relevant to estima tion of exposure (nonoccupational) of the general population, as we ll as information on health hazards (based principally on the weight of evidence assessm ents 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 scre ening context. The screening assessment does not represent an exhaustive or critical review of all available data. Rather, it presents a summary of the critical informati on 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 ar e 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 a nd incorporates input from other programs within these departments. This assessm ent has undergone external written peer
review/consultation. Comments on the technical portions relevant to human health were
received from Meridian Envi ronmental Inc. and Starodub & A ssociates. 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 th is screening assessment was subject to a 60-day public comment period. The critical information a nd 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 C 9 H 6 N 2 O 2 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- TD I 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/cm 3 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 r eacts with water, and solubility in water cannot be
determined. IUCLID 2000

Log K
ow TDI reacts with water and with octanol, therefore no
estimation of K
ow is made. IUCLID 2000

Log K
oc TDI reacts with water and with octanol, therefore no
estimation of K
oc is made.

Exp = experimental dataScreening 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 ch emical 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 indus trial 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 Secti on 71 of CEPA 1999, the quantity of TDI imported into Canada in 2006 was determined to be gr eater than10 million kil ograms (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 th e 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 exam ple of this would be the manufacture of flexible polyurethane foam. Emissions from industrial activities are principally to air. Another potential source of TD I emissions to the environment is the incineration of polyurethane waste. Because TDI is a reactiv e chemical, long range transport of TDI is not expected to contribute significant ly 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 sp ecialty polyurethane-based paints, varnishes and coatings, polyurethane adhesives, seal ants and mastic (IARC 1986; NTP 2005). It has been reported that mixtures of isocya nates, including TDI may be released when isocyanate-based paint, which is used extens ively for the factory-applied primer coat on automobiles is heated during grinding or sa nding of the surface (Karlsson et al. 2000).
Potential sources of TDI in food arise fr om the use of polyurethanes in inks and adhesives applied to food packaging, and pol yurethane elastomers in food handling equipment such as conveyor belts. If ther e 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, Ma y 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 isocya nate are intended for use only by trained contractors. The degree to which untrained in dividuals 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- toluen e diisocyanate isomers domina te industrial use of TDI. Pure 2,4- isomer is used in some specialty el astomers applications. Pure 2,6- isomer is
not a commercial industrial ch emical (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 reacte d with a polyol in the presence of a surfactant, catalyst, blowing agent and other process chemi cals to form PUF. Flexible PUF is used extensively in household furnitu re 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 Isocyana tes Panel, American Chemistry Council – ACC, Ottawa, 2007/08/08). Semi-flexible a nd 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 coatin gs 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 coatin gs 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(u rethane urea) cast el astomers based on TDI may be used in wheels, rollers, conveyors and similar products. TDI is used in the production of coatings for textiles for durabi lity 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 bi omedical applications of polyurethanes based on TDI have been reported elsewhere. In Canada, no products made with TDIbased polyurethane are licensed for use in biomedical applic ations. 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 Polyurethan e 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 Polyuret hane Industry in th e 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 (CanadaScreening 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 Cana da 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 de gradation as a result of photoge nerated 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 atmospheri c water was not significant. Tu ry et al. (2003) reported a half-life of 1.4 days for TDI based on experi mental 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 othe r 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 10 6 OH radicals/cm 3 (12-h day)

The Transport and Persistence Level III Mode l (TaPL3) (TaPL3 2000) is not considered appropriate in estimating characteristic travel distance (CTD) for TDI since the applicability domain of the model does not c over substances that re act in water or soil.
The CTD is defined as the maximum distance tr avelled in air by 63% of a substance; or
the distance that 37% of the substance ma y 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 th eir 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 da ys calculated according to Atkinson, 1989; and 1.7 days predicted by AOPWIN, 2000). Th e second consideration is that when a
substance like TDI transforms into other fo rms in water and soil, the chance for the substance to re-enter the atmosphere from wa ter and soil is reduced and this translates into a reduced potential for long-range transp ort. 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 po tential 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 minut e (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 TD I, 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-des cribed 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 (h alf-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 ha ve 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 indica tes 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 th an 2 days (see above) . TDI has a transient existence in water, moist soils and sediments due to rapid hydrolysis. Environmental fate modelling to estimate partiti oning 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 fo r TDI and its degradation products (LC 50 ’s and

EC 50 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, EC 50 and LC 50 >1000 mg/L; Van der Hoeven et al. 1992a,b) and birds (oral LC 50 ’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 re ported 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 e xposure of organisms in
the environment.

Based on the information available, TDI is un likely 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 envi ronmental media and dietary
sources in Canada were not lo cated. Reports of the concentra tion of TDI in air outside a manufacturing facility in North Carolina, US A that was subsequently closed (Levine et al. 2001) were not considered represen tative of exposures in Canada.

