## Report on Carcinogens, Twelfth Edition (201 1 )

National Toxicology Program, Department of Health and Human Services 

# Toluene Diisocyanates
CAS No. 26471-62-5 Reasonably anticipated to be a human carcinogen First listed in the Fourth Annual Report on Carcinogens (1985) Also known as TDI; 1,3-diisocyanatomethyl benzene; isocyanic acid, methyl- m -phenylene ester; or tolylene diisocyanate Isomers also known as toluene-2,4-diisocyanate and toluene-2,6- diisocyanate

CH 3

N CH 3
N N C O

C O C N
O C O

2,4-Toluene diisocyanate 2,6-T oluene diisoc yanate CAS No

. 584-84-9 CAS No

. 91-08-7 

## Carcinogenicity Toluene diisocyanates are reasonably anticipated to be human car

cinogens based on sufficient evidence of carcinogenicity from stud

ies in experimental animals. Cancer Studies in Experimental Animals Oral exposure to toluene diisocyanates caused tumors at several dif

ferent tissue sites in rats and mice. Administration of commercialgrade toluene diisocyanate (analyzed as 85% 2,4 isomer and 15% 2,6 isomer) by stomach tube caused liver tumors (hepatocellular ad

enoma) in female rats and mice, benign mammary-gland tumors (fibro adenoma) in female rats, and benign tumors of the pancreas (acinar-cell adenoma) in male rats. It also increased the combined incidences of benign and malignant tumors of subcutaneous tissue (fibroma and fibrosarcoma) in male rats and of the blood vessels (hemangioma and hemangiosarcoma) in female mice (NTP 1986).

Cancer Studies in Humans No epidemiological studies were identified that evaluated the rela

tionship between human cancer and exposure specifically to toluene diisocyanates. 

## Properties Toluene diisocyanates exist at room temperature as a clear, color

less to pale-yellow liquid with a pungent odor. They decompose in water, but are very soluble in acetone and benzene, and are mis

cible with ether, diglycol monomethyl ether, carbon tetrachloride, chloro benzene, kerosene, and olive oil. They are combustible when exposed to heat or flame and darken when exposed to sunlight (IARC 1999, HSDB 2009). 2,4-Toluene diisocyanate is available as a com

mercial product with purity of at least 99.5%, but most commonly as an 80:20 mixture of 2,4-toluene diisocyanate and 2,6-toluene diiso

cyanate (IARC 1986). Physical and chemical properties of toluene di

isocyanates are listed in the following table. Property Toluene diisocyanates mixed 2,4-Toluene diisocyanate 2,6-Toluene diisocyanate
Molecular weight a 174.2 174.2 174.2 Specific gravity at

25°C a (g/mL) 1.22 or 0.01 1.22 or 0.01 1.22 or 0.01 Melting point a 11°C to 14°C (FP) 19.5°C to 21.5°C 18.3°C Boiling point a 251°C 251°C 129°C to 133°C at 18 mm Hg Log K
ow b 3.74 3.74 3.74 Water solubility

at 25°C b 0.0376 g/L 0.0376 g/L decomposes
Vapor pressure a 2.30 × 10 –2
mm Hg at 25°C 8.0 × 10 –3
mm Hg at 20°C 2.1 × 10 –2
mm Hg at 25°C Vapor density

relative to air c 6 6 6

Sources: a HSDB 2009, b ChemIDplus 2009, c Akron 2009. FP = freezing point. 

## Use Toluene diisocyanates are used primarily to manufacture flexible polyurethane foams for use in furniture, bedding, and automotive and airline seats. Other, smaller uses are for polyurethane elasto

mers (for automobile bumper covers, industrial rollers, sport soles and boots, and mechanical goods) and coatings (for automotive refin

ishing, wood finishes, and high-performance anti-corrosion coatings) (ICIS 2009). Toluene diisocyanate–based rigid polyurethane foam is used in household refrigerators and for residential sheathing or com

mercial roofing in board or laminate form (IARC 1986). “Pour-inplace” or “spray-in” rigid foam is used as insulation for truck trailers, railroad freight cars, and cargo containers. Polyurethane-modified alkyds contain approximately 6% to 7% isocyanate, mostly toluene diisocyanates, and are used as coating materials, such as floor fin

ishes, wood finishes, and paints. Moisture-curing coatings are used as wood and concrete sealants and floor finishes. Aircraft, truck, and passenger-car coatings often are composed of toluene diisocyanate prepolymer systems. Castable urethane elastomers are used in appli

cations requiring strength, flexibility, and shock absorption, and are resistant to oil, solvents, and ultraviolet radiation. They are used in adhesive and sealant compounds and in automobile parts, shoe soles, rollerskate wheels, pond liners, and blood bags. They are also used in oil fields and mines. Certain elastomer products are produced from the pure 2,4 isomer rather than the 80:20 mixture. 

