Acute Exposure Guideline Levels for Selected Airborne Chemicals Volume 3 (2003) / Chapter Skim
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4. Diborane: Acute Exposure Guideline Levels
4. Diborane: Acute Exposure Guideline Levels
Pages 444-497
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From page 444... ...
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 445... ...
Animals exposed to lethal and nonlethal concentrations developed pulmonary hemorrhage, congestion, and edema, and death was related to these severe pulmonary changes. Recent studies in rats and mice have also uncovered the development of multifocal andlor diffuse inflammatory epithelial degeneration in the bronchioles following exposure to diborane.
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From page 446... ...
Further support for the UF of 3 is that signs of toxicity and repair of pulmonary lesions following acute exposure to nonlethal concentrations of diborane in animals were consistent with the human response reported by case reports. There appears to be a similar mechanism of toxicity among species because the cause of death from diborane exposure is due to acute pulmonary damage, including edema, hemorrhage, and congestion.
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From page 447... ...
Although n values have generally been derived using lethality data, it was considered appropriate in this case to use the nonlethal pulmonary changes. Toxicity studies demonstrated that the lung remained the target organ at al1 concentrations of exposure, and the biological response remained the same, becoming more severe with increasing concentration until death occurred from anoxia as a consequence of severe pulmonary changes.
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From page 448... ...
448 o · _1 no,, Cal Ct ¢ o V: Ed sly at as i_ .= o Do _ .E o .= o _ o .
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From page 449... ...
Because of its strong reducing character, diborane has many industrial uses; it is used as a rubber vulcanizer, a catalyst for olefin polymerization, an intestate in preparation of other boron hydrides, and a doping gas in the semiconductor industry (Budavari et al.
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HtJMAN TOXICITY DATA 2.~. Acute Lethality LCso values in humans have been reported to be 159 ppm for 15 min.
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From page 451... ...
In this paper, Rozendaal compared the symptoms that developed following diborane exposure with those of"metal fume fever." Lowe and Freeman (1957) conducted a survey of dispensary records and laboratory data from 83 people who were potentially exposed to boron hydrides during a 3 y period.
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There were 33 reported cases of subacute exposures, with ~ cases of respiratory involvement. Symptoms associated with exposure to low concentrations for longer periods included chest tightness, nonproductive cough, lightheadedness, headache, fatigue, and drowsiness.
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From page 453... ...
Commonly reported signs and symptoms associated with acute diborane exposure included chest tightness, nonproductive cough, dyspnea, precordial pain, fatigue, and wheezing. The symptoms developed shortly after exposure, and generally disappeared within a week.
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One of these dog's EEG returned to normal, while the other dog exhibited depressed cortical activity followed by bradycardia and finally ventricular fibrillation leading to death. Pulmonary edema was found in the dog during necropsy.
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Groups of 10 albino rats were exposed at approximately 175 ppm in a gas chamber for 15 min and then observed up to 10 ~ following exposure. Although some therapeutic drugs produced a slight decrease in mortality rate, all animals exposed to diborane had evidence of pulmonary edema and hemorrhage upon postmortem examination.
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study has been criticized for its lack of control data (for the acute study) , limited pathological data (especially the lack of changes in both rats and guinea pigs)
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, approximately 2.5 to 3 mo old, were exposed to various concentrations of diborane in a dynamic exposure chamber for 4 h (actual exposure concentrations not provided) (Iacobson and Lawson 1962~.
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by head exposure to an unknown concentration of diborane gas until the animals died. These rabbits were anesthetized by intravenous administration of approximately 30 mg pentobarbital sodium per kilogram body weight.
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From page 459... ...
In one experiment, three dogs were exposed to diborane at 6-14 ppm for 45 min to 4 h. The results of testing during this exposure period showed normal electrocardiograms, no effects on blood pressure, and only slight increases in respiration; however, postmortem examination showed severe pulmonary hemorrhages and slight pulmonary edema.
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From page 460... ...
Rats were placed in a dynamic exposure chamber, and diborane concentrations were measured at 1-min intervals with a toxic gas monitor. In the first phase of the study, groups of ~ O rats (~-wk-old)
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Histopathological examination revealed inflammatory epithelial degeneration in the bronchioles in the high-concentration group. Groups of 12 14-wk-old male Wistar rats were exposed at 0.
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From page 462... ...
The one dead mouse from the 8-h exposure group had findings consistent with pulmonary irritation, including mucous exudate, degeneration andnecrosis ofthe epithelial lining, and inflammatory cellular infiltration in the nasal cavity. Groups of 10 5-wk-old male ICR mice were exposed to diborane at 15 ppm for 4 h and sacrificed immediately, ~ 6, 3 6, or 2 wk after exposure, and controls were exposed to filtered room air for 4 h and sacrificed immediately or 2 wk after exposure (Uemura ~ 996~.
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Peribronchiolar thickening and infiltration of inflammatory cells into the bronchiolar walls were observed where inflammatory epithelial degeneration had previously been detected. Infiltration of lymphocytes into the subepi
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Exposures were conducted in an exposure chamber, and diborane concentrations were measured at Imin intervals with a toxic gas monitor. For the acute study, groups of 10 mice were exposed at ~ or 5 ppm for I, 2, 4, or ~ h, and control mice were exposed to filtered room air.
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(1995) investigated the effects of repeated inhalation exposures of diborane in 5-wk-old male ICR mice.
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1996~. Diborane concentrations were measured at 1-min intervals using a toxic gas monitor.
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From page 467... ...
Pathological changes resulting from acute diborane exposures included pulmonary edema, congestion, and hemorrhage. Recent studies in rats and mice have also uncovered the development of multifocal andJor diffuse inflammatory epithelial degeneration in the bronchioles following exposure to diborane.
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468 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED AIRBORNE CHEMICALS TABLE 4-5 Summary of Acute Lethal Inhalation Data in Laboratory Animals Concentration Exposure Species (ppm) Time Effect Reference Dog 350 15 min Death—pulmonary Kunkel et al.
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From page 469... ...
469 Cq in C<, ·_.
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470 x is UO A al C)
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From page 471... ...
471 Ct oo Cal ° ~ ~ ° ~ of o ~ ~m o X ~ ~ ._ ~ ._ ~ ~ 33 e a ° D D ~~ ~ ~ ~ D =~ · ~ at ~ O O O ~ an ~ ~ ~ 0 .~ ~ O ~ O O .= ~ o — ·= — ~4 .= q)
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From page 472... ...
It is likely that the mechanism of toxicity is due to direct interaction of diborane with cellular components, especially since diborane is such a potent reducer. There appears to be a similar mechanism of toxicity between species because the respiratory tract has consistently been the target organ, and the cause of death from diborane exposure has always been from pulmonary damage, including edema, hemorrhage, and congestion.
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From page 473... ...
Toxicity studies demonstrated that the lung remained the target organ at all concentrations of exposure, and the biological response remained the same, becoming more severe with increasing concentration until death occurred from anoxia
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DATA ANALYSTS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 The only quantifiable human data available was the reported odor threshold range of 24 mg/m3 (~.~-3.6 ppm)
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From page 475... ...
Further support of a value of 3 is that signs of toxicity and repair of pulmonary lesions following acute exposure to nonIethal concentrations in animals were consistent with the human response reported by case reports. There appears to be a similar mechanism oftoxicity between species because the cause of death from biborane exposure has always been from pulmonary damage, including edema, hemorrhage, and congestion.
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19964. The use of a higher UP would result in AEGL values that would be below concentrations causing effects in any species for an end point that is supposed to be disabling or cause irreversible effects in a human population.
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~ 995~. Mice exposed at ~ 5 ppm for 4 h developed pulmonary changes including edema, congestion, and inflammatory epithelial degeneration that were generally resolved or in the process of being resolved within 14 ~ postexposure (Uemura 1996~.
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From page 478... ...
The AEGL-2 was based on the lowest diborane concentration at which histopathological changes become evident in mate ICR mice. These lesions consisted of multifocal and/or diffuse severe inflammatory epithelial degeneration in the respiratorybronchioles.
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Abbreviation: NR, not recommended. in Figure 4-1 plots the diborane AEGL values along with the existing acute animal toxicity data for diborane in terms of the categories assigned to them.
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From page 480... ...
(AIHA 1996) The ERPG- 1 is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild, transient adverse health effects or without perceiving a clearly defined objectionable odor.
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However, nothing is known about the actual exposure concentrations. Data in animals have shown concentration-dependent respiratory effects including reversible histological respiratory lesions and pulmonary edema, hemorrhage, and/or congestion leading to death.
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I.~.l;4" FIGURE 4-1 Category plot of animal toxicity data compared to AEGL values. signs of toxicity and repair of pulmonary lesions following acute exposure to nonlethal concentrations in animals were consistent with the human response reported by case reports.
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1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution.
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1996. Development of pulmonary lesions following acute exposure to diborane in male ICR mice.
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1995. Acute and subacute inhalation toxicity of diborane in male ICR mice.
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Appendixes
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(1995) Toxicity end point: LOAE1: for inflammatory epithelial degeneration in the bronchioles in male TCR mice (4/10)
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From page 489... ...
used to generate a 4-h LCO! in male ICR mice were given in the study.
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490 ACUTE EXPOSURE GO/DEL/NE LEVELS FOR SELECTED A/RBORNE CHEM/CALS Intraspecies: 3 Calculations: (C/uncertainty factors~n x t = k (~9.17 ppm]
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From page 491... ...
(1995) investigating 1-, 2-, and 4-h exposures at 1, 5, or 15 ppm, with multifocal and/or diffuse inflammatory epithelial degeneration in the bronchioles as the end point of toxicity.
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From page 492... ...
ECso values were derived by probit analysis of the data, and were then analyzed using a linear regression analysis of the Tog-Iog transformation of a plot of C versus t to derived a value of n for diborane. The derived EC50 for the 1-, 2-, and 4-h exposures were 9.68, 5.07, and 2.72 ppm, respectively.
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From page 493... ...
End point/concentrationlrationale: 5 ppm for 2 h resulted in reversible inflammatory epithelial degeneration in the bronchioles. Uncertainty factors/rationale: Total uncertainty factor: 10 Interspecies:3- An interspecies UF of 3 was applied because the most sensitive species, the mouse, was used, and the end point of
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From page 494... ...
Data adequacy: Human case reports of accidental workplace exposure to diborane report reversible signs and symptoms of exposure including chest tightness, shortness of breath and dyspnea, wheezing, nonproductive cough, and precordial pain. However, nothing is known about the actual exposure concentrations.
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From page 495... ...
Uncertainties remain about interindividual variabilities in the toxic response to diborane, but the category plot (Figure 4-1) demonstrates that the AEGL values should be protective.
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From page 496... ...
. The lung was the target organ in all species tested, and the biological response remained the same, becoming more severe with increasing concentrations until death occurred from anoxia as a consequence of severe pulmonary changes.
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From page 497... ...
Lethality data from animals were considered appropriate for development of an AEGL-3 because the lung was the target organ in all species tested, and the biological response remained the same, becoming more severe with increasing concentrations until death occurred from anoxia as a consequence of severe pulmonary changes. Uncertainties remain about interindividual variabilities in the toxic response to diborane, but the category plot (Figure 4-1)
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