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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B1 Acetone Hector D. Garcia, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES Acetone is a clear, colorless, highly volatile, flammable liquid with a sweet, fruity aroma (odor threshold, 13 ppm) and excellent solvent properties. It forms explosive mixtures with air or oxygen. Formula: C3H6O Chemical name: Acetone Synonyms: Propanone, 2-propanone, dimethyl ketone, dimethylformaldehyde, dimethylketal, ketone propane, β-ketopropane, methyl ketone, pyroacetic acid, pyroacetic ether CAS no.: 67641 Molecular weight: 58.09 Boiling point: 56.48°C Melting point: –94.6°C Lower explosive limit: 2.6% (26,000 ppm) Upper explosive limit: 12.8% (128,000 ppm) Autoignition temperature: 465°C Flash point (closed cup): –17.8°C Density (15°C): 0.7972 Vapor pressure at 39.5°C: 400 mm Vapor pressure at 25°C: 200 mm Vapor density: 2.00
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Solubility: Infinitely soluble in water; miscible with alcohol, dimethylformamide, chloroform, most oils, and ether Conversion factors at 25°C, 1 atm: 1 ppm = 2.37 mg/m3; 1 mg/m3 = 0.421 ppm OCCURRENCE AND USE Acetone is emitted into the air from plants and trees, volcanic eruptions, forest fires, automobile exhaust, chemical manufacturing, tobacco smoke, wood burning, petroleum storage facilities, landfill sites, and solvent use (ATSDR 1994). Commercial acetone is obtained by a variety of manufacturing processes, such as fermentation (by-product of butyl alcohol manufacture) and chemical synthesis from isopropanol, cumene (by-product in phenol manufacture), and propane (by-product of oxidation cracking). Acetone is widely used as a general laboratory solvent; as an industrial solvent for fats, oils, waxes, resins, rubber, plastics, lacquers, varnishes, and rubber cements; and as a solvent to extract various materials from plant and animal substances. It is used in the manufacture of methyl isobutyl ketone, mesityl oxide, acetic acid (ketene process), diacetone alcohol, chloroform, iodoform, bromoform, explosives, airplane dopes, rayon, photographic films, and isoprene (Dietz 1991). Acetone is used to store acetylene, because it takes up 24 times its volume of the gas. It also is used in paint and varnish removers, in nail polish removers, in the purification of paraffin, and in hardening and dehydrating tissues. Acetone is a product of normal metabolism in humans and animals. It is produced during the breakdown of fat and is used in the synthesis of glucose and fat. Trace amounts are detectable in normal human blood (7 µmol/L) and urine (4-35 µmol/L) (Dietz 1991). Data from a NIOSH report (Stewart et al. 1975) on acetone suggests that normal blood acetone concentrations in women (1.8-4.2 mg%) are 2-3 times higher than those in men (0.5-1.4 mg%), but no other reports could be found to confirm that finding. Raised acetone concentrations in serum and breath are often indicative of altered metabolic states, such as diabetes, vitamin E deficiency, and fasting (Dietz 1991). Acetone is not routinely used in spacecraft during flight but might be used in payload experiments. Acetone is found in the spacecraft atmosphere on almost every mission at concentrations up to 8 ppm on Skylab (Liebich et al. 1975) and up to 1.2 ppm on shorter shuttle missions, probably because of crew metabolism and off-gassing.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TOXICOKINETICS AND METABOLISM Absorption DiVincenzo et al. (1973) reported that volunteers exposed to acetone at 100 or 500 ppm absorbed approximately 75% of the inhaled vapor into the blood-stream. Uptake of acetone was about 45% (39-52%) in eight men exposed for 2 h at 300 or 550 ppm (Wigaeus et al. 1981). The endogenous concentration of acetone in alveolar air was about 0.4 ppm, and the concentration of acetone in alveolar air during exposure at 300 or 550 ppm was 30-40% of the concentration in inspiratory air. Exhaled-breath concentrations of acetone rise during exposure and reach steady state in humans within 2 h during exposure (DiVincenzo et al. 1973). In rats, equilibrium between atmospheric acetone and absorbed acetone was approached after 3-4 h of exposure (Hallier et al. 1981). Breath concentrations of acetone are directly proportional to the concentration and duration of exposure and increase with physical activity because of increased pulmonary ventilation (DiVincenzo et al. 1973; Wigaeus et al. 1981). Vangala et al. (1991) found that a plateau of maximal alveolar-air concentration was reached after exposure to acetone at 990 ppm for 2 h by 16 male volunteers. The concentration of acetone in arterial and venous blood was found to increase linearly for up to 4 h of exposure with no indication that steady state was reached (DiVincenzo et al. 1973; Wigaeus et al. 1981; Brown et al. 1987). No significant difference in uptake or retention was found between men and women (Brown et al. 1987). Endogenous concentrations of acetone up to 10 µg/mL in blood were reported, and concentrations during diabetic ketoacidosis ranged from 100 to 700 µg/mL (Gamis and Wasserman 1988). Distribution Mice exposed to 2-[14C]-acetone vapor (500 ppm) for periods of 1 h to 5 d were examined for tissue distribution of radioactivity (Löf et al. 1980). The amount of radioactivity in tissues increased as the exposure time increased from 1 to 6 h but did not increase in most tissues at exposure times greater than 6 h (12 h, 24 h) (Löf et al. 1980). Liver and pancreas showed the highest concentration of radioactivity; the lowest concentrations were in muscles and white adipose tissue. After 3 or 5 d of exposure (6 h/d), the radioactive concentration was highest in brown adipose tissue, followed by liver and pancreas. In studies of the inhalation toxicokinetics of acetone in rats, Hallier et al. (1981) found that acetone is mainly, but not exclusively, distributed within the body water compartment under conditions of negligible metabolism (saturation of metabolizing enzymes). The kinetics of exhalation of acetone were strictly