The partitioning of TDI into environmental media was not estimated by modelling, but an
estimate of the maximum concentration of TD I 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 bu ilding with no stack us ing a model within EUSES (European Union System for the Evalua tion of Substances) gave the prediction of an annual air concentration of 6.7 E-3 μg/m 3 for a plant with a c ontinuous 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/m 3 . 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 populati on in the vicinity of the plant. Industrial releases of TDI in Canada are mainly to air and it is expected th at most TDI released to air will remain inScreening 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-l ife of less than two days (Tur y et al. 2003; Atkinson 1989).

The upper-bounding estimate of exposure to TD I via environmental media ranged from 0.21 μg/kg-bw (kilogram of body weight) per da y 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- a nd 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 resu lt of hydrolysis of 2,4- and 2,6- toluene diisocyanate have also been extracted fr om 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 availa ble for dermal or oral uptake. The degree to which the use of solvents may be respons ible 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 cushi ons, sheet foam, varnishes and sealants and found no detectable emissions of isocyanate s at an emission rate higher than 0.96 μg/m 2 /hour for coatings applied to surfaces or for pol yurethane foam. Kelly et al. (1999) further estimated an equilibrium concentra tion in household air based on the detection limit of the experimental method in this study and concluded that th e highest steady-state residential air concentration would be not more than 0.19 μg/m 3 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 ur ethane adhesive, paint and varnish were tested, but TDI was found when rigid polyuret hane foam was placed in an atmosphere with acetone vapour. The investigators estimat ed a flux rate of TDI and, based on average Japanese home size and ventilation rate, calc ulated an equilibrium concentration of 2,4-
TDI of 4.28 x 10 -2 ppb (305 μg/m 3 ) in Japanese houses. Rigi d polyurethane foam slab is not a building material typical ly used in Canadian resi dential construction and the
concentration of acetone in air used in the experiment does not represent normalScreening Assessment for TDIs (CAS RN 26471-62-5, CAS RN 584-84-9, CAS RN 91-08-7) July 2008

15 residential conditions; therefor e, the exposure described by Ka tsuyama et al. (2003) is not considered pertinent.

It has been shown experimentally that isoc yanate-based paints for concrete floors and
deck sealer emit measurable concentrations of 2,6-TDI to air followi ng application of the coating (Kelly et al. 1999; Jarand et al. 2002). Although the c oncentrations 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 es timate the maximum concentration of 2,6-TDI in a room during and five hours after pain ting a concrete floor with a two part polyurethane sealer, an estimate of the concentration of TDI in air of 24 μg/m 3 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 applicati on solely by licensed c ontractors. Given uncertainties regarding availability of this TD I-based sealer to Canadi an retail consumers, only the scenario based on the findings by Jara nd et al. (2002) was retained. It was determined that the product that was tested by Jarand et al. (2002) is av ailable at the retail level in Canada in 2008. The dermal exposur e 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 dos e is for a one hour exposure. It should be
further noted that use of such a concrete seal er is a relatively infre quent 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 polyuret hane 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 expos ure 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 inges tion than the 0.1 ng/kg-bw per day estimated for this scenario. The estimat ed 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 co nsidered to be very low. No data on the
concentration of toluene diis ocyanate in any environmental medium used to estimate human exposure were located. Confidence in the estimate of exposure from the use ofScreening 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 availa ble health effects information for toluene diisocyanate. The majority of the available da ta for TDI is on the mixture of isomers.

The International Agency for Research on Cancer (IARC) classified toluene diisocyanate as “possibly carcinogenic to humans” (Carci nogenicity Group 2B), ba sed on inadequate evidence for the carcinogenicity of toluen e diisocyanates in humans and sufficient evidence for the carcinogenicity of toluene di isocyanates in experimental animals (IARC 1986; IARC 1999). TDI has also been classifi ed by the European Commission (EC) as Category 3 for carcinogenicity (“causes c oncerns for humans owing to possible carcinogenic effects”) (European Commi ssion 1997, 2004; ESIS v.4.50 2006); and by the United States National Toxicology Program (N TP) as “reasonably anticipated to be a human carcinogen” (NTP 2005). These classi fications were base d on significantly
increased tumour incidences at multiple sites in mice and ra ts exposed orally by gavage for 2 years. Female mice exposed ora lly to 60 or 120 mg/kg-bw/day TDI had significantly increased hepatocellular ade nomas and combined hemangiomas (spleen, subcutaneous) and hemangiosarcomas (liver, ovaries, peritoneum) (NTP 1983). Female rats exposed orally to 60 or 120 mg/kg-bw/d ay TDI had significantly increased mammary gland fibroadenomas and pancre atic 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 ad enomas (significant at the high dose) (NTP 1983). In each study, the increased tumours we re 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/m 3 TDI for 2 years (Loeser 1983). The International Programme on Chemical Safety (IPCS 1987) noted that th e animals in this study were probably not given the maximum tolerated dose and theref ore the highest dose may not have been sufficient to detect a response. However, this was based on body we ight 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 EP A 1995) concluded that there were no exposure-related effects obser ved on mortality, organ weight s 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/m 3 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, ther e was no strong association or consistent pattern regarding the carcinogenicity of inha lation exposure to TDI from three industrial cohort studies and a population-based case-c ontrol 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 carc inogenic risk of TDI for humans."

