B2 1-Butanol

John T. James, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

National Aeronautics and Space Administration

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

1-Butanol is a colorless, flammable, volatile liquid with a sweet to rancid odor detectable at a threshold of about 0.8 ppm (2.5 mg/m 3) (Amoore and Hautala, 1983). Russian investigators have reported an odor threshold of 1.2 mg/m3 (Baikov and Khachaturyan, 1973).

Synonyms:

1-butyl alcohol, n-butanol, butyl alcohol

Formula:

CH3CH2CH2CH2OH

CAS number:

71-36-3

Molecular weight:

74.1

Boiling point:

118°C

Melting point:

-89°C

Specific gravity:

0.81

Vapor pressure:

6.5 mmHg at 20°C

Lower explosive limit (air):

1.4% (vol/vol)

Solubility:

Water solubility about 7%, miscible with organic solvents

Conversion factors:

1 ppm = 3.08 mg/m3

1 mg/m3 = 0.325 ppm



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 B2 1-Butanol John T. James, Ph.D. Johnson Space Center Toxicology Group Biomedical Operations and Research Branch National Aeronautics and Space Administration Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES 1-Butanol is a colorless, flammable, volatile liquid with a sweet to rancid odor detectable at a threshold of about 0.8 ppm (2.5 mg/m 3) (Amoore and Hautala, 1983). Russian investigators have reported an odor threshold of 1.2 mg/m3 (Baikov and Khachaturyan, 1973). Synonyms: 1-butyl alcohol, n-butanol, butyl alcohol Formula: CH3CH2CH2CH2OH CAS number: 71-36-3 Molecular weight: 74.1 Boiling point: 118°C Melting point: -89°C Specific gravity: 0.81 Vapor pressure: 6.5 mmHg at 20°C Lower explosive limit (air): 1.4% (vol/vol) Solubility: Water solubility about 7%, miscible with organic solvents Conversion factors: 1 ppm = 3.08 mg/m3 1 mg/m3 = 0.325 ppm

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 OCCURRENCE AND USE 1-Butanol is used in cosmetics, flavorings, brake fluids, degreasers, repellants, and as a solvent for many processes; it is used as an extractant in the manufacture of antibiotics, hormones, hop, vegetable oils, and vitamins (WHO, 1987; Lington and Bevan, 1994). This alcohol occurs naturally as a product of carbohydrate fermentation; therefore, it is present in alcoholic beverages, fruits, cheeses, and a variety of other foods (Brandt, 1987). Air inside mobile homes has been reported to contain 1-butanol in samples at a frequency of about 50% and at concentrations up to 0.08 mg/m3 (Connor et al., 1985). 1-Butanol has been found in about one third of the samples of air from recent space-shuttle flights at concentrations ranging from 0.01 to 1 mg/m3 (James et al., 1994). The primary source of this compound for spacecraft atmospheres is off-gassing from flight hardware; however, a small contribution (about 1 mg/d per human) might come from human metabolism. TOXICOKINETICS AND METABOLISM Absorption 1-Butanol is readily absorbed through the skin, respiratory tract, and gastrointestinal tract (WHO, 1987; DiVincenzo and Hamilton, 1979, Rumyantsev et al., 1975). Ästrand et al. (1976) found that 12 human subjects absorbed the alcohol vapor with 37-48% efficiency when inhaled at either 100 or 200 ppm, with or without exercise. After a 30-min exposure at 100 or 200 ppm, the arterial blood concentrations were only 0.3 and 0.5 mg/kg (3 and 5 mg/dL), respectively. Those concentrations doubled after 30 min of additional exposure of subjects exercising at a 50-watt intensity (light physical exercise). The concomitant venous concentrations of 1-butanol were roughly half those reported in arterial blood. In dogs exposed for 6 h at 50 ppm, the uptake by the respiratory system averaged 55% with 1-butanol at 22 ppm consistently found in the exhaled breath (DiVincenzo and Hamilton, 1979). It is noteworthy that in neither experiment could 1-butanol be detected in the blood of humans or dogs following exposures at 50 ppm. In rats exposed at 500 or 2000 ppm for 6 h, the serum concentrations of 1-buta-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 nol were undetectable or 0.09 mM (70 mg/dL), respectively (Aarstad et al., 1985). Distribution According to an abstract, all butanols studied, including 1-butanol, were freely distributed in the body according to water content of the tissue (Bechtel and Cornish, 1975). In several animal models, 1-butanol is rapidly removed from the blood and distributed to tissue compartments. After oral administration to rats of 1-butanol at 2 g/kg, the blood concentrations reached 19 mg% in 15 min, peaked at 51 mg% after 2 h, and fell off to 18 mg% after 4 h (Gaillard and Derache, 1965). In rats given oral doses at 0.5 g/kg, the peak serum concentration of 240 ppm (19 mg/dL) was reached in 45 to 50 min, and butanol was not detected after 2 to 3 h (detection limit not specified) (Bechtel and Cornish, 1975). These investigators reported that n-butylaldehyde was found in the serum as a metabolite. Likewise, male rats given 0.45 g/kg showed a maximum plasma concentration of 70 µg/mL (7 mg/dL) after 1 h and undetectable concentrations after 4 h (DiVincenzo and Hamilton, 1979). The blood concentration in rabbits was about 1.1 mg/mL (110 mg/dL) 1 h after oral administration of the butanol at 2 mL/kg (1.6 g/kg) but had declined to 0.3 mg/mL (30 mg/dL) 7 h after dosing (Saito, 1975). Elimination 1-Butanol is eliminated from the body by a variety of metabolic steps and routes in animals. Rats orally dosed with 0.45 g/kg of n-[1-14 C]butanol excreted 83 % of the dose as 14CO2 in the expired air, 4% in the urine, and < 1% in the feces within 24 h of administration (DiVincenzo and Hamilton, 1979). The major labeled components in the urine were sulfates, glucuronides, and urea. Similarly, in rabbits dosed orally at 16 mmol/3 kg (0.4 g/kg), only 1.8% of the dose was excreted as the glucuronide within 24 h (Kamil et al., 1953). Saito (1975) found that rabbits given 2 mL/kg (1.6 g/kg) eliminated less than 0.5% of the dose as unmetabolized alcohol in the breath or urine during the first 10 h. In