## Production Toluene diisocyanates have been produced commercially since the late 1930s (IARC 1986). In 1993, the production capacity for toluene diisocyanates in North America was estimated at more than 1 billion pounds (IARC 1999). In 2009, the United States had one producer of each isomer of toluene diisocyanate (2,4 and 2,6), three producers of the mixed isomer product (SRI 2009), one supplier of mixed tol

uene diisocyanates, three suppliers of 2,6

- toluene diisocyanate, and fourteen suppliers of 2,4

- toluene diisocyanate (ChemSources 2009). Reports filed under the U.S. Environmental Protection Agen

cy’s Toxic Substances Control Act Inventory Update Rule indicated that U.S. production plus imports of an 80:20 mixture of 2,4- and 2,6-toluene diisocyanate totaled 100 million to 500 million pounds in 1986, 500 million to 1 billion pounds from 1990 to 2002, and over 1 billion pounds in 2006 (EPA 2004, EPA 2009). The reported quan

tities of 2,4-toluene diisocyanate were 100 million to 500 million pounds in 1986 and 1990, falling to between 1 million and 10 mil

lion pounds from 1994 to 2002. Reported quantities of 2,6-toluene diisocyanate were 50 million to 100 million pounds in 1986 and 10 million to 50 million pounds in 1990; no inventory update reports for 2,6-toluene diisocyanate have been filed since 1990 (EPA 2004). 

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## Report on Carcinogens, Twelfth Edition (201 1 )

National Toxicology Program, Department of Health and Human Services U.S. imports of mixed isomers of toluene diisocyanate were 984,000 kg (2.1 million pounds) in 1989, reaching a low of 1,000 kg (2,200 lb) in 1996 and a peak of 15 million kilograms (32 million pounds) in 2006; 2008 imports were 500,000 kg (1.1 million pounds) (USITC 2009). U.S. imports of unmixed isomers were 426,000  kg (939,000 lb) in 1989, reaching a low of 9,000 kg (19,800 lb) in 1998 and a peak of 1.3 million kilograms (2.8 million pounds) in 2004; 2008 imports were 130,000 kg (286,000 lb) in 2008. U.S. exports of mixed isomers of toluene diisocyanate were 62 million kilograms (125 mil

lion pounds) in 1989, rising to a high of 277 million kilograms (609 million pounds) in 2003; they have since trended lower. U.S. exports of unmixed isomers of toluene diisocyanate peaked in 1994 at 46 mil

lion kilograms (101 million pounds), falling to a low of 3.9 million kilo grams (8.6 million pounds) in 2008. 

## Exposure The primary routes of potential human exposure to toluene diiso

cyanates are inhalation and dermal contact. Exposure to toluene di

isocyanates is primarily occupational; however, several commercially available household products may pose a risk of exposure to toluene diisocyanates to the general population if used indiscriminately. For example, consumers may be exposed to toluene diisocyanates vola

tilized from polyurethane varnishes during the application of such coatings (IPCS 1987). A model developed to predict the background concentration of toluene diisocyanate in Western Europe estimated that if annual toluene diisocyanate usage were 100,000 tons, the back

ground air concentration would be approximately 0.0001 μg/m 3 

### (Tury et al. 2003). According to EPA’s Toxics Release Inventory, environmental re

leases of mixed toluene diisocyanates were highest in 2001 and 2004, at over 125,000 lb; 45,642 lb was released in 2003. The same trend held for the individual isomers; however, releases were lowest in 1995 for 2,4-toluene diisocyanate and in 2002 for 2,6-toluene diisocyanate. In 2006, releases of toluene diisocyanates (mixed isomers), 2,4-toluene diisocyanate, and 2,6-toluene diisocyanate from 139 facilities totaled 73,778 lb (TRI 2009). Because of the high volatility of toluene diisocyanates, exposure can occur in all phases of its manufacture and use (IPCS 1987). Tol

uene diisocyanate occurs in the work environment, primarily in air, during its commercial production, handling, and processing and during the production of polyurethane foam and coated fabrics. However, manual handlers of uncured polyurethane foam were sig

nificantly more likely to have detectable urinary adducts of toluene diisocyanates than non-handlers working in areas with similar air concentrations of toluene diisocyanate (Austin 2007). The National Occupational Exposure Survey (conducted from 1981 to 1983) es