Although more recent epidemiological studies ar e available (Kerr et al. 2000; Mikoczy et al. 2004; Sorahan and Nichols 2002; Clark et al 2003), no internati onal assessments are yet available on these updated data and full we ight of evidence analyses of the overall epidemiological data are not practicable within the context of this screening assessment.

Based on the oral carcinogeni city study in male rats ou tlined 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 us ing cross-route extrap olation 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 ra t erythrocytes (inhala tion 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 sa mple size, subjects may have been occupationally exposed to numerous chemi cals in addition to TDI, and there was no consideration for smoking. Studies with smalle r sample sizes indica ted negative results for DNA strand breaks in human lymphocytes of workers (Marczyns ki 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 d iisocyanate 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 TD I was “probably genotoxic” due to TDI’s potential to react with DNA.

The primary target organs for non-neoplastic e ffects of exposure to TDI by the inhalation, dermal, and oral routes were the lung a nd respiratory tract. Inhalation and dermal exposure to TDI lead to respir atory 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 a nd can contribute to the development of isocyanate asthma (Bello et al 2007).. TDI ha s been classified for dermal and inhalation sensitization (“may cause sensitization by inha lation or skin contac t”) by the European Union (European Commission 1997, 2004; ESIS 2006). Exact exposure conditions and concentrations leading to sensitization have not been determined. However, inScreening 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/m 3 induced respiratory hypersensitivity in previously sensitized guinea pigs (Karol et al. 1981), and in humans, challenge at 1 ppb (0.007 mg/m 3 ) induced an asthmatic re sponse in previously sensitized humans (Lemière et al. 2002; Ott et al. 2003). This was observed in humanswho 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 (C ragg 2001). Also, there is evidence to show that asthmatic symptoms may contin ue 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 c oncentration (LOEC) for rep eated inhalation exposure to TDI was 1.9 ppb (0.014 mg/m 3 Human Equivalent Concentration derived by the US EPA (1995)) based on significantly decreased lung f unction in humans in a 5-year prospective occupational study (Diem et al. 1982). This wa s the critical study used for determination
of the chronic inhalation refe rence concentration (RfC) by th e US EPA (1995). The value of 0.014 mg/m 3 is considered to be a critical eff ect level for chronic exposure in this assessment. Several other long-term epidemio logical 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 concen tration (NOEC) (0.006 mg/m 3 ) and a LOEC could be
determined. The EPA noted difficulties and unc ertainties associated with quantitation of TDI exposure in epidemiological studies. E ffects on the respirator y system were also observed in experimental animals exposed vi a inhalation to TDI levels 5- to 26-fold higher than 0.014 mg/m 3 (LOAEC = 0.36 mg/m 3 in chronic rat study; LOEC = 0.07 mg/m 3 in 5-day guinea pig study).

The lowest-observed-effect level (LOEL) fo r 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). Microscopi c 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 m oderate as data for acute toxicity, repeated dose toxicity, carcinogenicity, genetic toxi city 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 ro ute 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 conjugate s with little diamine
formed. The differential formation of TDA via the two routes of exposure may contributeScreening 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 carcinoge nic 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 inhala tion exposure cannot be discounted, as it is
uncertain whether maximum tolerable doses were attained in the chronic inhalation
studies.

Characterization of Ri sk to Human Health

Based principally on weight of evidence base d assessments by severa l 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 i nhalation 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 c onsidered 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 ha s not been fully eluc idated, it cannot be precluded that the tumours observed in expe rimental 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 TD I 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/m 3 ) and the conservative upper-bounding exposure estima te via inhalation for TDI (1.06 μg/m 3 ), 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 effect s is 0.07-0.14 mg/m3 based effects on the respiratory system in a 5-day guinea pi g, a 6-month rat, and a 10-month dog study, respectively. This range of 0.07-0.14 mg/m 3 will be used for the general human population. Note that these le vels 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/m 3 ).