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 mice given an unspecified dose of n-[14C]-butanol, 21% of the label remained after 24 h and 5 % after 3 d, indicating accumulation of the isotope (Rumyantsev et al., 1975). Metabolism The metabolism of 1-butanol is very similar to that of ethanol. The butanol is metabolized to its aldehyde by hepatic alcohol dehydrogenase (ADH) and also by the cytochrome P-450 system, but not by catalase. The aldehyde is oxidized to the acid, which is further oxidized to CO2. The relative rates of oxidation of n-butrylaldehyde and acetaldehyde by aldehyde dehydrogenase isolated from human liver are comparable over a substrate concentration range of 0.05 to 3 mM (Blair and Bodley, 1969). A small fraction of the alcohol is conjugated in the liver and excreted by the kidneys (see above). The rate of oxidation of 1-butanol by ADH prepared from rat livers was twice the rate measured for ethanol oxidation (Arslanian et al., 1971). In vitro studies of rat-liver microsomes showed that the microsomal alcohol-oxidizing system accounts for non-ADH activity for butanol and other primary alcohols; however, for methanol and ethanol only, the catalase system also seems to be partially responsible for alcohol oxidation. Cederbaum et al. (1978) showed that 1-butanol is oxidized through a hydroxyl-radical-dependent pathway in rat-liver microsomes, but not through a catalase-dependent pathway. Morgan et al. (1982) compared the catalytic activity of various cytochrome P-450 isozymes for oxidation of alcohols in rabbit-liver microsomes after the rabbits had been exposed chronically to ethanol. Of the five isozymes tested, the predominant activity for both ethanol and 1-butanol appeared to be P-450LM3a, which was later called P-450IIE1 (Yang et al., 1990). Under the assay conditions used to study P-450 LM3a, the Km for 1-butanol was one fourth the Km for ethanol; however, the Vmax for each alcohol was similar (Morgan et al., 1982). Because the enzymes involved in metabolism of 1-butanol are similar to those involved in metabolism of ethanol, the kinetics of the oxidations can reasonably be expected to be qualitatively similar. In fact, isolated perfused rat livers have shown that both alcohols are oxidized according to zero-order kinetics above a certain concentration and ac-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 cording to first-order kinetics below that concentration (Auty and Branch, 1976). The concentration of butanol in the perfusate for transition from zero to first-order kinetics was approximately 0.8 mM (6 mg/dL). In an experiment to assess the ability of various inhaled butanols to induce cytochrome P-450 in the kidneys, lungs, and livers of rats exposed to 1-butanol at 500 ppm (6 h/d for 5 d) or 2000 ppm (6 h/d, 3 d), the only statistically significant increase after exposure was in the livers after the 2000-ppm exposures (Aarstad et al., 1985). Rumyantsev et al. (1975) reported a biphasic removal of n-[14C]butanol from liver and kidney of rats given an oral dose of unspecified concentration; however, specific data and half-lives were not given in the paper. TOXICITY SUMMARY Acute and Short-Term Exposures The short-term effects of airborne exposure to 1-butanol include irritation of mucosal surfaces, depression of the CNS, and ultimately death if extremely high concentrations are involved. Administration of single doses via routes other than inhalation have resulted in hepatotoxicity in rodents. Irritation Data on the irritancy properties of 1-butanol have been reported on industrial workers, human test subjects, and rodents. The data do not create a consistent impression of the irritation thresholds either in humans or in rodents. Results of brief human inhalation tests and industrial experience give conflicting results on the irritation threshold. Nelson et al. (1943) reported that 3- to 5-min exposures of 10 test subjects resulted in mild irritation of nose and throat in the majority of test subjects exposed at 25 ppm and eye irritation in the majority of subjects exposed at 50 ppm, which was considered an ''objectionable'' concentration. The test subjects indicated that a concentration below 25 ppm would be needed