timated that nearly 40,000 workers potentially were exposed to tol

uene diisocyanates (NIOSH 1990). Workers potentially exposed to toluene diisocyanates include adhesive workers, insulation workers, diisocyanate-resin workers, lacquer workers, organic-chemical syn

thesizers, paint sprayers, polyurethane makers, rubber workers, ship builders, textile processors, and wire-coating workers (IPCS 1987). Worker exposure to toluene diisocyanates is most likely to occur dur

ing sample collection, residue removal, spill clean-up, and equipment maintenance; employees are required to use air-line respirators dur

ing these operations. The highest exposure levels have occurred dur

ing the spray application of polyurethane foam. The construction industry uses polyurethane formulations in thermal insulation, adhe

sives, lacquers, and paints. In most cases, the foam is applied through air-spraying in confined spaces; exposure to concentrations above safe limits are a particular concern for the sprayers and their help

ers. In the United States, a typical modern housing unit of 1,800 ft 2 

### floor space, including furniture, carpet underlay, and bedding, con

tains 306 lb of flexible polyurethane foam. The transportation industry uses approximately 21% of flexible polyurethane foam for automo

bile seating and padding, resulting in the use of 24 to 31 lb of poly

urethane per automobile (IARC 1986). Studies summarized by the International Agency for Research on Cancer (IARC 1986, 1999) reported workplace air concentra

tions of toluene diisocyanates ranging from less than 1 to more than 1,000 μg/m 3 

### ; the current Occupational Safety and Health Administra

tion ceiling concentration is 0.02 ppm (~140 μg/m 3 

### ). Workplace air concentrations measured in 2005 close to the mixer in a polyurethane factory were up to 12.1 μg/m 3 

### for 2,4-toluene diisocyanate, 8.1 μg/m 3 

### for 2,6-toluene diisocyanate, and 20.2 μg/m 3 

### for total toluene diiso

cyanates (Tinnerberg and Mattsson 2008). Analysis of the isomeric composition of atmospheric toluene diisocyanates in a plant pro

ducing polyurethane foam found a higher concentration of the 2,6 isomer than of the 2,4 isomer, particularly at the finishing end of the production process. Median air concentrations of 2,4-toluene diiso

cyanate were 5.0 μg/m 3 

### for initial mixing and 2.3 μg/m 3 

### for finish

ing. The respective median concentrations for the 2,6 isomer were 6.4 and 7.8 μg/m 3 

### , with a maximum exceeding 450 μg/m 3 

### at the fin

ishing end. These findings were attributed to enhanced emission of the less chemically active 2,6 isomer from the cured foam bats and retention of the 2,4 isomer as a polymer. Aniline and the 2,4 and 2,6 isomers of toluene diisocyanate were detected under controlled ex

perimental conditions in the thermodegradation fumes of polyure

thane varnish used in the insulation of copper wire. Consistent with these findings, the compounds were also detected in the workplace atmosphere during the industrial production of polyurethane-coated wire (IARC 1986, 1999). Since 2001, exposure has been confirmed by measuring toluene di

isocyanate adducts in the plasma and urine of exposed workers. Tolu

enediamine, a metabolite of toluene diisocyanate, has been measured in the plasma at levels up to 27.2 ng/mL for 2,4-toluenediamine and 62.1 ng/mL for 2,6-toluenediamine (Tinnerberg and Mattsson 2008). Swedish workers manufacturing polyurethane products excreted 53.2 to 259.6 nmol of toluenediamine per gram of creatinine (Bolognesi et al. 2001). Concentrations of toluene diisocyanate in urine of oc

cupationally exposed workers ranged from 0 to 76 μg/L for the 2,4 isomer and from 0 to 31 μg/L for the 2,6 isomer. 

## Regulations Coast Guard, Department of Homeland Security Minimum requirements have been established for the safe transport of toluene diisocyanate on ships and barges. Department of Transportation (DOT) Toluene diisocyanate is considered a hazardous material, and special requirements have been set for marking, labeling, and transporting this material. Environmental Protection Agency (EPA) Clean Air Act National Emissions Standards for Hazardous Air Pollutants: 2,4-Toluene diisocyanate is listed as a hazardous air pollutant. New Source Performance Standards: Manufacture of diisocyanates is subject to certain provisions for the control of volatile organic compound emissions. Prevention of Accidental Release: Threshold quantity (TQ) = 10,000 lb. Comprehensive Environmental Response, Compensation, and Liability Act Reportable quantity (RQ) = 100 lb. Emergency Planning and Community Right-To-Know Act Toxics Release Inventory: 2,4-Toluene diisocyanate is subject to reporting requirements. Resource Conservation and Recovery Act Listed Hazardous Waste: Waste codes for which the listing is based wholly or partly on the presence of toluene diisocyanates = U223, K027. Listed as a hazardous constituent of waste.