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 mono-exponential, indicating that it does not distribute into a deep compartment. Excretion Hallier et al. (1981) studied the toxicokinetics of inhaled acetone in rats and found that metabolic elimination of acetone followed strict Michaelis-Menton saturation kinetics. The Km corresponded to 160 ppm in the atmosphere. The half-life of the concentration of acetone in exhaled breath of rats after removal from exposure was 2.1 h. Thus, acetone should not accumulate (in the rat) under conditions of intermittent daily exposure at low concentrations (≤ 250 ppm). That conclusion is supported by observations in workers occupationally exposed to acetone for 8 h daily; acetone concentrations in blood and urine showed no signs of accumulation (Baumann and Angerer 1979). Excretion of formate in the urine of rats after a single exposure to acetone was enhanced for 7 d, suggesting the existence of a formate pool in the body from which it is released, after a delay, in limited amounts. The main route of excretion is via the lungs, regardless of the route of exposure, with very little excreted in the urine. About half of the acetone is exhaled unchanged in humans and the other half is exhaled as carbon dioxide produced from metabolism of acetone. DiVincenzo et al. (1973) reported that the half-life was about 3 h for the elimination of acetone in expired air of volunteers exposed to acetone at 100 or 500 ppm. In human adult acute intoxications, the half-life of acetone in plasma was estimated at approximately 31 h (Ramu et al. 1978). Parmeggiani and Sassi (1954) exposed volunteers to acetone vapor at 833 ppm for 3 h twice daily with a 1-h break between exposures. They found concentrations of acetone at 190 µg/L in expired air at the end of the day. Sixteen hours later, the concentration of acetone in expired air had decreased to 32 µg/L. The concentration of acetone returned to background concentrations over the weekend. Those results suggest that repeated exposure to high concentrations of acetone might lead to slight accumulation during the workweek (Krasavage et al. 1982). Stewart et al. (1975) exposed 7 male volunteers to acetone at concentrations of 0, 200, 1000, or 1250 ppm and 10 female volunteers to acetone at 0 or 1000 ppm in a complex exposure schedule. Overall breath-decay curves obtained 1 h after exposure accurately reflect the time-weighted-average vapor concentration, whether the exposure is to a constant or varying concentration, and samples collected within a few minutes after exposure reflect the most recent
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 vapor concentration. A slight but significant accumulation of acetone occurred in the body following exposure at 1000 ppm, but that small amount did not affect the breath-decay curves. Metabolism Ramu et al. (1978) estimated that humans can metabolize acetone at a rate not exceeding 1 g/h. Using that estimate, a person inhaling 0.83 m3 of air per hour (20 m3 of air per 24 h) could metabolize in 1 h all the acetone absorbed during inhalation—assuming about 50% uptake of inhaled vapor into the bloodstream—if the concentration of acetone was no more than 2 g/0.83 m3 of air (i.e., 2.4 g/m3 or 1000 ppm). The expired air of mice exposed to 2-(14C)-acetone vapor (500 ppm) for periods of 1 h to 5 d (6 h/d) was analyzed for radioactive acetone, carbon dioxide, and carbon monoxide (Löf et al. 1980; Wigaeus et al. 1982). Carbon dioxide was a major constituent, and no detectable amounts of carbon monoxide were found in the expired air (Löf et al. 1980; Wigaeus et al. 1982). The amount of reduced hepatic glutathione was significantly lowered (percent reduction not stated) after 6 h of exposure at 500 ppm (Löf et al. 1980). No studies on the metabolism of acetone in humans were found, but several studies in rats showed that acetone can be metabolized via three gluconeogenic pathways, the first step being the hydroxylation of one of the methyl groups by acetone mono-oxygenase to form acetol (Dietz 1991). In hamsters, acetone is considered a nonmetabolizable endogenous and exogenous compound (Morris and Cavanagh 1987). TOXICITY SUMMARY Human exposure to acetone at atmospheric concentrations lower than 500 ppm is not commonly associated with any health hazards (Krasavage et al. 1982). Exceptions include slight irritant effects noted in unacclimatized subjects after short exposures (3-5 min) (Rowe and Wolf 1963) and possibly subtle physiological effects on the autonomic nervous system at 250 ppm (Matsushita et al. 1969a,b; Dick et al. 1988, 1989). At higher concentrations, manifestations of acute acetone toxicity are primarily a result of central-nervous-system (CNS) depression that ranges from lethargy, slurred speech, and ataxia to stupor, coma, and respiratory depression (Gamis and Wasserman 1988). Other adverse effects of high acetone concen-
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 trations include topical irritation and erythema (skin and mucosa), vomiting, hematemesis, polydipsia, polyuria, hyperglycemia, and occasionally metabolic acidosis (Gamis and Wasserman 1988). One Soviet investigator reported that four individuals acutely exposed (one by inhalation and three orally) to unspecified concentrations of acetone developed liver lesions, and two of the orally intoxicated individuals developed mild renal lesions (Mirchev 1977). The quality of this case-study report could not be evaluated because it was written in a non-Russian, Slavic language, probably Bulgarian, and only the abstract was translated to English. Thus, it could not be determined whether the four patients had also been exposed to other agents, such as alcohol, or might have had pre-existing lesions of the liver or kidneys. No other reports of acetone-related liver or renal lesions in humans or animals were found. Acute and Short-Term Exposures General Inhalation exposure to high concentrations of acetone (>1000 ppm) affects the nervous system, gastrointestinal tract, kidney, mucous membranes, and eyes. The following symptoms have been reported: CNS depression indicated by an initial stimulatory or excitatory restlessness phase followed by euphoria and hallucinations, narcosis, anesthesia, dyspnea, headache, vertigo, general muscular weakness including dysarthria and ataxia, and coma; nausea, vomiting, inflammation, and hematemesis; albuminuria, hematuria, and leukocyturia; irritation of the nose, throat, and bronchi and dry throat; irritation of the eyes and transient corneal and conjunctival injury; hyperglycemia and increases in bilirubin and urine urobilin (Rowe and Wolf 1963; Mirchev 1977; Nelson and Webb 1978; Geller et al. 1979a,b; Baselt 1982; Krasavage et al. 1982; Finkel 1983; Inoue 1983; Windholz 1983; Arena and Drew 1986; Grant 1986; ACGIH 1986). The toxic range of acetone was estimated to be 200 to 300 µg/mL in blood, with lethal concentrations estimated to be greater than 550 µg/mL (Gamis and Wasserman 1988). Intoxication was not observed, however, in volunteers with blood acetone concentrations up to 33 µg/mL from exposure by either ingestion or inhalation (Gamis and Wasserman 1988). The highest blood concentration of acetone reported (445 µg/mL) produced stupor, respiratory depression, and convulsions in a 30-mo-old who ingested nail-polish remover. Its anesthetic potency is greater than that of ethanol at equivalent blood concentrations (Gosselin et al. 1984). No permanent toxic sequelae have been reported (Gamis and Wasserman 1988).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Irritation Raleigh and McGee (1972) surveyed workers exposed for 8 h/d at an average atmospheric concentration of about 1000 ppm. Eye irritation was transient and generally occurred at atmospheric concentrations greater than 1000 ppm. There was no indication of CNS effects. The authors concluded that 1000 ppm produced no adverse effects except for slight, transient irritation of the eyes, nose, and throat. Matsushita et al. (1969a) exposed groups of five 22-y-old male students to acetone vapor at 0, 100, 250, 500, or 1000 ppm for 6 h, with a 45-min intermission after the third hour. Slight, transient irritation of the eyes, nose, and throat was noted at 100, 250, 500, and 1000 ppm. The odor of acetone was detected at 100 ppm, but acclimatization occurred rapidly. Nelson et al. (1943) reported that 3-5 min exposures at 200 ppm caused no nose and throat irritation in humans, and subjects estimated that the concentration could be tolerated for 8 h; 500 ppm, however, did cause nose and throat irritation (Nelson et al. 1943). Stewart et al. (1975) exposed 7 male volunteers to acetone at concentrations of 0, 200, 1000, or 1250 ppm and 10 female volunteers to acetone at 0 or 1000 ppm in a complex exposure schedule. During three control days, two subjects recorded slight eye irritation, one recorded throat irritation, and one developed a headache while in the chamber. During exposure at 200 ppm, two subjects reported eye irritation on d 1, two reported transient dizziness, one had a headache after 3 h of exposure, and two complained of tiredness. Odor intensity during the first week of exposure at 1000 ppm was reported to be stronger than during the previous week and was present throughout the exposure period. There were three complaints of eye and throat irritation and three complaints of tiredness. During the week of exposure at 1250 ppm, odor intensity and the number of complaints of eye and throat irritation remained the same as those at 1000 ppm (Stewart et al. 1975). Those findings are consistent with the findings of Matsushita et al. (1969a,b), who reported slight irritation, heavy-headedness, and lack of energy at 250 ppm, and Dick et al. (1988, 1989), who reported subtle neurological effects at 250 ppm. Immunological and Hematological Effects Matsushita et al. (1969a,b) reported statistically significant increases in white-blood-cell counts, increased eosinophil counts, and decreased phagocytic activity of neutrophils, compared with controls, in volunteers after a 6-h exposure or repeated 6-h/d exposures for 6 d to acetone at 500 ppm. No
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 significant differences in hematological measurements were seen in the volunteers exposed at 250 ppm compared with controls. According to a review by Koller (1993): ''Alteration of cell numbers (peripheral leukocyte and eosinophil counts) does not correlate with immune function. Severe changes in leukocyte counts can affect immune responses but need to be defined by immune function procedures." He concluded that "it would be premature to change existing permissible exposure standards based on these data in the absence of conducting a more thorough immunotoxicological assessment of acetone to determine if the immune system is a primary target organ" (Koller 1993). In another study, hematological findings were within normal limits in volunteers exposed to acetone at 500 ppm for 2 h (DiVincenzo et al. 1973) or at ≤ 1250 ppm intermittently for various durations in a study with a complex protocol (Stewart et al. 1975). Hematological effects observed in animals include bone-marrow hypoplasia in male rats, but not in female rats, exposed to acetone in drinking water for 14 d at a dose of 6942 mg/kg/d (Dietz 1991); macrocytic anemia in male rats exposed at ≥ 200 mg/kg/d; nonspecific hematological effects not indicative of anemia in female rats exposed at 3100 mg/kg/d via drinking water for 13 w (Dietz 1991); increased hemoglobin, hematocrit, and mean cell volume in male rats, but not in female rats, exposed by gavage at 2500 mg/kg/d for 46 d and in male and female rats exposed at that dose for 13 w (American Biogenics Corp. 1986, unpublished study, cited in ATSDR 1994, p. 99). In mice exposed at ≤ 12,725 mg/kg/d for 14 d, it was not clear whether bone marrow was examined, but in the 13-w study, no hematological effects or histologically observable lesions in hematopoietic