Evidence of Carcinogenicity December 1989
CIBs are distributed to representatives of academia, industry, organized labor, public health agencies, and public interest groups, as well as to Federal agencies responsible for ensuring the safety and health of workers.
Copies are available to individuals upon request from the Division of Standards Development and Technology Transfer, NIOSH (Robert A. Taft Laboratories, 4676 Columbia Parkway, Cincinnati, Ohio 45226). We welcome suggestions concerning the content, style, and distribution of these documents.
The purpose of this bulletin is to disseminate new information on the potential carcinogenicity of toluene diisocyanate (TDI) and toluenediamine (TDA). Recent data from studies of chronic toxicity in animals have produced evidence that cancer is associated with exposure to commercial-grade TDI (an 80:20 mixture of 2,4- and 2,6-TDI) and to 2,4-TDA, a reagent used in the manufacture of TDI and a hydrolysis product of TDI. The tumorigenic responses observed in both rats and mice treated with TDI and TDA meet the criteria of the Occupational Safety and Health Administration (OSHA) Cancer Policy for classifying a substance as a potential occupational carcinogen [Title 29 of the Code of Federal Regulations, Section 1990.112]. Because insufficient data exist to evaluate the carcinogenic potential of the other TDI and TDA isomers, NIOSH concludes that occupational exposure to all TDI and TDA isomers should be reduced. NIOSH therefore recommends that all the isomers of TDI and TDA be regarded as potential occupational carcinogens and that occupational exposures be limited to the lowest feasible concentrations. Although the potential for TDI- or TDA-induced cancer in humans has not been determined, reducing exposure to TDI and TDA in the workplace should reduce the risk.
NIOSH urges (1) that producers and users of TDI and TDA disseminate this information to their workers and customers, (2) that professional and trade associations and unions inform their members of the potential hazards of working with TDI and TDA, and (3) that appropriate engineering controls and work practices be used to minimize the exposure of workers. Readers seeking more detailed information on the studies cited in this CIB are encouraged to consult the original publication.
[signature] J. Donald Millar, M.D., D.T.P.H. (Lond.) Assistant Surgeon General Director, National Institute for Occupational Safety and Health Centers for Disease Control |
Experimental studies in animals have also demonstrated that 2,4-toluenediamine (TDA), a hydrolysis product of 2,4-TDI, is a carcinogen. When rats and mice were exposed orally to TDA, tumors were induced in the livers, skin, and mammary glands of both species. The National Institute for Occupational Safety and Health (NIOSH) concludes that the data on carcinogenicity provide sufficient evidence to warrant concern about the potential consequences of occupational exposure to TDI and TDA. The tumorigenic responses observed in both rats and mice treated with either TDI or TDA meet the criteria of the Occupational Safety and Health Administration (OSHA) Cancer Policy for classifying a substance as a potential occupational carcinogen [29 CFR 1990]. Although the carcinogenic potential of the other TDI and TDA isomers has not been adequately determined, exposure to all TDI and TDA isomers should be reduced. NIOSH therefore recommends that all the isomers of TDI and TDA be regarded as potential occupational carcinogens and that occupational exposures to TDI and TDA be limited to the lowest feasible concentrations. The potential for TDI- or TDA-induced cancer in humans has not been determined, but the risk of developing cancer should be decreased by reducing exposure to TDI and TDA in the workplace.
TDA is manufactured by nitrating toluene to produce dinitrotoluene, which is then catalytically reduced to TDA. TDA is a colorless solid that tends to darken on storage and exposure to air. Other chemical and physical properties of 2,4-TDA are listed in Table 1.
The major route of occupational exposure to TDI is by inhalation of the vapor; exposure may also occur through dermal contact during the handling of liquid TDI. Occupational exposure normally occurs during the production and use of TDI, particularly during the mixing and foaming processes in the polyurethane foam industry. Exposures to airborne TDI may also occur as a result of the melting or burning of polyurethane foams during firefighting. An estimated 34,466 workers were exposed to TDI in the United States during the period 1981 to 1983 [NIOSH 1983]. Representative information on die occurrence of air-borne TDI in the work environment is listed in the Appendix.
