4
Diborane1

Acute Exposure Guideline Levels

SUMMARY

Diborane (CAS Registry No. 19287–45–7) is a highly unstable gas, and it is combustible upon exposure to moist air or high heat. The presence of some contaminants may lower the ignition temperature to at or below room temperature. Because of its strong reducing character, it has many industrial uses; it can be used as a rubber vulcanizer, as a catalyst for olefin polymerization, as an intermediate in the production of other boron hy-

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This document was prepared by the AEGL Development Team comprising Claudia Troxel (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances including James Holler (Chemical Manager) and Robert Benson and George Rodgers (Chemical Reviewers). The NAC reviewed and revised the document and AEGLs 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 based on 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 3 4 Diborane1 Acute Exposure Guideline Levels SUMMARY Diborane (CAS Registry No. 19287–45–7) is a highly unstable gas, and it is combustible upon exposure to moist air or high heat. The presence of some contaminants may lower the ignition temperature to at or below room temperature. Because of its strong reducing character, it has many industrial uses; it can be used as a rubber vulcanizer, as a catalyst for olefin polymerization, as an intermediate in the production of other boron hy- 1   This document was prepared by the AEGL Development Team comprising Claudia Troxel (Oak Ridge National Laboratory) and members of the National Advisory Committee (NAC) on Acute Exposure Guideline Levels for Hazardous Substances including James Holler (Chemical Manager) and Robert Benson and George Rodgers (Chemical Reviewers). The NAC reviewed and revised the document and AEGLs 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 based on 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 3 drides, and as a doping gas in the semiconductor industry. Diborane was also investigated in the 1950s as a potential rocket fuel. Data on acute exposures of humans to diborane were limited to case reports of accidental work-related exposures. Signs and symptoms of exposure included chest tightness, shortness of breath and dyspnea, wheezing, nonproductive cough, and precordial pain. Workers exposed to diborane generally experienced a complete recovery within a short period following cessation of exposure. No quantitative information was given regarding the exposure terms of these individuals, and the data were therefore unsuitable for derivation of AEGLs. No reports of human fatalities after diborane exposure were found in the literature. Reported odor thresholds range from 1.8 parts per million (ppm) to 3.6 ppm. Data on lethal and nonlethal consequences of diborane exposure were available for several animal species, including dogs, rats, mice, hamsters, rabbits, and guinea pigs. Fifteen-minute LC50 values in rats ranged from 159 ppm to 182 ppm, and 4-hour (h) LC50 values ranged from 40 ppm to 80 ppm in rats and 29 ppm to 31.5 ppm in mice. 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 and/or diffuse inflammatory epithelial degeneration in the bronchioles following exposure to diborane. These pulmonary changes produced by exposure to nonlethal concentrations were completely reversible in rats by 2 weeks (wk) after an acute exposure and were being repaired in the mouse by 2 wk postexposure. The signs of toxicity and repair of pulmonary lesions following acute exposure to nonlethal concentrations in animals were similar to the human case reports. It is likely that the mechanism of toxicity is due to direct interaction of diborane with cellular components, especially because diborane is such a potent reducer. There appears to be a similar mechanism of toxicity among species, because the cause of death from diborane exposure has always been from pulmonary damage, including edema, hemorrhage, and congestion. Mice appeared to be the more sensitive species, and the mice data were therefore used for the derivations of AEGLs. An AEGL-1 value was not recommended because the AEGL-2 value is below the odor threshold of diborane and no other data pertaining to end points relevant to AEGL-1 definition were available. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 The AEGL-2 values were based on reversible histological changes in the lungs in male ICR mice following a 2-h acute inhalation exposure to diborane at 5 ppm. No effects were observed in mice exposed at 5 ppm for 1 h, and exposure at 5 ppm for 2 h resulted in 4/10 mice developing multifocal and/or diffuse inflammatory epithelial degeneration in the bronchioles (Nomiyama et al. 1995). Studies have demonstrated that these lesions are reversible. There were no other treatment-related changes, such as changes in behavior, appearance, body or organ weight, or hematological or clinical chemistry indices. A total uncertainty factor (UF) of 10 was applied to the AEGL-2 value. An interspecies UF of 3 was applied because the most sensitive species, the mouse, was used and the end point of toxicity, reversible histological changes in the lungs, was the most sensitive end point. 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. An intraspecies UF of 3 was applied because using the default UF of 10 generates AEGL values that are inconsistent with existing empirical data. For example, the derived 1-h AEGL-2 value is 1.0 ppm with a total UF of 10. Mice exposed at 1 ppm for up to 8 h exhibited no effects of diborane exposure (Nomiyama et al. 1995). In addition, mice exposed at 0.7 ppm for 6 h/day (d), 5 d/wk for up to 4 wk developed only slight pulmonary infiltration of polymorphous neutrophils (Nomiyama et al. 1995) and rats exposed at 0.96 ppm for 6 h/d, 5 d/wk for 8 wk developed changes in bronchoalveolar lavage fluid that were not accompanied by histopathological changes (Nomiyama et al. 1996). The use of a higher UF 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. The AEGL-3 values were based on the estimate of a 4-h LC01 of 9.2 ppm obtained by log-probit analysis of data from a 4-h LC50 study in male ICR mice (Uemura et al. 1995). A total UF of 10 was applied to the AEGL-3 value. An interspecies UF of 3 was applied because there did not appear to be much variation between species in sensitivity to lethal concentrations of diborane. The 4-h LC50 values determined by different authors for mice and rats were within a factor of 2.8 (4-h LC50 values ranged from