tissues were found (Dietz 1991). Thus, species and gender differences are apparent in the hematological effects of acetone in animals. CNS Toxicity Stewart et al. (1975) exposed 7 male volunteers to acetone at concentrations of 0, 200, 1000, or 1250 ppm and 10 female volunteers to acetone at 0 or 1000 ppm in a complex exposure schedule. The following neurological tests were performed daily on each subject: a modified Romberg and heel-to-toe equilibrium test (twice daily), spontaneous electroencephalogram (EEG) and visual-evoked responses (VER) (four times per day on Monday, Wednesday, and Friday), coordination test, arithmetic test, and detection of the number 3 in rows of random numbers. No alteration in the VER was observed at 200 or 1000 ppm, but male subjects exposed at 1250 ppm showed an increase in total VER amplitude. The spontaneous EEG was unaltered by any exposure condition. No decrements in cognitive test performance were seen during exposures. One
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 subject (an author) experienced an episode of vertigo after 40 min of exposure at 1000 ppm. He had previously been diagnosed with Bárány's paroxsymal vertigo and had experienced two similar episodes, which were also associated with exposure to high concentrations of a ketone. Two other subjects reported transient dizziness. When compared with values obtained after ≤48 h of no acetone exposure, simple reaction times were significantly prolonged (average, 16%) in five workers exposed during their 8-h shifts to acetone vapors from glue at concentrations of about 200 ppm (Israeli et al. 1977). Matsushita et al. (1969a,b) reported neurological effects, such as a feeling of tension, heavy eyes, heavy head, lack of energy, general weakness, and headache, in 22-y-old male volunteers the morning after exposure to acetone at 500 ppm for 6 h or repeatedly for 6 h/d for 6 d. Those complaints were rare after exposure at 250 ppm and were not seen at 100 ppm. Matsushita et al. (1969b) also reported 5-10% delayed visual reaction time in subjects exposed to acetone at 250 or 500 ppm for 6 h/d for 6 d. Examination of their data on the reaction time, however, reveals that "the values for the individuals within even the same group were scattered and a significant difference of p<0.05 could not be found between any of the acetone exposed groups and the control group" unless "all the numerical values obtained on the various measurement days were averaged and compared with the values on the first day of exposure" (Matsushita et al. 1969b) (i.e., the results during the first day of exposure were normalized to 100% and results from subsequent days were compared with those from the first day). Thus, no biologically significant effect on visual reaction time was seen in the 6 d of exposure. Dick et al. (1988, 1989) exposed 22 volunteers to acetone at 250 ppm for 4 h and found small but statistically significant differences between the volunteers and the controls in two measures of the auditory tone-discrimination task (a 7-14% increase in response time to detect a 760-Hz tone in a series of 750-Hz tones and a 25% increase in false alarms but no difference in the percent of correct hits) and on the anger-hostility scale (males only) of a psychological test, the profile of mood states (POMS). Although those effects are statistically significant, the small magnitude of the effects and the uncertain biological relevance of the end points argue against using them for the purpose of setting SMACs. No significant effects were seen in three other psychomotor tests (choice reaction time, visual vigilance, and memory scanning), one sensorimotor test (postural sway), and five of six scales of the POMS psychological test. A NOAEL of 125 ppm was reported for all measured effects when the subjects were simultaneously exposed to acetone at 125 ppm and to methyl ethyl ketone at 100 ppm. Measurement of acetone concentrations in venous blood indicated that the concentrations at 2 h were about 60% of those at 4 h. (Dick et al. 1988).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Eight men cleaning an indoor pit were exposed to acetone vapor at >12,000 ppm (Draeger tube measurements) for durations ranging from 2 min to 4 h. Seven of the eight experienced dizziness, a feeling of inebriation, throat and eye irritation, and weakness of the legs. After three 2-min exposures, one man complained of tightness of the chest lasting for about 4 h. Two of the four men who were exposed for >4 h lost consciousness (Ross 1973). One of the two men who lost consciousness was hospitalized for 4 d, but both returned to work 6 d after exposure. The short-term operant behavior of rats exposed to acetone by inhalation was examined by Goldberg et al. (1964). Female rats were trained according to an avoidance-escape paradigm. Groups were exposed at 3000, 6000, 12,000, or 16,000 ppm for 4 h/d, 5 d/w for 10 d. Body weight and growth were not affected at any dose, but escape behavior was suppressed, and ataxia was noted on d 1 in the 12,000- and 16,000-ppm groups. Avoidance behavior was inhibited in groups exposed at 6000 ppm, 12,000 ppm, and 16,000 ppm. Tolerance developed for all the reported neurobehavioral effects. Ataxia and Narcosis Bruckner and Peterson (1981) found that 4-w-old rats and mice exposed to acetone at 12,600 to 50,600 ppm for up to 3 h were slightly more sensitive to its narcotic effects than were 8- to 12-w-old animals. The animals were scored for ataxia (seen at 12,600 ppm), immobility in the absence of stimulation (seen at 19,000 ppm), hypnosis with arousal difficult (seen at 25,300 ppm), and unconsciousness (seen at 50,600 ppm with lethality after 2 h). The degree of CNS depression was linearly related to the exposure duration for a given concentration, and both the degree of CNS depression and the rapidity of its induction were dependent on the concentration of inhaled acetone. The time required for complete recovery from acetone's CNS effects was also dependent on the concentration inhaled: 9 h were required to recover from the effects of a 3-h exposure at 19,000 ppm, and 21 h were required to recover from a 3-h exposure at 25,300 ppm (Bruckner and Peterson 1981). Pulmonary Function and Cardiotoxicity The study of Stewart et al. (1975), described in the section on CNS toxicity, monitored a large number of end points. Acetone concentrations in the chamber air were monitored by spectrophotometry every 30 s and gas chromatography every 170 s. Acetone concentrations were measured in exhaled breath, blood, and urine. No significant changes from control EKGs were seen during exposures. No abnormalities were observed in pulmonary-function studies.