Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 2 (1996)

John T. James, Ph.D., and Harold L. Kaplan, Ph.D.

Johnson Space Center Toxicology Group

Biomedical Operations and Research Branch

Houston, Texas

Isopropyl alcohol is a colorless, volatile liquid at room temperature (Rowe and McCollister, 1982).

Isopropyl alcohol (IPA) is used commercially in the manufacture of acetone, as a solvent, and in skin lotions, cosmetics, and pharmaceuticals (Rowe and McCollister, 1982). It is widely used by the public in a 70% solution in water as rubbing alcohol to reduce fever and as a disinfectant.

The odor threshold in air is 22 ppm (Amoore and Hautala, 1983). Isopropanol is consistently found in air samples taken during shuttle flights at concentrations in the range of 0.1 to 10 mg/m³ (James et al., 1994). It originates from flight-hardware off-gassing and the use of IPA as a disinfectant and cleaner.

The pharmacokinetics and metabolism of IPA have been studied in animals using oral and intravenous (i.v.) administration and, to a limited extent, using inhalation. Acute toxicity inhalation studies show that IPA at high concentrations (near 20,000 ppm) is absorbed by the lungs rapidly and in sufficient quantities to cause central nervous system (CNS) depression and lethality within a few hours (Starrek, 1938 (cited by Lehman and Flurry, 1943; Rowe and McCollister, 1982); Carpenter et al., 1949). Apparently, sufficient IPA can be absorbed by rats in 4 h at 2000 ppm to induce what the authors report as slight anesthesia effects (Nakaseko et al., 1991a). Studies of anesthetized dogs given IPA injections into isolated segments of their alimentary tract showed that absorption is more rapid from the intestine than from the stomach and occurs rapidly (82% complete in 30 min) (Wax et al., 1949). In four workers exposed at a mean concentration of 410 ppm, the alveolar air contained an average of only 100 ppm, whereas nine workers exposed at an average of 140 ppm had an alveolar air concentration of only 56 ppm (Folland et al., 1976). This suggests a respiratory absorption of 60-75% in these concentration ranges. In a study of printing-plant workers exposed to IPA in a range of concentrations up to 260 ppm, the ratio of the alveolar concentration to the ambient concentration averaged 0.4, suggesting an uptake of about 60% (Brugnone et al., 1983).

Once IPA reaches the blood, it is distributed to the spinal fluid and brain, liver, kidney, and skeletal muscle in dogs (Wax et al., 1949).

The results did not suggest any pattern of preferential uptake by any of these organs, nor did the distribution depend on concentration of IPA.

The exact metabolic fate of IPA has not been established. Perfusion experiments with isolated rabbit liver demonstrated that the liver converts 30-50% of IPA to acetone (Ellis, 1952). Also in rabbits, IPA is conjugated with glucuronic acid, but only 10% of the intragastrically (i.g.) administered dose was accounted for in the urine as the glucuronide (Kamil et al., 1953). Acetone (19 ppm) was found in the expired air of four workers exposed to IPA at an average of 410 ppm, and an acetone concentration of 7.5 ppm was found in nine workers exposed at an average of 140 ppm (Folland et al., 1976). In another study involving 12 printing-plant workers exposed to IPA at 3-260 ppm for 7 h the elimination of acetone from the lungs reached a steady state in 6-7 h, suggesting that blood concentrations of IPA and acetone had also reached steady-state concentrations (Brugnone et al., 1983).

Limited data are available on the metabolism of IPA in animals and in humans. At the end of a 4-h exposure of rats to IPA at 8000 ppm, the blood concentrations of IPA and acetone were nearly equal; however, at exposures at 500 to 1000 ppm, the acetone-to-IPA ratio was about 3 (Laham et al., 1980). Twenty-four hours after ending the 8-h exposure to 8000 ppm, the blood concentrations of IPA and acetone were 0.008 and 0.110 mg/mL, respectively. In another study, after i.v. administration of 1 or 2 g/kg to pigeons, rats, rabbits, cats, and dogs, the rate of disappearance of alcohol from the blood during the 6 h after equilibration depended on the dose as well as the species (Lehman et al., 1945). In contrast to the linear disappearance of ethanol, the disappearance of IPA from the blood of dogs given large fractions of the fatal dose was more rapid a few hours after administration than at times approaching 24 h (Lehman et al., 1944). In two humans, who had ingested large doses of rubbing alcohol, and reportedly were heavy users

of alcoholic beverages, the concentrations of blood IPA were consistent with an exponential model with half-lives of 155 and 187 min (Daniel et al., 1981).

