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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 4 Toluene 2,4- and 2,6-Diisocyanate1 Acute Exposure Guideline Levels SUMMARY Toluene diisocyanate (TDI) is among a group of chemicals, the isocyanates, that are highly reactive compounds containing an −NCO group. TDI exists as both the 2,4- and 2,6-isomers, which are available commercially, usually in ratios of 65:35 or 80:20 (Karol 1986; WHO 1987). TDI has been used in the manufacture of polyurethane foam products as well as paints, varnishes, elastomers, and coatings (WHO 1987). Inhaled TDI causes irritation and sensitization of the respiratory tract. Sensitization may occur from either repeated exposure over a relatively long 1 This document was prepared by the AEGL Development Team comprising Carol Wood (Oak Ridge National Laboratory) and National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances member Steven Barbee (Chemical Manager). The NAC reviewed and revised the document and AEGL values as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels. The NRC subcommittee concludes that the AEGLs developed in this document are scientifically valid conclusions on the basis of the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 period of time (i.e., years), or it may consist of an induction phase precipitated by a relatively high concentration followed by a challenge phase in which sensitized individuals react to extremely low concentrations of TDI. Only irritation effects were considered in establishing AEGL values, because sensitized individuals are considered to be hypersusceptible. Although individuals with existing TDI sensitization are present in the general population, that presensitization cannot be estimated. If the number of individuals sensitized to TDI in the general population were quantifiable, a different approach to derivation of AEGL values might have been considered. At any of the AEGL levels, there might be individuals who have a strong reaction to TDI, and those individuals might not be protected within the definition of effects for each level. Human data were available for the derivation of AEGL-1 and AEGL-2. Fifteen asthmatic subjects were exposed to TDI at 0.01 parts per million (ppm) for 1 hour (h), and then after a rest of 45 minutes (min), they were exposed at 0.02 ppm for 1 h. A nonasthmatic referent group of 10 individuals was exposed at 0.02 ppm for 2 h (Baur 1985). None of the individuals had a history of isocyanate exposure, and the asthmatic subjects were not sensitized to TDI. Although no statistically significant differences in lung function parameters were observed among asthmatic subjects during or after exposure, nonpathological bronchial obstruction was indicated in several individuals. In the referent group, there was a significant increase in airway resistance immediately and at 30 min after the initiation of exposure, but none of the subjects developed bronchial obstruction. Both groups reported eye and throat irritation, cough, chest tightness, rhinitis, dyspnea, and/or headache, but time to onset of symptoms was not given. There was also no indication whether symptoms were more severe in asthmatic subjects that inhaled 0.01 or 0.02 ppm. Therefore, the 0.02-ppm concentration was identified as the basis for the 10-min, 30-min, and 1-h AEGL-1 values. The 0.01-ppm concentration was identified as the basis for the 4- and 8-h AEGL-1 values. It should be noted that the AEGL-1 values are below a reported odor detection threshold of 0.05 ppm (Henschler et al. 1962). Derivation of AEGL-2 was based on human data. Exposure of volunteers to TDI at 0.5 ppm for 30 min resulted in severe eye and throat irritation and lacrimation (Henschler et al. 1962). A higher exposure concentration was intolerable. Extrapolations were made using the equation Cn×t =k (C=concentration, t=time, and k is a constant), where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n=3 for extrapolating to the 10-min time point and n=1 for the 1-h and 4-h time points.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 The 4-h value was used for the 8-h value, because extrapolation to 8 h resulted in a concentration similar to that shown to be tolerated for >7 h with only mild effects. An uncertainty factor (UF) of 3 was applied to account for sensitive individuals; use of a greater UF results in values below those supported by human data for AEGL-2 effects. No human data were available for derivation of AEGL-3 values. Human fatalities attributed to TDI-induced chemical pneumonitis have occurred under unusual circumstances. Exposure concentrations in those accidents were not measured. Therefore, animal data were used to derive AEGL-3 values. On the basis of LC50 values (concentrations lethal to 50% of subjects), the species most sensitive to the effects of TDI is the mouse. The 4-h mouse LC50 of 9.7 ppm (Duncan et al. 1962) was divided by 3 to estimate a threshold of lethality based on the regression plot of mortality vs concentration. This estimated 4-h lethality threshold was used to extrapolate to the 30-min and 1- and 8-h AEGL-3 time points. Values were scaled using the equation Cn×t=k, where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n=3 for extrapolating to the 30-min and 1-h time points and n=1 for the 8-h time point. A total UF of 10 was applied, which includes 3 to account for sensitive individuals and 3 for interspecies extrapolation (use of a greater UF would result in values below those supported by human data for AEGL-3 effects). According to Section 2.7 of the standing operating procedures for the derivation of AEGLs (NRC 2001), 10-min values are not to be scaled from an experimental exposure time of ≥4 h. Therefore, the 30-min AEGL-3 value was also adopted as the 10-min value. 1. INTRODUCTION TDI is among a group of chemicals, the isocyanates, that are highly reactive compounds containing an −NCO group. TDI exists as both 2,4- and 2,6-isomers, which are available commercially, usually in ratios of 65:35 or 80:20 (Karol 1986; WHO 1987). An estimated 1,225 million pounds of TDI were produced in 2000, and greater than 90% was used in the manufacture of flexible urethane foams (CPS 2001). TDI is produced from the reaction of diaminotoluenes with phosgene in a closed system, and TDI has also been used in the manufacture of urethane paints, varnishes, elastomers, and coatings. The chemical may dimerize slowly at ambient temper-