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Subchronic and Chronic Exposures No subchronic or chronic studies of acetone exposure were found other than a retrospective occupational epidemiological study of cancer incidence. Carcinogenicity There is no evidence that occupational exposure to acetone is associated with an increased incidence of cancer in humans. Oglesby et al. (1949) saw no increased incidence of cancer or any other harmful effects in their review of the accumulated medical and acetone-exposure (200-3000 ppm) records in a production facility of cellulose acetate yarn over 18 y. Genotoxicity In unpublished studies by the National Toxicology Program (NTP, Research Triangle Park, NC, 1991), acetone was not mutagenic in Salmonella typhimurium strains TA97, TA98, TA100, TA1535, or TA1537 with or without metabolic activation. Acetone did not induce sister chromatid exchanges or chromosomal aberrations in Chinese hamster ovary cells at doses up to 5 mg/mL with or without S9, and it did not induce micronuclei or polychromatic erythrocytes in the peripheral blood of mice ingesting acetone at 5000-20,000 ppm in drinking water for 13 w. Reproductive Effects in Humans Stewart et al. (1975) exposed 10 female volunteers to acetone at 0 or 1000 ppm for 1 h, 3 h, or 7.5 h/d for 1 w. Three of the four female subjects exposed for 7.5 h/d experienced early menstrual periods after 4 d of exposure at 1000 ppm. Reproductive and Developmental Toxicity in Animals Mast et al. (1989) reported mild developmental toxicity and mild maternal toxicity in rats exposed to acetone at 11,000 ppm for 6 h/d, 7 d/w during d 6-19 of gestation, but no effects were seen at 2200 ppm. In the same study, mice exposed at 6600 ppm for 6 h/d, 7 d/w during d 6-17 of gestation had significant increases in resorptions and significant decreases in fetal weights. The effects on maternal weight were weak. At 2200 ppm, no effects were seen in mice.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RATIONALE FOR ACCEPTABLE CONCENTRATIONS Table 1-2 presents exposure limits set by other organizations and Table 3-1 presents the SMACs established by NASA. Of the effects of acetone exposure discussed above, irritation, explosion, and dizziness and fatigue are the only ones for which ACs will be set. Effects such TABLE 1-2 Exposure Limits Set by Other Organizations Organization Exposure Limit, ppm Reference ACGIH's TLV 500 (TWA) ACGIH 1997 ACGIH's STEL 750 (ceiling) ACGIH 1997 OSHA's PEL 750 (TWA) ACGIH 1991 OSHA's STEL 1000 ACGIH 1991 ATSDR's MRL 26 (acute, 4 h) ATSDR 1994 13 (intermediate and chronic) ATSDR 1994 NIOSH's REL 250 ACGIH 1991 NRC's 1-h EEGL 8500 NRC 1984 NRC's 24-h EEGL 1000 NRC 1984 NRC's 90-d CEGL 200 NRC 1984 TLV, Threshold Limit Value; TWA, time-weighted average; STEL, short-term exposure limit; PEL, permissible exposure limit; MRL, minimal risk level; REL, recommended exposure limit; EEGL, emergency exposure guidance level; CEGL, continuous exposure guidance level. TABLE 1-3 Spacecraft Maximum Allowable Concentrations Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 500 210 Fatigue 24 h 200 84 Fatigue 7 da 22 52 Fatigue, headache 30 d 22 52 Fatigue, headache 180 d 22 52 Fatigue, headache a Previous 7-d SMAC = 300 ppm (713 mg/m3).
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 as ataxia, immediate CNS depression, and death will be protected against by ACs that protect against more sensitive effects such as irritation or lethargy. Calculation using the guidelines established by the NRC (1992) to determine the highest acceptable concentration (AC) for each major end point and exposure duration is documented below. The resulting ACs for the various end points are complied in Table 1-4 and compared. SMAC values are set at each duration on the basis of the end point that yielded the lowest AC at that exposure duration. Irritation Mild, transitory irritation of the eyes, nose, and throat was reported in workers exposed for 8 h/d to atmospheric concentrations of acetone greater than 1000 ppm (Raleigh and McGee 1972). Such irritation would be acceptable for exposures of 1 h or 24 h. Thus, 1-h and 24-h ACs = 1000 ppm. For longer exposure times, no irritation is acceptable. Because irritation does not increase with longer exposure times, the ACs for exposures >24 h were based on Nelson's et al. (1943) 6-h NOAEL of 200 ppm. 7-d, 30-d, 180-d ACs = 200 ppm. Explosion Acetone is highly volatile, flammable, and explosive; therefore, care must be taken to prevent the formation of local high concentrations (26,000-128,000 ppm) of acetone vapor. With nominal shuttle air circulation and mixing, an AC of 0.1 times the lower explosive limit should protect against hazardous accumulation of pockets of concentrated acetone vapor. Thus, the AC for explosion is set at 2600 ppm. CNS Effects It is clear from Matsushita et al. (1969a) that acetone at 100 ppm induces no detectable effects in humans exposed for 6 h. For 1-h and 24-h SMACs, a