Studies with enzyme inhibitors indicate that oxidation of IPA to acetone is catalyzed by alcohol dehydrogenase (ADH). Pyrazole, an inhibitor of ADH and catalase, reduced the clearance of IPA from the blood of rats and slowed the rate of acetone production (Lester and Benson, 1970; Nordmann et al., 1973). In contrast, pre-exposure of rats to 3-amino-1,2,4-triazole, an inhibitor of catalase, did not result in blood alcohol or acetone concentrations that were different from concentrations in control animals (Nordmann et al., 1973).

Isopropyl alcohol vapor is irritating to the eyes and upper respiratory tract, and is a CNS depressant at higher concentrations. At 400 ppm, human volunteers exposed for 3-5 min experienced mild irritation of the eyes, nose, and throat (Nelson et al., 1943). At 800 ppm, the effects were not severe but were considered unsuitable for an 8-h workday. Most subjects estimated 200 ppm as the highest concentration satisfactory for 8 h.

No reports of CNS depressant effects in humans solely from inhalation of IPA vapor were found in the scientific literature; however, many cases of acute poisoning in humans from ingestion of IPA have been reported (Adelson, 1962; King et al., 1970). Common manifestations are nausea, vomiting, headache, and varying degrees of CNS depression, soon followed by coma with or without shock (Nelson et al., 1943). When shock is present, death might occur within the first 24 h. In a study of seven subjects given 10-15 cc IPA orally, Fuller and Hunter (1927) found increased blood pressure, sensations of warmth, and various degrees of dizziness and numbness. Tolerance was evident by reduced responses on successive days of administration.

Animals exposed to vapors of IPA exhibit signs of CNS depression, with the severity dependent on the concentration and duration of exposure. In mice, ataxia was produced in 12-26 min at a concentra-

tion of 24,000 ppm and was increasingly delayed with decreasing concentrations until, at 3250 ppm, 180-195 min of exposure were required (Starrek, 1938). Prostration of mice occurred in 37-46 min at a concentration of 24,000 ppm but required almost 6 h at 3250 ppm. The onset of narcosis ranged from 100 min at a concentration of 24,000 ppm to almost 8 h at 3250 ppm. Exposure at 12,800 ppm for 200 min or at 19,200 ppm for 160 min caused death in mice (Weese, 1928 (cited by Rowe and McCollister, 1982)). Mice exposed for 8 h at 2050 ppm did not show adverse effects (Starrek, 1938). The ability of IPA to induce CNS depression in rats appears to be comparable to its ability in mice. In rats, an 8-h exposure to IPA vapor at 16,000 ppm resulted in the deaths of four of six animals (Smyth and Carpenter, 1948). In rats exposed to IPA vapor for 4 h at 400, 2000, 4000, or 12,000 ppm, the CNS effects (reduced reaction to sound and dragging hind legs) were obvious only at the highest concentration. In the 2000- and 4000-ppm groups, the authors reported reduced activity and the possibility that anesthesia-type effects might have appeared in some rats during exposures as low as 2000 ppm (Nakaseko et al., 1991a).

The anesthetic dose (elimination of corneal reflect) and lethal dose of IPA by slow i.v. infusion were 2.5 and 6.5 g/kg, respectively, in rabbits and 2.7 and 4.1 g/kg, respectively, in dogs (Lehman and Chase, 1944). Although the anesthetic dose for the two species is almost identical, the anesthetic dose is about 40% of the fatal dose for the rabbit and 65 % for the dog.

