5
n-Butanol

John T. James, Ph.D., D.A.B.T.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas

BACKGROUND AND SUMMARY OF ORIGINAL APPROACH

The alcohol n-butanol is consistently found in International Space Station (ISS) atmospheric samples at concentrations below 0.1 part per million (ppm). The source is presumed to be off-gassing from materials present inside the vehicle. Since the original document on spacecraft maximum allowable concentrations (SMACs) was written (James 1996), one remarkable event involving n-butanol pollution of the ISS has occurred. It involved the thermal desorption of charcoal filters that accidentally had been positioned to adsorb atmospheric contaminants over a period of 6 months. The effluent compounds from that desorption included copious amounts of n-butanol, which produced concentrations several-fold above odor thresholds for that compound, and caused an emergency situation in the U.S. segment of the station. The crew took refuge for 30 h in the Russian segment of the ISS while the n-butanol and other pollutants were scrubbed from the atmosphere of the U.S. segment (James et al. 2003).

NASA set the original SMACs for n-butanol in the mid-1990s based primarily on its irritant properties (James 1996). The intensity and effect levels for irritation were gleaned from three human studies published in the 1940s. From these studies, the threshold for eye irritation was estimated to be between 50 and 100 ppm; thus, for a 1-h exposure, a concentration of 50 ppm was deemed acceptable. Given some evidence of increasing irritation sensitivity during the work week, the 24-h acceptable concentration (AC) was set at 25 ppm. Because adaptation to the presence of n-butanol would be expected, the long-term AC was set at 25 ppm (80 milligrams per cubic meter [mg/m3]) to protect against eye irritation.

The potential central nervous system (CNS) effects of n-butanol were considered in two ways. First, its potency in inducing CNS deficits has been noted to be 5-10 times greater than that of ethanol. Performance decrements have not



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5 n-Butanol John T. James, Ph.D., D.A.B.T. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas BACKGROUND AND SUMMARY OF ORIGINAL APPROACH The alcohol n-butanol is consistently found in International Space Station (ISS) atmospheric samples at concentrations below 0.1 part per million (ppm). The source is presumed to be off-gassing from materials present inside the vehi- cle. Since the original document on spacecraft maximum allowable concentra- tions (SMACs) was written (James 1996), one remarkable event involving n- butanol pollution of the ISS has occurred. It involved the thermal desorption of charcoal filters that accidentally had been positioned to adsorb atmospheric con- taminants over a period of 6 months. The effluent compounds from that desorp- tion included copious amounts of n-butanol, which produced concentrations several-fold above odor thresholds for that compound, and caused an emergency situation in the U.S. segment of the station. The crew took refuge for 30 h in the Russian segment of the ISS while the n-butanol and other pollutants were scrubbed from the atmosphere of the U.S. segment (James et al. 2003). NASA set the original SMACs for n-butanol in the mid-1990s based pri- marily on its irritant properties (James 1996). The intensity and effect levels for irritation were gleaned from three human studies published in the 1940s. From these studies, the threshold for eye irritation was estimated to be between 50 and 100 ppm; thus, for a 1-h exposure, a concentration of 50 ppm was deemed ac- ceptable. Given some evidence of increasing irritation sensitivity during the work week, the 24-h acceptable concentration (AC) was set at 25 ppm. Because adaptation to the presence of n-butanol would be expected, the long-term AC was set at 25 ppm (80 milligrams per cubic meter [mg/m3]) to protect against eye irritation. The potential central nervous system (CNS) effects of n-butanol were con- sidered in two ways. First, its potency in inducing CNS deficits has been noted to be 5-10 times greater than that of ethanol. Performance decrements have not 73

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74 SMACs for Selected Airborne Contaminants been reported for ethanol concentrations below 50 mg per liter (L) of blood; thus, blood concentrations of n-butanol below 5 mg/L would be acceptable. A stable blood concentration of n-butanol is attained after 30 min of inhalation at 100 ppm. That blood concentration is reported to be 3 mg/L (Astrand et al. 1976); therefore, an exposure to 100 ppm of n-butanol would not be expected to induce any CNS effects. This is consistent with a second approach that depends on epidemiologic evidence that CNS effects do not occur unless concentrations are well above 100 ppm (Tabershaw et al. 1944). Long-term inhalation exposures were not found, so we relied on a 90-d oral study in rats in which there were no pathology findings at a dose of 500 mg per kilogram of body weight per day (mg/kg/d) (TRL 1986). Using body surface modeling, a 40% uptake in the respiratory system, and a nominal human inhala- tion rate, this equates to humans breathing a concentration of 250 ppm. Apply- ing a 10-fold species factor gave an AC of 25 ppm for avoiding systemic effects (80 mg/m3) for exposures up to 90 d. The 180-d AC for such effects was set at half this value (90 d/180 d) to give 12 ppm as the 180-d AC. This was the lowest of the ACs, so the 180-d SMAC was set at 12 ppm or 40 mg/m3. The 7- and 30- d SMACs were set at 25 ppm. The SMACs are presented in Table 5-1. In summary, the original approach relied on irritation reports in humans, comparison of the relative CNS-depression potency and blood concentrations of ethanol and n-butanol, and rather weak evidence that long-term ingestion of n- butanol does not cause observable pathology in rats. CHANGES IN FUNDAMENTAL APPROACHES RECOMMENDED BY THE NATIONAL RESEARCH COUNCIL The toxicity database on n-butanol was, and still is, sparse and not suitable for any of the approaches sanctioned by the National Research Council such as benchmark dose analyses or the “ten Berge” approach for time-dose extrapola- tions. For example, the human exposure data on irritancy come from three hu- man studies published in the 1940s, and they give only a general idea of the ex- posure level at which most people would cease to experience irritation. As far as CNS effects are concerned, the data consist of blood concentrations of n-butanol that are deduced to be below the threshold for CNS effects by analogy with ethanol blood concentrations. Fortunately, these are reasonably consistent with an epidemiologic report that CNS effects are not observed at exposures below 100 ppm. For ototoxicity (a new end point), the data on rats show no effect at any exposure concentration (Crofton et al. 1994). Comparative data on n-butyl acetate (n-BA) are used to discount the relevance of putative hematologic and immunotoxicity effects of n-butanol. There are simply no data left on which to apply approaches that require discrete, quantitative end points. NASA has considered whether genetic differences in alcohol dehydro- genase (ADH) could affect the ability of certain individuals to deal with expo- sures to n-butanol. Because of the multiplicity of human ADH isoforms, which

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75 n-Butanol have the capacity to metabolize small-chain alcohols such as ethanol and n- butanol (Ehrig et al. 1988), and because cytochrome P450 enzymes can also catalyze ethanol and n-butanol oxidation, interindividual differences in clear- ance of these alcohols is relatively invariant. Variations among ethnic popula- tions are not large, as shown in a study of ethanol metabolism in African- Americans with genetic polymorphisms at the ADH2 locus (Thomasson et al. 1995). By analogy, this extends to metabolism of n-butanol; thus, we have not used a factor for interindividual variability in setting new SMACs for n-butanol. RELEVANT DATA SINCE 1993 Data from Samples of ISS Air The ISS has been operating for several years since the original SMACs for n-butanol were set. During this time, the nominal range of n-butanol concentra- tions has been from 0.02 to 0.08 ppm (0.05 to 0.25 mg/m3), with an occasional excursion to 0.3 ppm. After the attempted regeneration of the Metox canisters (used to purify air during extravehicular activity) on February 20, 2002, the con- centration of n-butanol reached 2.5 ppm (7.5 mg/m3), and the crew reported a noxious smell (other pollutants undoubtedly contributed to the odor). The aver- age odor threshold for this compound is reported to be 0.8 ppm (2.5 mg/m3) (Amoore and Hautala 1983); thus, this compound probably contributed to the smell the crew reported. Within 33 h, the trace contaminant control system of the U.S. laboratory module had reduced the concentration of n-butanol to 0.1 ppm, and the crew reported only a very faint odor when they reentered. Because this “noxious odor” event forced the crew to take refuge in the Russian segment of the ISS for 30 h, it suggests that we must rethink the importance of odor for space operations. TABLE 5-1 SMACs Set in Volume 3 for n-Butanol Safe Concentration mg/m3 Exposure Time Effect to Avoid ppm 1h 150 50 More than mild eye irritation 24 h 80 25 More than mild eye irritation 7d 80 25 Eye irritation, systemic injury 30 d 80 25 Eye irritation, systemic injury 180 d 40 12 Systemic injury, eye irritation Source: James 1996.

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76 SMACs for Selected Airborne Contaminants New Toxicity Data New toxicologic data relevant to n-butanol inhalation risk assessment con- sist primarily of physiologically based pharmacokinetic studies of n-butanol and n-BA (Barton et al. 2000, Teeguarden et al. 2005), a subchronic inhalation study of n-butanol (Korsak et al. 1994), an evaluation of the ototoxicity of several sol- vents in rats (Crofton et al. 1994), and a subchronic inhalation study looking at the general toxicity (David et al. 2001) and neurotoxicity (David et al. 1998) of n-BA. The first of these studies allows us to link n-butanol and n-BA exposures and also to link human and rat exposures to n-butanol. The n-BA study will al- low us to discount the apparent hematologic and immune effects suggested by the Korsak et al. (1994) report by comparing its findings with those reported in other studies. Finally, the ototoxicity study will enable us to evaluate old epide- miologic reports that n-butanol could cause ototoxicity. Putative Hematology and Immune Effects Korsak et al. (1994) exposed groups of 12 rats for 6 h/d, 5 d/wk to 50 or 100 ppm of n-butanol for 3 months. They evaluated some biochemical parame- ters, body and organ weights, rotorod performance (a measure of neuromuscular performance), and hematology. Their findings revealed primarily an effect on blood cells in samples from the tail vein as shown in Table 5-2. These inhalation results are compared with results from a gavage study of equal length done ear- lier in another laboratory (TRL 1986). However, a direct comparison is con- founded by the bolus nature of the gavage dose and the first-pass effects on the gavaged alcohol. Nonetheless, the findings appear to be difficult to reconcile, so given these data alone, we would be compelled to begin with the more relevant data from Korsak et al. (1994). Hematology data from David et al. (2001) provide compelling evidence that the apparent decrease in hematologic parameters reported by Korsak et al. (1994) are not real. The former investigators exposed male and female Sprague Dawley (SD) rats to n-BA at 0, 500, 1,500, and 3,000 ppm 6 h/d, 5 d/wk for 13 wk. They reported slight increases in hematologic parameters in the 3,000-ppm group (see Table 5-2 for male data). Because the hydrolysis of n-BA to n- butanol is 99% complete in 2.7 min in rats, we can establish an inhalation equivalent of n-butanol based on the relative absorption of the compounds. The acetate is 100% absorbed, whereas the alcohol is absorbed at 40% to 50% in the respiratory system (Barton et al. 2000). According to the physiologically based pharmacokinetic modeling of Barton et al. (2000), an inhalation exposure to rats of 500 ppm of n-butanol is equivalent to an exposure to 820 ppm of n-BA, both giving 26 µM n-butanol as a steady-state blood concentration and identical areas under the curve (0.16 µmol × h/mL). These exposures were taken to be no- observed-adverse-effect levels (NOAELs) by these authors.

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TABLE 5-2 Comparison of Blood Parameters in Male Rats after 3 Months of Exposure to n-Butanol or n-BA n-Butanol n-Butanol Daily Gavage Dosing n-BA (Korsak et al. 1994) (TRL 1986) (David et al. 2001) 0 50 100 0 mg/ 30 mg/ 125 mg/ 500 mg/ 0 500 1,500 3,000 Parameter ppm ppm ppm kg/d kg/d kg/d kg/d ppm ppm ppm ppm Hct, % 40.0 38.6 38.5 44.8 43.5 44.0 43.3 42.3 42.1 42.0 45.1a HgB, g/dL 15.9 14.2b 14.1b 14.9 14.7 14.6 14.4 14.2 14.1 14.1 15.1a 9.97 9.45 8.35b 7.93 7.89 7.84 7.74 8.1 8.2 8.2 8.6a RBC, × 106/mm3 10.5 13.1 16.5b 9.6 11.5 11.0 9.5 10.0 10.3 8.8 8.0 WBC, × 103/mm3 a P < 0.05 statistically significant difference compared with controls. b P < 0.01 statistically significant difference compared with controls. Abbreviations: Hct, hematocrit; HgB, hemoglobin; RBC, red blood cells; WBC, white blood cells. 77

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78 SMACs for Selected Airborne Contaminants Similarly, Teeguarden et al. (2005) found in their modeling that in rats in- haling 100 ppm, the steady-state concentration of n-butanol was 5.5 µM if the administered compound was n-butanol, whereas if the administered compound was n-BA, the steady-state blood concentration was 7.4 µM. Thus, we must conclude that inhalation of a specific concentration of n-BA results in higher blood concentrations of n-butanol than inhalation of the same concentration of n-butanol. Thus, the data of David et al. (2001) showing no hematologic effects from exposure to n-BA suggests that the hematologic results on n-butanol re- ported by Korsak et al. (1994) may be misleading. Another approach to understanding the Korsak et al. (1994) report is to ask whether other small-chain alcohols exhibit similar hematotoxicity by inhala- tion. No subchronic studies of either 1-propanol or 1-pentanol could be identi- fied; however, two subchronic inhalation studies were found on 2-propanol. In the first study (Nakaseko et al. 1991), male rats were exposed 4 h/d, 5 d/wk for 3 months to 2-propanol concentrations of 0, 400, 1,000, 4,000, or 8,000 ppm. The authors reported a significant lowering of the red blood cell count after 12 wk of exposure to 2-propanol at 4,000 ppm and more rapid effects in the 8,000-ppm group; however, 4 wk after the exposure ended there were no effects (perhaps also 1 wk after the end of exposure, but the figure is too small to answer defini- tively). In another study (Burleigh-Flayer et al. 1994), male and female rats and mice were exposed 6 h/d, 5d/wk for 13 wk to 2-propanol vapor at concentrations of 0, 100, 500, 1,500, or 5,000 ppm. A slight anemia was observed at 6 wk in the highest-concentration group of male and female rats, but it was not observed at 14 wk. From this result, it was concluded that 2-propanol induces hematologic effects only at concentrations 40 to 50 times higher than those n-butanol concen- trations that Korsak et al. (1994) reported to be hematotoxic. Furthermore, the effects of 2-propanol on red cell parameters are transient. One further interesting argument against using the Korsak et al. (1994) finding centers on reports in the same paper that m-xylene also induces hemato- toxicity with about the same potency as n-butanol. Both compounds apparently have mild effects at 50 ppm and more pronounced effects at 100 ppm (e.g., about a 20% decrease in red blood cell count). This must be considered in light of a report from the same laboratory 2 years earlier in which rats of the same strain were exposed 6 h/d, 5d/wk for 3 months to 1,000 ppm of m-xylene (Kor- sak et al. 1992). Twenty-four h after exposure terminated, no statistically sig- nificant exposure-related changes were found for hematologic parameters except for differential white blood cell counts (EPA 2003). The paper published in 1994 makes no reference to the 1992 paper. In summary, n-butanol will not be treated as a hematotoxicant for three reasons: (1) n-BA inhalation exposures equivalent to much higher concentra- tions of n-butanol do not show an effect (David et al. 2001), (2) subchronic inha- lation studies of other small-chain alcohols show transient effects only at 40 to 50 times the concentration of n-butanol that supposedly induced hematotoxicity,

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79 n-Butanol and (3) the hematologic results on xylene from the same laboratory are inconsis- tent (Korsak et al. 1992, 1994). Neurotoxicity The key new data for this effect come from a study by David et al. (1998) in which rats exposed for 6 h/d, 5 d/wk for 14 wk to n-BA at concentrations of 0, 500, 1,500, and 3,000 ppm were subjected to a battery of functional neu- rologic tests to detect neuropathology. The study noted that “minimal to minor” reduced activity levels were observed at the two highest doses during exposures; however, the severity of the reduced activity did not increase as the exposures progressed to 14 wk. No effects on activity were noted in the controls or in the 500-ppm group. The authors concluded that 3,000 ppm was a NOAEL for cu- mulative neurotoxicity; however, we cannot accept reduced activity as a no- effect end point because it might be associated with a reduced capability to per- form complex tasks. We will take 500 ppm n-BA as the neurotoxicity NOAEL from this study, and this is equivalent to 820 ppm of n-butanol. Ototoxicity This adverse effect was not considered in the original SMAC document; however, for completeness it is noted here that an old report of ototoxicity that some groups had used to set human exposure limits has been superseded by more recent findings (Velazquez et al. 1969). Crofton et al. (1994) exposed rats for 6 to 8 h/d, 5 d/wk for 5 d to various solvents at concentrations ranging from 1,600 to 4,000 ppm. They conducted auditory testing 5 to 8 wk after exposure using reflex modification audiometry to define thresholds for frequencies from 0.5 to 40 kilohertz. Hearing deficits were found in the midfrequency range for all solvents except n-butanol, which caused no hearing loss, even at 4,000 ppm. This is the ototoxicity NOAEL for n-butanol regardless of time of exposure. NEW RISK ASSESSMENT APPROACHES Our approach to dealing with compounds that have a significant odor at concentrations well below those that could cause adverse health effects will be to continue to set SMACs based on potential physical harm but include a foot- note in the table describing the concentrations where the presence of the com- pound may create an unpleasant odor. One issue with this approach is that odor sensitivities appear to change during spaceflight; therefore, even if there were ground-based data describing odor properties in detail, their applicability to the spaceflight situation would be questionable. Other issues center on adaptation to odors with time. There are few specific data describing this phenomenon. We point out that the situation for air is different than for water. Crews will be forced to breathe air with an unpleasant smell when their supply of fresh

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80 SMACs for Selected Airborne Contaminants air or their respirators are expended, even though the air is not harmful. They will adapt to the presence of a continuous odor. However, they can choose not to ingest water that tastes or smells bad, even if it is not harmful. They will not adapt to this because they experience the odor only when trying to drink water. Thus, our concerns with health risks from reduced water consumption caused by poor aesthetic properties of the water do not have a parallel concern for breath- ing air. RATIONALE FOR REVISIONS TO THE PREVIOUS SMACS Odor Thresholds and Noxious Odors The odor thresholds reported for n-butanol have been summarized from 29 original sources (Amoore and Hautala 1983) dating from 1892. The thresholds ranged from 0.05 to 60 ppm (0.15 to 190 mg/m3), more than 3 orders of magni- tude. This provides no more than a rough guide to which concentrations might represent the threshold of detection. Hematotoxicity and Immunotoxicity Based on the information presented in Table 5-2, we will not do a risk as- sessment on the apparent hematologic and immune effects suggested by the in- halation study of Korsak et al. (1994). Neurotoxicity As pointed out previously, exposures equivalent to 820 ppm of n-butanol (500 ppm n-BA) elicited no detectable effect in rats given a subchronic inhala- tion exposure. The AC is as follows: AC (neurotoxicity) = 820 ppm (NOAEL) × 1/10 (species) = 80 ppm This result is consistent with the earlier neurotoxicity estimate based on analogies to ethanol and from epidemiologic evidence. Because there is no cu- mulative neurotoxicity (David et al. 1998), this AC will be taken as applicable to all exposure times. Ototoxicity The data from Crofton et al. (1994) revealed that styrene, xylenes, toluene, and 1,1,2-trichloroethylene at 1,600 to 3,500 ppm caused midfrequency hearing loss in rats exposed for 5 d, but 4,000 ppm of n-butanol did not. This is suffi- cient evidence that n-butanol is not a significant ototoxicant; therefore, we will

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81 n-Butanol take 4,000 ppm to be a NOAEL regardless of time of exposure. The AC for oto- toxicity is as follows: AC (ototoxicity) = 4000 ppm (NOAEL) × 1/10 (species) = 400 ppm This applies to indefinite exposure times. Note that we will not consider nasal injury from the n-BA exposures as relevant to n-butanol exposures be- cause the effect is probably mediated through hydrolysis of the acetate to the alcohol and acetic acid, a process that does not occur when the exposure is only to an alcohol. RATIONALE FOR THE 1,000-DAY SMAC Unfortunately, there are no long-term data on n-butanol by any route of administration; however, neither n-butanol nor its metabolites (organic alde- hydes and acids) are expected to accumulate at exposures below 50 ppm beyond that achieved from short-term n-butanol exposures, so we do not expect an in- creased risk of adverse effects with prolonged exposure times. This conclusion is supported by the observation of David et al. (1998) that cumulative neurotox- icity was not observed using a battery of end points during a subchronic study of n-BA. Accordingly, the 1,000-d SMAC was set at the same value, 12 ppm, as the 180-d SMAC. COMPARISON OF SMACS WITH OTHER AIR QUALITY LIMITS The current threshold limit value (TLV) for n-butanol is 20 ppm (60 mg/m3) to protect against irritation. The Occupational Safety and Health Ad- ministration (OSHA) permissible exposure limit (PEL) is 100 ppm (300 mg/m3), and the National Institute for Occupational Safety and Health (NIOSH) ceiling limit is 50 ppm (150 mg/m3). Our long-term exposure limits (Table 5-3) of 12 and 25 ppm (40 or 80 mg/m3) straddle the TLV of 20 ppm and are well below the PEL of 100 ppm. The 1-h SMAC and the NIOSH ceiling limit are the same. RECOMMENDATIONS FOR ADDITIONAL RESEARCH A detailed review of the odor threshold work, which is beyond the scope of this review, might suggest a more focused statement about odor thresholds and noxious concentrations; however, one is plagued by anecdotal reports from crew that odor perceptions in space can be quite different than on the ground.

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82 TABLE 5-3 ACs for n-Butanol Toxicitya,b and Proposed SMACs Uncertainty Factors Acceptable Concentrations, mg/m3 Effect Reference Species Species Time Small n 1-h 24-h 7-d 30-d 180-d 1,000-d Mild irritation at 3 studies (see Human, 1 1 1 150 80 80 80 80 80 150 mg/m3 text) n >100 CNS epidemiology Tabershaw et Human 1 1 1 300 300 300 300 300 300 NOAEL al. (1944) CNS ethanol Several Human 1 1 1 300 300 300 300 300 300 comparison references (see text) Systemic injury, TRL (1986) Rat 10 1 or 1 n/a n/a 80 80 40 40 oral NOAEL Haber’s (92 d) rule SMACs 150 80 80 80 40 40 a The only value that has changed from the original SMACs is the addition of the 1,000-d value. b The odor threshold and noxious odor concentrations are uncertain. These concentrations may not preclude odor detection by the crew. Abbreviation: n/a, not applicable.

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84 SMACs for Selected Airborne Contaminants for n-butanol using a physiologically based pharmacokinetic model for n-butyl acetate and metabolites n-butanol and n-butyric acid. Toxicol. Sci. 85(1):429-446. Thomasson, H.R., J.D. Beard, and T.K. Li. 1995. ADH2 gene polymorphisms are deter- minants of alcohol pharmacokinetics. Alcohol. Clin. Exp. Res. 19(6):1494-1499. TRL (Toxicology Research Laboratories). 1986. Rat Oral Subchronic Toxicity Study of Normal Butanol. TRL Study No. 032-006. Toxicology Research Laboratories, Muskegon, MI. Velazquez, J., R. Escobar, and A. Almaraz. 1969. Audiologic impairment due to n-bytil alcohol exposition. Pp. 231-234 in Proceedings of the 16th International Congress on Occupational Health. Tokyo: Excerpta Medica Foundation.