Comparison of the critical effect levels for acute non-neoplastic effect s via inhalation in sensitized humans (i.e. 7-70 μg/m 3 ) and the conservative upper-bounding exposure
estimate via inhalation for TDI from consumer products (i.e. 24 μg/m 3 ) 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/m 3 ) and the conservative upper-bounding exposure estimate via inhalation for TDI from consumer products (i.e. 24 μg/m 3 ) 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-neoplas tic effects and exposure via inhalation to the general population and for consum er 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 e nvironmental media representative of daily exposure were located for Canada or elsewh ere. Modelling of e nvironmental 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 th e concentration of TDI 100 me tres from a plant producing polyurethane foam was used to give an upper-bounding estimat e 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 consum er products is not know n 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 o ccur 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 expe rimental 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 biol ogical diversity, or that constitute or may constitute a danger to the environment on which life depends.

On the basis of the carcinogenicity of TDI, fo r which there may be a probability of harm at any level of exposure, as well as the pot ential inadequacy of the margins between estimated exposure to the genera l population or exposure from products and critical effect levels for non-cancer effects, it is concluded th at TDI be considered as a substance that may be entering the environment in a quantit y 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 criter ia 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

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32 Appendix 1. Upper-bounding estimates of da ily intake of 2,4- toluene diisocyanate and 2,6- toluene diisocyanate by the general population in Canada

Estimated intake ( μ g/kg-bw per day) of TDI by various age groups

0–6 months 1 Route of

exposure

formula
fed 2 not formula
fed 0.5–4

years 3 5–11

years 4 12–19

years 5 20–59

years 6 60+

years 7

Air 8 0.30 0.64 0.50 0.28 0.24 0.21
Drinking

water 9 _ _ _ _ _ _

Food and beverages 10 _

_ _ _ _ _ _

Soil 11

_ _ _ _ _ _ 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 m 3 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 m 3 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 m 3 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 m 3 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 m 3 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 m 3 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/m 3 (see Exposure Assessment, this report). Ambi ent 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 assu med 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 th e 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 ( μ g/kg-bw per day)

Concrete
sealer
Version 1 From Jarand et al. (2002), a commercially ava ilable two-part concrete deck sealer tested
in an environmental chamber re leased 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 m 2 , approx. 215 sq. ft.
Room volume = 50 m 3 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 -1 x 9500 g sealer/coat x 1 coat x 1 hour = 3.6 E-3 g TDI.

Assuming 50% of TDI released to air is adsorb ed 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/m 3

. 50 m 3 g x 1.5

Assuming one hour of light work by an adult weighing 70.9 kg, breathing 1.3 m 3 /hour,
the estimated dose is

24 μg/m 3 x 1.3 m 3 /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-4Screening 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 levels 1 /Results
Laboratory animals and in vitro
Acute toxicity Lowest oral LD 50 (rat): 3060 mg/kg (Harton and Rawl 1976, cited in IPCS 1987) Additional studies: Woolrich 1982, cited in IPCS 1987

Lowest inhalation LC 50 (rat) = 57 mg/m 3 (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 LD 50 (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/m 3 based on increased responsiveness of tracheal smoot h 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/m 3 based on histological changes in nasal cavity and upper respiratory tract of F1 generation rats (Tyl and Neeper-Bradley 1989, cited in US EPA 1 995; published as Tyl et al. 1999b); elevated antibody titres, decreased pulmonary functio n 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 sacr ifice (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 carcinom a in a low-dose female and an increase in liver neoplastic nodules in females (no incide nces 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 levels 1 /Results 0.36 or 1.07 mg/m 3 . There was no significant difference in tumour incidences and typesbetween 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-rela ted 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/m 3 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/m 3 based on significantly increased
chronic and necrotic rhinitis in female rats.

Developmental toxicity Lowest inhalation LOEC : 0.5 ppm (3.57 mg/m 3 ) 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/m 3 ). 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/m 3 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 isom ers) (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 is omers) (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 levels 1 /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-TD I) (Gulati et al. 1989, cited in IARC 1999).

Unscheduled DNA synthesis: Negative: rat primary hepatocytes without activati on (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 activa tion (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; Goosse ns 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 re sult in skin sensitization (Ebino et al 2001).

A single exposure may also cause an imme diate or delayed asthmatic reaction in previously exposed individuals. Single challenge exposures at levels as low as 0.03 mg/m 3 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/m 3 ) based on decreased lung function in a prospective occupational study (Diem et al. 1982, cited in US EPA 1995). The decreased lung function was expr essed 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 levels 1 /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 sens itization 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/m 3 ) 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. LD 50 = lethal dose; LOEL = lowest-observed-effect level.