The principal effect of IPA administered intragastrically to rats, rabbits, and dogs was depression of the CNS, with salivation, retching, and vomiting (Lehman and Chase, 1944). The LD₅₀ values for the rat, rabbit, and dog were 5.3, 5.1, and 4.9 g/kg, respectively. Surviving animals recovered rapidly from the depressant effects completely returned to normal behavior. In another study, the oral LD₅₀ in young adult rats was 4.7 g/kg, and the first observable toxic signs were at a dose of 2.4 g/kg (Kimura et al., 1971).

Rats were unaffected except for slight intoxication when exposed intermittently over a week (total number of exposure hours not given) to

air supposedly saturated with IPA vapor (Macht, 1922). Mice exposed to IPA at 10,900 ppm, 4 h/d, for a total of 123 h of exposure were narcotized but survived (Weese, 1928). Slight, reversible fatty changes were observed in the liver. Pregnant rats were exposed to IPA at 10,000, 7000, and 3500 ppm, 7 h/d, for 19 d. No effects were observed clinically at 3500 ppm; however, unsteady gait was observed at the end of early 7000-ppm exposures but was not noticeable after the later exposures (Nelson et al., 1988). The rats were narcotized at the end of early 10,000-ppm exposures, but the effect diminished in later exposures. Since the goal of the study was teratogenic effects, the dams were not subjected to pathology evaluation.

Daily ingestion by human volunteers of IPA at 2.6 or 6.4 mg/kg in a flavored syrup diluted with water for 6 w did not result in adverse signs or symptoms (Wills et al., 1969). There were also no significant changes in clinical chemistry measurements of blood or urine, BSP excretion, optical properties of the eyes, or the general well-being of the subjects.

Rats exposed to IPA vapor at 8.4 ppm, 24 h/d, for 3 mo showed alterations in reflexes, enzyme activities, BSP retention, leukocyte count, total nucleic acids, urine coproporphyrin, and morphology of the lung, liver, spleen, and CNS (Baykov et al., 1974). At 1.0 ppm, there were lesser changes in some of these end points, and at 0.27 ppm, there were no alterations. These findings are difficult to evaluate in view of their variance with other data and inadequate details on experimental design and statistical analysis.

Ingestion by rats of IPA in drinking water at 0.5-5% for 27 w did not result in any definite toxic signs other than a slight retardation of growth and the probable accidental death of some animals (Lehman and Chase, 1944). There were no gross or microscopic abnormalities in the brain, pituitary, lungs, heart, liver, spleen, kidneys, or adrenals.

Ingestion by three dogs of IPA in drinking water at 4% for 1 h daily (average of 1.3 g/kg/d) over 6 mo produced inebriation for 3-5 h daily but otherwise normal, healthy behavior (Lehman et al., 1945). At the end of 6 mo, an i.v. test dose indicated the development of tolerance manifested by a decreased response to IPA and an increased rate of

removal of alcohol from the blood. Histopathological changes were limited to the kidneys of one and the brains of two of the three dogs.

In contrast to the report by Baykov et al. (1974), 3-mo intermittent exposures of rats to IPA were without adverse effect up to 1000 ppm (Nakaseko et al., 1991b). Rats were exposed 4 h/d, 5 d/w, and were evaluated for hematological, clinical chemistry, and organ-weight changes. At concentrations of 4000 and 8000 ppm, mucous membrane irritation was evident, and a decrease in red-blood-cell (RBC) count occurred. At 8000 ppm, there was an increase in liver enzymes, and liver and spleen weights were reduced. Using 8-h daily exposures, 5 d/w for 20 w, the authors found delayed transmission velocity in the tail peripheral nerve in rats exposed at 8000 ppm but not in rats exposed at 1000 ppm (Nakaseko et al., 1991b).

The reproductive and developmental effects were studied in rats given 2.5% IPA in their drinking water over two generations (Lehman et al., 1945). First-generation males and females had retarded growth early in life, but nearly caught up with the control group by the 13th week. The second-generation rats showed no retardation of growth in either sex. The study is certainly incomplete by modern standards; however, the authors conclude that IPA does not produce deleterious effects on reproductive function or embryonic development.

Developmental effects have been reported in rats, but only at IPA concentrations that are toxic to the dams (Nelson et al., 1988). There were increased resorptions and decreased fetal weights from dams exposed at 10,000 ppm, 7 h/d, for 19 d. These results might have been due to IPA's being administered excessively early in gestation. Only decreased fetal weights were seen after exposures to IPA at 7000 ppm, and no effects were seen after exposures at 3500 ppm. The dams were narcotized at 10,000 ppm and showed mild CNS effects at 7000 ppm.

Recently, a Tier 1 (Toxic Substances Control Act) mutagenicity evaluation has been completed in response to recognition that regulatory

risk assessment on IPA was hampered by insufficient data. In eight strains of Salmonella tested with and without S-9 activation, IPA was not found to be mutagenic (Zeigler et al., 1992). In vitro sister chromatid exchange assays using V79 cells, with and without S-9 activation, were also negative for mutagenic activity (Vonder Hude et al., 1987). Further demonstration of the lack of mutagenic activity of IPA was reported in a Chinese hamster ovary gene mutation assay and in a bone-marrow micronucleus test (Kapp et al., 1993).

In the early 1940s, suspicion was raised that a carcinogen was involved in the industrial process used to produce isopropanol. Eventually, studies in mice showed that isopropyl oil, a waste product of the production, was most likely the cause of the observed human cancers (Weil et al., 1952). No tumorigenic activity was observed in mice exposed to IPA vapor at 4000 ppm, 3-7 h/d, 5 d/w, for 5-8 mo or when IPA was administered by skin painting or subcutaneous injection (Weil et al., 1952). Epidemiological studies of workers in isopropyl alcohol plants in the United States and United Kingdom have not shown a significant excess of mortalities or malignant diseases (Alderson and Rattan, 1986).

Isopropyl alcohol has been shown to potentiate the toxicity of several halogenated hydrocarbons. In rats, intubation of IPA at 2.3 g/kg for 16-18 h before exposure to carbon tetrachloride vapor at 1000 ppm caused significantly greater serum SGOT activity than that produced by carbon tetrachloride alone (Cornish and Adefuin, 1967). Pre-exposure of rats with IPA before intraperitoneally injected carbon tetrachloride resulted in increased serum SGPT activity, hepatic triglyceride content, and total serum bilirubin and in decreased hepatic glucose-6-phosphatase activity (Traiger and Plaa, 1971). Suggested mechanisms for the potentiation include lysosomal alterations, changes in the endoplasmic reticulum, stimulation of drug-metabolizing enzymes, and increased sensitivity of hepatocytes to carbon tetrachloride (Coté et al., 1974).

In mice, pre-exposure with IPA or acetone by gavage potentiated the hepatotoxic response to chloroform, 1,1,2-trichloroethane, and trichloroethylene, as measured by serum SGPT activity, but not to 1,1,1-trichloroethane (Traiger and Plaa, 1974).

In an industrial exposure of workers, toxic effects, including renal failure and hepatitis, were attributed to the potentiation of carbon tetrachloride toxicity by IPA, following the inhalation of vapors of the two chemicals (Folland et al., 1976).

CNS depression should be of primary concern in setting SMAC values for IPA vapor; however, hepatotoxicity must also be considered because of early reports of fatty liver in mice (Weese, 1928) and liver enzyme elevation after prolonged exposures at high concentrations (Nakaseko et al., 1991b). One investigator has also reported conduction decreases in peripheral nerves after prolonged high exposure

(Nakaseko et al., 1991b). Additionally, the vapor has the potential to cause irritation of the eyes and upper respiratory passages. Although mild irritation might be acceptable under emergency short-term conditions, long-term SMACs should protect against all adverse effects during prolonged exposure. Finally, in setting acceptable concentrations (ACs), the Baykov et al. (1974) report will be disregarded because it is not consistent with the weight of evidence from other studies. Guidelines from the National Research Council's Committee on Toxicology have been used to structure the rationale for astronaut exposure limits (NRC, 1984).

A combination of animal inhalation studies, structure-activity arguments, and human-worker studies were used to derive ACs to protect against CNS effects. Based on graphical data derived from mice exposed to various IPA concentrations up to 8 h, a no-observed-adverse-effect level (NOAEL) for ataxia (first instability) could be estimated (Lehman and Flury, 1943). For a 1-h exposure, that value was 12,000 ppm (30 mg/L); however, clinically evident ataxia is not a sensitive end point for CNS effects. The question is what factor would be suitable to correct the ataxia NOAEL to a true NOAEL? A factor of 2 appears to be suitable based on two arguments. First, it was noted that increasing the 1-h IPA concentration to 22,000 ppm (approximately doubling the 12,000 ppm value) resulted in more serious CNS effects; specifically, the mice became prone. That result suggests that halving the 12,000-ppm value would greatly reduce the magnitude of any CNS effects. Second, ethanol appears to have approximately the same capacity as IPA to induce CNS effects in mice by inhalation (ethanol at 13,300 ppm in 100 min induces ataxia) (Rowe and McCollister, 1982). The CNS effects of ethanol are such that doubling the concentration from 0.06-0.08% to 0.12-0.15% causes the CNS effect to increase from ''beginning of uncertainty'' to "stupor" (Rowe and McCollister, 1982). Using this NOAEL correction factor of 2, the 1-h AC based on CNS effects was calculated as follows:

This value is consistent with rat data from Nakeseko et al. (1991b) in which they report that animals exposed to IPA at 8000 ppm did not show effects of anesthesia resulting from the first half of 4-h (or 8-h) exposures. In 4-h exposures, Nakeseko et al. (1991a) clearly observed CNS effects in less than 1 h at a concentration of 12,000 ppm, but no definite CNS effects were reported after a 4-h exposure at 2000 ppm.

To protect against CNS depression for exposure periods longer than 1 h, an exposure concentration must be found that avoids accumulation of blood concentrations of IPA or acetone that is associated with CNS depression. In nine workers exposed during a 7-h work shift to average concentrations between 40 and 200 ppm (average 110 ppm), Brugnone et al. (1983) made the following observations:

• The uptake of IPA from the air was about 60%.
• IPA was not detectable in blood or urine (limit of detection was 1 mg/L).
• In three workers exposed to IPA at 193-202 ppm, the blood acetone average was 7.2-8.2 mg/L.
• Blood acetone concentrations with IPA exposures were highly correlated.
• The slope of the regression lines (IPA exposure vs. blood acetone concentration) suggested a steady state after 3 h of exposure.

These data indicate that any CNS effects would correlate with blood acetone concentrations rather than IPA concentrations. In 22 subjects exposed to acetone at 250 ppm, the blood concentrations after 4 h averaged 15 mg/L, and there were slight psychomotor performance decrements; however, at exposures to acetone at 125 ppm (plus methyl ethyl ketone at 100 ppm) the blood acetaldehyde concentration averaged 10 mg/L, and no performance decrements could be deleted (Dick et al., 1988). This latter blood acetone concentration (10 mg/L) is slightly above that seen in the three most heavily exposed workers (7-8 mg/L) from the Brugnone IPA study. Since a steady state is reached between IPA exposure and blood acetone after 3 h of exposure, it may be concluded that 100-ppm IPA is a safe concentration to avoid CNS effects even during prolonged exposure.

This conclusion is consistent with mouse data showing no ataxia at 2050 ppm after an 8-h exposure (Starrek, 1938). Using the factor of 2 to correct the ataxia NOAEL to a true NOAEL (see discussion above)

and noting that accumulation after 8 h would be negligible, the AC to avoid CNS effects for long exposures was calculated as follows:

Prolonged exposure of a total of 800 h induced decreases in peripheral nerve conduction velocity in rats exposed to IPA at 8000 ppm but not in those exposed at 1000 ppm (Nakaseko et al., 1991b). This finding was used to set a 30-d (720 h) AC as follows:

Exposures of approximately 10 human subjects to IPA at concentrations of 200, 400, and 800 ppm for 3-5 min resulted in mild irritation at 400 ppm and the conclusion, by the test subjects, that 200 ppm would be satisfactory for 8 h (Nelson et al., 1943). Even though the study leaves some doubt about how such conclusions were reached, it appears that 400 ppm would be acceptable for 1-h exposures because tolerance to the irritating sensation of alcohols develops quickly. The 200-ppm value would be more suitable for a 24-h exposure where the risk of irritation would have to be minimal. Irritation would not be acceptable for long-term exposure; hence, a long-term NOAEL was calculated using the recommended approach for studies involving a small number (n = 10) of test subjects. Specifically,

Hence, the 7-, 30-, and 180-d ACs to prevent irritation from IPA were all set at 60 ppm.

Liver injury is not usually thought of as an important effect of IPA exposure; however, an early study involving repeated inhalation exposure of mice reported reversible fatty changes in the liver (Weese, 1928). A lowest-observed-adverse-effect level (LOAEL) for liver effects was a cumulative exposure of 123 h (in 4-h segments) at 11,000 ppm. Based on this observation, the 24-h AC was 110 ppm with uncertainty factors of 10 for LOAEL to NOAEL and 10 for species extrapolation. This may be extended to 7 d by reducing the value by 168 ÷ 123 to give 80 ppm. Extending estimates to longer times was based on the 4000-ppm NOAEL reported in rats exposed 20 h/w for 13 w (Nakeseko et al., 1991b).

The 7-d AC based on liver injury calculated that way gave an AC of 400 ppm. The 30-d AC was calculated by applying a time factor based on Haber's rule (720 ÷ 260) to derive an AC of 140 ppm.

Many of the IPA toxicity studies, particularly the inhalation studies, were completed 40 or more years ago. Over that time, many new regulatory guidelines have been developed to provide data that are more useful for setting human-exposure standards. In addition, methods of measuring CNS effects in animals, and performance decrements in humans have improved considerably over the past 40 years. Hence, standardized inhalation studies in rodents, including a long-term, continuous-exposure study with multiple end-point assessments (to determine the accuracy of Baykov et al., 1974), are needed to resolve questions of dose-response and target organs. Short-term human inhalation studies are needed to better understand IPA irritancy and tolerance phenomena. Finally, metabolic studies are needed to better define the adsorption, metabolism, and fate of inhaled IPA.

NOTE ADDED IN PROOF

As this document was going to press, two studies were published that address many of the recommendations above. Slauter et al. (Slauter, R.W., D.P. Coleman, N.F. Gaudette, R.H. McKee, L.W. Masten, T.H. Gardiner, D.E. Strother, T.R. Tyler, and A.R. Jeffcoat. 1994. Fundam. Appl. Toxicol 23:407-420) reported valuable data on the distribution, metabolism, and excretion of IPA in rats and mice exposed for 6 h at a concentration of 500 or 5000 ppm. Burleigh-Flayer et al. (Burleigh-Flayer, H.D., M.W. Gill, D.E. Strother, L.W. Masten, R.H. McKee, T.R. Tyler, T. Gardiner. 1994. Fundam. Appl. Toxicol 23:421-428) showed that repeated exposures to IPA for 13 w produced clearly toxic effects in rats and mice only at a concentration of 5000 ppm. Nephropathy was found in male rats at lower exposures, but this type of lesion has questionable relevance to human risk assessment. Clinical signs of CNS effects (narcosis, ataxia, and hypoactivity) were reported in some mice during, but not immediately after, exposures at 1500 ppm; however, later exposures of mice at 2500 ppm did not fully confirm the presence of CNS effects such as ataxia at 1500 ppm (H.D. Burleigh-Flayer, Busby Run Research Center, Union Carbide Chemicals and Plastics Co., Export, Pa., personal commun., 1995). Additional new studies on IPA will be published soon and a re-evaluation of the SMACs in light of the new data should be completed at that time.

Adelson, L. 1962. Fatal intoxication with isopropyl alcohol (rubbing alcohol). Am. J. Clin. Pathol. 38:144-151.

Alderson, M.R., and N.S. Rattan. 1986. Mortality of workers on an isopropyl alcohol plant and two MEK dewaxing plants. Br. J. Ind. Med. 37:85-89.

Amoore, J.E., and E. Hautala. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatiles for 214 industrial chemicals in air and water dilution. J. Appl. Toxicol. 3:272-290.

Baykov, B.K., O.Y. Gorlova, Y.V. Novikov, T.V. Yudina, and A.N. Sergeyev. 1974. [Hygienic standardization of the daily average

maximum admissible concentrations of propyl and isopropyl alcohols in the atmosphere.] Gig. Sanit. 4:6-13.

Brugnone, F., L. Perbellini, P. Apostoli, M. Bellorri, and D. Caretta. 1983. Isopropanol exposure: Environmental and biological monitoring in a printing works. Br. J. Ind. Med. 40:160-168.

Carpenter, C.P., H.F. Smyth, Jr., and U.C. Pozzani. 1949. The assay of acute vapor toxicity, and the grading and interpretation of results on 96 chemical compounds. J. Ind. Hyg. Toxicol. 31:343-346.

Cornish, H.H., and J. Adefuin. 1967. Potentiation of carbon tetrachloride toxicity by aliphatic alcohols. Arch. Environ. Health 14: 447-449.

Coté, M.G., G.J. Traiger, and G.L. Plaa. 1974. Effect of isopropanol-induced potentiation of carbon tetrachloride on rat hepatic ultrastructure. Toxicol. Appl. Pharmacol. 30:14-25.

Daniel, D.R., B.H. McAnalley, and J.C. Garriott. 1981. Isopropyl alcohol metabolism after acute intoxication in humans. J. Anal. Toxicol. 5:110-112.

Dick, R.B., W.D. Brown, J.V. Selzer, B.J. Taylor, and R. Shukla. 1988. Effects of short-duration exposures to acetone and methyl ethyl ketone. Toxicol. Lett. 43:31-49.

Ellis, F.W. 1952. The role of the liver in the metabolic disposition of isopropyl alcohol. J. Pharmacol. Exp. Ther. 105:427-436.

Folland, D.S., W. Schaffner, H.E. Ginn, O.B. Crofford, and D.R. McMurray. 1976. Carbon tetrachloride toxicity potentiated by isopropyl alcohol. JAMA 236:1853-1856.

Fuller, H.C., and O.B. Hunter. 1927. Isopropyl alcohol-an investigation of its physiologic properties. J. Lab. Clin. Med. 12:326-349.

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, 46. The metabolism of aliphatic alcohols, the glucuronic acid conjugation of acyclic aliphatic alcohols. Biochem. J. 53:129-136.

Kapp, R.W., D.J. Marino, T.H. Gardiner, L.W. Masten, R.H. McKee, T.R. Taylor, J.L. Ivell, and R.R. Young. 1993. In vitro and in vivo assays of isopropanol for mutagenicity. Environ. Mol. Mutagen 22:93-100.

Kimura, E.T., D.M. Ebert, and P.W. Dodge. 1971. Acute toxicity and limits of solvent residue or sixteen organic solvents . Toxicol. Appl. Pharmacol. 19:699-704.

King, L.H., K.P. Breadley, and D.L. Shires. 1970. Hemodialysis for isopropanol alcohol poisoning. JAMA 211:1855.

Laham, S., M. Potvin, K. Schrader, and I. Marino. 1980. Studies on inhalation toxicity of 2-propanol. Drug Chem. Toxicol. 3:343-360.

Lehman, A.J., and H.F. Chase. 1944. The acute and chronic toxicity of isopropyl alcohol. J. Lab. Clin. Med. 29:561-567.

Lehman, A.J., H. Schwerma, and E. Richards. 1944. Isopropyl alcohol: rate of disappearance from the bloodstream of dogs after intravenous and oral administration. J. Pharmacol. Exp. Ther. 82:196-201.