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 slight degree of adverse effects is acceptable as long as the effects do not limit an astronaut's ability to perform during an emergency. The slight adverse effects at 200 ppm reported by Stewart et al. (1975) and those at 250 ppm reported by Matsushita et al. (1969a) are acceptable for short-term exposures (24 h), and on the basis of the 1000-ppm results in the Stewart study and the 500-ppm results in the Matsushita study, a 1-h exposure at 500 ppm should not affect performance. Stewart et al. (1975) used cognitive tests (coordination, arithmetic, and inspection), neurological measures (equilibrium and EEG), and pulmonary functions to determine the effect of repeated exposure to acetone. No acetone-induced changes were found in any of those objective measures of adverse effects, even after repeated daily exposures at 1000 ppm. Subjects were also asked to report their subjective responses to their exposure several times during the exposure. The subjective responses were as follows: Controls, 4-d exposure: 2 subjects reported slight irritation on 3 of 4 d 1 subject reported throat irritation 1 subject reported headache 200-ppm, 4-d exposure: 2 subjects reported eye irritation on d 1 2 subjects reported transient dizziness 1 subject reported a headache 2 subjects complained of tiredness 1000-ppm, 4- to 7-d exposure: 3 subjects complained of eye and throat irritation 3 subjects complained of tiredness Although dizziness would ordinarily be a concern, the transient nature of the effect and the lack of its appearance during the 1000-ppm exposures provide convincing evidence that the effect is marginal at best. Although tiredness was reported by several subjects, their objectively measured performance was never significantly affected. Based on the extensive exposures done by Stewart and co-workers, a 1-h AC of 1000 ppm appears acceptable; however, the data from Matsushita et al. (1969a,b) need to be considered as well. The effects reported by Matsushita et al. (1969b) for repeated exposures at 250 ppm might be a concern because they could compromise performance. The morning after each of six repeated exposures, six subjects were asked whether they felt any of the following effects "clearly (2 points) or "a little" (1 point): heavy head, headache, general weakness, lack of energy, or heavy eyes.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Toxicokinetic analysis of the data reported by Matsushita et al. (1969a) indicates that immediate-irritation effects and potential delayed CNS effects must be considered for the 1-h AC. During the first 90 min of the single 6-h exposure to acetone at 500 ppm, the degree of irritation reported was scored at 4-5 out of a possible 10. That means that most of the subjects felt a little irritation, or two of the subjects clearly felt irritation and the rest felt nothing. That degree of irritation is acceptable for a 1-h contingency exposure. The morning after the single 6-h exposure at 500 ppm, Matsushita et al. (1969a) reported that most subjects clearly felt tension, heavy eyes, and a lack of energy. The scores reported by those exposed at 250 ppm could have been attained either by one-half of the subjects having no complaints and the other half feeling a little tension, heavy eyes, and lack of energy or by most feeling nothing and one clearly feeling the symptoms. The symptoms are the result of a cumulative 6-h exposure to acetone. It can be estimated from the Matsushita data that the blood concentration of acetone after 1 h of exposure at 500 ppm would be no more than the blood concentration after 6 h of exposure at 250 ppm. Hence, any delayed systemic symptoms due to a 1-h exposure at 500 ppm are unlikely to be worse than those from a 6-h exposure at 250 ppm. Accordingly, 1-h AC = 500 ppm. In nonworking subjects exposed at 250 ppm, there was a significant increase the following day in the incidence of lack of energy compared with working controls. (No report was given of nonworking controls.) General weakness was reported with similar incidence in both groups, and it is not clear how that differs from lack of energy. Somewhat similar effects (e.g., tiredness) were reported by Stewart et al. (1975) during the 200-ppm exposures without measurable performance decrements. Because the Matsushita observations are subjective, we conclude that exposures of 200 ppm are very unlikely to impair the crew's ability to perform its tasks for exposure periods up to 24 h. Hence, 24-h AC = 200 ppm. The long-term ACs (7-180 d) must be set to avoid any adverse effects. Hence, one must begin with the 100-ppm NOAEL reported by Matsushita et al. (1969a) in five test subjects exposed for 6 h. Repeated exposures up to 1000 ppm suggest that adverse effects do not become worse with prolonged exposure (Matsushita et al. (1969b). (The Stewart study suggests a tolerance to acetone.) Furthermore, blood concentrations during exposures at 100 ppm do not increase
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 after 3 h; hence, we conclude that 100 ppm is below the threshold for effects such as irritation, headache, and loss of energy no matter how long the exposure lasts. The ACs are as follows: 7 -d, 30 -d, 180 -d AC = 100 ppm × = 22 ppm. A safety factor of was used to account for the uncertainty in the NOAEL because of the small number (n = 5) of test subjects. Reproductive Effects After 4 d of exposure to acetone at 1000 ppm for 7 h/d, women volunteers experienced premature menstrual periods. Other than transient irritation, no other adverse effects were reported (Stewart et al. 1975). NASA tests female astronauts for pregnancy before flight and those found to be pregnant are not permitted to fly; therefore, premature menses is not considered an adverse effect and will not be used to set an AC. Spaceflight Considerations None of the end points induced by exposure to acetone is expected to be affected by launch, microgravity, or re-entry. RECOMMENDATIONS A continuous inhalation exposure study of acetone at concentrations of 100 to 1000 ppm needs to be conducted on 10 or more human volunteers per exposure group. The study should include several objective measures, such as CNS effects (e.g., reaction times, visual acuity, and work capacity) and effects on menstrual cycle and hormonal levels, as well as subjective measures, such as sleepiness and headache. A chronic exposure, continuous inhalation study of the immunotoxic and hematotoxic effects of acetone exposure on bone-marrow cells in rodents or primates is needed.