Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 4 (2004) / Chapter Skim
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Appendix 4: Toluene 2,4- and 2,6- Diisocyanate: Acute Exposure Guideline Levels
Appendix 4: Toluene 2,4- and 2,6- Diisocyanate: Acute Exposure Guideline Levels
Pages 198-249
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From page 198... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subcommittee on Acute Exposure Guideline Levels.
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From page 199... ...
In the referent group, there was a significant increase in airway resistance immediately and at 30 min after the initiation of exposure, but none ofthe 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.
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From page 200... ...
In the absence of en empirically derived, chemical-specif~c exponent, scaling was performed using n = 3 for extrapolating to the 30-min and 1 -h time points and n = 1 for the S-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)
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From page 201... ...
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)
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HUMAN TOXICITY DATA 2.1. Acute Lethality Human fatalities from TDI exposure are not common.
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. This study neither identified the isocyanate isomers nor correlated the prevalence of clinical signs in the workers and the exposure concentrations and durations.
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From page 204... ...
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.
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From page 205... ...
Ithough the mean exposure values determined in this study are close to the detection limit ofthe 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.
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From page 206... ...
Five ofthe 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 ofthe symptoms lasted for several hours post-exposure.
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From page 207... ...
In 10 individuals with positive methacholine challenge tests, 2,4-TDI inhalation challenge testing et up to 20 ppb (142 ~g/m3) for 15 min resulted in no change in LEVI (Moller et al.1986~.
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From page 208... ...
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 uncomfort able 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 uncomfort able 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 mini 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.
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From page 209... ...
Pulmonary effects after TDI inhalation may be either a direct irritant response or the result of an immunologic sensitivity that develops over time. Generally, exposure at <0.02 ppm does not elicit a response; however, asthmatic subjects may develop minor irritation and subclinical increases in Raw at that concentration.
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From page 210... ...
At concentrations above 5 ppm, mouth-breathing was observed after 1 h of exposure. Histopathologic examinations ofthe respiratory tracts off~ve animals per group per time point revealed focal coagulation necrosis and desquamation of the superficial epithelial lining of the trachea and major bronchi.
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From page 211... ...
At concentrations above 5 ppm, mouth-breathing was observed after 1 h of exposure. Among surviving animals, histopathologic examination of the respiratory tracts of five animals per group per time point revealed focal coagulation necrosis and desquamation ofthe superficial epithelial lining of the trachea and major bronchi.
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From page 212... ...
At concentrations above 5 ppm, mouth-breathing was observed after 1 h of exposure. Histopathologic examination of the respiratory tracts of five animals per group per time point revealed focal coagulation necrosis and desquamation of the superficial epithelial lining ofthe trachea end major bronchi.
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From page 213... ...
were exposed head-only for 5 4,3 hid at concentrations ranging from 0.12 ppm to 7.60 ppm. Sensory irritation was measured as decreased respiratory rate.
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From page 214... ...
Furthermore, the data showed that both 2,4- and 2,6-TDI caused sensitization in the guinea pigs, and that either isomer elicited a hypersensitive reaction regardless of the isomer used for sensitization. However, at necropsy, only the animals given sensitization and challenge exposures to 2,6-TDI showed an increase in red zones in the lungs, suggesting that 2,6-TDI is more irritating than 2,4-TDI.
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From page 215... ...
Of particular interest, however, was the initial sharp drop in respiratory rate during the first 15 min. followed by a gradual decline during the remainder of the exposure period.
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From page 216... ...
It is apparent from the development ofthe response and the C x t values that respiratory irritation is mainly dependent on concentration and only slightly dependent on duration of exposure. In another series of experiments, those same authors showed that the decrease in respiratory rate was due to irritation ofthe upper respiratory tract, because exposure by intratracheal instillation failed to result in decreased respiratory rate (Sangha and Alarie 1979~.
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From page 217... ...
3.4. Genotoxicity No information was found regarding potential genotoxicity of TDI in laboratory animals.
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From page 218... ...
In a series of LC50 experiments with rats, mice, guinea pigs, and rabbits, animals exhibited concentration-dependent signs of toxicity during exposure such as mouthbreathing, lacrimation, salivation, andrestlessness. Histopathologic examination of the respiratory tract revealed focal coagulation necrosis and
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From page 219... ...
219 as sit as so as o o .~ an Ct .~ Cal ·_I Em ·_I ¢ V]
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From page 220... ...
1991~. Male Hartley guinea pigs were exposed by whole-body inhalation to 4C-labeled 2,4-TDI for 1 h.
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From page 221... ...
1982~. Subchronic or chronic inhalation studies in rats, mice, and hamsters indicate that the nasal turbinates are the primary target organ in rodents and that the frank pathology there can be attributed to direct chemical deposition and irritation (Kociba et al.1979; Loeser 1983; Owen 1983~.
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From page 223... ...
Both delayed- and immediate-type hypersensitivity reactions occurred in all sensitized groups. Furthermore, the data showed that both 2,4-TDI and 2,6-TDI caused respiratory sensitization in the guinea pigs, and that either isomer elicited a hypersensitive reaction regardless ofthe isomer used for sensitization.
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From page 224... ...
Systemic effects have been well-documented after MIC inhalation exposure but not after TDI exposure. For example, in laboratory animal studies, the fetal and neonatal deaths resulting from inhalation exposure to MIC did not occur following maternal exposure to TDI.
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From page 225... ...
The guinea pig has been studied extensively as a model for TDI-induced asthma. However, pulmonary hyper-reactivity in guinea pigs only develops in sensitized animals challenged with TDI-protein conjugate (Karol et al 1980~.
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From page 226... ...
In the healthy referent group, there was a significant increase in airway resistance immediately after and 30 min after the beginning 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.
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From page 227... ...
Extrapolations across time were not performed. Because the asthmatic subjects tolerated 0.02 ppm for 1 h afterpre-exposure at 0.01 ppm, it is assumed that the asthmatic population could tolerate the lower concentration for a longer duration.
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From page 228... ...
The O.O1-ppm exposure concentration for the longer time points is reasonable because data suggest that the adverse health effects of inhaled TDI are more concentration-dependent than durationdependent. Controlled inhalation at 0.02 ppm was tolerated by asthmatic subjects for 1 h.
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From page 230... ...
Decreased respiratory rate in the mouse model has been shown to correspond with sensory irritation in humans. When an irritant such as TDI enters the nasal mucosa, the trigeminal nerve endings are stimulated, resulting in an inhibition of respiration (Alarie 1981~.
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From page 231... ...
Also, complaints of respiratory irritation occurred in both asthmatic subjects and healthy controls (Baur 1985~.
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From page 232... ...
Reported human fatalities occurred under unusual circumstances, and exposure concentrations were not measured. Acute exposure reports emphasize that the respiratory tract is the primary target, and pulmonary edema develops subsequent to the irritation brought on by the corrosive properties of TDI.
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From page 233... ...
Presensitized individuals might exist in the general population, but the rate of TDI sensitization cannot tee predicted. If the rate of sensitization in the general population were quantifiable, the committee might have considered a different approach to derivation of AEGL values.
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From page 234... ...
for 2,4TDI is 0.02 ppm (OSHA 1995~. The IDLH is based on acute inhalation toxicity data in animals, but was not based on data obtained from the exposures of humans or animals sensitized to TDI (NIOSH 1996~.
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From page 235... ...
The IDLH for TDI is based on acute inhalation toxicity data in animals, but is not based on data obtained from the exposures of individuals or animals already sensitized to TDI. CACGIH TLV-TWA (Threshold Limit Value-time-weighted average of the American Conference of Governmental Industrial Hygienists)
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From page 236... ...
Because the nonlethal and lethal effects in humans and animals are qualitatively similar, the animal data were considered relevant and appropriate for developing AEGL values as described in the standing operating procedures of the National Advisory Committee for AEGLs (NRC 2001~. The most notable data deficiencies were the absence of quantitative human exposure data, the absence of a well-def~ned exposure-response curve for the toxic effects in animals, a lack of understanding of individual variability in the toxic response to TDI, and a lack of information on the extent of cross-reactivity between isocyanates.
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From page 237... ...
A five year longitudinal study of polyurethane foam workers. III Report No.
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From page 238... ...
1977. Toluene Di-isocyanate: Acute Inhalation Toxicity in the Rat.
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From page 239... ...
1989. Uptake and distribution of 14C during and following inhalation exposure to radioactive toluene diisocyanate.
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From page 240... ...
2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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From page 241... ...
1994a. Respiratory sensitization study in guinea pigs: Controls challengedwith2,4- or2,6- toluene diisocyanate (TDI)
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From page 242... ...
: 14 D} vY LCso 1 · Rat 13.9 + 1 . 52 X Guinea Pig 12.7 + 2.66 Rabbit 11.0 *
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From page 243... ...
1962 Toxicity end points: Severe eye and throat irritation in humans exposed at 0.5 ppm for 30 min
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From page 244... ...
1986; NRC 2001) , n = 3 for extrapolating to the 10-min time point, n = 1 for extrapolating to the 1-, 4-, and S-h time points Uncertainty factors: 3 for intraspecies variability (not protecting hypersusceptible individuals)
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From page 245... ...
TOLUENE 2,4- AND 2,6-DIISOCYANATE 245 n = 3 for extrapolating to the 10-min, 30-min, and 1 h time points; (3.23~3 x 4.0 = 135.21 ppm h n = 1 for extrapolating to the S-h time point; (3.23~ x 4.0 = 12.92 ppm h Uncertainty factors: 10 (3 for intraspecies variability and 3 for interspecies variability Calculations: 10-min, 30-min, anc! 1-h time points (~C/UFs)
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From page 246... ...
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.
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From page 247... ...
Data quality and support for the AEGL values: Some individuals with preexisting 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.
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From page 248... ...
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.
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From page 249... ...
TOLUENE 2,4- AND 2,6-DIISOCYANATE 249 AEGL-3 Continued 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.
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