Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 3 (2003) / Chapter Skim
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3. Methyl Isocyanate: Acute Exposure Guideline Levels
3. Methyl Isocyanate: Acute Exposure Guideline Levels
Pages 384-443
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From page 384... ...
Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Subco~uttee on Acute Exposure Guideline Levels.
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From page 385... ...
Placental weights and fetal body weights were significantly reduced at all concentrations. Exposures to concentrations at 9 ppm and 15 ppm resulted in deaths of two dams in each group, a significant increase in complete litter resorption among surviving dams, and fetuses with significant reduc
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From page 386... ...
The experimental concentrations were reduced by a factor of 3 to estimate a threshold for effects on cardiac arrhythmias or fetal body weights. A total uncertainty factor (UF)
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From page 387... ...
~ 985~. Signs of severe respiratory tract irritation were reported for victims of the Bhopal disaster and autopsies reveaTed the cause of death to be pulmonary edema (Varma and Guest ~ 993~.
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From page 388... ...
HUMAN TOXICITY DATA 2.1. BhopalDisaster On the night of December 2/3, 1984, an estimated 30 tons of MTC gas were released over Bhopal, India from a carbamate factory when water entered the storage tank.
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The most frequently reported symptoms were burning and/or watering of the eyes, coughing, respiratory distress, pulmonary congestion, nausea, vomiting, muscle weakness, and CNS involvement secondary to hypoxia (Kamat et al. 1985; Misra et al.
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From page 390... ...
Of interest here are reports comparing the effects of MIC with effects following exposure to related chemicals. In general, isocyanate exposures produce immunologic sensitization.
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From page 391... ...
No exposure concentrations or durations were given (Union Carbide 1973~. Another letter (Union Carbide 1966)
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From page 392... ...
Additional experimental details were not available. In a slightly larger study, seven mate volunteers were exposed to nominal concentrations at 0.3, 1.0, 2.5, or 5.0 ppm for 1 min or ~ ppm for 10 min (Mellon Institute 1963a)
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From page 393... ...
Ofthe 486 live births, 14.2% of the infants died within 30 ~ as compared with a background infant death rate of 2.6-3%. None of these surveys reported stage of pregnancy et the time of exposure, severity of maternal symptoms, or concentrations or duration of exposure.
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ANIMAL TOXICITY DATA 3.~. Acute Lethality LC50 values for guinea pigs, rats, and mice are summarized in Table 34.
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1985, (male and female) 1986 Guinea pigs Not stated 10.6 4 Mellon Institute (not stated)
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From page 396... ...
3.~.2. Guinea Pigs Groups of eight mate English short-haired guinea pigs were exposed for 3 h to analytical concentrations of MIC at 6, 13, 19, 27, or 37 ppm (Ferguson and Alarie 1991~.
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Severity of these lesions was concentration-related, and epithelial regeneration was observed in survivors (Fowler and Dodd 1 9 8 5, 1 9 8 6~. Female Hartley guinea pigs (minimum of four per group)
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From page 398... ...
Groups of four mate guinea pigs were exposed to "metered" (nominal) concentrations of MIC at ~ 5.63, 3 ~ .25, or 62.5 ppm for 4 h followed by a 14-d observation period (Mellon Institute 1966~.
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From page 399... ...
Clinical signs included lacrimation and/or perinasal wetness, irregular or labored breathing, decreased activity, and ataxia as well as body-weight Toss during the observation period. Gross observations included dark red to brown material encrusted around the mouth, nares, and eyes and lung congestion.
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From page 400... ...
Female Wistar rats (N= 5 to 8) were exposed whole-body to analytical concentrations of MIC at 297, 420, 528.7, or 665.7 ppm for 30 min in a static exposure chamber (Vijayaraghavan and Kaushik 1987~.
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Upon removal from the chamber, concentration-related clinical signs included weakness, ruffled fur, respiratory distress (gasping, moist rates, open mouth, abdominal breathing) , and decreased body-weight gain.
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Male LAC:P rats (N= 3/concentration/time point) were exposed whole-body to MIC for ~ h in a static exposure chamber, and lesions of the respiratory tract were assessed at various time points over 3 wk.
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From page 403... ...
Following exposure at 105 ppm, one animal died 10 dpostexposure, and another died 6 wk postexposure. Animals exposed at 105 ppm were examined for ultrastructural changes in the respiratory tract.
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From page 404... ...
Additional details on the exposure system, generation of the test atmospheres, and monitoring of chamber concentrations were not provided. Histological lesions in the lungs of mate Lister rats were assessed up to 10 wk following a single 30-min exposure to nominal concentrations at 233, 465, or 930 ppm in static exposure chambers.
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From page 405... ...
Clinical signs included lacrimation, dyspnea, nasal discharge, and gasping (Eastman Kodak 19661.
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From page 406... ...
Clinical signs at 25.4 ppm included lacrimation and/or perinasal wetness, irregular or labored breathing, decreased activity, ataxia, and/or hypothermia as well as body-weight loss in all treated groups during the observation period. Gross observations included mild perinasal exudate and discoloration of the lungs.
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From page 407... ...
Guinea Pigs Tissue hypoxia and metabolic acidosis were observed in female Hartley guinea pigs (N= 2 to 3) statically exposed at 240 or 628 ppm for 15 min (Fedde et al.
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The potential of inhaled MIC to cause respiratory sensitization was investigated in guinea pigs (Mellon Institute 1970~. Adult mate albino guinea pigs were exposed to an analytical concentration at ~ ppm for 2 in/d, 3 times per week for 3 wk.
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From page 409... ...
but details of deaths were not reported. Body weights of rats exposed at 10 ppm were significantly decreased throughout the 6-mo study.
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Group mean values for maternal body weights, fetal weights, and placental weights were significantly ~ ~ 0.05; Student's l-test) reduced to 87%, 82%, and 85°/O, respectively, of the control levels.
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1994~. Concentration-related decreases in maternal body weights occurred during gestation, and average fetal body weights and lengths were reduced in all treated groups.
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In a dominant lethal assay, 24 male Wistar rats were exposed using a whole-body protocol to MIC at 1,344 ppm for ~ min in a static exposure chamber and sequentially mated to unexposed females for 3 wk (Agarwal and Bose 1992~. Total deaths among exposed males during days 1-7, 8-14, and 15-21 were 13, 5, and 3, respectively.
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From page 413... ...
~989~. MTC failed to induce mutations in any of five strains of Salmonella or in the Drosophila sex-linked recessive lethal assay following exposure of mates by inhalation, feeding, or injection (Mason et al.
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From page 414... ...
Maternal toxicity was observed in both species following exposures at z9 ppm. Fetal body weights were decreased following a single maternal exposure at 9 ppm for 3 h in rats and at ~2 ppm for 3 h in mice (Varma et al.
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The uptake and distribution of '4C-MIC was measured in arterial blood of guinea pigs following exposure to concentrations at 0.5-15 ppm for periods of 1-6 h (Ferguson et al.
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In addition, lesions ofthe respiratory tract of guinea pigs were more severe than lesions observed in rats and mice. Mice and rats are generally obligate nasal breathers, whereas guinea pigs are optimal mouth breathers when exposed to respiratory irritants.
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, ocular and upper respiratory tract irritation and lacrimation were reported after exposure at 0.5 ppm for 10 min (Mellon Institute 1970) and at ~ ppm for 10 min (Mellon Institute 1963a)
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respectively, and nose and throat irritation were reported by 3/7 after 9 min (Mellon Institute 1963a)
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Placental weights and fetal body weights were significantly reduced at all MIC concentrations. Maternal toxicity was evident as deaths of two of the ~ ~ treated dams in the 9- and 1 5-ppm groups and decreased maternal body weights at ~ 5 ppm.
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(0.02) for effects on fetal body weight and cardiac arrhythmias.
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From page 421... ...
exposed at 9 ppm for 3 h on GD 10 or 8, respectively, had increased resorptions and decreased maternal body weights, fetal body weights, and placental weights.
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AEGL-2 is based on Tower fetal body weights in mice and cardiac arrhythmias in rats. AEGL-3 is based on decreased neonatal survival in mice.
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From page 423... ...
The ERPG-3 was based on nonlethal acute inhalation data in mice and guinea pigs (5.4 ppm for 6 h and 10.6 ppm for 2 h, respectively) and the ~ -h LCso of 41.3 ppm in rats; in contrast, the AEGL-3 was based on fetotoxicity in rodents following maternal exposure during gestation.
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From page 424... ...
The ERPG-1 for MIC is teased onbeliefthat nearly all individuals could tee exposed to this concentration without experiencing or developing serious effects. The ERPG-2 is the maximum airborne concentration below which it is believed nearly
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From page 425... ...
The ERPG-3 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing life-threatening health effects. The ERPG-3 for MIC is based on acute inhalation data in which exposure of 5.4 ppm for 6 h were nonlethal in mice, 10.6 ppm for 2 h was nonlethal in guinea pigs, and the 1-h LC50 for rats is 41.3 ppm.
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From page 426... ...
Animal data have shown concentrationdependent effects including irritation and histological lesions ofthe respiratory tract, developmental toxicity, and neonatal and adult lethality. Because the nonlethal and lethal effects in humans and animals are qualitatively similar, the animal data were considered relevant and appropriate for development of AEGL values as described in the standing operating procedures of the National Advisory Committee for AEGLs.
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From page 427... ...
1987. Sensory and pulmonary irritation of methyl isocyanate in mice and pulmonary irritation and possible cyanidelike effects of methyl isocyanate in guinea pigs.
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1981. Methyl isocyanate four-hour acute LCso inhalation study on rats and guinea pigs.
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1985. Respiratory tract changes in guinea pigs, rats, and mice following acute exposure to methyl isocyanate vapor.
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1993. Autoradiographic analyses of guinea pig airway tissues following inhalation exposure to 14Clabeled methyl isocyanate.
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1970. Acute inhalation toxicity, human response to low concentrations, guinea pig sensitization, and cross sensitization to other isocyanates.
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2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals.
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1987. Ultrastructural changes in the nasal mucosa of Fischer 344 rats and B6C3F1 mice following an acute exposure to methyl isocyanate.
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1993. The Bhopal accident and methyl isocyanate toxicity.
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Appendixes
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From page 437... ...
( 1 987) Toxicity end point: Decreased fetal body weights in offspring from mice exposed at 2 ppm for 3 h on GD ~ and cardiac arrhyth mias in rats exposed at 3 ppm for 2 h; the concentra tions were reduced by a factor of 3 to estimate a threshold for effects.
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From page 438... ...
A factor of 10 was applied for intraspecies variation because the mechanism of ac tion for developmental toxicity is unknown.
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METHYL /SOCYANATE 439 Calculations: (Ci/uncertainty factors)
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From page 440... ...
. Effects: 2, 6, 9, and 15 ppm, reduced fetal body weights; 9 and 15 ppm, increases in complete litter resorption and maternal mortality; 30 ppm, mortality of all animals; 10 ppm, increased minute ventilation during CO2 challenge and increased wet and dry lung weights 4 mo after exposure; 3 and 10 ppm, increase in cardiac arrhy~mias 4 mo after exposure.
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From page 441... ...
Modifying factor: None Animal to human dosimetric adjustment: Insufficient data Time scaling: Cat x t = k Data quality and support for the AEGL values: AEGL-2 values for MIC were based on two well conducted animal studies and are supported by human data.
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From page 442... ...
Modifying factor: none Animal to human dosimetric adjustment: Insufficient data Time Scaling: C1 x t = k Data quality and support for the AEGL values: AEGL-3 values for MIC were based on a well conducted animal study and supported by other animal data.
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From page 443... ...
~~ arm Ha APPENDIX D CAlECO~ PLOT FOR EM ISOC~41E 1 000.0 100.0 Ann 1 0.0 ~ 0 60 120 180 L .. 940 300 360 420 480 ~InU~S Hum - No EM Hum - D_Hu~ - Dada o Knit - No EM ante - D-~Unlay - Dawns Anti - Sag ~1 ante ^EOL FIGS D-1 Catego~plot of an ad ^1 data coaxed 10 AEOLvalues.
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