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 1-4 Acceptable Concentrations End Point, Exposure Uncertainty Factors Acceptable Concentrations, ppm Data, Reference Species NOAEL Time Species Spaceflight 1 h 24 h 7 d 30 d 180 d Irritation Human 10 1 1 1 1000 1000 200 200 200 LOAEL, 1000 ppm for 8 h; NOAEL, 200 ppm for 6 h (Raleigh and McGee 1972) Explosion —a 10 1 — 1 2600 2600 2600 2600 2600 LELb, 26,000 ppm (Sax 1984) Fatigue, headache Human 10/√n 1 1 1 500 200 22 22 22 NOAEL, 100 ppm for 6 h (Stewart et al. 1975; Matsushita et al. 1969a,b) (n = 5) SMACs 500 200 22 22 22 a—, not applicable. bLEL, lower explosive limit.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 REFERENCES ATSDR. 1994. Toxicological Profile for Acetone. TP-93/01. U.S. Department of Health and Human Services, Agency for Toxic Substances and Disease Registry, Atlanta, GA. ACGIH. 1986. Acetone. Pp.6-7 in Documentation of the Threshold Limit Values and Biological Exposure Indices, 5th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1991. Guide to Occupational Exposure Values—1991. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1997. 1997 TLVs and BEIs. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. Arena, J.M., and R.H. Drew, eds. 1986. Poisoning: Toxicology, Symptoms, Treatments, 5th Ed. Springfield, IL: Charles C. Thomas. Baselt, R.C. 1982. Acetone. Pp 9-10 in Disposition of Toxic Drugs and Chemicals in Man. Davis, CA: Biomedical Publications. Baumann, K., and J. Angerer. 1979. Untersuchengen zur frage der beruflichen lösungmittelbelastung mit aceton. Verh. Dtch. Ges Arbeitmedizin. Gentner Stuttgart 20:403-408. Brown, W.D., J.V.Setzer, and R.B.Dick. 1987. Body burden profiles of single and mixed solvent exposures. J. Occup. Med. 29:877-883. Bruckner, J.V., and R.G. Peterson. 1981. Evaluation of toluene and acetone inhalant abuse. I. Pharmacology and Pharmacodynamics. Toxicol. Appl. Pharmacol. 61:27-38. Chieli, E., M. Saviozzi, P. Puccini, V. Longo, and P.G. Gervasi. 1990. Possible role of the acetone-inducible cytochrome P-450IIE1 in the metabolism and hepatotoxicity of thiobenzamide. Arch. Toxicol. 64(2):122-127. Cunningham, J., M. Sharkawi, and G.L. Plaa. 1989. Pharmacological and metabolic interactions between ethanol and methyl n-butyl ketone, methyl isobutyl ketone, methyl ethyl ketone, or acetone in mice. Fundam. Appl. Toxicol. 13:102-109. Dick, R.B., W.D. Brown J.V. Setzer, B.J. Taylor, and R. Shukla. 1988. Effects of short duration exposures to acetone and methyl ethyl ketone. Toxicol. Lett. 43:31-49. Dick, R.B., J.V. Setzer, B.J. Taylor, and R. Shukla. 1989. Neurobehavioural effects of short duration exposures to acetone and methyl ethyl ketone. Br.J. Ind. Med. 46:111-121. Dietz, D. 1991. Toxicity Studies of Acetone (CAS No.67-64-1) in F344/N Rats and B6C3F1 Mice (Drinking Water Studies). NIH Publ. No. 91-3122. National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, NC. DiVincenzo, G.D., F.J. Yanno, and B.D.Astill. 1973. Exposure of man and dog to low concentrations of acetone vapor. Am. Ind. Hyg. Assoc. J. 34:329-336. Finkel, A.J. 1983. Acetone. Pp. 210-211 in Hamilton and Hardy's Industrial Toxicology, 4th Ed. Boston: John Wright.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Freeman, J.J., and E.P. Hayes. 1985. Acetone potentiation of acute acetonitrile toxicity in rats. J. Toxicol. Environ. Health 15:609-621. Freeman, J.J., and E.P. Hayes. 1988. Microsomal metabolism of acetonitrile to cyanide. Biochem. Pharmacol. 37:1153-1159. Gamis, A.S. and G.S. Wasserman. 1988. Acute acetone intoxication in a pediatric patient. Pediat. Emer. Care 4:24-26. Geller, I., E.M. Gause, H. Kaplan, and R.J. Hartmann. 1979a. Effects of acetone, methyl ethyl ketone and methyl isobutyl ketone on a match-to-sample task in the baboon. Pharmacol. Biochem. Behav. 11:401-406. Geller, I., R.J. Hartmann, S.R. Randle, and E.M. Gause. 1979b. Effects of acetone and toluene vapors on multiple schedule performance of rats. Pharmacol. Biochem. Behav. 11:395-399. Glatt, J., L. DeBalle, and F. Oesch. 1981. Ethanol- or acetone-pretreatment of mice strongly enhances the bacterial mutagenicity of dimethylnitrosamine in assays mediated by liver subcellular fraction, but not in host-mediated assays . Carcinogenesis 2:1057-1067. Goldberg, M.E., H.E. Johnson, U.C. Pozzani, and F.H. Smyth, Jr. 1964. Effect of repeated inhalation of vapors of industrial solvents on animal behavior. Evaluation of nine solvent vapors on pole-climb performance in rats. Am. Ind. Hyg. Assoc. J. 25:369-375. Gosselin, R.E., R.P. Smith, and H.C. Hodge, eds. 1984. P. II-183 in Clinical Toxicology of Commercial Products, 5th Ed. Baltimore, MD: Williams & Wilkins. Grant, M. 1986. Acetone. Toxicology of the Eye. Springfield, IL: Charles C. Thomas. Hallier, E., J.G. Filser, and H.M. Bolt. 1981. Inhalation pharmacokinetics based on gas uptake studies. II. Pharmacokinetics of acetone in rats. Arch. Toxicol. 47:293-304. Hewitt, W.R., H. Miyajima, M.G. Coté, and G.L. Plaa. 1980. Modification of haloalkane-induced hepatotoxicity by exogenous ketones and metabolic ketosis. Fed. Proc. Fed. Am. Soc. Exp. Biol. 39:3118-3123. Inoue, R. 1983. Acetone and derivatives. Pp. 38-39 in Encyclopedia of Occupational Health and Safety, 3rd Rev. Ed., L. Parmeggiani, ed. Geneva: International Labour Organization. Israeli, R.v., Y. Zoref, Z. Tessler, and J. Braver. 1977. Reaktionszeit als Mittel zur Aceton-TLV-(MAK)-Wentbestimmung. Zentralbl. Arbeitsmed. 8:197-199. Johansson, I., and M. Ingelman-Sundberg. 1988. Benzene metabolism by ethanol-, acetone-, and benzene-inducible cytochrome P-450 (IIE1) in rat and rabbit liver microsomes. Cancer Res. 48:5837-5890. Koller, L.D. 1993. Review: Experimental Studies for Determining the Maximum Permissible Concentrations of Acetone. College of Veterinary Medicine, Oregon State University, Corvallis, OR. Krasavage, W.J., J.L. O'Donoghue. and G.D. DiVincenzo. 1982. Ketones. Pp. 4709-4727 in Patty's Industrial Hygiene and Toxicology, Vol. 2C, 3rd Rev. Ed., G.D.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Clayton and F.E. Clayton, eds. New York: John Wiley & Sons. Liebich, H.M., W. Bertsch, A. Zlatkis, and H.J. Schneider. 1975. Volatile organic components in the Skylab 4 spacecraft atmosphere. Aviat. Space Environ. Med. 46:1002-1007. Liu, J., C. Sato, and F. Marumo. 1991. Characterization of the acetominophen-glutathione conjugation reaction by liver microsomes: Species difference in the effects of acetone. Toxicol. Lett. 56:269-274. Lo, H.H., V.J. Teets, D.J. Yang, P.I. Brown, and G.O. Rankin. 1987. Acetone effects on N-(3,5-dichlorophenyl)succinamide-induced nephrotoxicity. Toxicol. Lett. 38(1-2):161-168. Löf, A., M. Nordqvist, and E. Wigaeus. 1980. Inhalation exposure of mice to acetone [abstract]. Toxicol. Lett. Special Issue 1:213. Lorr, N.A., K.W. Miller, H.R. Chung, and C.S. Yang. 1984. Potentiation of the hepatotoxicity of N-nitrosodimethylamine by fasting, diabetes, acetone, and isopropanol. Toxicol. Appl. Pharmacol. 73:423-431. Mast, T.J., R.L. Rommereim, R.J. Weigel, R.B. Westerberg, B.A. Schwetz, and R.E. Morrissey. 1989. Developmental toxicity study of acetone in mice and rats [abstract]. Teratology 39(5):468. Matsushita, T., T. Yoshea, A. Yoshimune, T. Inoue, F. Yamaka, and H. Suzuki. 1969a. Experimental studies for determining the maximum permissible concentration of acetone — 1. Biologic reactions in the one-day exposure to acetone. Jpn. J. Ind. Health 11:477-485. Matsushita, T., E. Goshima, H. Miyagaki, K. Maeda, Y. Takeuchi, and T. Inoue. 1969b. Experimental studies for determining the maximum permissible concentration of acetone — 2. Biological reaction in the six-day exposure to acetone. Jpn. J. Ind. Health 11:507-511. Mikalsen, A., J. Alexander, R.A. Andersen, and M. Ingelman-Sundberg. 1991. Effect of in vivo chromate, acetone and combined treatment on rat liver in vitro microsomal chromium(VI) reductive activity and on cytochrome P450 expression. Pharmacol. Toxicol. 68:456-463. Mirchev, N. 1977. Hepatorenal lesions after acute acetone intoxication [in Bulgarian]. Vutr. Boles 17:89-92. Moldeus, P., and V. Gergely. 1980. Effect of acetone on the activation of acetaminophen. Toxicol. Appl. Pharmacol. 53:8-13. Morris, J.B., and D.G. Cavanagh. 1987. Metabolism and deposition of propanol and acetone vapors in the upper respiratory tract of the hamster. Fundam. Appl. Toxicol. 9:34-40. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, D.C.: National Academy Press. NRC. 1984. Pp. 5-26 in Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 1. Washington, D.C.: National Academy Press. NTP. 1991. P. 15 in Toxicity Studies of Acetone in F344/N Rats and B6C3F1 Mice
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 (Drinking Water Studies). NTP Tox 3. NIH Publ. No. 91-3122. National Institute of Environmental Health Sciences, National Toxicology Program, Research Triangle Park, NC. Nelson, D.L., and B.P. Webb. 1978. Acetone. Pp. 179-191 in Kirk-Othmer Encyclopedia of Chemical Toxicology, Vol. 1, 3rd Ed., Grayson, M., ed. New York: John Wiley & Sons. Nelson, K.W., J.F. Ege, M. Ross, L.E. Woodman, and L. Silverman. 1943. Sensory response to certain industrial solvent vapors. J. Ind. Hyg. Toxicol. 25:282-285. Oglesby, F.L., J.L. Williams, and D.W. Fassett. 1949. Eighteen-year experience with acetone. Annual Meeting of the American Industrial Hygiene Association, Detroit, MI. Parmeggiani, L., and C. Sassi. 1954. Occupational poisoning with acetone—Clinical disturbances, investigations in workrooms and physiopathological research [In Italian] Med. Lav. 45:431-468. Raleigh, R.L., and W.A. McGee. 1972. Effects of short high concentration exposures to acetone as determined by observation in the work area. J. Occup. Med. 14:607-610. Ramu, A., J. Rosenbaum, and T. Blaschke. 1978. Disposition of acetone following acute acetone intoxication. West. J. Med. 129:429-432. Ross, D.S. 1973. Acute acetone intoxication involving eight male workers. Ann. Occup. Hyg. 16:73-75. Rowe, V.K., and M.A. Wolf. 1963. Ketones. Pp. 1719-1731 in Patty's Industrial Hygiene and Toxicology, Vol. 2, 2nd Rev. Ed., G.D. Clayton and F.E. Clayton, eds. New York: John Wiley & Sons. Sax, N.I. 1984. Acetone. P. 89 in Dangerous Properties of Industrial Materials, 6th Ed. New York: Van Nostrand Reinhold. Sipes, I.G., M.L. Slocumb, and G. Holtzman. 1978. Stimulation of microsomal dimethylnitrosamine-N-demethylase by pretreatment of mice with acetone. Chem. -Biol. Interact. 21:155-166. Stewart, R.D., C.L. Hake, A. Wu, S.A. Graff, H.V. Forster, W.H. Keeler, A.J. Lebrun, P.E. Newton, and R.J. Soto. 1975. Acetone: Development of a Biologic Standard for the Industrial Worker by Breath Analysis. National Institute for Occupational Safety and Health, Cincinnati, OH. Available from NTIS, Springfield, VA., Doc. No. PB82-172917. Tindberg, N., and M. Ingelman-Sundberg. 1989. Cytochrome P-450 and oxygen toxicity. Oxygen-dependent induction of ethanol-inducible cytochrome P-450 (IIE1) in rat liver and lung. Biochemistry 28:4499-4504. Vangala, R.R., M. Blaszkewicz, H.M. Bolt, K. Golka, and E. Kiesswetter. 1991. Acute experimental exposures to acetone and ethyl acetate. Arch. Toxicol. Suppl. 14:259-262. Wigaeus, E., S. Holm, and I. Åstrand. 1981. Exposure to acetone. Uptake and elimination in man. Scand. J. Work Environ. Health 7:84-94.
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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Wigaeus, E., A. Löf, and M. Nordqvist. 1982. Distribution and elimination of 2-[14C]-acetone in mice after inhalation exposure. Scand. J. Work Environ. Health 8:121-128. Windholz, M., ed. 1983. Acetone. P. 10 in The Merck Index, 10th Ed. Rahway, NJ: Merck & Co. Yoo, J.S.H., H. Ishizaki, and C.S. Yang. 1990. Roles of cytochrome-P450IIE1 in the dealkylation and denitrosation of N-nitrosodiethylamine in rat liver microsomes. Carcinogenesis 7:2239-2243.
Representative terms from entire chapter: