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Butane
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Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:


AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1 This document was prepared by the AEGL Development Team composed of Peter Bos (RIVM, The Dutch National Institute of Public Health and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Managers Jonathan Borak and Larry Gephart (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). 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) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded 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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1 Butane1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Peter Bos (RIVM, The Dutch National Institute of Public Health and the Environment), Julie M. Klotzbach (Syracuse Research Corporation), Chemical Managers Jonathan Borak and Larry Gephart (National Advisory Committee [NAC] on Acute Exposure Guideline Lev- els for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed neces- sary. Both the document and the AEGL values were then reviewed by the National Re- search Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC com- mittee has concluded 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). 13

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14 Acute Exposure Guideline Levels effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic re- sponses, could experience the effects described at concentrations below the cor- responding AEGL. SUMMARY Butane is a colorless gas with a faint disagreeable odor, although it is con- sidered to be odorless by some. It is poorly soluble in water. The lower explo- sive limit is 1.9%. Butane is produced from natural gas. Its main uses are in the production of chemicals like ethylene and 1,3-butadiene, as a refrigerant, as an aerosol propellant, as a constituent in liquefied petroleum gas, and as the main component of gas lighter refills. Because it is easily accessible, butane is often used in inhalant abuse. The toxicity of butane is low. Huge exposure concentrations can be as- sumed in butane abuse. The predominant effects observed in abuse cases are central nervous system (CNS) and cardiac effects. Case studies also reveal that serious brain damage and underdeveloped organs can occur in fetuses in case of high single exposures during the week 27 or 30 of pregnancy. Quantitative data for setting AEGL values are sparse. Quantitative human data include an old study with human volunteers focused on the warning properties of butane. Mortality from butane in mice and rats is preceded by CNS effects. Some data are available on cardiac effects in dogs, but they are insufficient for setting AEGL values. Data on CNS effects are available for mice and guinea pigs. Bu- tane was negative in the bacterial reverse-mutation assay (Ames test). Carcino- genicity studies and studies on reproductive toxicity are lacking.

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15 Butane The AEGL-1 values for butane are based on observations in a study with volunteers on the warning properties of short exposures to butane (Patty and Yant 1929). It was concluded that 10,000 ppm (10-min exposure) was a bound- ary for drowsiness. An intraspecies uncertainty factor of 1 is considered ade- quate because the concentration-response curve for CNS-effects appears to be very steep; thus, interindividual variability will be relatively small. Also, no noticeable irritation was reported at concentrations up to 100,000 ppm (probably for a few min), and a larger uncertainty factor of 3 would lead to unrealistically low AEGL-1 values. Available data suggest a relatively high value for n (Stoughton and Lamson 1936), so time extrapolation was performed using n = 3. Data on butane (Gill et al. 1991) and propane (Stewart et al. 1977) indicate that steady-state plasma concentrations for butane will be reached within 30 min. By analogy to other CNS-depressing substances, the effects of butane are assumed to be solely concentration dependent. Therefore, time extrapolation was per- formed from 10 min to 30- and 60-min exposures, where the steady-state con- centration was calculated. The calculated values for AEGL-1 are presented in Table 1-1. The values are considered protective of the irregular breathing ob- served in guinea pigs exposed to butane at 21,000-28,000 ppm for up to 2 h (Nuckolls 1933). The calculated 10-min AEGL-1 value is greater than 50% of the lower explosive limit for butane, and the other AEGL-1 values are greater than than 10% of the lower explosive limit. The AEGL-2 values for butane are based on a study with guinea pigs ex- posed to butane for 2 h at concentrations between 50,000 and 56,000 ppm (Nuckolls 1933). Animals had a “dazed appearance,” but were able to walk. Therefore, the effects were considered not to be serious enough to impair escape and the lower value in this range (50,000 ppm) was used as starting point for the derivation of AEGL-2 values. Small interindividual differences are expected because the effects are attributed to butane itself and no relevant differences in kinetics are assumed. However, a large uncertainty factor is not necessary con- sidering the steep concentration-response curve; a large factor also would lead to unrealistically low AEGL-2 values that would be similar to the AEGL-1 values. Thus, a total uncertainty factor of 3 is considered sufficient. Time extrapolation was performed using n = 3 for similar reasons as for AEGL-1. No increase in effect from longer durations of exposure is expected for concentration- dependent effects after reaching a steady state. For the same reasons as for AEGL-1, steady-state plasma concentrations will be reached within 30 min of exposure. Thus, the AEGL-2 values for 30-min and 1, 4, and 8 h will be set equal to the 2-h concentration. The AEGL-2 values for the 10-min exposure is derived by time scaling according to the dose-response regression equation Cn × t = k, using n = 3. The calculated 10-min AEGL-2 value is greater than the lower explosive limit and that the other AEGL-2 values are greater than 50% of the lower explosive limit. The AEGL-3 values for butane are based on an acute exposure study with rats and mice (Shugaev 1969). Mice and rats were exposed to butane for 2 and 4 h, respectively. The reported data allowed the calculation of LC01s (lethal con-

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16 Acute Exposure Guideline Levels centrations, 1% lethality). The 2-h LC01 for mice was 160,000 ppm and the 4-h LC01 for rats was 172,000 ppm. The 2-h LC01 for mice was chosen as starting point for AEGL-3 derivation, because mice appear to be the more susceptible species and 160,000 ppm was the lowest concentration tested. A total uncer- tainty factor of 3 is considered sufficient to account for toxicokinetic and toxi- codynamic differences between individuals and interspecies differences for the following reasons. The effects are attributed to butane itself and no relevant dif- ferences in kinetics are assumed. The data are from a species with a relatively high susceptibility to butane. The concentration-response curve appears to be very steep indicating that a large uncertainty factor is unnecessary. Further, a larger factor would lead to unrealistically low values that would be similar to the AEGL-2 values. Time scaling was conducted similar to that performed for AEGL-2 values. The AEGL-3 values for 30 min and for 1, 4 and 8 h of exposure were set equal to that for the 2-h AEGL value. The AEGL-3 values for the 10- min exposure were derived by time scaling according to the dose-response re- gression equation Cn × t = k, using n = 3. The calculated 10-min value of 77,000 ppm is supported by the data from Patty and Yant (1929). They reported that exposure to slowly increasing concentrations of butane up to 50,000 ppm (total exposure duration at least 10 min) and a short exposure (duration not specified) to 100,000 ppm on the same day did not result in serious complaints (Patty and Yant 1929). All of the AEGL-3 values are greater than the lower explosive limit for butane. The AEGL values for butane are presented in Table 1-1. TABLE 1-1 Summary of AEGL Values for Butane End Point Classification 10 min 30 min 1h 4h 8h (Reference) See belowa 6,900 ppm b 5,500 ppm b 5,500 ppm b 5,500 ppm b AEGL-1 Drowsiness in (nondisabling) (16,000 (13,000 (13,000 (13,000 humans (Patty mg/m3) mg/m3) mg/m3) mg/m3) and Yant 1929) See belowc See belowd See belowd See belowd See belowd AEGL-2 Dazed (disabling) appearance in guinea pigs (Nuckolls 1933) See belowe See belowe See belowe See belowe See belowe AEGL-3 LC01 in mice (lethal) (Shugaev 1969) a The 10-min AEGL-1 value is 10,000 ppm (24,000 mg/m3), which is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety con- siderations against the hazard of explosion must be taken into account. b The AEGL-1 value is greater than 10% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, safety considerations against the hazard of explosion must be taken into account. c The 10-min AEGL-2 value is 24,000 ppm (57,000 mg/m3), which is greater than the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. d The AEGL-2 values for 30 min and 1, 4, and 8 h are 17,000 ppm (40,000 mg/m3), which is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. There-

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17 Butane fore, extreme safety considerations against the hazard of explosion must be taken into account. e The 10-min AEGL-3 value is 77,000 ppm (180,000 mg/m3). The AEGL-3 values for 30 min and 1, 4, and 8 h are 53,000 ppm (130,000 mg/m3). These values are greater than the lower explosive limit for butane in air of 19,000 ppm). Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. 1. INTRODUCTION Butane is produced from raw natural gas and from petroleum streams ob- tained by catalytic cracking, catalytic reforming, and other refining processes. Butane is used in the production of ethylene and 1,3-butadiene, in the synthesis of a number of chemicals, as a refrigerant and an aerosol propellant, in the blending of gasoline or motor fuel, as a constituent in liquefied petroleum gas, and as an extraction solvent in deasphalting processes (Low et al. 1987). Butane used in gas lighter refills consists of butane with small amounts of isobutane and propane. Chemical and physical data for butane are presented in Table 1-2. 2. HUMAN TOXICITY DATA Most reports of butane intoxication are from cases of butane abuse or sui- cide attempts. These data are only briefly described because they provide no clear dose-response data and, for abuse cases, subjects generally have a history of repeated exposure, so tolerance to butane could have developed (Evans and Raistrick 1987). In addition, abuse of other volatile organic solvents cannot be excluded. Data on intoxication by liquefied petroleum gas (a mixture of pre- dominantly propane and butane in varying proportions) were not considered. 2.1. Acute Lethality 2.1.1. Case Reports Substance abuse is one of the predominant causes of death from butane in- toxication. Fuel gases containing butane appeared to be responsible for about 30% of deaths from solvent abuse in the United Kingdom and aerosol propel- lants for about 20% (Adgey et al. 1995). In 2000, 64 deaths were associated with abuse of volatile substances; over 50% of the deaths were attributed to gas fuel inhalation, mainly butane lighter refills (Chaudhry 2002). In Virginia, 39 cases of people who likely died as a direct consequence abusing an inhalant were found between 1987 and 1996. Thirteen of these cases were associated with bu- tane (Bowen et al. 1999). Clear central nervous system (CNS) effects were re- ported by butane abusers, including disturbed behavior, slow speech, elated mood, hallucinations, and illusionary experiences.

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18 Acute Exposure Guideline Levels TABLE 1-2 Chemical and Physical Properties for Butane Parameter Value Reference Synonyms Diethyl; methylethylmethane Lewis 1999 CAS registry no. 106-97-8 Chemical formula C4H10 Molecular weight 58.14 Lewis 1999 Physical state Gas Lewis 1999 Color Colorless Lewis 1999 Odor Odorless Faint disagreeable odora Lewis 1999 Melting point -138.35°C Cavender 1994 Boiling point -0.5°C Cavender 1994 Density Low et al. 1987; Lide 1999 Vapor 2.07 (air = 1) 0.601 g/cm3 at -0.5°C (water = 1) Liquid 0.573 g/cm3 at -25°C (water = 1) Solubility 61 mg/L in water at 25°C Low et al. 1987 Vapor pressure 243 kPa (25°C) ECB 2000 Flammability Extremely flammable ECB 2000 Explosive Lower explosive limit = 1.9% Lewis 1999 3 Conversion factors 1 mg/m = 0.422 ppm Low et al. 1987 1 ppm = 2.37 mg/m3 a Although butane is considered odorless by some, it has been reported that the odor of butane can be detected at concentrations of 1.2-6.2 ppm (2.85-14.63 mg/m3) (Ruth 1986). Graefe et al. (1999) described a fatal case of a 19-year-old male. He had a history of butane abuse. Froth was present in the trachea and bronchi; pulmonary edema was also reported. The highest concentrations of butane were found in the liver (310 μg/g), brain (282 μg/g), blood (129 μg/mL), and kidneys (54 μg/g). A 14-year-old boy was found unconsciousness as a result of butane abuse; he died 34 h after the exposure despite resuscitation efforts (Rieder-Scharinger et al. 2000). Death was attributed to multiple organ failure involving the CNS (brain edema), cardiovascular system, pulmonary system, and the liver. A 13-year-old boy died from butane abuse (Nishi et al. 1985). The cause of death was cardiac arrhythmia and lung edema. The boy had undergone an operation for a cardiac ventricular septal defect at the age of 10. Butane concen- trations in his tissues were highest in fat (4.5 μL/g) and brain (3.9 μL/g), fol- lowed by kidney (2.1 μL/g), liver (2.0 μL/g), spleen (1.5 μL/g), heart (1.2 μL/g), and blood (0.9 μL/g). Propane and isobutane were also detected.

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19 Butane 2.2. Nonlethal Toxicity 2.2.1. Case Reports In nonfatal cases, butane appears to have frequently affected the heart and brain. Most of these cases involved inhalant abusers with repetitive exposure to butane. Severe encephalopathy was observed in a 15-year-old girl as the result of abusive butane inhalation. She had been inhaling butane repeatedly for 4 weeks until an acute incident occurred. Cardiopulmonary resuscitation was needed. Repeated magnetic-resonance-imaging scans revealed disintegration of gray matter, increasing cerebral atrophy, and destruction of basal ganglia. Electroe- ncephalography showed strongly diminished basal activity with flat amplitude (Döring et al. 2002). A 15-year-old boy, who was known to inhale butane from a plastic bag, had bilateral hemispheric infarcts (Bauman et al. 1991). Another 15- year-old boy suffered from right-sided hemiparesis after butane abuse; he did not lose consciousness. A computed tomography (CT) head scan on the day fol- lowing admission to the hospital was normal. At the time of discharge (after 5 days), he still had pronounced upper limb, proximal muscle weakness and a hemiplegic gait (Gray and Lazarus 1993). In another case of butane abuse, a swollen brain was observed in a 15-year-old girl without a history of butane abuse (Williams and Cole 1998), while a CT head scan showed no abnormalities in a 17-year-old male with a 3-year history of butane abuse (Edwards and Wen- stone 2000). Ventricular tachycardia and ventricular fibrillation were noted in a 15- year-old boy, who was found unresponsive and cyanotic. He was known to in- hale butane from a plastic bag. During his hospitalization his cardiac status im- proved but brain functions remained disturbed (Bauman et al. 1991). A 17-year- old male with a 3-year history of butane abuse was found collapsed and showing ventricular fibrillation. He was resuscitated during which he received epineph- rine. An electrocardiogram showed an acute anterolateral infarction. Recovery was slow and complicated by acute renal failure and recurrent pulmonary edema (Edwards and Wenstone 2000). Roberts et al. (1990) described a 16-year-old boy who was found unconscious. He had been abusing lighter fuel for two months. The boy suffered from asystolic cardiac arrest and cardiopulmonary resuscitation was commenced. The patient was discharged 10 days after admit- tance to the hospital. Gunn et al. (1989) described ventricular fibrillation in a 15- year-old boy with a habit of lighter-fuel abuse. A few moments after one such episode of abuse he experienced severe anterior chest pain. He ran downstairs where he collapsed. An ambulance arrived within 5 min. The boy suffered from sinus tachycardia and a widespread ST-segment elevation was noted. A 15-year- old girl, without history of butane abuse, had been inhaling butane intermittently over a period of 2 h. She collapsed when running away from the police (Wil- liams and Cole 1998). On admission to the hospital, there was no spontaneous respiration; an electrocardiogram showed sinus tachycardia with marked T-wave

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20 Acute Exposure Guideline Levels inversion in the anterolateral leads. A CT scan showed a very tight swollen brain. For 5 days she remained cardiovascularly stable with persistent T-wave inversion on the electrocardiogram. It was concluded that the most plausible cause was a direct effect of butane on the myocardium. Butane could have caused cardiac sensitization, and a surge of adrenaline would have caused the arrhythmia rather than hypoxic arrest. Adgey et al. (1995) describe a case of a 16-year-old boy who collapsed following inhalation of butane from a cigarette lighter refill. The initial cardiac rhythm was ventricular asystole. Cardiopulmon- ary resuscitation was commenced. The electrocardiogram showed T-wave inver- sion across the anterior chest leads. Cartwright et al. (1983) reported pleural effusions and pulmonary infil- trates in a 19-year-old man who had been “fire-breathing.” He had filled his oral cavity with butane from a cigarette lighter and forcefully expelled it over a flame. Because butane is heavier than air, the pulmonary effects were consid- ered to be the result of descending butane gas into the tracheobronchial tree by gravity. 2.2.2. Experimental Studies Patty and Yant (1929) studied the warning properties of several alkanes, including butane. In a continuous exposure test, subjects were exposed to butane at slowly increasing concentrations up to 50,000 ppm for an unknown duration (but at least 10 min). In an intermittent exposure test, subjects were exposed at fixed concentration for a short, unspecified duration. The concentrations of bu- tane in the intermittent exposure test were approximately 1,000, 2,000, 5,000, 7,000, 10,000, 20,000, and 100,000 ppm. Exposure groups consisted of 3- 6 laboratory or clerical personnel (males and females, 20-30 years of age). Sub- jects first underwent the continuous exposure test, followed on the same day by the intermittent exposure test after a recovery period. The chamber concentra- tion was periodically analyzed. Odor detection was rated by means of an odor scale ranging from 0 (no detectable odor) to 5 (intense effect, may bite or irri- tate). Individual scores did not differ much from the average scores. Butane could not be detected in the continuous exposure test at concentrations up to 50,000 ppm. In the intermittent exposure test, butane at 18,000 ppm was de- scribed as having a “weak odor, readily perceptible” (mean score of 2). The score for odor detection was below 4 (cogent, forcible odor) at 100,000 ppm. The physiologic responses were very briefly reported. Although a table in the report indicated that exposure to butane at 10,000 ppm for 10 min caused drowsiness, this was contradicted by a statement in the text that 10-min expo- sure to butane 10,000 ppm caused no symptoms. 2.2.3. Occupational and Epidemiological Studies No data were available.

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21 Butane 2.3. Neurotoxicity Several case reports of intentional butane exposure indicate that butane in- duces neurotoxicity. Severe encephalopathy was observed in a 15-year-old girl as the result of butane abuse. She had been inhaling butane repeatedly for 4 weeks, until an acute incident occurred that required cardiopulmonary resuscita- tion. Repeated magnetic resonance imaging over the following weeks revealed disintegration of gray matter, increasing cerebral atrophy, and destruction of basal ganglia. An electroencephalogram showed strongly diminished basal ac- tivity with flat amplitude (Döring et al. 2002). A 15-year-old boy who was known to inhale butane from a plastic bag had bilateral hemispheric infarcts (Bauman et al. 1991). Another 15-year-old boy suffered from right-sided hemi- paresis after butane abuse; he did not lose consciousness. A CT head scan on the day following admission to the hospital was normal. At the time of discharge (5 days later), he still had pronounced upper limb, proximal muscle weakness and a hemiplegic gait (Gray and Lazarus 1993). In another case, a swollen brain was observed in a 15-year-old girl without a history of butane abuse (Williams and Cole 1998), whereas a CT head scan showed no abnormalities in a 17-year-old male with a 3-year history of butane abuse (Edwards and Wenstone 2000). A 15-year-old boy was found unresponsive and cyanotic after reportedly inhaling butane from a plastic bag. Ventricular tachycardia and ventricular fib- rillation were noted. Cardiac status improved during hospitalization, but brain functions remained disturbed (Bauman et al. 1991). A 15-year-old girl without a history of butane abuse inhaled butane intermittently over a 2-h period. She col- lapsed when running away from the police (Williams and Cole 1998). On ad- mission to the hospital, there was no spontaneous respiration; a CT scan showed a very tight, swollen brain and an electrocardiogram showed sinus tachycardia with marked T-wave inversion in the anterolateral leads. 2.4. Developmental and Reproductive Toxicity A pregnant 34-year-old woman accidentally inhaled butane in during week 27 of her pregnancy. She was found unconscious and required mechanical ventilation for 5 h. The exposure duration and concentration of butane were not reported, nor was the amount of time that elapsed before resuscitation com- menced. She gradually regained consciousness and was discharged 48 h after admission. An ultrasound at week 39 of the pregnancy showed an almost com- plete absence of brain tissue in the fetus. The female child was delivered nor- mally and appeared in good condition. A CT scan at 7 days post-partum re- vealed an almost complete absence of both cerebral hemispheres in the newborn. The thalamus, brainstem, and cerebellum were preserved (Fernàndez et al. 1986). A 25-year-old pregnant woman tried to commit suicide by inhaling butane at 30-weeks gestation. She was found comatose and needed resuscitation. The

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22 Acute Exposure Guideline Levels duration and concentration of butane exposure were not reported, nor was the amount of time that elapsed before resuscitation commenced. Spontaneous labor occurred at 36 weeks. The infant did not breathe spontaneously; he was resusci- tated, intubated, and ventilated artificially, but died 11 h after birth (Gosseye et al. 1982). The infant’s brain weighed 99 g (mean normal weight is 308 g), and the general appearance of the convolutions corresponded to about 30 weeks of maturation. A severe encephalomalacia was noted. The kidneys were underde- veloped, and the heart showed some foci of fibrosis in the subendocardial myo- cardium. The lungs were poorly aerated and the alveoli contained a number of squamous cells. Other viscera were reported to be unremarkable. 2.5. Genotoxicity No data were available. 2.6. Carcinogenicity No data were available. 2.7. Summary A number of fatal and nonfatal cases related to butane abuse or suicide at- tempts have been described. Quantitative exposure estimates are lacking for all cases. In the case of butane abuse, most of the health effects described in case reports are thought to be induced by repeated exposures and abuse of other chemicals cannot be ruled out. Organs that were most often seriously affected in these cases were the brain and heart. A 10-min exposure to butane at 10,000 ppm caused drowsiness in human volunteers. These were probably rather minor effects. Butane was reported to be “readily perceptible” at a concentration of 18,000 ppm. No irritation was noted at 100,000 ppm (exposure duration not specified but was probably for a few minutes). Inhalation of butane during pregnancy (weeks 27 and 30 of gestation) at concentrations that produced unconsciousness in the mother caused clearly un- derdeveloped brains in two fetuses. In both cases, the effects were attributed intrauterine anoxia. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Monkeys No data were available.

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23 Butane 3.1.2. Dogs Butane at concentrations of 200,000-250,000 ppm produced “relaxation” in dogs (number and sex not specified), but caused death after a short time (Stoughton and Lamson 1936). No further details were given. 3.1.3. Rats Shugaev (1969) exposed rats (sex and strain not specified) to varying con- centrations of butane for 4 h. The number of animals was not specified but the results suggest that the exposure groups consisted of 6 animals. Exposure con- centrations were reported to be controlled by gas chromatography, but no infor- mation about the concentrations of butane tested or the duration of the post- exposure observation period was provided. The experimental data were analyzed by probit analysis. A 4-h LC50 (lethal concentration 50% lethality) of 278,000 ppm (658 g/m3) was reported, with 95% confidence limits of 252,000-302,000 ppm. Most rats died during the third or fourth hour of exposure. The LC16 was calculated to be 227,000 ppm (537 g/m3) and the LC84 to be 333,000 ppm (790 g/m3). Mean butane concentrations in organs at the LC50 were 7.5 μg/g in the brain, 4.9 μg/g in the liver, 4.4 μg/g in the kidneys, 5.2 μg/g in the spleen, and 20.9 μg/g in perinephric fat. 3.1.4. Mice Shugaev (1969) exposed mice (sex and strain not specified) to various bu- tane concentrations for 2 h. The number of animals was not specified but the results suggest that exposure groups consisted of 6 animals. Exposure concentra- tions were reported to be controlled by gas chromatography, but no information about the concentrations of butane tested or the duration of the post-exposure observation period was provided. The experimental data were analyzed by pro- bit analysis. A 2-h LC50 of 287,000 ppm (680 g/m3) was reported, with 95% confidence limits of 252,000-327,000 ppm. Most of the mice died during the second hour of exposure. The LC16 was calculated to be 224,000 ppm (530 g/m3) and the LC84 to be 363,000 ppm (860 g/m3). The mean butane concentra- tion in the brain of dead mice at the LC50 was 7.8 μg/g. Groups of mice (sex and strain not specified) were exposed to butane at concentrations of 130,000, 220,000, 270,000, or 310,000 ppm; 6 mice were tested at the lowest concentration, and 10 mice at each of the higher concentra- tions (Stoughton and Lamson 1936). The animals were observed for 24-48 h after exposure. Although it was not clearly described, the study description sug- gests that the animals were exposed under static conditions in a closed-chamber setting. The animals were observed for 48 h after exposure. Effects observed were “light anesthesia,” “loss of posture” (complete anesthesia), and death. Ex- posure to butane at 270,000 ppm for 2 h was lethal to 4 of 10 mice; the average