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 for an 8-h occupational exposure. Unfortunately, the investigators relied on nominal concentrations, had a subjective assessment method, and did not extend the exposures to determine if the subjects would adapt to the concentrations. In contrast to that result, Ästrand et al. (1976) exposed 12 human subjects for 0.5 to 2 h to 1-butanol at concentrations of 100 or 200 ppm. There was no indication that the subjects found the exposure disagreeable. Tabershaw et al. (1944) surveyed workers at six industrial sites where exposures to 1-butanol ranged from 5 to 115 ppm. "Much" eye irritation was found at four of the six plants, but a threshold for irritation could not be gleaned from the data. The authors concluded that eye inflammation resulted if the workers were exposed at concentrations above 50 ppm. A 10-y study of 15 workers (additional subjects added later) exposed at concentrations ranging from 100 to 200 ppm concluded that eye irritation resulting in corneal inflammation, lacrimation, and photophobia were occasionally encountered in workers exposed at 200 ppm (Sterner et al., 1949). Complaints of irritation in association with exposures at 100 ppm were "rare." Because both studies in workers seemed to use adequate analytical techniques, but were limited by subjective assessments of irritation end points, it is difficult to select one result over the other. It seems prudent to conclude that a concentration of 50 ppm poses some risk of mild irritation in persons who have not adapted to 1-butanol. Several studies of sensory irritation in rodents have been published. Kane et al. (1980) reported that the RD50 (concentration giving a 50% depression in the breathing rate) in mice was 4800 ppm. De Ceaurriz et al. (1981) found an RD50 of 1270 ppm in mice and suggested that 127 ppm (10% of the RD50) would be an uncomfortable but tolerable concentration. Kristiansen et al. (1988) estimated a threshold response (RD0) of 233 ppm and an RD50 of 12,000 ppm in mice. Korsak et al. (1993) reported an RD50 of 3000 ppm in mice. These data are not particularly useful in suggesting an irritation threshold in humans. CNS Effects Narcotic effects have been demonstrated in animals given large liquid doses or high-concentration exposures to the alcohol vapor. Munch (1972) reported that the ND50 (dose causing stupor or loss of voluntary movement in half the animals) for a single oral dose to rabbits was 11

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 mmol/kg (0.8 g/kg). After 12 h of exposure to the vapor at 22 mg/L, 6 of 10 mice were anesthetized; a 23-h exposure at 27 mg/L anesthetized 9 of 10 mice (McOmie and Anderson, 1949). Rumyantsev et al. (1979) reported, without giving exposure times, that 50% and 100% of mice were anesthetized when exposed at 15.1 mg/L and 15.3 mg/L, respectively. In a study of alcohol-induced hypothermia and decreased Rotorod performance in mice given a single oral dose, no effects were observed when blood concentrations were at or below 16 mg/dL. This concentration was achieved either 10 min after a dose of 0.5 g/kg or 40 min after a dose of 1.0 g/kg was administered (Maickel and Nash, 1985). Hypothermia was a more sensitive end point, but was not be considered an adverse effect. An ID50 (mean airborne concentration associated with a 50% decrease in immobility in the behavioral despair swimming test) of 620 ppm was found for mice exposed for 4 h (De Ceaurriz et al., 1983). The implications of this result in terms of adverse effects that might occur in humans is unclear. Light Adaptation There is some evidence that 1-butanol might affect the ability of the eye to adapt to changes in light intensity. Baikov and Khachaturyan (1973) found that three test subjects exposed for 5 min at 1.2 mg/m 3 had slowed darkness-adaptation rates compared with pre-exposure adaptation rates. A slower rate was not observed during exposures at 0.9 mg/m3. Similarly, three test subjects exhibited a slower reaction time to light increases after exposures at 0.7 mg/m3, but not after exposures at 0.5 mg/m3. At best, the findings can only be considered preliminary because of the incompleteness of the report and the small number of test subjects. Hepatotoxicity Damage to the liver has been reported in mice exposed at dosages approaching the LD50. Delayed deaths in mice given an intraperitoneal (ip) injection of 1-butanol (or other butanols) were attributed to development of liver injury (Maickel and McFadden, 1979).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Lethality Death has been caused in experimental animals by using a variety of routes for administration of 1-butanol. Death was induced in 4 of 10 mice exposed to 1-butanol vapor for 23 h at a concentration of 27 mg/L (McOmie and Anderson, 1949). The LD50 (7-d observation) in mice given an ip injection was 0.25 g/kg (Maickel and McFadden, 1979). The rat oral LD50 (14-d observation) was reported to be 4.4 g/kg (Smyth et al., 1951). The LD50 in male rats was reported to be 2.7 g/kg of body weight (Rumyantsev et al., 1979). In rabbits, the single oral dose giving an LD50 has been reported as 47 mmol/kg (3.5 g/kg) or 3 mL/kg (2.4 g/kg) (Munch, 1972; Maickel and McFadden, 1979). In dogs, the blood concentration associated with cardiac arrest was 84 mg/dL (MacGregor et al., 1964). Subchronic and Chronic Exposures Data on the long-term effects of 1-butanol are available from inhalation-exposure studies of animals, oral-exposure studies of animals, and epidemiological studies of exposed workers. Inhalation Exposures Long-term inhalation-exposure studies of 1-butanol have been of mixed quality and have often been reported in an incomplete format. The adverse effects alleged as a result of inhalation exposure to 1-butanol are widespread in such studies. These reports are in contrast to a subchronic oral-exposure study conducted by Toxicology Research Laboratories in the late 1980s in which no adverse effects except ataxia were found in rats (TRL, 1986). Because the reported effects in the inhalation studies are so diverse and the primary issue is the quality of each study rather than the findings, the studies will be discussed individually. In an early study by Smyth and Smyth (1928), it was reported that 28 to 64 exposures of guinea pigs to 1-butanol at 100 ppm (4 h/d for 6-7 d/w) caused anemia, lymphocytopenia, hemorrhage, and liver and renal degeneration. Although the test material was once-distilled, no