## Report on Carcinogens, Twelfth Edition (201 1 )

National Toxicology Program, Department of Health and Human Services Occupational Safety and Health Administration (OSHA) While this section accurately identifies OSHA’s legally enforceable PELs for this substance in 2010, specific PELs may not reflect the more current studies and may not adequately protect workers. Ceiling concentration = 0.02 ppm (0.14 mg/m 3 ) for toluene-2,4-diisocyanate. 

## Guidelines National Institute for Occupational Safety and Health (NIOSH) Immediately dangerous to life and health (IDLH) limit = 2.5 ppm for toluene-2,4

- diisocy anate. Toluene-2,4-diisocyanate is listed as a potential occupational carcinogen. 

## References
Akron. 2009. The Chemical Database . The Department of Chemistry at the University of Akron. http://ull. chemistry.uakron.edu/erd and search on CAS number. Last accessed: 9/30/09. Austin S. 2007. Biological monitoring of TDI-derived amines in polyurethane foam production. Occup Med (Lond) 57(6): 444-448. 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(6): 737-772. ChemIDplus. 2009. ChemIDplus Advanced . National Library of Medicine. http://chem.sis.nlm.nih.gov/ chemidplus/chemidheavy.jsp and select Registry Number and search on CAS number. Last accessed: 7/15/09. ChemSources. 2009. Chem Sources - Chemical Search. Chemical Sources International. http://www. chemsources.com/chemonline.html and search on toluene diisocyanate. Last accessed: 7/15/09. EPA. 2004. Non-confidential IUR Production Volume Information. U.S. Environmental Protection Agency. http://www.epa.gov/oppt/iur/tools/data/2002-vol.html and search on CAS number. Last accessed: 4/21/05. EPA. 2009. Non-confidential 2006 IUR Records by Chemical, Including Manufacturing, Processing and Use Information. U.S. Environmental Protection Agency. http://cfpub.epa.gov/iursearch/2006_iur_ natlcheminfo.cfm?id=2588. Last accessed: 5/09. HSDB. 2009. Hazardous Substances Data Bank. National Library of Medicine. http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB and search on CAS number. Last accessed: 7/15/09. IARC. 1986. Toluene diisocyanate. In Some Chemicals Used in Plastics and Elastomers IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 39. Lyon, France: International Agency for Research on Cancer. pp. 287-323. IARC. 1999. Toluene diisocyanates. In Re-evaluation of Some Organic Chemicals, Hydrazine, and Hydrogen Peroxide. IARC Monographs on the Evaluation of Carcinogenic Risk of Chemicals to Humans, vol. 71. Lyon, France: International Agency for Research on Cancer. pp. 865-879. ICIS. 2009. Toluene Di-isocyanate (TDI) Uses and Outlook. ICIS Chemical Intelligence. Last updated 11/09. http://www.icis.com/v2/chemicals/9076541/toluene-diisocyanate/uses.html. IPCS. 1987. Environmental Health Criteria No. 75. Toluene Diisocyanates . International Programme on Chemical Safety. http://www.inchem.org/documents/ehc/ehc/ehc75.htm. NIOSH. 1990. National Occupational Exposure Survey (1981-83). National Institute for Occupational Safety and Health. Last updated: 7/1/90. http://www.cdc.gov/noes/noes1/x3117sic.html. NTP. 1986. Toxicology and Carcinogenesis Studies of Commercial Grade of 2,4 (80%)- and 2,6 (20%)- Toluene Diisocyanate (CAS No. 26471-62-5) in F344 Rats and B6C3F 1 Mice (Gavage Studies). Technical Report Series no. 251. Research Triangle Park, NC: National Toxicology Program. 194 pp. SRI. 2009. Directory of Chemical Producers. Menlo Park, CA: SRI Consulting. Database edition. Last accessed: 7/15/09. Tinnerberg H, Mattsson C. 2008. Usage of air monitoring and biomarkers of isocyanate exposure to assess the effect of a control intervention. Ann Occup Hyg 52(3): 187-194. TRI. 2009. TRI Explorer Chemical Report. U.S. Environmental Protection Agency. http://www.epa.gov/ triexplorer and select Toluene Diisocyanates. Last accessed: 7/15/09. 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 Manag Assoc 53(1): 61-66. USITC. 2009. USITC Interactive Tariff and Trade DataWeb. United States International Trade Commission. http://dataweb.usitc.gov/scripts/user_set.asp and search on HTS no. 292910. Last accessed: 7/15/09

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