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37 Butane TABLE 1-9 Continued Exposure Duration Guideline 10 min 30 min 1h 4h 8h REL-TWA 800 ppm (NIOSH)g MAK 1,000 ppm (Germany)h MAK Peak 2,000 ppm Limit (Germany)i MAC (The 600 ppm Netherlands)j a The 10-min AEGL-1 value is 10,000 ppm (24,000 mg/m3), which is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety con- siderations against the hazard of explosion must be taken into account. b The AEGL-1 value is greater than 10% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, safety considerations against the hazard of explosion must be taken into account. c The 10-min AEGL-2 value is 24,000 ppm (57,000 mg/m3), which is greater than the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. d The AEGL-2 values for 30 min and 1, 4, and 8 h are 17,000 ppm (40,000 mg/m3), which is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. There- fore, extreme safety considerations against the hazard of explosion must be taken into account. e The 10-min AEGL-3 value is 77,000 ppm (180,000 mg/m3). The AEGL-3 values for 30 min and 1, 4, and 8 h are 53,000 ppm (130,000 mg/m3). These values are greater than the lower explosive limit for butane in air of 19,000 ppm). Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. f TLV-TWA (threshold limit value - time weighted average, American Conference of Governmental Industrial Hygienists) (ACGIH 2007) is the time-weighted average con- centration for a normal 8-h workday and a 40-h workweek, to which nearly all workers may be repeatedly exposed, day after day, without adverse effect. g REL-TWA (recommended exposure limit - time weighted average, National Institute for Occupational Safety and Health) (NIOSH 2010) is defined analogous to the ACGIH TLV-TWA. h MAK (maximale arbeitsplatzkonzentration [maximum workplace concentration]) (Deutsche Forschungsgemeinschaft [German Research Association] (DFG 2007) is de- fined analogous to the ACGIH TLV-TWA. i MAK spitzenbegrenzung (peak limit,German Research Association (DFG 2007) consti- tutes the maximum concentration to which workers can be exposed for a period up to 60 min with no more than three exposure periods per work shift; total exposure may not exceed the 8-h MAK. j MAC (maximaal aanvaaarde concentratie [maximal accepted concentration]) (Dutch Expert Committee for Occupational Standards, The Netherlands (MSZV 2004) is defined analogous to the ACGIH TLV-TWA.

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38 Acute Exposure Guideline Levels The case reports do not provide an adequate basis for AEGL values. The only study with human volunteers (Patty and Yant 1929) is rather old and fo- cused on the warning properties of butane. 9. REFERENCES ACGIH (American Conference of Government and Industrial Hygienists). 2007. Butane (CAS Reg. No. 106-97-8). TLVs and BEIs. Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents and Bio- logical Exposure Indices. American Conference of Government and Industrial Hy- gienists: Cincinnati, OH. Adgey, A.A.J., P.W. Johnston, and S. McMechan. 1995. Sudden cardiac death and sub- stance abuse. Resuscitation 29(3):219-221. Bauman, J.J., B.S. Dean, and E.P. Krenzelok. 1991. Myocardial infarction and neurodev- astation following butane inhalation. Vet. Hum. Toxicol. 33(4):389. Bowen, S.E., J. Daniel, and R.L. Balster. 1999. Deaths associated with inhalant abuse in Virginia from 1987 to 1996. Drug Alcohol Depend. 53(3):239-245. Cartwright, T.R., D. Brown, and R.E. Brashear. 1983. Pulmonary infiltrates following butane ‘fire-breathing’. Arch. Intern. Med. 143(10):2007-2008. Cavender, F. 1994. Aliphatic hydrocarbons. Pp. 1221-1239 in Patty’s Industrial Hygiene and Toxicology, 4th Ed., Vol. 2B, G.D. Clayton, and F.E. Clayton, eds. New York: John Wiley & Sons. Chaudhry, S. 2002. Deaths from volatile substance misuse fall. BMJ 325(7356):122. Chenoweth, M.B. 1946. Ventricular fibrillation induced by hydrocarbons and epineph- rine. J. Ind. Hyg. Toxicol. 28:151-158. DFG (Deutsche Forschungsgemeinschaft). 2007. List of MAK and BAT Values 2007. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 43. Weinheim, Federal Republic of Germany: Wiley VCH. Döring, G., F.A. Baumeister, J. Peters, and J. von der Beek. 2002. Butane abuse associ- ated encephalopathy. Klin. Paediatr. 214(5):295-298. Drummond, I. 1993. Light hydrocarbon gases: A narcotic, asphyxiant, or flammable haz- ard? Appl. Occup. Environ. Hyg. 8(2):120-125. ECB (European Chemicals Bureau). 2000. Butane, pure. EINECS No. 203-448-7. IUCLID Dataset. European Commission, European Chemicals Bureau [online]. Available: http://esis.jrc.ec.europa.eu/doc/existing-chemicals/IUCLID/data_sheets/ 106978.pdf [accessed Jan. 12, 2012] Edwards, K.E., and R. Wenstone. 2000. Successful resuscitation from recurrent ventricu- lar fibrillation secondary to butane inhalation. Br. J. Anaesth. 84(6):803-805. Evans, A.C., and D. Raistrick. 1987. Phenomenology of intoxication with toluene-based adhesives and butane gas. Br. J. Psychiatry 150:769-773. Fernàndez, F., A. Pèrez-Higueras, R. Hernàndez, A. Verdú, C. Sánchez, A. González, and J. Quero. 1986. Hydrancephaly after maternal butane-gas intoxication during pregnancy. Dev. Med. Child Neurol. 28(3):361-363. Frommer, U., V. Ullrich, and H.J. Staudinger. 1970. Hydroxylation of aliphatic com- pounds by liver microsomes, I. The distribution pattern of isomeric alcohols. H.-S. Z. Physiol. Chem. 351(8):903-912. Gill, R., S.E. Hatchett, C.G. Broster, M.D. Osselton, J.D. Ramsey, H.K. Wilson, and A.H. Wilcox. 1991. The response of evidential breath alcohol testing instruments

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39 Butane with subjects exposed to organic solvents and gases. I. Toluene, 1,1,1- trichloroethane and butane. Med. Sci. Law 31(3):187-200. Gosseye, S., M.C. Golaire, and J.C. Larroche. 1982. Cerebral, renal and splenic lesions due to fetal anoxia and their relationship to malformations. Dev. Med. Child Neurol. 24(4):510-518. Graefe, A., R.K. Müller, R. Vock, H. Trauer, and H.J. Wehran. 1999. Fatal propane- putane poisoning [in German]. Arch. Kriminol. 203(1-2):27-31. Gray, M.Y., and J.H. Lazarus. 1993. Butane inhalation and hemiparesis. J. Toxicol. Clin. Toxicol. 31(3):483-485. Gunn, J., J. Wilson, and A.F. Mackintosh. 1989. Butane sniffing causing ventricular fib- rillation. Lancet 1(8638):617. Krantz, J.C., Jr., C.J. Carr, and J.F. Vitcha. 1948. Anesthesia. XXXI. A study of cyclic and noncyclic hydrocarbons on cardiac automaticity. J. Pharmacol. Exp. Ther. 94(3):315-318. Lewis, R.J., ed. 1999. Sax’s Dangerous Properties of Industrial Materials, 10th Ed. New York: Wiley. Lide, D.R., ed. 1999. Handbook of Chemistry and Physics, 80th Ed. Boca Raton, FL: CRC Press. Low, L.K., J.R. Meeks, and C.R. Mackerer. 1987. n-Butane (CAS Reg. No. 106-97-8). Pp. 267-272 in Ethel Browning’s Toxicity and Metabolism of Industrial Solvents, 2nd Ed., Vol. 1. Hydrocarbons R. Snyder, ed. New York: Elsevier. Moore, A.F. 1982. Final report of the safety assessment of isobutane, isopentane, n- butane, and propane. J. Am. Coll. Toxicol. 1(4):127-142. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: n-Butaan. Den Haag: SDU Uitgevers [online]. Available: http://www.las rook.net/lasrookNL/maclijst2004.htm [accessed Jan. 12, 2012]. NIOSH (National Institute for Occupational Safety and Health). 2010. NIOSH Pocket Guide to Chemical Hazards: n-Butane. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occu- pational Safety and Health, Cincinnati, OH [online]. Available: http://www.cdc. gov/niosh/npg/npgd0068.html [accessed Jan. 12, 2012]. Nishi, K., N. Ito, J. Mizumoto, K. Wada, T. Yamada, Y. Mitsukuni, and S. Kamimura. 1985. Death associated with butane inhalation: Report of a case. Nihon Hoigaku Zasshi 39(3):214-216. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency 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: Na- tional Academy Press. Nuckolls, A.H. 1933. Underwriters’ Laboratoris Report on the Comparative Life, Fire, and Explosion Hazards of Common Refrigerants. Miscellaneous Hazards No. 2375. Chicago, IL: National Board of Fire Underwriters. Patty, F.A., and W.P. Yant. 1929. Odor Intensity and Symptoms Produced by Commer- cial Propane, Butane, Pentane, Hexane, and Heptane Vapor. U.S. Bureau of Mines Report of Investigation No 2979. Washington, DC: U.S. Department of Com- merce, Bureau of Mines. Paulussen, J.J.C., C.M. Mahieu, and P.M.J. Bos. 1998. Default Values in Occupational Risk Assessment. TNO Report V98.390. TNO Nutrition and Food Research Institute, Zeist, The Netherlands.

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40 Acute Exposure Guideline Levels Rieder-Scharinger, J., R. Peer, W. Rabl, W. Hasibeder, and W. Schrobersberger. 2000. Multiple organ failure following inhalation of butane gas: A case report [in German]. Wien Klin. Wochenschr. 112(24):1049-1052. Roberts, M.J., R.A. McIvor, and A.A. Adgey. 1990. Asystole following butane gas inha- lation. Br. J. Hosp. Med. 44(4):294. Ruth, J.H. 1986. Odor thresholds and irritation levels of several chemical substances: A review. Am. Ind. Hyg. Assoc. J. 47(3):A142-A151. Shimizu, H., Y. Suzuki, N. Takemura, S. Goto, and H. Matsushita. 1985. The results of microbial mutation test for forty-three industrial chemicals. Sangyo Igaku 27(6):400-419. Shugaev, B.B. 1969. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch. Environ. Health 18(6):878-882. Stewart, R.D., A.A. Hermann, E.D. Baretta, H.V. Foster, J.J. Sikora, P.E. Newton, and R.J. Soto. 1977. Acute and Repetitive Human Exposure to Isobutane and Propane. Report no. CTFA-MCOW-ENVM-BP-77-1, April 1977. National Clearinghouse for Federal Scientific and Technical Information, Springfield, VA. Stoughton, R.W., and P.D. Lamson. 1936. The relative anesthetic activity of the butanes and pentanes. J. Pharmacol. Exp. Ther. 58:74-77. 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. Haz- ard. Mater. 13(3):301-309. Tsukamoto, S., S. Chiba, T. Muto, T. Ishikawa, and M. Shimamura. 1985. Studies on the metabolism of volatile hydrocarbons in propane gas (LPG) inhalation: Detection of the metabolites. Nihon Hoigaku Zasshi 39(2):124-130. Williams, D.R., and S.J. Cole. 1998. Ventricular fibrillation following butane gas inhala- tion. Resuscitation 37(1):43-45. Zakhari, S. 1977. Butane. Pp. 55-59 in Non Fluorinated Propellants and Solvents for Aerosols, L. Goldberg, ed. Cleveland, OH: CRC Press.

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41 Butane APPENDIX A DERIVATION OF AEGL VALUES FOR BUTANE Derivation of AEGL-1 Values Key study: Patty, F.A., and W.P. Yant. 1929. Odor Intensity and Symptoms Produced by Commercial Propane, Butane, Pentane, Hexane, and Heptane Vapor. U.S. Bureau of Mines Report of Investigation. No 2979. Washington, DC: U.S. Department of Commerce, Bureau of Mines. Toxicity end point: 10-min exposure to 10,000 ppm is the no- observed-adverse-effect level for CNS depression. C3 × t = k for extrapolation to 30 min and 60 min; Time scaling: flatlining assumed from 60 min to 4- and 8-h exposure (based on 60-min steady-state concentration). k = (10,000 ppm)3 × 10 min = 1013 ppm3-min Uncertainty factors: 1 for interindividual variability Calculations: 10,000 ppma (24,000 mg/m3) 10-min AEGL-1: C3 × 30 min = 1013 ppm3-min 30-min AEGL-1: C = 6,900 ppmb (rounded) (16,000 mg/m3) C3 × 60 min = 1013 ppm3-min 1-h AEGL-1: C = 5,500 ppmb (rounded) (13,000 mg/m3) Set equivalent to 1-h AEGL-1 of 5,500 ppmb 4-h AEGL-1: (13,000 mg/m3) Set equivalent to 1-h AEGL-1 of 5,500 ppmb 8-h AEGL-1: (13,000 mg/m3) a The AEGL-1 value is greater than 10% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, safety considerations against the hazard of explosion must be taken into account. b The 10-min AEGL-1 value is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety considerations against the hazard of explo- sion must be taken into account.

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42 Acute Exposure Guideline Levels Derivation of AEGL-2 Values Key study: Nuckolls, A.H. 1933. Underwriters’ Laboratoris Report on the Comparative Life, Fire, and Explosion Hazards of Common Refrigerants. Miscellaneous Hazards No. 2375. Chicago, IL: National Board of Fire Underwriters. Toxicity end point: CNS depression, no effects consistent with definition of AEGL-2 in guinea pigs exposed to butane at 50,000 ppm for 2 h. C3 × t = k for extrapolation to 10 min, flatlining Time scaling: assumed from 30 min to 8-h exposure (based on 2-h steady-state concentration). k = (50,000 ppm)3 × 30 min = 3.8 × 1015 ppm3-min Uncertainty factors: Total uncertainty factor of 3 for differences between species and individuals. Calculations: C3 × 10 min = 3.8 × 1015 ppm3-min 10-min AEGL-2: C = 72,112 ppm 72,112 ÷ 3 = 24,000 ppma (rounded) (= 57,000 mg/m3) 30-min AEGL-2: C = 50,000 ppm (2-h steady state concentration) 50,000 ppm ÷ 3 = 17,000 ppmb (rounded) (40,000 mg/m3) 1-h AEGL-2: Set equivalent to the 30-min AEGL-2 of 17,000 ppmb (40,000 mg/m3) 4-h AEGL-2: Set equivalent to the 30-min AEGL-2 of 17,000 ppmb (40,000 mg/m3) 8-h AEGL-2: Set equivalent to the 30-min AEGL-2 of 17,000 ppmb (40,000 mg/m3) a The 10-min AEGL-2 value is greater than the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety considerations against the hazard of explosion must be taken into account. b The AEGL-2 value is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety considerations against the hazard of explosion must be taken into account.

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43 Butane Derivation of AEGL-3 Values Key study: Shugaev, B.B. 1969. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch. Environ. Health 18(6):878-882. Toxicity end point: Lethality study in mice exposed for 2 h. The calculated 2-h LC01 is 160,000 ppm. C3 × t = k for extrapolation to 10 min, flatlining Time scaling: assumed from 30 min to 8-h exposure (based on 2-h steady-state concentration). k = (160,000 ppm)3 × 30 min = 1.2 × 1017 ppm3-min Uncertainty factors: Total uncertainty factor of 3 for differences between species and individuals. Calculations: C3 × 10 min = 1.2 × 1017 ppm3-min 10-min AEGL-3: C = 230,760 ppm 230,760 ÷ 3 = 77,000 ppm (rounded) (18,000 mg/m3) 30-min AEGL-3: C = 160,000 ppm (2-h steady state concentration) 160,000 ppm ÷ 3 = 53,000 ppma (rounded) (130,000 mg/m3) 1-h AEGL-3: Set equivalent to the 30-min AGEL-3 of 53,000 ppma (130,000mg/m3) 4-h AEGL-3: Set equivalent to the 30-min AGEL-3 of 53,000 ppma (130,000mg/m3) 8-h AEGL-3: Set equivalent to the 30-min AGEL-3 of 53,000 ppma (130,000mg/m3) a The AEGL-3 values are greater than the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety considerations against the hazard of explosion must be taken into account.

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44 Acute Exposure Guideline Levels APPENDIX B CATEGORY GRAPH FOR BUTANE Butane Toxicity 1000000 100000 AEGL - 3 AEGL - 2 Human - No effect 10000 Human Discomfort AEGL - 1 Human - Disabling Animal - No effect ppm 1000 Animal - Discomfort Animal Disabling 100 Animal - Some Lethality Animal - Lethal AEGL 10 1 0 60 120 180 240 300 360 420 480 Minutes FIGURE B-1 Category graph of toxicity data and AEGLs values for butane.

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45 Butane APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR BUTANE Derivation Summary for Butane AEGL-1 VALUES 10 min 30 min 1h 4h 8h See belowa b b b 5,500 ppmb 6,900 ppm 5,500 ppm 5,500 ppm (16,000 mg/m ) (13,000 mg/m ) (13,000 mg/m ) (13,000 mg/m3) 3 3 3 Key reference: Patty, F.A., and W.P. Yant 1929. Odor Intensity and Symptoms Produced by Commercial Propane, Butane, Pentane, Hexane, and Heptane Vapor. U.S. Bureau of Mines Report of Investigation. No 2979. Washington, DC: U.S. Department of Commerce, Bureau of Mines. Test species/Strain/Number: Groups of 3- 6 human subjects (male and female, ages 20-30 years). The study was on the warning properties of several alkanes. Exposure route/Concentrations/Durations: Subjects were exposed at slowly increasing concentrations up to 50,000 ppm (continuous exposure test, total exposure was at least 10 min), followed by exposure to fixed exposure concentrations for a short duration (exact duration unknown) on the same day (intermittent exposure test). The fixed exposure concentrations were approximately 1,000, 2,000, 5,000, 7,000, 10,000, 20,000, and 100,000 ppm. Effects: No odor detection and no irritation were reported during the continuous exposure test. Drowsiness reported after a 10-min exposure to butane 10,000 ppm was considered to be of minor severity. No details on CNS effects were presented for the higher exposure concentrations. No irritation was reported at 100,000 ppm for 10 min. End point/Concentration/Rationale: No AEGL-1 effects at 10,000 ppm for 10 min. Uncertainty factors/Rationale: Total uncertainty factor: 1 Interspecies: 1, test subjects were humans. Intraspecies: 1, concentration-response curve appears to be very steep indicating small interindividual variability; no irritation at 100,000 ppm for 10 min; larger factor will result in unrealistically low values compared with occupational standards. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: n = 3 for time scaling from 10 to 60 min (animal data suggest high value of n); because steady state is reached within 30 min, the values for the 4- and 8-h exposures were set equivalent to the 60-min value. Data adequacy: Database is relatively poor but the values are supported by the available animal data. a The AEGL-1 value is 10,000 ppm (23,700 mg/m3), which is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account.

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46 Acute Exposure Guideline Levels b The AEGL value is greater than 10% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, safety considerations against the hazard of explosion must be taken into account. AEGL-2 VALUES 10 min 30 min 1h 4h 8h a b b b See belowb See below See below See below See below Key reference: Nuckolls, A.H. 1933. Underwriters’ Laboratoris Report on the Comparative Life, Fire, and Explosion Hazards of Common Refrigerants. Miscellaneous Hazards No. 2375. Chicago, IL: National Board of Fire Underwriters. Test species/Strain/Number: Guinea pigs, 3 animals per every concentration-time combination. Exposure route/Concentrations/Durations: Inhalation for 5, 30, 60, or 120 min at 21,000-28,000 ppm or 50,000-56,000 ppm. Effects: At 21,000-28,000 ppm, occasional irregular and rapid breathing, did not worsen during exposure, and rapid recovery after exposure ended. At 50,000-56,000 ppm, irregular breathing and dazed appearance during second hour of exposure, but animals were able to walk End point/Concentration/Rationale: Animals had dazed appearance but were able to walk at 50,000 ppm (lower concentration in the exposure range). Uncertainty factors/Rationale: Total uncertainty factor: A total uncertainty factor of 3 is considered sufficient for toxicokinetic and toxicodynamic differences between individuals and interspecies differences. The effects are attributed to butane itself and no relevant differences in kinetics are assumed, so only small interindividual differences are expected. The concentration-response curve appears to be very steep indicating that a large uncertainty factor is unnecessary. Further, a larger uncertainty factor would lead to unrealistically low values for AEGL-2 that would be similar to the AEGL-1 values. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: A steady state is reached within 30 min, and the effects are considered to be concentration dependent. Therefore, the starting point for the 30-min and the 1-, 4-, and 8-h values were the 2-h steady-state value of 50,000 ppm. For extrapolation from 30 to 10 min, n = 3. Data adequacy: Although case reports of butane exposure indicate potential for cardiac sensitization (analogous to propane), this end point has not been studied. a The 10-min AEGL-2 value is 24,000 ppm (57,000 mg/m3), which is greater than the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety consid- erations against the hazard of explosion must be taken into account. b The AEGL-2 value for 30-min and 1-, 4-, and 8-h exposures is 17,000 ppm (40,000 mg/m3), which is greater than 50% of the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety considerations against the hazard of explosion must be taken into account.

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47 Butane AEGL-3 VALUES 10 min 30 min 1h 4h 8h a a a See below See belowa a See below See below See below Key reference: Shugaev, B.B. 1969. Concentrations of hydrocarbons in tissues as a measure of toxicity. Arch. Environ. Health 18(6):878-882. Test species/Strain/Number: Mice, strain and number not specified. Exposure route/Concentrations/Durations: Inhalation for 2 h, butane concentrations not specified. Effects: LC16 = 224,000 ppm; LC50 = 287,000 ppm; LC84 = 363,000 ppm A 2-h LC01 was calculated to be 160,000 ppm. End point/Concentration/Rationale: Lethal concentration, 1% lethality Uncertainty factors/Rationale: Total uncertainty factor: A total uncertainty factor of 3 is considered sufficient because the effects are attributed to butane itself, and no relevant differences in kinetics are assumed. A species with a relatively high susceptibility is used. The concentration-response curve appears to be very steep indicating that a large factor s unnecessary. Further, a larger uncertainty factor would lead to unrealistically low values for AEGL-3, which would be similar to the AEGL-2 values. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applicable Time scaling: A steady state is reached within 30 min, and the effects are considered to be concentration dependent. Therefore, the starting point for the 30-min and the 1-, 4-, and 8-h values were the 2-h steady-state value of 160,000 ppm. For extrapolation from 30 to 10 min, n = 3. Data adequacy: The results of the key study in mice are comparable with the results from a second study in mice. The 10-min value is supported by human data. Exposure to slowly increasing concentrations of butane up to 50,000 ppm (total exposure duration at least 10 min) and a short exposure (exact duration unknown) at 100,000 ppm on the same day did not result in serious complaints. a The 10-min AEGL-3 values is 77,000 ppm (180,000 mg/m3), and the AEGL-3 value for 30 min and 1, 4, and 8 h is 53,000 ppm (130,000 mg/m3). All of the AEGL-3 values are greater than the lower explosive limit for butane in air of 19,000 ppm. Therefore, extreme safety considerations against the hazard of explosion must be taken into account.