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 report of purity or of analytical methods used was given to determine exact exposures. The findings were based on groups of three exposed animals; however, the findings were striking in view of negative findings on other solvents, such as ethyl acetate (200 ppm) and ethanol (3000 ppm). The authors conclude that butyl alcohol should be used with caution and only in small amounts in lacquers. Industrial experience and other testing in rodents suggest that these early results are not representative of the toxicity potential of 1-butanol. Several continuous inhalation studies have been reported in the Russian literature. The World Health Organization (WHO, 1987) reported that Baikov and Khachaturyan (1973) studied rats exposed for 92 d at 0.03 ppm or 7.1 ppm for a variety of effects. According to the WHO summary, no effects occurred at the low concentration; however, at the high concentration, there was a decrease in blood RNA and DNA, an increase in leukocyte luminescence, and changes in the activity of several enzymes. In fact, the Baikov and Khachaturyan (1973) study cited in the WHO report is a short-term human inhalation study involving 18 subjects exposed at concentrations of 0.5 to 1.2 mg/m3 (see acute exposures section). In mice continuously exposed to 1-butanol vapor at 0.8, 6.6, and 40 mg/m3 for 30 d, Kolesnikov (1975) reported an increased tolerance to the narcotic effects of a single oral dose of 1-butanol (details not given). In addition, the hexenal sleep time was approximately halved in the two highest exposure groups. The erythrocyte acid resistance in rats given the identical exposure concentrations as the mice was different from controls in the middle-exposure group, but the description of the results for other groups indicated that there was no dose response for this end point. This brief report lacks sufficient detail to be useful. For example, there is no description of compound purity, analytical methods (except to say that a GC was used), statistical methods, chamber dynamics, or tabulation of results. In another Russian investigation, which appears to be the overall study from which the report of Kolesnikov (1975) was extracted, rats and mice were exposed continuously at 0.8, 6.6 and 40 mg/m3 for 120 d (Rumyantsev et al., 1976). Inconsistent and possibly transient changes were reported in both species when evaluated by the "motor-defensive method." The mid-and high-exposure groups (and possibly the lowest exposure group) had significant decreases in oxygen consumption (magnitude not given) after 120 d, and the blood cholines-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 terase activity changed (statistical significance not given) but later returned to control levels in the high-exposure group. Transient changes were noted in alanine aminotransferase (SGPT) and reticulocyte counts. Histopathological changes were noted in rats and included disrupted blood circulation, atelectasis, and pulmonary emphysema. The changes were greatest for the mid-and high-exposure groups, but some changes were noted in the lowest exposure group. In view of results from other investigators (e.g., Baikov and Khachaturyan, 1973), these authors concluded that negative effects were observed at 6.6 mg/m3 but that the effects at 1 and 0.8 mg/m3 were not adverse. Unfortunately, this study lacks detail on the test material, analytical methods, chamber dynamics, statistical methods, and tabulation of findings. These results are not consistent with the lack of pulmonary and hematological effects reported by Sterner et al. (1949) in workers exposed at 100 to 200 ppm for up to 10 y. Oral Exposures Although the continuous inhalation studies reported by the Russians are not directly comparable to the 13-w oral gavage study, there are striking contrasts in the details reported and the adverse effects found. The oral study involved 92-93 d of daily administration of 1-butanol at 0, 30, 125, or 500 mg/kg to male and female rats (30 per sex per group). The only unequivocal effect induced by the alcohol was ataxia and hypoactivity in the highest exposure group during the last 6 w of the administration (TRL, 1986). No treatment-related effects were noted in the rats given 30 or 125 mg/kg/d. At the interim 6-w sacrifice, a statistically significant decrease of < 5% in red-blood-cell (RBC) indices was noted in females of the highest exposure group, but the effect was not observed in males and and was not present in females sacrificed at the end of the study. The only end point in common with the Russian studies is SGPT changes, which the Russians reported as increased transiently at the 60-d sacrifice in all exposure groups (Rumyantsev et al., 1976). The TRL results showed no changes in this enzyme, which is indicative of liver injury, at either the interim or final sacrifice. Reticulocytes were not counted in the TRL study because the protocol specified that this count would not be done unless there were clear signs of anemia in the test animals.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 By estimating the total doses delivered and blood concentrations of 1-butanol in the 120-d Russian study and in the 92-d U.S. study, the inconsistencies in the results become readily apparent. From the results of DiVincenzo and Hamilton (1979), the gavage of 0.5 g/kg should result in a blood concentration of about 7 mg/dL at 1 h, followed by a decrease to undetectable concentrations after 4 h. The inhalation results of Aarstad et al. (1985), showing undetected blood concentrations at exposures of 500 ppm (1500 mg/m3), suggest that the highest concentration in the Russian studies (40 mg/m3) would not result in significant concentrations of the alcohol in the blood. In the 92-d rat oral-exposure study, assuming an average body weight of 1/3 kg, the dose delivered was 15,000 mg over the entire study. In the 120-d inhalation study, assuming a daily inhalation volume of 0.15 m3/d and an uptake of 50%, the cumulative amount delivered to rats exposed to the highest concentration was 360 mg. Thus, the dose delivered to the rats in the oral study was approximately 40-fold greater than the dose delivered in the inhalation study, yet the oral study produced no adverse effects (except narcosis), and the inhalation study suggested many adverse effects. Even though the 92-d study was done using a noninhalation route, it will be used in preference to the 120-d study because the former study is much more thoroughly documented. Epidemiological Studies in Workers All epidemiological studies of workers are at least 25 y old and generally do not have the rigor found in more recent studies. A survey of six plants involving several hundred workers in which exposures to 1-butanol varied from 5 to 115 ppm showed that the primary adverse effects were eye inflammation if exposures were above 50 ppm, and systemic effects (headache and vertigo) if the concentrations were above 100 ppm (Tabershaw et al., 1944). It was not apparent that these investigators looked for other adverse effects, such as pulmonary or hepatic damage. Sterner et al. (1949) reported no evidence of pulmonary injury and no hematological effects in workers exposed at 100 to 200 ppm for up to 10 y. Workers exposed at 200 ppm occasionally developed blurring of vision, lacrimation, and photophobia, which became more severe toward the end of the work week. Ophthalmic examination revealed slight-to-moderate corneal edema, with injection and mild

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Concentration Exposure Duration Species Effects References Inhalation 5100 ppm Unspecified Rat ND100 (anesthesia) Rumyantsev et al., 1979 6000 ppm 7 h/d, 6 w Rat (male) No effect on mating capability Nelson et al., 1989a 7000 ppm 12 h Mouse 6/10 anesthetized McOmie and Anderson, 1949 8600 ppm 23 h Mouse 9/10 anesthetized, 4/10 dead McOmie and Anderson, 1949 Oral 0.125g/kg/d 92 d Rat NOEL for all parameters measured TRL, 1986 0.5 g/kg/d 92 d Rat Ataxia and hypoactivity in last 6 w TRL, 1986 0.8 g/kg Singledose Mouse ND50 Munch, 1972 1.0 g/kg Singledose Mouse NOEL for Rotorod performance Maickel and Nash, 1985

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 2-2 Exposure Limits Set or Recommended by Other Organizations Agency or Organization Exposure Limit, ppm Reference ACGIH's TLV 50 (ceiling), intended to change to 25 ppm ACGIH, 1995 OSHA's PEL 100 (transitional), 50 ppm ceiling (''final'' rule) U.S. Dept. of Labor, 1995 TLV, Threshold Limit Value; PEL, permissible exposure limit. TABLE 2-3 Spacecraft Maximum Allowable Concentrations Exposure Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 50 150 Eye irritation 24 h 25 80 Eye irritation 7 d 25 80 Eye irritation, systemic injury 30 d 25 80 Eye irritation, systemic injury 180 d 12 40 Systemic injury RATIONALE FOR ACCEPTABLE CONCENTRATIONS Acceptable concentrations (ACs) must be set to protect against excess risk of irritation and CNS effects due to exposure to 1-butanol. The data on hepatotoxicity suggest that it does not occur unless exposures approach lethal concentrations, and the data on light adaptation are insufficient for setting an acceptable concentration. Epidemiological data are mixed, and the findings on audiological deficits were not convincing in view of the other health effects detected in the workers. In 1987, WHO considered the available data (including the Russian data) inadequate to assess the human health risks or to set an occupational exposure limit. The 92-d oral gavage study in rats was not available to WHO at the time; however, it is clear that they were not willing to rely

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 on the Russian data that they had tabulated. Likewise, the rationale below does not rely on the Russian data. The guidelines provided by the National Research Council were used as a framework for developing the SMACs (NRC, 1992). Irritation and Inflammation of the Eyes Based on the information from three studies (Nelson et al., 1943; Tabershaw et al., 1944; Sterner et al., 1949), the threshold for eye irritation is between 50 and 100 ppm (150 and 300 mg/m3). The weight of evidence suggests that any irritation at 50 ppm will be mild and therefore acceptable for 1-h exposures. The comment by Sterner et al. (1949) that the effects on the eyes become worse during the work week suggests that a 24-h continuous exposure must be below 50 ppm to ensure that no more than mild irritation will occur; 25 ppm was judged to be suitable to achieve that goal. For longer exposures, a 25-ppm limit should protect against irritation indefinitely, because some degree of adaptation could be expected. CNS Effects Tabershaw et al. (1944) concluded from their study of workers that systemic effects will not appear until 100 ppm is greatly exceeded, and Sterner et al. (1949) did not report any CNS effects in the workers they studied. Unfortunately, no attempt was made in either study to take objective measurements of performance in the exposed workers. It is clear, however, from animal studies that narcosis or decrements in rotorod performance can be induced by inhalation or other routes of administration, but the findings were not appropriate to use for setting human exposure limits because of the severity of the end points. Any CNS effects in humans would have to be mediated through 1-butanol concentrations in the blood. A stable blood concentration of about 3 mg/dL (arterial) was attained in test subjects after 30 min of inhalation of 1-butanol at 100 ppm (Ästrand et al., 1976). Several animal studies have shown that 1-butanol is 5 to 10 times more effective than ethanol in inducing hypothermia, decreased performance in the tilted-plane test, or respiratory arrest (Maickel and Nash, 1985; Wallgren, 1960; Mac-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Gregor et al., 1964). The threshold blood concentration of ethanol at which performance decrements are not detectable is 50 mg/dL (Kennedy, 1993). Hence, even if 1-butanol were 10-fold more potent in inducing CNS effects than ethanol, the blood concentrations associated with a 100-ppm exposure would be below an effect level. The AC for all exposure times to prevent CNS effects was set at 100 ppm. This approach to setting the AC is in general agreement with the epidemiological reports on exposed workers. Long-Term Systemic Injury The 92-d oral-exposure rat data, even though it is not directly pertinent to continuous inhalation exposures, can be extrapolated to a human estimate (TRL, 1986). For reasons discussed in the toxicity section, the Russian data were not used to set ACs. Except for narcosis, rats given 0.5 g/kg/d were without adverse effects. Assuming that the rats' average weight was 0.33 kg and extrapolating on a body-surface basis to 70-kg humans, the equivalent dose for humans is 0.5 g/kg/d × 0.33 kg × (70 kg/0.33 kg)0.67 = 6 g/d, as a NOAEL for 92 d of exposure. This can be equated to a human inhalation dose by assuming a 40% uptake of the alcohol and a 20-m3/d inhalation volume. The airborne concentration necessary to deliver 6 g/d was calculated as follows: CNOAEL = 6000 mg/d ÷ (20 m3/d × 0.4) = 750 mg/m3. Even though the dose was scaled from rats to humans, interspecies differences might exist in metabolism and tissue susceptibility, so a species factor is needed. For a 90-d exposure, the AC is AC (90 d) = 750 mg/m3 ÷ 10 (species) = 75 mg/m3 (25 ppm). That AC also is the AC for 7- and 30-d exposures. Because the oral study lasted only 90 d, the 180-d AC should be set using a time factor of 2 (180/90), which results in a 180-d AC of 40 mg/m3 (12 ppm).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Spaceflight Effects The toxic effects induced by 1-butanol are not expected to be increased by the microgravity-induced physiological and biochemical changes in astronauts.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 TABLE 2-4 Acceptable Concentrations     Uncertainty Factors Acceptable Concentrations, mg/m3 Effect, Data, Reference Species Species Time Small n 1 h 24 h 7 d 30 d 180 d Eye irritation   Mild irritation at 150 mg/m3 (three studies; see text) Human, n > 100 1 1 1 150 80 80 80 80 CNS effects   Epidemiology, no effects (Tabershaw et al., 1944) Human 1 1 1 300 300 300 300 300 Compared with ethanol Human - - - 300 300 300 300 300 (see text)   Systemic injury   Oral NOAEL (92 d) Rat 10 1 or HR 1 - - 80 80 80 (TRL, 1986)   SMACs         150 80 80 80 40 —, Data not considered applicable to the exposure time; HR, Haber's rule.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 RECOMMENDATIONS The analysis of available data to derive ACs involved unproven assumptions and uncertainties that need to be resolved to improve the data base for setting the SMACs. A short-term human inhalation study is needed to measure the irritation thresholds and uptake of the compound over several hours (at least) and to quantify performance decrements at higher concentrations of exposure. The long-term data are problematic because of the differences reported by Russian investigators when compared with results from this country. A continuous inhalation exposure of rodents for at least 30 d is needed to determine the validity of earlier reports. End points should include those traditionally used in this country and as many of the Russian end points as possible. REFERENCES Aarstad, K., K. Zahlsen, and O. G. Nilsen. 1985. Inhalation of butanols: Changes in the cytochrome P-450 enzyme system. Arch. Toxicol. Suppl. 8:418-421. ACGIH. 1995. 1995-1996 Threshold Limit Values and Biological Exposure Indices . American Conference of Governmental Industrial Hygienists, Cincinnati, Ohio. Amoore, J. E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3(6):272-290. Arslanian, M. J., E. Pascoe, and J. G. Reinhold. 1971. Rat liver alcohol dehydrogenase. Biochem. J. 125:1039-1047. Ästrand, I., P. Övrum, T. Lindqvist, and M. Hultengren. 1976. Exposure to butyl alcohol uptake and distribution in man. Scand. J. Work Environ. Health 3:165-175. Auty, R. M., and R. A. Branch. 1976. The elimination of ethyl, n-propyl, n-butyl and iso-amyl alcohols by the isolated perfused rat liver. J. Pharmacol. Exp. Ther. 197(3):669-674. Baikov, B. K., and M. Kh. Khachaturyan. 1973. Hygiene assessment of the reflex effect exerted on the body by small concentrations of butyl alcohol inhaled from the atmosphere. Gig. Sanit. 12:7-11. Bechtel, D., and H. Cornish. 1975. Metabolism and biological dispo-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 sition of butyl alcohols in the rat. Toxicol. Appl. Pharmacol. 33:175. Blair, A. H., and F. H. Bodley. 1969. Human liver aldehyde dehydrogenase: Partial purification and properties. Can. J. Biochem. 47:265-272 Brandt, K. R. 1987. Final report on the safety assessment of n-butyl alcohol. J. Am. Coll. Toxicol. 6(3):403-424. Cederbaum, A. I., E. Dicker, and G. Cohen. 1978. Effect of hydroxyl radical scavengers on microsomal oxidation of alcohols and on associated microsomal reactions. Biochemistry 17:3058-3064. Connor, T. H., J. C. Theiss, H. A. Hanna, D. K. Monteith, and T. S. Matney. 1985. Genotoxicity of organic chemicals frequently found in the air of mobile homes. Toxicol. Lett. 25:33-40. Cornish, H. H., and J. Adefuin. 1967. Potentiation of carbon tetrachloride toxicity by aliphatic alcohols. Arch. Environ. Health. 14:447-449. De Ceaurriz, J. C., J. C. Micillino, P. Bonnet, and J. P. Guenier. 1981. Sensory irritation caused by various industrial airborne chemicals. Toxicol. Lett. 9:137-143. De Ceaurriz, J., J. P. Desiles, P. Bonnet, B. Marignac, J. Muller, and J. P. Guenier. 1983. Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents. Toxicol. Appl. Pharmacol. 67:383-389. DiVincenzo, G. D., and M. L. Hamilton. 1979. Fate of n-butanol in rats after oral administration and its uptake by dogs after inhalation or skin application. Toxicol. Appl. Pharmacol. 48:317-325. Gaillard, D., and R. Derache. 1965. Métabolisation de différents alcools. Présents dans les boissons alcooliques chez le rat. Pharmacie Montpellier 25:51-62. James, J. T., T. F. Limero, H. J. Leano, J. F. Boyd, and P. A. Covington. 1994. Volatile organic contaminants found in the habitable environment of the space shuttle: STS-26 to STS-55. Aviat. Space Environ. Med. 65:851-857. Kamil, I. A., J. N. Smith, and R. T. Williams. 1953. Studies in detoxication. Biochem J. 53:129-136. Kane, L. E., R. Domroske, and Y. Alarie. 1980. Evaluation of sensory irritation from some common industrial solvents. Am. Ind. Hyg. Assoc. J. 41:451-455. Kolesnikov, P. A. 1975. Habituation to butyl alcohol. Gig. Sanit. 5:104-105.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Korsak, Z., R. Swiercz, and R. Jedrychowski. 1993. Effects of acute combined exposure to n-butyl alcohol and m-xylene. Pol. J. Occup. Med. Environ. Health 6(1):35-41. Kristiansen, U., A. M. Vinggaard, and G. D. Nielsen. 1988. The effects of n-butanol vapour on respiratory rate and tidal volume. Arch. Toxicol. 61:229-236. Lasne, C., Z. W. Gu, W. Venegas, and I. Chouroulinkov. 1984. Mutat. Res. 130:273-282. Lington, A. W., and C. Bevan. 1994. Alcohols. Pp. 2585-2760 in Pattys Industrial Hygiene and Toxicology , 4th Ed., G. D. Clayton and F. E. Clayton, eds. New York: Wiley-Interscience. MacGregor, D. C., E. Schönbaum, and W. G. Bigelow. 1964. Acute toxicity studies on ethanol, propanol, and butanol. Can. J. Physiol. Pharmacol. 42(6):689-696. Maickel, R. P., and D. P. McFadden. 1979. Acute toxicology of butyl nitrites and butyl alcohols. Res. Commun. Chem. Pathol. Pharmacol. 26(1):75-83. Maickel, R. P., and J. F. Nash, Jr. 1985. Differing effects of short-chain alcohols on body temperature and coordinated muscular activity in mice. Neuropharmacology 24(1):83-89. McCann, J., E. Choi, E. Yamasaki, and B. N. Ames. 1975. Detection of carcinogens as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc. Natl. Acad. Sci. USA 72(12):5135-5139. McOmie, W. A., and H. H. Anderson. 1949. Comparative toxicologic effects of some isobutyl carbinols and ketones. Univ. Calif. Berkeley Publ. Pharmacol. 2:217-230. Morgan, E. T., D. R. Koop, and M. J. Coon. 1982. Catalytic activity of cytochrome P-450 isozyme 3a isolated from liver microsomes of ethanol-treated rabbits. J. Biol. Chem. 257:13951-13957 Munch, J. C. 1972. Aliphatic alcohols and alkyl esters: Narcotic and lethal potencies to tadpoles and to rabbits. Ind. Med. 41(4):31-33. Nelson, K. W., J. F. Ege, Jr., M. Ross, L. E. Woodman, and L. Silverman. 1943. Sensory response to certain industrial solvent vapors. J. Ind. Hyg. Toxicol. 25:282-285. Nelson, B. K., W. S. Brightwell, A. Khan, J. R. Burg, and P. T. Goad. 1989a. Lack of selective developmental toxicity of three butanol isomers administered by inhalation to rats. Fundam. Appl. Toxicol. 12:469-479. Nelson, B. K., W. S. Brightwell, S. K. Robertson, A. Khan, E. F. Krieg,

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 3 Jr., and V. J. Massari. 1989b. Behavioral teratology investigation of 1-butanol in rats. Neurotoxicol. Teratol. 11:313-315. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. Obe, G., and H. Ristow. 1977. Acetaldehyde, but not ethanol, induces sister chromatid exchanges in Chinese hamster cells in vitro. Mutat. Res. 56:211-213. Rumyantsev, A. P., V. G. Geer, N. A. Ostroumova, B. A. Spirin, and L. G. Shakhidzhanian. 1975. Experimental data about cumulative properties of butyl alcohol. Gig. Sanit. 10:112-113 Rumyantsev, A. P., N. A. Ostroumova, S. A. Astapova, Z. R. Kustova, Y. A. Lobanova, L. V. Tiunova, V. V. Chernikova, and P. A. Kolesnikov. 1976. Sanitary-toxicological features of butyl alcohol under conditions of prolonged inhalation. Gig. Sanit. 11:12-15. Rumyantsev, A. P., N. A. Ostroumova, S. A. Astapova, Z. R. Kustova, I. Ya. Lobanova, L. V. Tiunova, and V. V. Chernikova. 1979. Toxicology of butyl alcohol. Khim. Prom.-st. Ser. Toksikol. Sanit. Khim. Plastmass 2:24-26 Saito, M. 1975. Studies on the metabolism of lower alcohols. Nichidai Igaku Zasashi 34:569-585. Smyth, H. F., and H. F. Smyth, Jr. 1928. Inhalation experiments with certain lacquer solvents. J. Ind. Hyg. 10:261-271. Smyth, H. F., Jr., C. P. Carpenter, and C. S. Weil. 1951. Range-finding toxicity data: List IV. Arch. Ind. Hyg. Occup. Med. 4:119-122. Sterner, J. H., H. C. Crouch, H. F. Brockmyre, and M. Cusack. 1949. A ten-year study of butyl alcohol exposure. Am. Ind. Hyg. Assoc. Q. 10(3):53-59. Tabershaw, I. R., J. P. Fahy, and J. B. Skinner. 1944. Industrial exposure to butanol. J. Ind. Hyg. Toxicol. 26:328-330. TRL. 1986. Rat oral subchronic toxicity study of normal butanol. TRL Study No. 032-006. Toxicology Research Laboratories, Muskegon, Mich. U.S. Department of Labor. 1995. Air Contaminants—Permissible Exposure Limits. Title 29, Code of Federal Regulations, Part 1910, Section 1910.1000. Washington, D.C.: U.S. Government Printing Office. Velazquez, J., R. Escobar, and A. Almaraz. 1969. Audiologic impair-

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