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 29 ppm to 31.5 ppm in mice and from 40 ppm to 80 ppm in rats). 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. An intraspecies UF of 3 was applied because using the default UF of 10 generates AEGL values that are inconsistent with existing empirical data. For example, the derived 1-h AEGL-3 value is 3.7 ppm with a total UF of 10. Mice exposed at 5 ppm for up to 4 h developed only inflammatory epithelial degeneration in the bronchioles, with exposure for 8 h resulting in increased lung weights (Nomiyama et al. 1995). Mice exposed at 15 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 d postexposure (Uemura 1996). The use of a higher UF would result in AEGL values that would be below concentrations causing effects in any species for an end point which is supposed to be life-threatening in a human population. The derived AEGL values were scaled to 10-minute (min), 30-min, 1 -h, 4-h, and 8-h exposures using Cn×t=k. To calculate n for diborane, a regression plot of the EC50 values was derived from the studies by Nomiyama et al. (1995) and Uemura et al. (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. 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 all 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. From the regression analysis, the derived value of n=1 was used in the temporal scaling of all the AEGL values (C1×t=k; Haber’s law). The 10-min AEGL-3 value was set equal to the 30-min value of 7.3 ppm because the NAC considers it inappropriate to extrapolate from the exposure duration of 4 h to 10 min. Although it is considered appropriate to extrapolate from a 2-h exposure to a 10-min exposure duration in the AEGL-2 derivation, the 10-min value of 6.0 ppm would approach that of the 10-min AEGL-3 value of 7.3 ppm. Therefore, the 10-min AEGL-2 value was set equal to the 30-min value. The AEGL values are listed in the table below.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 4–1 Summary of AEGL Values for Diborane Classification 10 min 30 min 1 h 4 h 8 h End Point (Reference) AEGL-1 (Nondisabling) NRa NR NR NR NR Not recommended because the AEGL-2 value is below the odor threshold, and no other data pertaining to end points relevant to the AEGL-1 definition were available AEGL-2 (Disabling) 2.0 ppm (2.2 mg/m3) 2.0 ppm (2.2 mg/m3) 1.0 ppm (1.1 mg/m3) 0.25 ppm (0.28 mg/m3) 0.13 ppm (0.14 mg/m3) LOAEL for pulmonary changes in male ICR mice; 5 ppm for 2 h (Nomiyama et al. 1995) AEGL-3 (Lethality) 7.3 ppm (8.0 mg/m3) 7.3 ppm (8.0 mg/m3) 3.7 ppm (4.1 mg/m3) 0.92 ppm (1.0 mg/m3) 0.46 ppm (0.51 mg/m3) 4-h LC01 of 9.2 ppm estimated from a 4-h LC50 in male ICR mice (Uemura et al. 1995) aAbsence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. Abbreviation: NR, not recommended.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 1. INTRODUCTION Although the boron hydrides were first described in 1879, their possible uses were not investigated until the military became interested in their potential for use as rocket fuels in the 1950s (Rozendaal 1951; Stumpe 1960). The three most studied boron hydrides were pentaborane, a liquid, decaborane, a solid, and diborane, a gas. Diborane is highly unstable and can spontaneously combust at temperatures of 40–50 °C. The presence of contaminants may lower the ignition temperature to at or below room temperature (Budavari et al. 1996). It rapidly hydrolyzes in water to produce boric acid, hydrogen, and heat. Because of its strong reducing character, diborane has many industrial uses; it is used as a rubber vulcanizer, a catalyst for olefin polymerization, an intermediate in preparation of other boron hydrides, and a doping gas in the semiconductor industry (Budavari et al. 1996). “Certain base adducts of borane, BH3, such as (C2H5)3N.BH3 [1722– 26–5], (CH3)2S.BH3 [13292–87–0], tetrahydrofuranborane [14044–65–6], and C4H8O.BH3 are more easily and safely handled than B2H6 and are commercially available. They find wide use as reducing agents and in hydroboration reactions” (Rudolph 1978). Currently, diborane is one of the most used speciality gases in the semiconductor industry in Japan (655 kg consumed in 1993), and its increasing usage has prompted more refined toxicity studies than were previously available in the literature (Nomiyama et al. 1996). Information on diborane production and use data in the United States is limited. Two companies in the United States are listed as producing diborane: one having the capacity to produce 45 metric tons per year, and the other producing diborane on demand. Dopants in general, including boron trifluoride, diborane, arsine, and phosphine, were predicted to have a 9% average annual growth rate between 1994 and 1999 (Chemical Economics Handbook 1996). The physicochemical data of diborane are presented in Table 4–2. The odor of diborane is described as repulsive and sickly sweet (Budavari et al. 1996). The median detectable odor concentration of diborane was determined to be 2–4 mg/m3 (1.8–3.6 ppm) (Krackow 1953) and 2.5 ppm (Amoore and Hautala 1983), which is above the occupational exposure limits set for this compound (ACGIH 1991, 1996). Toxicity data in humans were limited to case reports. Studies addressing lethal, nonlethal, and reproductive toxicity of diborane in experimental animals were available.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 TABLE 4–2 Chemical And Physical Data Parameter Value Reference Synonyms Boroethane, diboron hexahydride, boron hydride Budavari et al. 1996; ACGIH 1991 Molecular formula B2H6 Budavari et al. 1996 Molecular weight 27.67 Budavari et al. 1996 CAS Registry Number 19287–45–7 ACGIH 1991 Physical state Gas Budavari et al. 1996 Color Colorless Budavari et al. 1996 Solubility Hydrolyzes in water Budavari et al. 1996 Vapor pressure >1 atm at 20 °C 27,460 mm Hg (15 °C) ACGIH 1991; Lockheed Martin Energy Systems, Inc. 1988 Specific gravity (water=1) 0.210 (15 °C) Budavari et al. 1996 Density (air=1) 0.965 Braker and Mossman 1980 Melting point −165 °C Budavari et al. 1996 Boiling point −92 5 °C Budavari et al. 1996 Flammability limits Spontaneous ignition in air at 40– 50 °C Budavari et al. 1996 Conversion factors 1 ppm=1.1 mg/m3 1 mg/m3 =0.91 ppm ACGIH 1996 2. HUMAN TOXICITY DATA 2.1. Acute Lethality LC50 values in humans have been reported to be 159 ppm for 15 min, and 30–90 mg/m3 (27–82 ppm) for 4 h (Braker and Mossman 1980;