Lehman, A.J., H. Schwerma, and E. Richards. 1945. Isopropyl alcohol: Acquired tolerance in dogs, rate of disappearance from the bloodstream in various species, and effects on successive generation of rats. J. Pharmacol. Exp. Ther. 85:61-69.

Lehman, K.B., and F. Flury. 1943. Pp. 207-208 in Toxicology and Hygiene of Industrial Solvents. Baltimore, Md.: Williams & Wilkins.

Lester, D., and G.D. Benson. 1970. Alcohol oxidation in rats inhibited by pyrazole, oximes, and amides. Science 169:282-284.

Macht, D.I. 1922. Pharmacological examination of isopropyl alcohol. Arch. Int. Pharmacodyn. Ther. 26:285-289.

Nakaseko, H., K. Teramoto, and S. Horiguchi. 1991a. Toxicity of isopropyl alcohol. Part I: Single inhalation exposure in rats. Jpn. J. Ind. Health 33:198-199.

Nakaseko, H., K. Teramoto, and S. Horiguchi. 1991b. Toxicity of isopropyl alcohol. Part 2: Repeated inhalation exposure in rats. Jpn. J. Ind. Health 33:200-201.

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, D.R. MacKenzie, A. Khan, J.R. Burg, and W.W. Weigel. 1988. Teratogenicity of n-propanol and isopropanol administered at high inhalation concentrations to rats. Food Chem. Toxicol. 26:247-254.

Nordmann, R., Y. Giudicelli, F. Beauge, M. Clement, C. Ribiere, H. Roach, and J. Nordmann. 1973. Studies on the mechanism involved in the isopropanol-induced fatty liver. Biochim. Biophys. Acta 326:1-11.

NRC. 1984. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 2. Washington, D.C.: National Academy Press.

Rowe, V.K., and S.B. McCollister. 1982. Alcohols. Pp. 4527-4708 in Patty's Industrial Hygiene and Toxicology, Vol. 2C, 3rd Rev. Ed. New York: John Wiley & Sons.

Smyth, H.F., Jr., and C.P. Carpenter. 1948. Further experience with the range finding test in the industrial toxicology laboratory. J. Ind. Hyg. Toxicol. 30:63-68.

Starrek, E. 1938. Dissertation. Würzburg, Germany.

Traiger, G.J., and G.L. Plaa. 1971. Differences in the potentiation of carbon tetrachloride in rats by ethanol and isopropanol pretreatment. Toxicol. Appl. Pharmacol. 20:105-112.

Traiger, G.J., and G.L. Plaa. 1974. Chlorinated bycarbon toxicity-potentiation by isopropyl alcohol and acetone. Arch. Environ. Health 28:276-278.

Von der Hude, W., M. Scheutwinkel, U. Gramlich, B. Fibler, and A. Basler. 1987. Genotoxicity of three-carbon compounds evaluated in the SEC test in vitro. Environ. Mutagen 9:401-410.

Wax, J., F.W. Ellis, and A.J. Lehman. 1949. Absorption and distribution of isopropyl alcohol. J. Pharmacol. Exp. Ther. 97:229-237.

Weese, H. 1928. [Comparative studies of the efficacy and toxicity of the vapors of lower aliphatic alcohols.] Arch. Exp. Pathol. Pharmakol. 135:118-130.

Weil, C.S., H.F. Smyth, Jr., and T.W. Nale. 1952. Quest for a suspected industrial carcinogen. Arch. Ind. Hyg. Occup. Med. 5:535-547.

Wills, J.H., E.M. Jameson, and F. Coulston. 1969. Effects on man of daily ingestion of small doses of isopropyl alcohol. Toxicol. Appl. Pharmacol. 15:560-565.

Zeigler, E., B. Anderson, S. Haworth, T. Lawlor, and K. Mortelmans. 1992. Salmonella mutagenicity tests. V. Results from the testing of 311 chemicals. Environ. Mol. Mutagen 19(Suppl. 21):2-141.