Chemical and Physical Properties of Commercial-grade
TDI (80% 2, 4-TDI and 20%
2,6-TDI)* and 2, 4-TDA **
Chemical identity | TDI | 2,4 TDA |
CAS*** registry number | 26471-62-5 | 95-80-7 |
RTECS accession number | NQ9490000 | XS9625000 |
Synonyms | Tolylene diisocyanate; isocyanic acid; methyl-metaphenylene isocyanate | 3-Amino-p-toluidine; 1, 3-diamino-4-methyl-benzene; 4-methyl-phenylenediamine; 2,4-diamino-toluene |
Formula | CH3C6H3 (NCO)2 | CH3C6H3 (NH2)2 |
Molecular weight | 174.2 | 122.2 |
Flash point | 135°C (275°F) | 149°C (300°F) |
Specific gravity of liquid | 1.22 at 25°C (77°F) | 1.045 at 100°C (212°F) |
Boiling point | 250°C (482°F) | 292°C (558°F) |
Freezing/melting point | 20° to 22°C (68° to 72°F) | 99°C (210°F) |
Vapor pressure | 0.05 mm Hg at 25°C (77°F) | 1.0 mm Hg at 107°C (224°F) |
Solubility in: | ||
Water | Insoluble | Soluble |
Alcohol | Soluble | Soluble |
Ethyl ether | Soluble | Soluble |
Acetone | Soluble | Unspecified |
Benzene | Soluble | Soluble |
Carbon tetrachloride | Soluble | Unspecified |
Workers may be exposed to TDA by dermal contact and, less frequently, by inhalation. Although solid TDA does not normally present an inhalation hazard, it may also be handled and shipped in the molten state, at which time the vapors may present a hazard. An estimated 8,513 workers were exposed to TDA in the United States (luring the period 1981 to 1923 [NIOSH 1983]. Potential for worker exposure is minimal because more than 99% of the TDA produced is used captively to produce TDI, usually at the same site [NTP 1985]. During the manufacture of TDA, TDA concentrations have ranged from 0.0002 to 0.1241 parts of TDA per million parts (ppm) of air, or 0.001 to 0.620 milligrams per cubic meter (mg/m3) [Ahrenholz and Meyer 1980,1982].
In an inhalation study [Loeser 1983], groups of 126 male and 126 female Sprague-Dawley CD rats and groups of 120 male and 120 female CD-1 mice were exposed to 0, 0.05, or 0. 15 ppm of commercial-grade TDI for 6 hours/day, 5 days/week over a 2-year period. The results showed no TDI-induced neoplasms in either species. The exposure levels used by Loeser have been criticized because they did not achieve a maximum tolerated dose (i.e., the highest dose that produces some toxic response without compromising an animal's survival for its full expected life span) [NTP 1986]. Thus the doses may not have been sufficient to produce a carcinogenic response.
Target Doses and Estimated Average Doses of TDI Received* [NTP 1986]
Rats | Mice | |||||||
Males | Females | Males | Females | |||||
Item | I** | II | I | II | I | II | I | II |
Target dose, mg/kg per day | 30 | 60 | 60 | 120 | 120 | 240 | 60 | 120 |
Estimated average dose received, mg/kg per day | 23 | 49 | 49 | 108 | 108 | 202 | 49 | 108 |
% of target dose received | 77 | 82 | 82 | 90 | 90 | 84 | 82 | 90 |
A subsequent National Cancer Institute (NCI) evaluation of 2,4-TDA also showed it to be carcinogenic in F344/N rats and B6C3F1 mice [NCI 1979]. Groups of 50 male and 50 female F344/N rats were given 2,4-TDA in the diet ad libitum at of 125 or 250 ppm for 40 weeks. Because weight gain was excessively depressed in both treated groups, doses were reduced to 50 and 100 ppm, respectively, and the treatment was continued for additional periods of 63 weeks for the low-dose groups, 39 weeks for the high-dose females. Control groups of 20 male and 20 female rats were fed the basal diet, When incidences of hepatocellular carcinomas and neoplastic nodules were combined, dose-related linear trends occurred in males (p=0.014) and females (p=0.008). In addition, the incidence of mammary gland fibroademonas was dose-related in treated female rats and statistically significant for those on the high dose (P<0.001). Furthermore male rats showed a significantly increased incidence of subcutaneous fibromas (p=0.004).
In another part of the NCI evaluation of TDA [NCI 1979], groups of 50 male and 50 female B6C3F1 mice received 2,4-TDA in the diet ad libitum at concentrations of 100 or 200 ppm for 101 weeks. Control groups of 20 male and 20 female mice were fed the basal diet. A statistically significant incidence of hepatocellular carcinomas occurred in low-dose (p=0.007) and high-dose (p=0.008) female mice; a statistically significant increase also occurred in the incidence of lymphomas (p<0.001) in the low-dose female mice. No significant increase in tumors occurred in male mice treated with 2,4-TDA.
The carcinogenic potential of 2,5-TDA was tested as its sulfate salt in F344 rats and B6C3F1 mice [NCI 1978]. Groups of 50 male and 50 female F344 rats were administered 0.06% or 0.2% 2,5-TDA sulfate in their diets ad libitum for 78 weeks followed by 28 to 31 weeks of observation. Groups of 50 male and 50 female B6C3F1 mice were administered 0.06% or 0.1% 2,5-TDA sulfate in their diets ad libitum for 78 weeks followed by 16 to 19 weeks of observation. All control groups (25 or 50 animals each) were fed the basal diet. NCI [1978] reported that a statistically significant incidence of lung tumors in high-dose female mice was not considered convincing evidence of a compound-related carcinogenic effect because high-dose and control mice were received in separate shipments mid housed in separate rooms. Other flaws in the experimental design of this bioassay included using different mouse strains for the sub-chronic and chronic toxicity studies and placing the high-dose rats on the 2,5-TDA diet 11 months after the low-dose rats. In addition, low-dose mice began receiving their diet 2 weeks before the control group and 6 months before the high-dose group. Furthermore, the high-dose mice began receiving their diet 2 months after their controls. Under the conditions of this bioassay, 2,5-TDA sulfate was not carcinogenic in F344 rats or B6C3F1 mice [NCI 1978].
The dihydrochloride salt of the 2,6-isomer of TDA was tested for carcinogenicity in F344/N rats and B6C3F1 mice [NCI 1980]. Groups of 50 F344/N rats of each sex were given 2,6-TDA dihydrochloride in the diet ad libitum at concentrations of 250 or 500 ppm for 103 weeks; they were then observed for an additional week. Groups of 50 B6C3F1 mice of each sex were given 2,6-TDA dihydrochloride hi the diet ad libitum at concentrations of 50 or 100 ppm. for 103 weeks; they were then observed for an additional week. A dose-related but not statistically significant incidence of liver tumors occurred in treated male rats and female mice. The investigators concluded that under the conditions of this study, 2,6-TDA dihydrochtoride was not carcinogenic for F344/N rats or B6C3F1 mice [NCI 1980].
NCI review panels for the 2,5- and 2,6-TDA studies have suggested that both 2,5- and 2,6-TDA be considered for retesting because of deficiencies in experimental design and study conduct and because both compounds were mutagenic in various S. typhimurium strains [NCI 1978, 1980].
Clement Associates, Inc. [1982] independently reviewed a 1982 draft of the NTP TDI gavage study [NTP 1986] and the TDI inhalation study [Loeser 1983] for the International Isocyanate Institute, Inc. Because inhalation is the normal route of exposure to TDI, Clement Associates considered the [Loeser 1983] study the more useful of the two for assessing the carcinogenic potential of TDI for humans, despite the lack of a maximum tolerated dose in the [Loeser 1983] study. They further believed that the [Loeser 1983] study adequately supported the conclusion that TDI was not carcinogenic to rats and mice under the conditions tested.
On the basis of studies in animals [Ito et al. 1969; NCI 1979], [IARC 1978, 1979, 1982] concluded that there is sufficient evidence to demonstrate the carcinogenicity of 2,4-TDA. IARC assigns a classification of 2B to chemicals for which there is sufficient evidence of carcinogenicity in animals and inadequate data in humans. In addition, NTP lists 2,4-TDA as a substance "which may reasonably be anticipated to be a carcinogen" because there is sufficient evidence of carcinogenicity in experimental animals even though no evidence exists for humans [NTP 1985].
Currently, there is no epidemiologic evidence that any isomer of TDI or TDA has induced cancer in exposed workers; however, the positive data in other mammalian species suggest that the potential exists. NIOSH therefore concludes that commercial-grade TDI and 2,4-TDA are potential occupational carcinogens.
The excess cancer risk for workers exposed to TDI and TDA has not yet been quantified, but the probability of developing cancer should be decreased by minimizing exposure. Employers should therefore assess the conditions under which workers may be exposed to TDI and TDA and reduce exposures to the lowest feasible concentrations.
If the initial survey indicates that no worker is exposed to TDI or TDA, sampling is recommended annually or whenever there are changes in production, process, controls, work practices, or weather conditions that may affect exposure conditions. If work environments are found to contain measurable concentrations of TDI or TDA, workers must wear respirators, and sampling should be conducted weekly until no measurable concentrations of TDI or TDA are noted in two consecutive surveys. Sampling should be conducted again 6 months after the second negative survey. If no measurable concentrations of TDI or TDA are noted after two consecutive biannual surveys, sampling should be conducted annually or whenever changes in production, process, controls, work practices, or weather conditions may affect exposure conditions.
The NIOSH Occupational Exposure Sampling Strategy Manual [Leidel et al. 1977] provides guidance for developing efficient strategies to monitor worker exposure to toxic chemicals. This manual contains information on determining the need for exposure monitoring, the number of samples to be collected, and appropriate sampling times.
When TDI is present as an aerosol, NIOSH investigators determine its concentration by a modification of Method MDHS 25, developed by the Occupational Medicine and Hygiene Laboratory of Her Majesty's Health and Safety Executive [Health and Safety Executive 1987]. Air is sampled at a flow rate of 1 L/min through an impinger containing a solution of toluene and 1-(2-methoxyphenyl) piperazine, which reacts with isocyanates to form ureas. The sample is treated in the laboratory with acetic anhydride and then evaporated to dryness. After the residue is dissolved in methanol, the ureas are quantified by liquid chromatography with electrochemical detection. The lower limit of 2,4-TDI quantification for this method is 0.002 mg/m3 for a 100-L air sample.
A sampling and analysis method for 2,4- or 2,6-TDA is OSHA Method 65 [Elskamp 1987]. Air is sampled at a flow rate of 1 L/min through a 37-millimeter (mm) glass fiber filter coated with sulfuric acid. Within 10 hours (hr) after sampling, the filter must be transferred to 2 milliliters (mL) of water for storage. The aqueous solution is treated in the laboratory with sodium hydroxide and shaken with toluene; an aliquot of the resulting toluene solution is then treated with heptafluorobutyryl anhydride. The resulting bis(heptafluorobutyryl)amides formed from the 2,4- and 2,6-TDA are quantified by gas chromatography with electron-capture detection. With a 100-L air sample, the lower limit of quantification is 0.00006 mg/m3 for 2,4- and 2,6-TDA. In this method, 2,4- and 2,6-TDI are positive interferences to the determination of the corresponding diamine.
Although not validated by NIOSH, other published methods may also be suitable for monitoring TDA in the workplace. Some of these methods yield quantitative data for both the diamines and the diisocyanates [Holdren et al. 1984; Skarping et al. 1985; Dalene et al. 1988], whereas another method quantifies both diamines and diisocyanates as the diamine [Skarping et al. 1981].
Closed-system operations provide the most effective means for reducing worker exposures to TDI and TDA. Closed systems should be used for producing, storing, transferring, packaging, and processing TDI and TDA. Exhaust ventilation systems should be designed to capture and contain vapors and particulates. Guidance for designing local exhaust ventilation systems can be found in Recommended Industrial Ventilation Guidelines [Hagopian and Bastress 1976], Industrial Ventilation: A Manual of Recommended Practice [ACGIH 1986], and American National Standard Fundamentals Governing the Design and Operation of Local Exhaust Systems [ANSI 1979].
Ventilation equipment should be checked at least every 3 months to ensure adequate performance. System effectiveness should also be checked when there are any changes in production, process, or control that might significantly increase TDI and TDA exposures.
Any respiratory protection program must, at a minimum, meet the requirements of 29 CFR 1910.134. Respirators must be approved by NIOSH and the Mine Safety and Health Administration (MSHA). A complete respiratory protection program should include (1) regular training and medical evaluation of personnel and (2) fit testing, periodic environmental monitoring, and maintenance, inspection, cleaning, and storage of equipment. The program should be evaluated regularly. The following publications contain additional information about selection, fit testing, use, storage, and cleaning of respiratory equipment: Guide to Industrial Respiratory Protection [NIOSH 1987a] and NIOSH Respirator Decision Logic [NIOSH 1987b].
The following procedures should be followed if TDI is spilled [III 1980]:
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Concentrations of Toluene Diisocyanate (TDI) in the Workplace*
Air concentration** | |||
Source of exposure and year of study | No. of samples | Mean or range of means (mg/m3) | Reference |
TDI production: 1956-1974 1973-1978 | Unspecified 1949 | <0.028-0.43 0.0142*** | Porter et al. [1975] Diem et al. [1982] |
Polyurethane foam production (pouring and molding): | |||
1955 | >10 | 0.28-2.71 | Walworth and Virchow [1959] |
1956 | >130 | ND-3.13 | Walworth and Virchow [1959] |
1957 | >20 | ND-19.95 | Walworth and Virchow [1959] |
1964 | 28 | 0.054.239 | Glass and Thom [1964] |
1965 | Unspecified | 0.142-0.214 | Peters et al. [1968] |
1966 | 24 | ND-0.214 | Peters et al. [1969] |
1967 | 8 | ND-0.085 | Peters et al. [1969] |
1972 | Unspecified | 0.142-0.085 | Wegman et al. [1974] |
1972-1974 | 286 | 0.142-0.036 | Wegman et al. [1982] |
1974-1976 | 138 | 0.007-0.050 | Wegman et al. [1982] |
1973 | 11 | 0.005-0.007*** | Vandervort and Shama [1973] |
1973 | 21 | 0.053-0.356 | Markel and Shama [1974] |
1973 | 418 | 0.009-0.016*** | Musk et al. [1982] |
1974 (2,4-isomer) | 6 | 0.021*** | Chrostek and Cromer [1975] |
1974 | 540 | 0.010-0.011*** | Musk et al. [1982] |
1974 | 8 | 0.123*** | Gunter and Lucas [1975] |
1975 | 6 | 0.379*** | Gunter [1975] |
1975 | 10 | 0.004-0.017*** | Roper and Cromer [1975] |
1975 | 624 | 0.006-0.011*** | Musk et al. [1982] |
1976 | 461 | 0.003-0.009*** | Musk et al. [1982] |
1978 | 21 | 0.036-0.041*** | White and Wegman [1978] |
1981 | 12 | 0.002-0.004*** | Burroughs and Moody [1982] |
1981 | 7 | 0.003*** | Almaguer et al. [1982] |
1981 | 4 | 0.054-0.140 | Andersson et al. [1982] |
1984 (2, 4-isomer) | 20 | 0.007-0.011*** | Lee and Bennett [1986] |
1984 (2, 6-isomer) | 20 | 0.004-0.004*** | Lee and Bennett [1986] |
Polyurethane foam spray application: 1979 | 12 | 0.121-0.199*** | Hosein and Farkas [1981] |
Polyurethane spray paint use: 1960 1974 | 3 13 | 0.712 0.015-0.02*** | Maxon [1964] Hervin and Thoburn [1975] |
Heating of polyurethane foam: 1987 | 6 | 0.015*** | Daniels et al. [1987] |
TDI release from
insulation (1 meter from polyurethane floor in a ship's hold): 1983 | 6 | 0.138 | Hobara et al. [1984] |
TDI release from
coated fabric (in a seat cover factory): 1979 | Unspecified | 0.002-0.021 | White et al. [1980] |
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