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Lockheed Martin Energy Systems, Inc. 1988). However, no references were cited and no information was given regarding the derivation of these values. These values are therefore inappropriate for use in derivations of AEGLs. 2.2. Nonlethal Toxicity 2.2.1. Case Reports There are no studies in humans reporting the effects following exposures to known concentrations of diborane. The case reports in the literature concerning accidental workplace exposures provide some characterization of signs and symptoms associated with diborane poisoning. It is doubtful that workplace exposures were limited to diborane alone, but most likely included exposures to other chemicals such as the similar boron hydrides decaborane and pentaborane. In 1957, Rozendaal summarized case reports of workers exposed to boron hydrides. One worker developed fatigue, shortness of breath, chills, and fever a few hours after diborane exposure. He was later diagnosed with “pneumonia” and treated with penicillin and made a complete recovery in 3 d. 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. They noted that 2 out of 38 people exposed to diborane were hospitalized. Commonly reported symptoms of exposure included tightness, heaviness, and burning sensations of the chest, shortness of breath, a nonproductive cough, and precordial pain. Chest X-rays from the two hospitalized patients showed nonspecific infiltration, which cleared up in 1–2 d. Chronic exposures to low levels of diborane were associated with central nervous system-type symptoms, including lightheadedness, dizziness, vertigo, chills, and fever. Muscular weakness and fatigue were often noted but were generally gone by the next day. Tremors, which seldom occurred, were localized and of short duration. Rousch (1959) described similar symptoms in workers exposed to diborane and commented that if exposed men were asked to describe their symptoms most referred to cough, chest tightness, and headache, adding that only a “few whiffs” of the gas were needed to develop the symptoms.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 The symptoms tended to develop within a few minutes and generally lasted a few hours. Cordasco et al. (1962) described the effects of boron hydride exposures recorded between 1956 and 1960. Of the 26 cases of acute diborane exposures, 18 exhibited respiratory problems, including chest tightness and pain, dyspnea, nonproductive cough, and wheezing, generally lasting from 3 to 5 d. Ten percent of the cases experienced nausea, anorexia, and hyper-salivation. There were 33 reported cases of subacute exposures, with 8 cases of respiratory involvement. Symptoms associated with exposure to low concentrations for longer periods included chest tightness, nonproductive cough, lightheadedness, headache, fatigue, and drowsiness. Inspiratory and expiratory rhonchi were the most prominent clinical findings during chest examinations of patients exposed both on an acute and subacute basis. Cordasco also recounted two case reports of acute exposures to diborane. One exposed worker developed breathing difficulty, severe tightness in the upper chest, weakness, and slight twitching of the hands, all of which continued for 2 h. Dyspnea and cough continued over the next 3 d, and rales were heard in both lungs. A chest X-ray showed infiltration in both lungs. Five days after exposure, the patient’s cough and dyspnea were gone, and his lungs were clear. Thirteen days later, the worker was again exposed to diborane, and he experienced severe shortness of breath and diffuse chest tightness. Examination indicated medium dry rales in the posterior bases of the lungs, and a chest X-ray showed “pneumonitis.” The patient was treated with penicillin and chloramphenicol, and he was asymptomatic 7 d later. A chest X-ray 3 wk after exposure showed a disappearance of the lesions. The second patient exposed to diborane immediately developed shortness of breath, vertigo, and dry cough. He was given oxygen for 20 min, after which he felt fine. He was again exposed to diborane 6 d later and developed a dry cough. He had moist rales at both bases of the lungs 7 d later, and an X-ray taken 9 d after the second exposure revealed pneumonitis in both bases. The patient received treatment with penicillin and isoproterenol and returned to normal shortly thereafter. 2.2.2. Epidemiology Studies Epidemiologic studies regarding human exposure to diborane were not found in the available literature.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 2.2.3. Other Reported odor thresholds for diborane are 2–4 mg/m3 (1.8–3.6 ppm) (Krackow 1953) and 2.5 ppm (Amoore and Hautala 1983). 2.3. Developmental and Reproductive Effects No human developmental and reproductive toxicity data concerning diborane were found in the available literature. 2.4. Genotoxicity No human genotoxicity data on diborane were found in the available literature. 2.5. Carcinogenicity No data were found in the available literature regarding the carcinogenic potential of diborane. 2.6. Summary While there were several case reports describing the effects of diborane exposure in humans, exposure durations and concentrations were missing, and it was doubtful that workplace exposures were limited to just diborane. 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. Three patients showed signs of apparent “pneumonitis” or “pneumonia” and experienced a complete recovery. Repeated and chronic exposures produced signs and symptoms such as headache, lightheadedness, fatigue, dizziness, chest tightness, and cough. No carcinogenicity, reproductive, or developmental toxicity data in humans were available.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Dogs A dog anesthetized by intravenous administration of pentobarbital sodium was exposed to diborane at 350 ppm for 15 min by intratracheal cannulation (Kunkel et al. 1956). The concentration of diborane was calculated from the measured rates of air and diborane flow into a gas chamber, and the mixture was then delivered from the chamber to the animal by a polyethylene tube. The exposed dog’s blood pressure began to drop and its respiration and thoracic movements were increased within 5 min of gassing. The animal died 4 min after exposure ceased, by which time edema fluid was noted to be flowing from the tracheal cannula. A terminal ECG showed sinus bradycardia and increased T-wave voltage. Signs of pulmonary congestion, hemorrhage, and edema were found during necropsy. In addition, the liver was congested and casts were found in the renal tubules. Using the same method of exposure, three more anesthetized dogs were exposed at 40–125 ppm for 2–2.5 h (Kunkel et al. 1956). Exposure to diborane increased intestinal peristalsis in all dogs and produced hyperactivity of the EEG in two of the three dogs. 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. A second dog had died by the end of the experiment, showing gross evidence of pulmonary edema. The dogs used by Kunkel et al. were of mixed breed and gender. Comstock et al. (1954) exposed male beagle dogs to diborane at 6 or 0.8–1.7 mg/m3 (5 or 0.7–1.5 ppm) in a gassing chamber for 6 h/d, 5 d/wk, for up to 6 months (mo). By the twenty-fifth exposure, there was 100% mortality (2/2) in the dogs exposed at 6 mg/m3 (5 ppm). The dogs developed respiratory distress as soon as the first exposure, and exhibited signs of respiratory infection by the ninth exposure. Pathological examination of one of the dogs revealed acute and chronic nasopharyngitis, acute tracheitis, chronic bronchitis and bronchopneumonia, and liver and kidney congestion. At the lower concentrations, death occurred in one of two dogs after 130 exposures. The dog that died exhibited hyperpnea and anorexia,

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 Appendixes

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX A Derivation of AEGL Values Derivation of AEGL-1 An AEGL-1 value was not derived because it was not appropriate. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. The AEGL-2 value is below the odor threshold of diborane and no other data pertaining to end points relevant to AEGL-1 definition were available. Derivation of AEGL-2 Key study: Nomiyama et al. (1995) Toxicity end point: LOAEL for inflammatory epithelial degeneration in the bronchioles in male ICR mice (4/10) was 5 ppm for 2 h. Scaling: C1×t=k (based on concentration and exposure relationships in Nomiyama et al. [1995] and Uemura et al. [1995]). Uncertainty factors: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 Calculations: (C/uncertainty factors)n×t=k   ([5 ppm]/10)1×2 h=1 ppm·h 10-min AEGL-2: Although it is considered appropriate to extrapolate from a 2-h exposure to a 10-min exposure duration, the 10-min value of 6.0 ppm approaches that of the 10-

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3   min AEGL-3 value of 7.3 ppm. Therefore, the 10-min value was set equal to the 30-min value.   10-min AEGL-2=(20 ppm)/10=2 ppm 30-min AEGL-2: C1×0.5 h=1 ppm·h C1=2 ppm C=2 ppm 1-h AEGL-2: C1×1 h=1 ppm·h C1=1 ppm C=1 ppm 4-h AEGL-2: C1×4 h=1 ppm·h C1=0.25 ppm C=0.25 ppm 8-h AEGL-1: C1×8 h=1 ppm·h C1=0.125 ppm C=0.13 ppm Derivation of AEGL-3 Key study: Uemura et al. (1995) Toxicity end point: The data (mortality ratios versus concentration) used to generate a 4-h LC01 in male ICR mice were given in the study. Based on those data, an LC01 value in mice was calculated to be approximately 9.2 ppm. Scaling: C1×t=k (based on concentration and exposure relationships in Nomiyama et al. [1995] and Uemura et al. [1995]). Uncertainity factors Total uncertainty factor: 10 Interspecies: 3

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3   Intraspecies: 3 Calculations: (C/uncertainty factors)n×t=k   ([9.17 ppm]/10)1×4 h=3.668 ppm·h 10-min AEGL-3: Inappropriate to scale from 4 h to 10 min; the 10-min value was set equal to the 30-min value.   10-min AEGL-3=7.3 ppm 30-min AEGL-3: C1×0.5 h=3.668 ppm·h C1=7.336 ppm C=7.3 ppm 1-h AEGL-3: C1×1 h=3.668 ppm·h C1=3.668 ppm C=3.7 ppm 4-h AEGL-3: C1×4 h=3.668 ppm·h C1=0.917 ppm C=0.92 ppm 8-h AEGL-3: C1×8 h=3.668 ppm·h C1=0.4585 ppm C=0.46 ppm

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX B Time Scaling Calculations The relationship between dose and time for any given chemical is a function of the physical and chemical properties of the substance and the unique toxicological and pharmacological properties of the individual substance. Historically, the relationship according to Haber (1924), commonly called Haber’s law (NRC 1993a) or Haber’s rule (i.e., C×t=k, where C=exposure concentration, t=exposure duration, and k=a constant) has been used to relate exposure concentration and duration to effect (Rinehart and Hatch 1964). This concept states that exposure concentration and exposure duration may be reciprocally adjusted to maintain a cumulative exposure constant (k) and that this cumulative exposure constant will always reflect a specific quantitative and qualitative response. This inverse relationship of concentration and time may be valid when the toxic response to a chemical is equally dependent upon the concentration and the exposure duration. However, an assessment by ten Berge et al. (1986) of LC50 data for certain chemicals revealed chemical-specific relationships between exposure concentration and exposure duration that were often exponential. This relationship can be expressed by the equation Cn×t= k, where n represents a chemical specific, and even a toxic-end-point specific, exponent. The relationship described by this equation is basically the form of a linear regression analysis of the log-log transformation of a plot of C versus t. Ten Berge et al. (1986) examined the airborne concentration (C) and short-term exposure duration (t) relationship relative to death for approximately 20 chemicals and found that the empirically derived value of n ranged from 0.8 to 3.5 among this group of chemicals. Hence, these workers showed that the value of the exponent n in the equation Cn×t= k quantitatively defines the relationship between exposure concentration and exposure duration for a given chemical and for a specific health effect end point. Habers rule is the special case where n=1. As the value of n increases, the plot of concentration versus time yields a progressive decrease in the slope of the curve. To calculate n for diborane, a regression plot of the EC50 values was derived from the studies by Nomiyama et al. (1995) and Uemura et al. (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. Although n values have generally been

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 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 all 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. EC50 values were derived by probit analysis of the data, and were then analyzed using a linear regression analysis of the log-log 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. Linear regression analysis of plot of log-log transformation of plot of C versus t: Time (min) Concentration Log Time Log Concentration 240 2.72 2.3802 0.4346 120 5.07 2.0792 0.7050 60 9.68 1.7782 0.9859 n=1.09 Regression plot of EC50 values—concentration versus time.

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 APPENDIX C DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR DIBORANE (CAS No. 19287–45–7) AEGL-1 10 min 30 min 1 h 4 h 8 h NR NR NR NR NR Data adequacy: Although the odor threshold could be considered relevant to an AEGL-1 because the odor is considered repulsive, the AEGL-2 value is below the odor threshold and this end point is therefore not appropriate. No other human or animal data pertaining to end points relevant to the AEGL-1 definition were available. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. Abbreviation: NR, not recommended. AEGL-2 10 min 30 min 1 h 4 h 8 h 2.0 ppm 2.0 ppm 1.0 ppm 0.25 ppm 0.13 ppm Key reference: Nomiyama, T., Omae, K., Uemura, T., Nakashima, H., Takebayashi, T., Ishizuka, C., Yamazaki, K., and Sakurai, H. 1995. No-observed-effect level of diborane on the respiratory organs of male mice in acute and subacute inhalation experiments. J. Occup. Health. 37:157–160. Test species/strain/gender/number: Young male ICR mice, 10 per exposure group. Exposure route/concentrations/durations: Inhalation; 5 ppm for 1, 2, 4, or 8 h. Effects: 5 ppm: 1 h, no effects; 2 h, inflammatory epithelial degeneration in the bronchioles (4/10); 4 h, inflammatory epithelial degeneration in the bronchioles (9/10); 8 h, inflammatory epithelial degeneration in the bronchioles (10/10). End point/concentration/rationale: 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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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 toxicity, reversible histological changes in the lungs, was the most sensitive end point. Further support of a value of 3 is that 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. There appears to be a similar mechanism of toxicity between species because the cause of death from diborane exposure has always been from pulmonary damage, including edema, hemorrhage, and congestion. Intraspecies: 3—An intraspecies uncertainty factor of 3 was applied because using the default uncertainty factor of 10 generates AEGL values that are inconsistent with existing empirical data. For example, the derived 1-h AEGL-2 value is 1.0 ppm with a total uncertainty factor of 10. Mice exposed at 1 ppm for up to 8 h exhibited no effects of diborane exposure (Nomiyama et al 1995). Mice exposed at 0.7 ppm for 6 h/d, 5 d/wk for up to 4 wk developed only slight pulmonary infiltration of polymorphous neutrophils (Nomiyama et al. 1995) and rats exposed at 0.96 ppm for 6 h/d, 5 d/wk for 8 wk developed changes in bronchoalveolar lavage fluid that were not accompanied by histopathological changes (Nomiyama et al. 1996). The use of a higher uncertainty factor 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. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable Time acaling: Cn×t=k where n=1; based on a regression plot of the EC50 values derived from the studies by Nomiyama et al. (1995) and Uemura et al. (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. Although it is considered appropriate to extrapolate from a 2-h exposure to a 10-min exposure duration, the 10-min value of 6.0 ppm approaches that of the 10-min AEGL-3 value of 7.3 ppm. Therefore, the 10-min value was set equal to the 30-min value. 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. Data in animals have shown concentration and time dependent respiratory effects including reversible histological respiratory lesions and pulmonary edema, hemorrhage, and/or congestion leading to death. These signs of toxicity and repair of pulmonary lesions following acute

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 exposure to nonlethal concentrations in animals were consistent with the human response reported by case reports. Therefore, the animal data are considered appropriate for development of an AEGL-2. 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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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 AEGL-3 10 min 30 min 1 h 4 h 8 h 7.3 ppm 7.3 ppm 3.7 ppm 0.92 ppm 0.46 ppm Key reference: Uemura, T., Omae, K., Nakashima, H., Sakurai, H., Yamazaki, K., Shibata, T., Mori, K., Kudo, M., Kanoh, H., and Tati, M. 1995. Acute and subacute inhalation toxicity of diborane in male ICR mice. Arch. Toxicol. 69:397–404. Test species/strain/gender/number: Young male ICR mice, 10 per exposure group. Exposure route/concentrations/durations: Inhalation: 0, 11.3, 22.1, 35.1, 37.7, 44.8 ppm for 4 h. Effects: Concentration Mortality       11.3 ppm 0/10       22.1 ppm 3/10       35.1 ppm 3/10       37.7 ppm 9/10       44.8 ppm 9/10     LC50: 31.5 ppm (provided in reference) LC01: 9.17 ppm (calculated by log-probit analysis) End point/concentration/rationale: 9.17 ppm for 4 h was the calculated LC01, which is the threshold for lethality, a defined end point for the AEGL-3. Uncertainty Factors/Rationale: Total uncertainty factor: 10 Interspecies: 3—An interspecies uncertainty factor of 3 was applied because there did not appear to be much variation between species in sensitivity to lethal concentrations of diborane. The 4-h LC50 values determined by different authors for mice and rats were within a factor of 2.8 (4-h LC50 values ranged from 29 ppm to 31.5 ppm in mice and from 40 ppm to 80 ppm in rats). 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. Intraspecies: 3—An intraspecies uncertainty factor of 3 was applied because using the default uncertainty factor of 10 generates AEGL values that are inconsistent with existing empirical data. For example, the derived 1-h AEGL-3 value is 3.7 ppm with a total uncertainty factor of 10. Mice exposed at 5 ppm for up to 4 h developed only inflammatory epithelial degeneration in the bronchioles, with exposure for 8 h additionally resulting in increased lung weights (Nomiyama et al. 1995). Mice exposed at 15 ppm for 4 h developed pulmonary changes including

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Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 3 edema, congestion, and inflammatory epithelial degeneration that were generally resolved or in the process of being resolved within 14 d postexposure (Uemura 1996). The use of a higher uncertainty factor would result in AEGL values that would be below concentrations causing effects in any species for an end point which is supposed to be life-threatening in a human population. Modifying factor: Not applicable Animal to human dosimetric adjustment: Not applicable Time Scaling: Cn×t=k where n=1; based on a regression plot of the EC50 values derived from the studies by Nomiyama et al. (1995) and Uemura et al. (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. The 10-min AEGL-3 value was set equal to the 30-min value of 7.3 ppm because the NAC considers it inappropriate to extrapolate from the exposure duration of 4 h to 10 min. Data adequacy: Information about the lethality of diborane in humans was not available. 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) demonstrates that the AEGL values should be protective.