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 4–1 Summary of AEGLs Values for Toluene 2,4- and 2,6-Diisocyanate (ppm [mg/m3]) Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1 (Nondisabling) 0.02 (0.14) 0.02 (0.14) 0.02 (0.14) 0.01 (0.07) 0.01 (0.07) Chest tightness, eye and throat irritation (Baur 1985) AEGL-2 (Disabling) 0.24 (1.71) 0.17 (1.21) 0.083 (0.59) 0.021 (0.15) 0.021 (0.15) Severe eye and throat irritation, lacrimation (Henschler et al. 1962) AEGL-3 (Lethal) 0.65 (4.63) 0.65 (4.63) 0.51 (3.63) 0.32 (2.28) 0.16 (0.93) 4-h LC50 in the mouse (Duncan et al. 1962) Abbreviations: mg/m3, milligrams per cubic meter; ppm, parts per million. atures and more rapidly at higher temperatures, and trimerization occurs at 100–200°C (WHO 1987). The odor threshold for 2,4- and 2,6-TDI was found to be 0.05 ppm (Henschler et al. 1962). In early human primary irritation testing with 2,4-TDI, 50% of subjects reported the least detectable odor at 0.4 ppm. Irritation of the nose and throat occurred at 0.5 ppm, and an appreciable odor was noted at 0.8 ppm (Zapp 1957; Wilson and Wilson 1959). Toxicological effects to the respiratory tract from inhaled TDI may be divided into two distinct categories: (1) primary irritation and (2) immunologic hypersensitivity. The chemically reactive isocyanate group has been suggested as the cause of both effects. The primary irritation associated with inhaled TDI is a nonspecific inflammatory response characteristic of that produced by other primary irritants. Inflammation is also a consequence of sensitization, but it is caused by an immunologically mediated reaction leading to antibody formation (Karol 1986; WHO 1987), and that response is individual-specific. Sensitization consists of an induction phase precipitated by a relatively high concentration, followed by a challenge phase in which immunologically sensitized individuals react to extremely low concentrations of TDI that are, in some persons, below the current ACGIH Threshold Limit Value (TLV) of 5 ppb. Some studies showed detection of IgE antibodies in sensitized individuals, although others found variable or negative results (Karol 1986). IgG antibodies specific to TDI have been detected in both asymptomatic and symptomatic workers (Baur 1985). The immune-mediated inflammatory response of the respiratory
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 4–2 Physicochemical Data for Toluene Diisocyanate Parameter Value Reference Synonyms TDI; tolylene diisocyanate Budavari et al. 1996 CAS registry no. 584–84–9 (2,4-TDI) 91–08–7 (2,6-TDI) Chemical formula C9H6N2O2 Budavari et al. 1996 Molecular weight 174.16 Budavari et al. 1996 Physical state Clear yellow liquid Shiotsuka 1987b Vapor pressure 0.011 mm Hg at 25°C 3.2 mm Hg at 100°C Woolrich 1982 Vapor density (air=1) 6.0 ACGIH 1991 Specific gravity 1.22 g/cm3 Shiotsuka 1987b Boiling/flash point 251°C/132°C (open cup) ACGIH 1991 Solubility in water Reacts with water ACGIH 1991 Conversion factors 1 ppm=7.12 mg/m3 1 mg/m3=0.14 ppm Hartung 1994 tract has been characterized by persistent activation of lymphocytes, chronic expression of certain cytokines (Maestrelli et al. 1995), neutrophilia, eosinophilia (Fabbri et al. 1987), and decreased lymphocyte cAMP levels (Butcher et al. 1979). The physicochemical properties of TDI are given in Table 4–2 (above). 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Human fatalities from TDI exposure are not common. Accidents have involved unusual circumstances. TDI concentrations were not measured, and the isomer was not always identified. In one case, a worker was trapped in a room following the explosion of a storage vessel. The victim was unconscious for an unknown but extended exposure duration (Horspool and Doe 1977). A second report involved a salvage diver who was blowing polyurethane foam in the hold of a ship. When his air supply failed, he removed his mask and was exposed to an atmosphere containing a high (but
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 unknown) concentration of Freon and 2,4-TDI. The diver was unconscious and submerged in sea water when rescued. He died 4 days (d) later despite extensive resuscitative efforts (Linaweaver 1972). Deaths in both of those cases appeared to be due to pulmonary edema subsequent to chemical pneumonitis. 2.2. Nonlethal Toxicity 2.2.1. Case Reports A 50-y-old male was drenched in TDI (isomer mixture not specified) when a hose detached from a tanker truck he was helping to unload. The individual had no history of respiratory illness, asthma, or allergic disease. Shortly after exposure, he developed shortness of breath, wheezing, and cough. Evaluation 12 y later showed persistent asthma and variable airway obstruction despite no further exposure to isocyanates. However, his asthma became more severe after exposure to other irritants in the workplace. An asthmatic attack was provoked by challenge with 10 ppb (71.2 µg/m3) TDI for 8 min (Moller et al. 1986). In contrast to the above report, TDI sensitivity was lost in a worker 11 months (mo) after removal from exposure, and nonspecific bronchial hyper-responsiveness resolved after 17 mo despite the continued presence of serum IgE antibodies (Butcher et al. 1982). The TDI isomer was not reported for either the occupational exposure or the experimental challenge testing. Isocyanate vapor concentrations have been measured to estimate worker exposure during the spray application of polyurethane foam. Personal samplers were attached to the sprayers, but the exact location of the samplers (i.e., breathing zone) was not specified. Average exposure concentrations ranged from 0.021 ppm to 0.045 ppm, and exposure durations ranged from 105 min to 442 min. No head or eye protection was provided except for the voluntary use of plastic bags over the heads of the sprayers. Reddening of the eyes and lacrimation were observed in “numerous” workers during the course of the study (Hosein and Farkas 1981). This study neither identified the isocyanate isomers nor correlated the prevalence of clinical signs in the workers and the exposure concentrations and durations. Case reports of TDI intoxication at 15 plants involved in polyurethane operations (most likely involving mixed isomers) were investigated by the Massachusetts Department of Labor and Industries (Elkins et al. 1962).
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Workers complained of eye and throat irritation, tightness of the chest, nausea and vomiting, nonproductive cough, and restlessness despite the control of TDI vapor concentrations according to the standard in effect at that time. Milder effects were documented in plants with maximum workroom concentrations at 0.02 ppm, and more severe effects were documented in plants with maximum workroom concentrations at ≥0.07 ppm. The authors concluded that the maximum allowable concentration of 0.1 ppm was too high and recommended that a limit of 0.01 ppm be adopted. Current occupational exposure standards are given in Section 8.2 of this document. Workers in a manufacturing plant involved in the production of isocyanate foam complained of coughing, sore throat, dyspnea, fatigue, and night sweats (Hama 1957). A change in the manufacturing process placed workers in a poorly ventilated room, which resulted in symptoms in 12 of 12 workers. Isocyanate concentrations (isomer not specified) ranging from 0.03 ppm to 0.07 ppm were measured in the room (assumed to be area samples). Following the return to previous manufacturing processes, no complaints or symptoms of exposure have occurred, and measured concentrations of isocyanates were found to be <0.03 ppm. Seven men developed cough, dyspnea, chest pain, wheezing, and hemoptysis following exposure to a plastic varnish containing TDI (isomer not specified). Air samples taken in the work area—after temporary measures had been implemented to improve ventilation—contained 0.08 ppm to 0.1 ppm. Six of the seven individuals had varying degrees of respiratory impairment, as determined by timed vital capacity. Improvement was noted in five when reexamined at 2–2.5 mo after exposure (Maxon 1964). 2.2.2. Epidemiologic Studies Numerous occupational studies have evaluated pulmonary function in workers exposed to TDI. However, most have failed to account for confounding factors such as smoking status, sampling methods that failed to detect and quantify both isomers, high rates of annual FEV1 (forced expiratory volume in 1 second) decline in control populations, and high intra- and interindividual variation in lung-function testing (EPA 1996). A study by Diem et al. (1982, as cited in EPA 1996) accounted for those factors and followed TDI production workers prospectively over a 5-y period. Investigators identified two exposure groups, defined as low and high, with arithmetic mean concentrations for never-smokers of 0.9 ppb and 1.9 ppb (6.41 µg/m3 and 13.53 µg/m3), respectively. Never-smokers in the high TDI exposure category had a significant (p≤0.001) decline in FEV1 and forced
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 expiratory flow at 25–75% when compared with never-smokers in the low-exposure category. Similar results in FEV1 were found when the same groups were recategorized on the basis of time spent inhaling workplace air containing a concentration above 20 ppb (142.4 µg/m3). The U.S. Environmental Protection Agency (EPA) (1996) used the Diem et al. (1982, as cited in EPA 1996) study to calculate a reference concentration (RfC) of 0.98× 10−5 ppm. EPA (1996) concluded that “[although the mean exposure values determined in this study are close to the detection limit of the sampling and detection method, the values are considered accurate because they were obtained by continuous monitoring over the entire workday.” One of the largest occupational studies of polyurethane foam workers was conducted by Bugler et al. (1991). That 5-y study was designed to investigate the risk of sensitization to isocyanates and the longitudinal change in ventilatory capacity. Personal exposures were measured using modified MCM paper tape monitors. Low, intermediate, and high exposure groups were identified with average TDI exposures of 0.3, 0.6, and 1.2 ppb (2.14, 4.27, and 8.54 µg/m3), respectively. There were no significant effects of exposure as measured by changes in the rate of decline in several parameters of pulmonary function. Over 5 y, the rate of sensitization among the original subjects was 3.1%, or 0.6% per year. Of note is the 4% rate of sensitization among new hires. Overall, in 47% of workers diagnosed, sensitization occurred after exposure to TDI concentrations less than 20 ppb (142.4 µg/m3) (Bugler et al. 1991). A major problem with this study was that the limit of detection was only 4 ppb (28.48 µg/m3), indicating that estimates of cumulative daily exposures were based on measurements below the limit of quantitation (Garabrant and Levine 1994). A comprehensive review of the epidemiological studies on TDI was prepared by Garabrant and Levine (1994). Those authors concluded that respiratory sensitization occurs in less than 1% of subjects per year who are exposed to TDI at levels below 20 ppb (142 µg/m3), and that sensitization is almost entirely attributable to short-term excursions above that level. 2.2.3. Experimental Studies Provocative inhalation challenge tests using 2,4- and 2,6-TDI (80:20) were administered to 15 asthmatic subjects and 10 healthy controls (Baur 1985). None of the individuals had a history of isocyanate exposure, and the asthmatic subjects were not sensitized to TDI. All individuals classified as asthmatic had a history of asthmatic episodes and a significant response to acetylcholine challenge test. Asthmatic subjects were exposed to TDI at
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 0.01 ppm for 1 h, and then, after a rest of 45 min, they were exposed at 0.02 ppm (0.142 milligrams per cubic meter [mg/m3]) for 1 h. Controls were exposed to TDI at 0.02 ppm for 2 h. In the control group, there was a statistically significant (p≤0.05) increase in airway resistance (Raw) immediately after and 30 min after the beginning of exposure. For the asthmatic group, no statistically significant differences were observed from pretest group mean values for lung function parameters during or after exposure. However, eight of 15 individuals had an increase in Raw of >50%, and four of those subjects had significant bronchial obstruction, which was defined as an increase in specific airway resistance of >50%. Specific airway resistance was calculated as the product of the Raw multiplied by the intrathoracic gas volume. More important, among the asthmatics, no individual decrease in FEV1 of more than 20% was observed. The increases in Raw and decreases in FEV1 are not considered pathologic for the asthmatic subjects because the changes were relatively minor and inconsistent within individuals. Individual values for Raw and FEV1 in several of the asthmatic subjects following TDI exposure are given in Table 4–3. Increases in Raw did not correspond with decreases in FEV1, and neither parameter could be used as an indication of reported discomfort. For example, individual 8 had the greatest increase in Raw (3.2 times), but the FEV1 showed essentially no decline (3.51 L vs 3.41 L). Individual 9 also showed no decline in FEV1 (4.01 L vs 3.91 L) and had a 1.5-time increase in Raw. Individual 5, who had the greatest decline in FEV1, reported no symptoms of discomfort. Five of the asthmatic individuals complained of chest tightness, rhinitis, cough, dyspnea, throat irritation, and/or headache during exposure; three controls reported eye irritation and/or cough. Some of the symptoms lasted for several hours post-exposure. The study author concluded that some people with pre-existing bronchial hyper-reactivity respond to TDI at or below the ACGIH short-term exposure limit (STEL=0.02 ppm) (see Section 8.2) with bronchial obstruction (Baur 1985). Henschler et al. (1962) exposed six healthy male volunteers to 2,4- and 2,6-TDI (65:35), 2,4-TDI, or 2,6-TDI at measured concentrations ranging from 0.01 ppm to 1.3 ppm for 30 min. The volunteers were exposed at all concentrations, but at only one concentration per day, and the concentrations were randomly selected. Volunteers had no prior knowledge of the isomer or concentration selected. The results are summarized in Table 4–4. The odor threshold was found to be 0.05 ppm. A concentration-dependent increase in sensory irritation was reported. There was slight eye and nose irritation at 0.1 ppm and marked discomfort at ≥0.5 ppm. 2,6-TDI appeared slightly more irritating than the 2,4-isomer, but was similar to the mixture.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 4–3 Increase in Raw Compared with FEV1 Following Exposure to Toluene Diisocyanate in Asthmatic Subjects Individual Maximum increase in Raw FEV1 (L) Symptoms Before TDI Exposure Lowest Value After TDI Exposurea 3 1.5× 3.0 2.5 Rhinitis, throat burning sensation, mild cough 5 2.0× 3.7 3.1 None 6 1.7× 4.8 4.4 Chest tightness 8 3.2× 3.5 3.4 Cough, chest tightness, dyspnea 9 1.5× 4.0 3.9 None aNone of the individuals experienced a >20% decline in FEV1. Source: Data from Baur 1985. No adverse effects were reported in two healthy men exposed to 2,4-and 2,6-TDI (30:70) at up to 9.8 ppb (70 µg/m3) for 4 h (Brorson et al. 1991) or in five healthy men exposed to 2,4- and 2,6-TDI (65:35) at 5.6 ppb (40 µg/m3) for 7.5 h (Skarping et al. 1991). No further details of those studies were reported. In 10 individuals with positive methacholine challenge tests, 2,4-TDI inhalation challenge testing at up to 20 ppb (142 µg/m3) for 15 min resulted in no change in FEV1 (Moller et al. 1986). No further details of this study were reported. Four adults with occupational asthma associated with exposure to isocyanates were challenged with TDI (isomer not specified), and their responses were assessed (Vandenplas et al. 1993). The duration of work exposure ranged from 7 to 17 y, and the duration of symptoms ranged from 0.5 to 10 y. Subjects were exposed at varying concentrations (5, 10, 15, and 20 ppb [35.6, 71.2, 106.8, 142.4 µg/m3]) for 1–90 min such that the C×t product remained constant. A positive asthmatic response was defined as a ≥20% drop in FEV1. Although the effective C×t was highly variable between individuals (45–450 ppb-min), it remained constant for each person. Therefore, the authors concluded that both concentration and duration of exposure determined the occurrence of an asthmatic reaction in sensitized
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 TABLE 4–4 Effects of Controlled Inhalation Exposure to Toluene Diisocyanate in Volunteersa Concentration (ppm) Effect 0.01 or 0.02 2,4/2,6; 2,4; 2,6: no odor perception, no effects 0.05 2,4/2,6: odor noted immediately upon entering the room; after about 5 min of exposure, 3/6 volunteers experienced a slight “tingling” sensation of the eyes described as lacrimation urge without tears 2,4: weak odor perception, no eye irritation 2,6: odor was stronger as compared with the 2,4-isomer 0.075 2,6/2,4: odor became stronger; slight burning of the eyes occurred after 1–6 min, but there was no lacrimation; with deeper breaths, volunteers experienced tickling or a slight stabbing pain in the nose 0.08 2,4: slight conjunctival irritation and tickling of nose 2,6: eye and nose irritation more severe as compared with same concentration of the 2,4-isomer; effects on throat were perceived as dryness, not scratching sensation 0.10 2,4/2,6: eye and nose irritation became more severe described as resembling a cold (catarrh) 2,4: more pronounced conjunctival irritation and tickling of nose 2,6: eye and nose irritation more severe as compared with same concentration of the 2,4-isomer; effects on throat were perceived as dryness, not scratching sensation 0.20 2,4: eye irritation was perceived by 2/5 as stinging and uncomfortable 2,6: eye and nose irritation more severe as compared with same concentration of the 2,4-isomer; effects on throat were perceived as dryness, not scratching sensation 0.50 2,4/2,6: lacrimation, but eye irritation was still tolerable; one had copious nasal secretion that was associated with “stinging” nasal pain; all had scratchy and burning sensations in the throat, without cough 2,4: eye irritation was perceived by all as stinging and uncomfortable with lacrimation 2,6: effects similar to the 2,4-isomer 1.3 2,4/2,6: two individuals were able to remain in the room for 10 min; irritation was intolerable; several hours later, cold-like symptoms with cough persisted aSix healthy male volunteers were exposed to one concentration per day in random order. Source: data from Henschler et al. 1962.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 IARC (International Agency for Research on Cancer). 1985. Some Chemicals Used in Plastics and Elastomers. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans, Vol. 39. Lyon, France: IARC. Pp. 287–323. Karol, M.H., C.Dixon, M.Brady, and Y.Alarie. 1980. Immunologic sensitization and pulmonary hypersensitivity by repeated inhalation of aromatic isocyanates. Toxicol. Appl. Pharmacol. 53:260–270. Karol, M.H. 1983. Concentration-dependent immunologic response to toluene diisocyanate (TDI) following inhalation exposure. Toxicol. Appl. Pharmacol. 68:229–241. Karol, M.H. 1986. Respiratory effects of inhaled isocyanates. CRC Crit. Rev. Toxicol. 16:349–379. Kennedy, A.L., M.F.Stock, Y.Alarie, and W.E.Brown. 1989. Uptake and distribution of 14C during and following inhalation exposure to radioactive toluene diisocyanate. Toxicol. Appl. Pharmacol. 100:280–292. Kimmerle, G. 1976. Acute inhalation toxicity of diisocyanates, polymer isocyanates and coating systems on rats. Report No. 6200. Institute for Toxicology, Wuppertal-Elberfeld, Germany. Pp. 32. Kociba, R.J., D.G.Keyes, and E.L.Wolfe. 1979. Histopathological observations on selected tissues of Syrian hamsters exposed by inhalation to vapors of toluene diisocyanate (TDI) for 6 hours/day, 5 days/week for 4 weeks. Report No. NA-A-12. The Dow Chemical Company, Midland, MI. Pp. 5. Linaweaver, P.G. 1972. Prevention of accidents resulting from exposure to high concentrations of foaming chemicals. J. Occup. Med. 14:24–30. Loeser, E. 1983. Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluene-diisocyanate (80/20) in rats and mice. Toxicol. Lett. 15:71–81. Maestrelli, P., A.Di Stefano, P.Occari, G.Turato, G.Milani, F.Pivirotto, C.E. Mapp, L.M.Fabbri, and M.Saetta. 1995. Cytokines in the airway mucosa of subjects with asthma induced by toluene diisocyanate. Am J. Respir. Crit. Care Med. 151:607–612. Maxon, F.C. 1964. Respiratory irritation from toluene diisocyanate. Arch. Environ. Health 8:755–758. Ministry of Social Affairs and Employment (SDU Uitgevers). 2000. Nationale MAC (Maximum Allowable Concentration) List, 2000. Ministry of Social Affairs and Employment, The Hague, The Netherlands. Moller, D.R., R.T.McKay, I.L.Bernstein, and S.M.Brooks. 1986. Persistent airways disease caused by toluene diisocyanate. Am. Rev. Respir. Dis. 134:175–6. NCI (National Cancer Institute). 1979. Bioassay of 2,4-diaminotoluene for possible carcinogenicity. Technical Report Series No. 162, CAS No. 95–80–7, NCI-CR-TR-162. National Cancer Institute, National Institutes of Health, Bethesda, MD. NIOSH (National Institute for Occupational Safety and Health). 1996. Toluene 2,4-Diisocyanate. Documentation for Immediately Dangerous to Life or Health
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Concentrations (IDLHs). NIOSH, Cincinnati, OH [Online]. Available: http://www.cdc.gov/nios/idlh/584849.html. NIOSH (National Institute for Occupational Safety and Health). 1997. NIOSH Pocket Guide to Chemical Hazards. NIOSH, Cincinnati, OH [Online]. Available: http://www.cdc.gov/niosh/npg/npgd0621.html. NRC (National Research Council). 1993. Guidelines for Developing Community Emergency Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: National Academy Press. NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of commercial grade 2,4 (80%)- and 2,6 (20%)-toluene diisocyanate (CAS No. 26471–62–5) in F344/N rats and B6C3F1 mice (gavage studies). NTP-TR-251. National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC. Owen, P.E. 1983. The toxicity and carcinogenicity to rats of toluene diisocyanate vapour administered by inhalation for a period of 113 weeks Addendum report volume 1. Report No. 2507–484/1. Hazleton Laboratories Europe Ltd., Harrogate, England. Sangha, G.K., and Y.Alarie. 1979. Sensory irritation by toluene diisocyanate in single and repeated exposures. Toxicol. Appl. Pharmacol. 50:533–547. Scheerens, H., T.L.Buckley, T.Muis, H.Van Loveren, and F.P.Nijkamp. 1996. The involvement of sensory neuropeptides in toluene diisocyanate-induced tracheal hyperreactivity in the mouse airways. Br. J. Pharmacol. 119:1665–1671. Shiotsuka, R.N. 1987a. Sensory irritation study of MONDUR TDS in male Sprague-Dawley rats. Study no. 86–341–01. Stilwell, KS: Mobay Corporation. Shiotsuka, R.N. 1987b. Sensory irritation study of MONDUR TD-80 in Sprague-Dawley rats. Study no. 86–341–02. Stilwell, KS: Mobay Corporation. Skarping, G., T.Brorson, and S.Carsten. 1991. Biological monitoring of isocyanates and related amines III. Test chamber exposure of humans to toluene diisocyanate. Int. Arch. Occup. Environ. Health 63:83–88. Stevens, M.A., and R.Palmer. 1970. The effect of tolylene diisocyanate on certain laboratory animals. Proc. R. Soc. Med. 63:380–382. ten Berge, W.F., A.Zwart, and L.M.Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard. Mat. 13:301–309. Timchalk, C., F.A.Smith, and M.J.Bartels. 1992. Metabolic fate of 14C-toluene 2,4-diisocyanate in Fischer 344 rats. File number 10910. International Isocyanate Institute. Dow Chemical Co., Midland, MI. Timchalk, C., F.A.Smith, and M.J.Bartels. 1994. Route-dependent comparative metabolism of [14C]toluene 2,4-diisocyanate and [14C]toluene 2,4-diamine in Fischer 344 rats. Toxicol. Appl. Pharmacol. 124:181–190.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Tyl, R.W. 1988. Developmental toxicity study of inhaled toluene diisocyanate vapor in CD (Sprague-Dawley) rats. Project NA-AB-50. International Isocyanate Institute. Bushy Run Research Center, Export, PA. Tyl, R.W., and T.L.Neeper-Bradley. 1989. Two-generation reproduction study of inhaled toluene diisocyanate in CD (Sprague-Dawley) rats. Final report (51–576, dated 17 March 1989). Project NA-AB-50. International Isocyanate Institute. Bushy Run Research Center, Export, PA. Vandenplas, O., A.Cartier, H.Ghezzo, Y.Cloutier, and J.-L.Malo. 1993. Response to isocyanates: Effect of concentration, duration of exposure, and dose. Am. Rev. Respir. Dis. 147:1287–1290. Warren, D.L. 1994a. Respiratory sensitization study in guinea pigs: Controls challenged with 2,4- or 2,6- toluene diisocyanate (TDI). Project AM-AB-89-II. File number 11120. International Isocyanate Institute. Miles, Inc., Stilwell, KS. Warren, D.L. 1994b. Respiratory sensitization study with 2,4- or 2,6-toluene diisocyanate (TDI) in guinea pigs. Project AM-AB-89. File number 10992. International Isocyanate Institute. Miles, Inc., Stilwell, KS. Wazeter, F.X. 1964a. Six-hour acute inhalation toxicity study in rats. No. 100–012. International Research and Developmental Corp. Wazeter, F.X. 1964b. Acute inhalation exposure in male albino rats. No. 203–006. International Research and Developmental Corp. Weyel, D.A., B.S.Rodney, and Y.Alarie. 1982. Sensory irritation, pulmonary irritation, and acute lethality of a polymeric isocyanate and sensory irritation of 2,6-toluene diisocyanate. Toxicol. Appl. Pharmacol. 64:423–430. WHO (World Health Organization). 1987. Toluene diisocyanates. Environmental Health Criteria 75. Geneva: World Health Organization. Wilson, R.H., and G.L.Wilson. 1959. Toxicology of diisocyanates. J. Occup. Med. 1:448–450. Wong, K.-L., M.H.Karol, and Y.Alarie. 1985. Use of repeated CO2 challenges to evaluate the pulmonary performance of guinea pigs exposed to toluene diisocyanate. J. Toxicol. Environ. Health 15:137–148. Woolrich, P.F. 1982. Toxicology, industrial hygiene and medical control of TDI, MDI and PMPPI. Am. Ind. Hyg. Assoc. J. 43:89–97. Zapp, J.A. 1957. Hazards of isocyanates in polyurethane foam plastic production. Arch. Ind. Health 15:324–330.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX A LC50 Probit Plot FIGURE 4A-1 LC50 probit plot. Source: Duncan et al. 1962. Reprinted with permission from the American Industrial Hygiene Association Journal, copyright 1962, AIHA.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX B Derivation of AEGL Values Derivation of AEGL-1 Key study: Baur 1985 Toxicity end point: Asthmatic subjects experienced cough, rhinitis, chest tightness, dyspnea, throat irritation, and/or headache from exposure at 0.01 ppm for 1 h, and then, after a rest, at 0.02 ppm for another hour. Time-scaling: None Uncertainty factors: None—asthmatic people are considered a sensitive population Modifying factor: None 10-min AEGL-1: 0.02 ppm 30-min AEGL-1: 0.02 ppm 1-h AEGL-1: 0.02 ppm 4-h AEGL-1: 0.01 ppm 8-h AEGL-1: 0.01 ppm Derivation of AEGL-2 Key study: Henschler et al. 1962 Toxicity end points: Severe eye and throat irritation in humans exposed at 0.5 ppm for 30 min
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 Time-scaling: Cn×t=k (ten Berge et al. 1986; NRC 2001), n=3 for extrapolating to the 10-min time point, n=1 for extrapolating to the 1-, 4-, and 8-h time points Uncertainty factors: 3 for intraspecies variability (not protecting hypersusceptible individuals) Calculations: 10-min time point (C/UFs)3×t=k (0.5/3)3×0.5 h=0.0023 ppm3·h 1-, 4-, and 8-h time points (C/UFs)1×t=k (0.5/3)1×0.5 h=0.083 ppm·h 10-min AEGL-2: (0.0023 ppm3·h/0.167 h)=0.24 ppm 30-min AEGL-2: 0.5 ppm/3=0.17 ppm 1-h AEGL-2: (0.083 ppm·h/1 h)=0.083 ppm 4-h AEGL-2: (0.083 ppm·h/4 h)=0.021 ppm 8-h AEGL-2: 0.021 ppm Derivation of AEGL-3 Key Study: Duncan et al. 1962 Toxicity end point: The 4-h LC50 of 9.7 ppm in mice was used for derivation of AEGL-3 values. An approximate threshold for lethality is obtained by dividing the LC50 by 3. Time-scaling: Cn×t=k (ten Berge et al. 1986)
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 n=3 for extrapolating to the 10-min, 30-min, and 1-h time points; (3.23)3×4.0=135.21 ppm·h n=1 for extrapolating to the 8-h time point; (3.23)1×4.0=12.92 ppm·h Uncertainty factors: 10 (3 for intraspecies variability and 3 for interspecies variability Calculations: 10-min, 30-min, and 1-h time points (C/UFs)3×t=k (3.23/10)3×4h=0.135 ppm3·h 8-h time point (C/uncertainty factors)1×t=k (3.23/10)1×4 h=1.292 ppm·hr 10-min AEGL-2: 0.65 ppm 30-min AEGL-2: (0.135 ppm3·h/0.5 h)=0.65 ppm 1-hAEGL-2: (0.135 ppm3·h/1 h)=0.51 ppm 4-h AEGL-2: (3.23 ppm/10)=0.32 ppm 8-h AEGL-2: (1.292 ppm·h/8 h)=0.16 ppm
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 APPENDIX C DERIVATION SUMMARY ACUTE EXPOSURE GUIDELINE LEVELS FOR TOLUENE 2,4- AND 2,6-DIISOCYANATE (CAS Nos. 584–84–9 and 91–08–7) AEGL-1 10 min 30 min 1 h 4 h 8 h 0.02 ppm 0.02 ppm 0.02 ppm 0.01 ppm 0.01 ppm Key reference: Baur, X. 1985. Isocyanate hypersensitivity. Final report to the International Isocyanate Institute. III File No. 10349; III Project: E-AB-19. Test species/strain/number: Human subjects, gender not given; 10 healthy controls and 15 asthmatics Exposure route/concentrations/durations: Inhalation; 0.02 ppm for 2 h (controls); 0.01 ppm for 1 h, 45 min rest, 0.02 ppm for 1 h (asthmatics) Effects: Controls—significant increase in airway resistence (Raw) immediately and 30 min after beginning of exposure; eye irritation and/or cough. Asthmatics—no change in lung function parameters; chest tightness, rhinitis, cough, dyspnea, throat irritation, and/or headache End point/concentration/rationale: Some (5/15) asthmatic humans exposed for 1 h at 0.01 ppm and, after a 45 min rest, at 0.02 ppm for another hour experienced chest tightness, rhinitis, cough, dyspnea, throat irritation, and/or headache. Uncertainty factors/rationale: Total uncertainty factor: None Interspecies: Not applicable, human data used Intraspecies: 1, asthmatics were used as the test population Modifying factor: None Animal to human dosimetric adjustment: Not applicable Time-scaling: Extrapolation to time points was not conducted. Because the asthmatics tolerated 0.02 ppm for 1 h after pre-exposure at 0.01 ppm, it is assumed that this population could tolerate the lower concentration for a longer duration. Data quality and support for the AEGL values: AEGL-1 values are considered conservative and should be protective of the toxic effects of TDI outside those expected as defined under AEGL-1.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 AEGL-2 10 min 30 min 1 h 4 h 8 h 0.24 ppm 0.17 ppm 0.083 ppm 0.021 ppm 0.02 ppm Key reference: Henschler, D., Assman, W., and Meyer, K.-O. 1962. On the toxicology of toluenediisocyanate [in German]. Archiv. für Toxikologie 19:364–387 Test species/strain/number: Human, healthy male, 6 Exposure route/concentrations/durations: 0.01–1.3 ppm 2,4/2,6-, 2,4-, or 2,6-TDI for 30 min Effects: Effects were similar for both isomers and the mixture. 0.1 ppm: eye and nose irritation; ≥0.5 ppm: marked discomfort, lacrimation, nasal secretion (determinant for AEGL-2); 1.3 ppm: intolerable. End point/concentration/rationale: Humans exposed at 0.5 ppm for 30 min experienced pronounced irritation (marked discomfort, lacrimation, nasal secretion) Uncertainty factors/rationale: Total uncertainty factor: 3 Interspecies: Not applicaple, human data used Intraspecies: 3. The use of a higher uncertainty factor would make the AEGL-2 values similar to AEGL-1 values, which are based on levels that asthmatic humans can tolerate. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable Time-scaling: Cn×t=k where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an emphirically derived, chemical-specific exponent, scaling was performed using n=1 for extrapolating to the 10-min time point and n=3 for the 1- and 4-h time points. The 4-h value is also used for the 8-h value because extrapolation to 8 h resulted in a concentration similar to that causing mild effects in polyurethane foam sprayers exposed for >7 h (Hosein and Farkas 1981) and in manufacturing workers on 8-h shifts (Hama 1957). Data quality and support for the AEGL values: Some individuals with pre-existing bronchial hyper-reactivity have been shown to respond to TDI with nonpathologic bronchial obstruction (4/15), but no significant differences were observed in lung function parameters. AEGL-2 values also supported by animal data.
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 AEGL-3 10 min 30 min 1 h 4 h 8 h 0.65 ppm 0.65 ppm 0.51 ppm 0.32 ppm 0.16 ppm Key reference: Duncan, B., Scheel, L.D., Fairchild, E.J., Killens, R., and Graham, S. 1962. Toluene diisocyanate inhalation toxicity: pathology and mortality. Am. Indus. Hygiene Assoc. J. 23:447–456. Test species/strain/number: Mice, 120 total animals Exposure route/concentrations/durations: Inhalation, 0.1, 1.0, 2, 5, 10, 20, or 34 ppm for 4 h Effects: 9.7 ppm 4-h LC50 in the mouse: concentration dependent signs of toxicity included mouth breathing, lacrimation, salivation, and restlessness; Histopathologic examination of surviving animals: coagulation necrosis and desquamation of the superficial epithelial lining of the trachea and major bronchi, cleared by day 7 post-exposure in the 2 ppm group. End point/concentration/rationale: 3.23 ppm is an estimated lethality threshold obtained by dividing the 4-h mouse LC50 by 3. That is approximately equal to the LC01 obtained by extrapolating the probit plot in the Duncan et al. (1962) paper. Uncertainty factors/rationale: Total uncertainty factor: 10 Interspecies: 3. The LC50 was determined in the rat, guinea pig, rabbit, and mouse. The 4-h LC50 values ranged from 9.7 ppm in the mouse to 13.9 ppm in the rat. These results argue for low variability between species. In addition, the use of a higher uncertainty factor would place the AEGL-3 levels in the range of the AEGL-2 values, which were set based on human data. The most sensitive species, the mouse, was used to derive the AEGL-3 values. Intraspecies: 3. Use of a greater uncertainty factor would result in values below those supported by human data for AEGL-3 effects. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable Time-scaling: Cn×t=k where n ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of an empirically derived, chemical-specific exponent, scaling was performed using n=1 for extrapolating to the 30-min and 1-h time points and n=3 for the 8-h time point. The 10-min AEGL-3 value was flatlined from the 30-min value. Data quality and support for the AEGL values: Presensitized individuals might exist in the general population, but the rate of sensitization cannot be predicted. If the rate of sensitization to TDI in the general population were
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Acute Exposure Guideline Levels for Selected Airborne Chemicals, Volume 4 quantifiable, the committee might have considered lower values for AEGL-3. At the AEGL-3 levels, individuals who have a stronger reaction to TDI might not be protected from severe effects. The mouse appears to be the most sensitive species tested, although LC50 values did not vary greatly.
Representative terms from entire chapter: