B12

4-Methyl-2-Pentanone

King Lit Wong, Ph.D.

Johnson Space Center Toxicology Group

Medical Operations Branch

Houston, Texas

PHYSICAL AND CHEMICAL PROPERTIES

4-Methyl-2-pentanone or methyl isobutyl Ketone (MIBK) is a clear liquid with a sweet odor (ACGIH 1991). According to a review by Amoore and Hautala (1983), the odor threshold of MIBK in air is 0.68 ppm. In a study by Dick et al. (1992), 17 human volunteers were exposed to MIBK at a concentration of 88 ppm for 4 h, and they reported a statistically significantly higher incidence of strong odor than the 8 volunteers in the control group. The odor, however, was not unpleasant (Dick et al. 1992). Other properties of MIBK are listed as follows (ACGIH 1991).

Formula:

CH3COCH2CH2(CH3)2

CAS no.:

108-10-1

Synonym:

Methyl isobutyl ketone; hexone

Molecular weight:

100.2

Boiling point:

115.8°C

Melting point:

–84.7°C

Vapor pressure:

15 torr at 25°C

Conversion factors at 25°C, 1 atm:

1 ppm = 4.09 mg/m3

 

1 mg/m3 = 0.24 ppm

OCCURRENCE AND USE

As a solvent, MIBK is used in paints, varnishes, lacquers, aircraft dopes, rubber cements, and adhesives (ACGIH 1991). It is not used per se in Spacecraft, but



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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 B12 4-Methyl-2-Pentanone King Lit Wong, Ph.D. Johnson Space Center Toxicology Group Medical Operations Branch Houston, Texas PHYSICAL AND CHEMICAL PROPERTIES 4-Methyl-2-pentanone or methyl isobutyl Ketone (MIBK) is a clear liquid with a sweet odor (ACGIH 1991). According to a review by Amoore and Hautala (1983), the odor threshold of MIBK in air is 0.68 ppm. In a study by Dick et al. (1992), 17 human volunteers were exposed to MIBK at a concentration of 88 ppm for 4 h, and they reported a statistically significantly higher incidence of strong odor than the 8 volunteers in the control group. The odor, however, was not unpleasant (Dick et al. 1992). Other properties of MIBK are listed as follows (ACGIH 1991). Formula: CH3COCH2CH2(CH3)2 CAS no.: 108-10-1 Synonym: Methyl isobutyl ketone; hexone Molecular weight: 100.2 Boiling point: 115.8°C Melting point: –84.7°C Vapor pressure: 15 torr at 25°C Conversion factors at 25°C, 1 atm: 1 ppm = 4.09 mg/m3   1 mg/m3 = 0.24 ppm OCCURRENCE AND USE As a solvent, MIBK is used in paints, varnishes, lacquers, aircraft dopes, rubber cements, and adhesives (ACGIH 1991). It is not used per se in Spacecraft, but

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 it has been found in air samples taken inside the spacecraft during some space-shuttle missions probably as a result of off-gassing (James et al. 1994). For instance, MIBK was detected at a high of 0.002 to 0.006 mg/m3 (0.0005 to 0.015 ppm) in two missions and 0.01 to 0.06 mg/m3 (0.0024 to 0.015 ppm) in another four missions (Huntoon 1990, 1991, 1992a,b,c, 1994). During a mission in 1992, MIBK was measured at a high of 0.41 mg/m3 (0.10 ppm) (Huntoon 1992d). TOXICOKINETICS AND METABOLISM Absorption MIBK vapor is absorbed relatively well in humans. Hjelm et al. (1990) measured the pulmonary retention of inhaled MIBK in eight men exposed to MIBK at 10, 100, or 200 mg/m3 (2.4, 24, or 49 ppm) for 2 h by comparing the exhaled concentration with the inhaled concentration. Regardless of the exposure concentration, about 60% of the inhaled MIBK was retained by the body. The respiratory retention rate was fairly constant during the 2-h exposure. The blood concentration of MIBK rose quite rapidly, and no plateau was reached during the 2-h exposure. Another study, however, shows that MIBK blood concentration can reach a plateau in 2 h. Dick et al. (1992) conducted a neurobehavioral study in which MIBK concentrations in the blood and the breath were measured in human volunteers exposed to MIBK at 88 ppm for 4 h. The mean concentrations in 13 men and 12 women combined are presented in Table 12-1. MIBK reached plateau concentrations in the blood and breath as early as 2 h into the exposure. MIBK absorption is not as well studied in rodents as in humans. Duguay and Plaa (1993) measured the plasma concentration of MIBK given by inhala- TABLE 12-1 Blood and Breath Concentrations in Volunteers Exposed to MIBK at 88 ppm (Dick et al. 1992)   2-h Exposure 4-h Exposure 90-min Post-Exposure 20-h Post-Exposure MIBK in blood (µg/mL) 10.6 10.5 0.2 NDa MIBK in breath (ppm) 0.6 0.6 0.1 ND a ND, below detection limit.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 tion in a study on MIBK's potentiation of the cholestatic effects of taurocholate or manganese bilirubin in rats. MIBK reached about 5, 8, or 14 µg/mL in the plasma 1 h after a 4-h exposure of rats at 200, 400, or 600 ppm. Distribution The distribution of MIBK in blood was studied by Lam et al. (1990). In rats exposed to MIBK at 512 ppm for 2 h, MIBK reached a concentration of 25.3 µg/mL in blood with 51.2% distributed to red blood cells (RBCs) and the balance in plasma immediately after the exposure. Apparently, MIBK distributed similarly in human blood because Lam et al. (1990) found that 49.4% of MIBK added to human blood in vitro at 0.8 mg/mL resided with RBCs. For human RBCs, 68% of MIBK was associated with hemoglobin. In human plasma, 80% of MIBK was associated with plasma proteins. Therefore, the majority of MIBK in human blood was associated with proteins. Metabolism Based on studies in rodents, MIBK is metabolized by either oxidation at the omega-1 carbon to form a hydroxylated ketone or reduction of the carbonyl group to form an alcohol. DiVincenzo et al. (1976) identified 4-hydroxy-4-methyl-2-pentanone and 4-methyl-2-pentanol as the MIBK metabolites in the serum of guinea pigs administered MIBK at 450 mg/kg intraperitoneally. MIBK was cleared from the serum with a half-life of 66 min in guinea pigs. The two metabolites of MIBK were not always found in MIBK-exposed rats. For instance, MIBK has been shown by Hirota (1991) to be metabolized into 4-methyl-2-pentanol in rats given MIBK intraperitoneally at 100-300 mg/kg. In contrast, Duguay and Plaa (1993) could not detect 4-methyl-2-pentanol in the plasma of rats 1 h after a 4-h inhalation exposure to MIBK at 200 ppm, but 4-hydroxy-4-methyl-2-pentanone was found at 5 µg/mL. However, both 4-hydroxy-4-methyl-2-pentanone (at about 6-7 µg/mL) and 4-methyl-2-pentanol (at about 4-5 µg/mL) were detected in the plasma of rats 1 h after a 4-h exposure to MIBK at 400 or 600 ppm (Duguay and Plaa 1993). Excretion In the eight men studied by Hjelm et al. (1990), about 0.04% of the MIBK dose was excreted in the urine as MIBK within 3 h after a 2-h inhalation

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 exposure to MIBK at 10, 100, or 200 mg/m3 (2.4, 24, or 49 ppm). The urinary concentrations of MIBK's metabolites, 4-methyl-2-pentanol and 4-hydroxy-4-methyl-2-pentanone, were below the detection limit of 5 nmol/L at 0.5 or 3 h post-exposure. The total body clearance of MIBK was 1.6 L of blood per hour per kilogram of body weight in these men (Hjelm et al. 1990). However, in another study, Hjelm et al. (1991) found that the total body clearance was 12 L of blood per hour per kilogram of body weight in guinea pigs infused with MIBK intravenously. The reason for the large difference in MIBK's total body clearance between men and guinea pigs is unknown. Hirota (1991) studied the elimination of MIBK in rats exposed intraperitoneally at 100-300 mg/kg. The major route of MIBK elimination was exhalation via the lungs, which accounted for 41% of the dose. The concentration of MIBK in the exhaled air declined with a half-life of 0.6 h after reaching a maximum at 0.5 h after the injection. Two minor routes of MIBK elimination were urinary excretion of MIBK and 4-methyl-2-pentanol. MIBK in the urine attained a maximum concentration within 3 h of the injection and then it declined with a half-life of 1.8 h. The concentration of 4-methyl-2-pentanol reached its peak within 3-6 h of the injection and then decreased with a half-life of 3.2 h. TOXICITY SUMMARY Most of what is known about MIBK's toxicity is from in vivo experimentation, but there is one report of an in vitro study. Huang et al. (1993) showed that about 45 µM of MIBK inhibited Na-K ATPase activity and the binding of dihydroalprenolol by 50% in mouse synaptosomes. Dihydroalprenolol binds to beta-adrenergic receptors, the binding of which is influenced by fluidity changes in membranes. The in vitro data suggest that MIBK can affect synaptosome membranes. However, whether the membrane effects are manifested as adverse effects in vivo is unknown. Acute and Short-Term Exposures In vivo studies demonstrated that MIBK exposures can lead to mucosal irritation, central-nervous-system (CNS) depression, renal damage, changes in hepatic weight, and death. Because negative findings in toxicity studies are as important as positive findings in the setting of exposure limits, some of the negative findings will first be discussed, followed by descriptions of positive findings. MacEwen et al. (1971) continuously exposed 4 monkeys, 8 dogs, 50

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 rats, and 40 mice to MIBK at 100 or 200 ppm at an atmospheric pressure of 725 mmHg (equivalent to 95 or 190 ppm at 760 mmHg) for 2 w. They detected no toxic signs during exposure. After the exposure, there were no changes in hematology (the red- and white-blood-cell counts, hematocrit, hemoglobin concentration) and clinical chemistry (the plasma concentrations of sodium, potassium, calcium, total phosphorus, chloride, cholesterol, total bilirubin, albumin, total protein, uric acid, creatinine, glucose, and alkaline phosphatase, as well as blood urea nitrogen) in dogs and monkeys. The exposure caused no changes in blood gases in dogs or in EEGs in monkeys. Mucosal Irritation There were four studies of MIBK's irritation properties in human volunteers, but three of them were conducted without sham-exposed controls (Hjelm et al. 1990; Dick et al. 1992; Iregren et al. 1993). Dick et al. (1992) reported a properly controlled human study in which 17 volunteers exposed to MIBK at 88 ppm for 4 h did not find the exposure objectionable. There were no significant differences in the incidence of throat irritation, lacrimation, nausea, or headache between the two groups. Dick et al. (1992) concluded that their data support the contention that the short-term exposure limit of 75 ppm proposed by the Occupational Safety and Health Administration would prevent irritation. Silverman et al. (1946) exposed 12 human subjects to various concentrations of MIBK for 15 min while diverting their thoughts from the exposure by showing them a movie; however, no sham exposure was done. MIBK exposures at concentrations higher than 200 ppm produced nose or throat irritation in the majority of the subjects. An exposure at 200 ppm resulted in eye irritation and an objectionable odor in the majority of the subjects. Most of the subjects estimated that an exposure at 100 ppm would be tolerable for 8 h. Iregren et al. (1993) exposed six men and six women to MIBK at 10 or 200 mg/m3 (2.4 or 49 ppm) for 2 h (with light exercise at 50 W in the first 1.5 h and resting in bed in the remaining 0.5 h). Unfortunately, no air-exposed controls were used. Irritation was determined by asking the subjects to give a rating in a questionnaire one time before exposure and six times during the exposure. The irritation ratings during the 49-ppm exposure were consistently higher than those in the 2.4-ppm exposure (higher by at least one arbitrary unit) (Iregren et al. 1993). However, the irritation ratings at 49 ppm were not statistically different from those at 2.4 ppm. That is because "the irritation level is fairly high already at exposure to 10 mg/m3 of MIBK" (in the first four questionnaires

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 administered during the exposure at 10 mg/m3 (2.4 ppm), the irritation ratings were higher than the pre-exposure ratings by 1.5 to 2.5 arbitrary units) (Iregren et al. 1993). The authors stated that that "finding may be interpreted as an indication of a high potential for MIBK to induce irritation already at low concentrations." However, they did not reveal the severity of the irritation represented by one arbitrary unit. In addition, the absence of a sham-exposed control group makes the interpretation of the data of Iregren et al. (1993) difficult. Another human study with no control exposure was conducted by Hjelm et al. (1990), who reported that nose and throat irritation were the most common symptoms. Three of eight men exposed to MIBK at 100 or 200 mg/m3 (24 or 49 ppm) for 2 h during light exercise experienced nose and throat irritation, and one of eight experienced the irritation at 10 mg/m3 (2.4 ppm) (Hjelm et al. 1990). Based on the ordinal data, no clear concentration-response relationship was seen. The subjects rated the irritation from 0 to 5 and gave an average rating of about 0.2, 0.4, or 0.3 at 20-50 min into the 2-h exposure to MIBK at 2.4, 24, or 49 ppm, respectively. Hjelm et al. (1990) did not reveal the qualitative equivalents of the numerical scores (e.g., whether a score of 1 represented mild irritation), so the severity of the irritation reported during MIBK exposure in the responsive men is unknown. More important, no sham-exposed control group was used by Hjelm et al. (1990). The same test subjects were exposed to MIBK at three concentrations on different days after having been informed of the maximum exposure concentration. Even though they did not know of the sequence of the exposure, the fact that they were aware that each 2-h exposure involved MIBK could create a bias in their reporting symptoms. In addition to humans, laboratory animals can exhibit irritation signs when exposed to MIBK. McOmie and Anderson (1946) reported that all mice exposed to MIBK at 43-100 g/m3 (10,300-24,000 ppm) exhibited signs of mucosal irritation, such as nose pawing, eye closing, the ruffling of fur, and the humping of back. According to de Ceaurriz et al. (1981), MIBK is a sensory irritant because a 5-min exposure at 3200 ppm was irritating in mice, reducing the respiratory rate by 50%. In guinea pigs exposed to MIBK at 10,000-28,000 ppm by Specht (1938), the animals squinted and rubbed their eyes and noses violently, indicating severe mucosal irritation in 1 min. Specht saw salivation after 2 min. The respiratory rate fell to 35/min after 25 min of exposure and the guinea pigs later died (Specht 1938). Finally, Phillips et al. (1987) exposed rats and mice to MIBK at 0, 100, 500, or 2000 ppm, 6 h/d, 5 d/w for 2 w. They observed lacrimation in rats and mice exposed to 2000 ppm. MIBK's acute exposures at lower concentrations are not known to produce overt irritation in laboratory animals. In the 2-w study performed by Phillips

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 et al. (1987), no lacrimation was detected in rats and mice exposed to MIBK at 500 or 100 ppm. MacEwen et al. (1971) continuously exposed 4 monkeys, 8 dogs, 50 rats, and 40 mice at either 200 or 100 ppm at 725 mmHg, which was equivalent to 190 or 95 ppm, respectively, at 760 mmHg for 2 w. They monitored for any toxic sign and mortality during the exposure but failed to detect any, indicating the absence of overt mucosal irritation. CNS Effects and Death Three studies of the effects of MIBK on the CNS in humans were found (Hjelm et al 1990; Dick et al. 1992; Iregren et al. 1993). The overall conclusion from these three studies is that MIBK has no detrimental CNS effects for acute exposures at concentrations up to 88 ppm. A properly controlled study was conducted by Dick et al. (1992), who reported that during a 4-h exposure of 10 men and 7 women to MIBK at 88 ppm, there were no significant changes in the choice reaction time, simple reaction time, ability to simultaneously perform an auditory tone discrimination task together with a compensatory visual tracking task, memory scanning, postural steadiness, and mood states after 45 min or 2.75 h of exposure. The exposure also did not change the average score in visual vigilance. However, the performance of female volunteers in the visual vigilance test was positively correlated with the MIBK concentrations in blood (Dick et al. 1992). That means women with higher MIBK concentrations in blood performed better than women with lower MIBK concentrations, so it was not an adverse effect. Iregren et al. (1993) exposed six men and six women to MIBK at 10 or 200 mg/m3 (2.4 or 49 ppm) for 2 h (with light exercise at 50 W in the first 1.5 h and resting in bed in the remaining 0.5 h), but no air-exposed controls were used. During the exposure at 49 ppm, significantly more complaints of fatigue and other unnamed CNS symptoms were recorded than during the exposure at 2.4 ppm. However, there were no differences in simple reaction time and the ability to add between the 49- and the 2.4-ppm groups. In a study without a sham-exposed control group, Hjelm et al. (1990) reported that a 2-h exposure at 10, 100, or 200 mg/m3 (2.4, 24, or 49 ppm) had no effects on mood, reaction time, and ability to do addition in eight men. However, an exposure at 24 or 49 ppm resulted in headache and vertigo in two of the eight subjects, and 2.4 ppm caused vertigo but no headache in one subject. Because the test subjects knew that they would be exposed to MIBK, these isolated cases of headache and vertigo could be a result of their subjective bias toward chemical exposures.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Geller et al. (1979a) reported MIBK's effect on the discrimination behavior of juvenile male baboons. Four baboons were continuously exposed to MIBK at 50 ppm for 1 w. Except for the fourth and fifth day, a panel with three levers was presented to each of the baboons for 2 h everyday. A visual stimulus was presented periodically and a banana pellet would be rewarded if the baboon pressed the correct lever by matching the stimulus. The exposure did not affect the accuracy of discrimination (i.e., the percentage of correct matches) (Geller et al. 1979a,b). However, the mean response time was increased in one of the four baboons on the first and second days and in all four baboons on the third, sixth, and seventh days of exposure at 50 ppm (Geller et al. 1979a). The authors theorized that this "effect could be an early manifestation of the incoordination and narcosis which are observed at much higher concentrations." De Ceaurriz et al. (1983, 1984) performed a series of experiments using the "behavioral despair" swimming test with industrial solvents. The test consisted of exposing groups of 10 mice to air or one of four concentrations of a solvent for 4 h. Every 5 min, one of the mice was placed in 10-cm deep water for about 30 min. In such a situation, mice tend to exhibit two types of behavior: an escape-directed behavior of intense swimming in the first 2 min and a continuous immobile posture after the first 2 min (de Ceaurriz et al. 1983). De Ceaurriz et al. (1983, 1984) found that industrial solvent vapors reduced the duration of immobility in the first 3 min. At 662 ppm, the immobility duration was reduced by 25% (de Ceaurriz et al. 1983). It took 803 ppm to halve the immobility duration (de Ceaurriz et al. 1983). The authors believed that such a reduction was an extension of the initial escape behavior of mice in water, but they admitted that more studies were needed to elucidate the meaning of the reduction of immobility (de Ceaurriz et al. 1983; de Ceaurriz et al. 1984). Garcia et al. (1978) studied the behavioral effects of MIBK exposure in rats. Hungry rats were trained to press a lever to obtain food. A paired t test with the data presented by Garcia et al. (1978) shows that a 3-h exposure of these rats at 25 ppm did not cause any significant change in the number of times the lever was pressed per minute at a p<0.05 level. McOmie and Anderson (1949) exposed mice to MIBK vapors at various high concentrations and observed the mice for the loss of righting reflex (as a determination of anesthesia), and death. Some of their data, including the mortality ratios, are summarized in Table 12-2. Phillips et al. (1987) performed a 2-w study with rats and mice exposed to MIBK at 0, 100, 500, or 2000 ppm, 6 h/d, 5 d/w. There were no deaths in the exposure groups, but they observed isolated incidences of lethargy in rats and mice in the 2000-ppm group.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 12-2 Effects of Acute MIBK Exposures at High Concentrations on Mice (McOmie and Anderson 1949) MIBK Concentration Exposure Duration, h Ratioa Mortality Ratiob g/m3 ppm 100 24,000 0.25 0:10 0:10 86 20,600 1.00 22:22 21:22 82 19,500 1.25 10:10 5:10 82 19,500 0.50 30:33 18:33 63 15,000 6.00 0:6 0:6 43 10,300 5.00 0:8 0:8 a Number of mice without righting reflex and number of mice exposed. b Pulmonary congestion, hemorrhages, and pneumonia were found in dead mice. Renal Effects In the study by MacEwen et al. (1971) in which monkeys, dogs, rats, and mice of unspecified sex were continuously exposed to MIBK at 95 or 190 ppm for 2 w, there were no changes in the organ-weight-to-body-weight ratio for heart, lung, and spleen in rats. However, the ratio was raised for kidneys in rats exposed to MIBK at 95 or 190 ppm. The only histological change in the exposed monkeys, dogs, rats, and mice was toxic nephrosis (i.e., hyaline-droplet nephrosis) in the proximal tubules of rats exposed to MIBK at 95 or 190 ppm. Phillips et al. (1987) also conducted a 2-w exposure with MIBK. Rats and mice were exposed for 6 h/d, 5 d/w for 2 w at 0, 100, 500, or 2000 ppm. There were no exposure-related changes in body weight. The kidney-weight-to-body-weight ratio was increased in male rats in the 2000-ppm group, but it was not changed in other groups. Phillips et al. (1987) detected an increased incidence of hyaline droplets and epithelial regeneration in proximal tubular cells in only the male rats exposed to MIBK at 2000 ppm. Hepatic Effect In rats exposed continuously to MIBK at 95 or 190 ppm for 2 w, the liver-weight-to-body-weight ratio was increased in rats exposed to MIBK at 190 ppm (MacEwen et al. 1971). Similarly, in the 2-w study performed by Phillips et al.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 (1987), the liver-weight-to-body-weight ratio was raised in both female and male rats exposed to MIBK at 2000 ppm, 6 h/d, 5 d/w for 2 w. It was also increased in male rats exposed to MIBK at 500 ppm (Phillips et al. 1987). No hepatic histopathological change was detected by either MacEwen et al. (1971) or Phillips et al. (1987) in the exposed rats. Subchronic and Chronic Exposures Long-term MIBK exposures have been shown to cause toxic effects similar to those in acute exposures. For instance, renal and hepatic effects are known to be produced in long-term MIBK exposures. However, hypercholesterolemia has also been reported in long-term MIBK exposures, but it has never been found in short-term studies. Hypercholesterolemia Phillips et al. (1987) exposed rats and mice to MIBK at 0, 50, 250, or 1000 ppm, 6 h/d, 5 d/w for 14 w. According to the authors, there were no exposure-related hematological effects. Regarding serum chemistry, serum cholesterol increased 35% and 23% in the male rats of the 1000-ppm and the 250-ppm groups, respectively. There were, however, no MIBK-related changes in the serum concentrations of sodium, potassium, total calcium, glucose, total protein, and albumin. Hypercholesterolemia is not detected in another long-term MIBK study. MacEwen et al. (1971) performed a subchronic study with male laboratory animals (100 rats, 8 dogs, and 2 monkeys per group). The animals were exposed to air or MIBK at 410 mg/m3 at an atmospheric pressure of 5 psi with 68% oxygen and 32% nitrogen for 90 d. The MIBK exposure concentration was equivalent to 100 ppm at an atmospheric pressure of 14.7 psi or 760 mmHg. The exposure did not significantly change the hematology (the red-and white-blood-cell counts, hematocrit, and hemoglobin concentration) and clinical chemistry (the plasma concentrations of sodium, potassium, calcium, total phosphorus, chloride, cholesterol, total bilirubin, albumin, total protein, uric acid, creatinine, glucose, and alkaline phosphatase; the serum acid phosphatase and serum glucuronidase activities; as well as blood urea nitrogen) in dogs and monkeys. In the 90-d exposure of male rats, there were no differences in body growth between the exposed and control rats (MacEwen et al. 1971).

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Renal Effects In the study of male laboratory animals conducted by MacEwen et al. (1971), the 90-d continuous exposure to MIBK at 100 ppm equivalent caused no changes in organ-weight-to-body-weight ratios for organs of male rats except that the liver- and kidney-weight-to-body-weight ratios were raised. The exposure also produced no histopathological changes in male rats except for hyaline-droplet degeneration of the proximal tubules. Similarly, in the 14-w exposure of rats and mice to MIBK at 0, 50, 250, or 1000 ppm for 6 h/d, 5 d/w, Phillips et al. (1987) reported that the only histopathological change was the presence of hyaline droplets in the kidney of male rats exposed to MIBK at 1000 or 250 ppm. The urinary excretion of glucose was increased in male rats exposed to MIBK at 1000 or 250 ppm by 55% or 37%, respectively. For some unknown reason, glucose urinary excretion also was increased 26% in female mice exposed to MIBK at 1000 ppm. The total protein urinary excretion was increased only in male rats exposed to MIBK at 1000 ppm. However, there were no exposure-related changes in the serum concentrations of creatinine and urea nitrogen. Hepatic Effects Chen et al. (1991) studied the liver function of 180 workers exposed to a mixture of solvents in paint manufacturing or spraying. The mean time-weighted-average concentrations of the solvents were the following: MIBK at 10 ppm, xylene at 75 ppm, toluene at 72 ppm, acetone at 24 ppm, benzene at 4 ppm, methyl ethyl ketone at 9 ppm, ethyl acetate at 4 ppm, and butyl acetate at 7 ppm. Chen et al. (1991) separated the workers into three groups based on the sum of the ratios of the exposure concentration of each compound versus its Threshold Limit Value (TLV). The low-exposure group had a sum of 0 to 0.38. The short-term high-exposure group also had a sum of 0 to 0.38, but the group members spent 30-90 min per day in a poorly ventilated painting booth exposed to MIBK at 115 ppm, toluene at 391 ppm, xylene at 192 ppm, ethyl acetate at 165 ppm, benzene at 40 ppm, and butyl acetate at 81 ppm. The long-term high-exposure group had a sum of 0.25 to 9.83. Chen et al. (1991) reported that the serum activities of gamma-glutamyl transferase were higher in the short-term and long-term high-exposure groups than in the low-exposure group. However, the serum activities of aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase, as well as the serum concentration of bile acid did not change with the exposure concentrations. Because the

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 weight-to-body-weight ratio. Fetotoxicity was seen in the mice exposed to MIBK at 3000 ppm, as evidenced by decreased fetal body weight per litter, reduced skeletal ossification, and increased fetal deaths. There was no fetotoxicity in other groups of exposed animals. No embryotoxicity or fetal malformations were detected in any exposure groups. Interaction with Other Chemicals Abou-Donia et al. (1985) demonstrated that MIBK inhalation potentiated the neurotoxicity of n-hexane. In chickens exposed to n-hexane at 1000 ppm together with MIBK at 10-1000 ppm for 29 d, Lapadula et al. (1991) showed that "MIBK selectively induced cytochrome P-450 isozymes leading to the metabolic activation" of n-hexane. Cytochrome P-450 content and benzphetamine N-demethylase activity increased with increasing MIBK exposure concentration. Table 12-3 presents a summary of the inhalation toxicity data on MIBK.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 12-3 Toxicity Summary of Inhalation Studies Concentration, ppm Exposure Duration Species Effects Reference 24 or 49 2 h Human (light exercise) Nose and throat irritation; no effects on mood, reaction time, and ability to add Iregren et al. 1993 49 2 h Human (light exercise) Higher rating for irritation than 2.4 ppm; more complaints of fatigue than 2.4 ppm Iregren et al. 1993 88 4 h Human Strong odor; no irritation, nausea, headache, or CNS effects Dick et al. 1992 200 15 min Human Eye irritation and objectionable odor Silverman et al. 1946 25 3 h Rat No effect on the number of times a lever was pressed to get food Garcia et al. 1978 50 24 h/d, 7 d/w for 1 w Baboon No effect on accuracy of discrimination; increased response time on the 3rd, 6th, and 7th d Geller et al. 1979a 95 or 190 24 h/d, 7 d/w for 2 w Monkey, dog, rat, and mouse No toxic signs; no change in hematology and clinical chemistry; raised relative kidney weight and liver weight; toxic nephrosis in rats; normal clearance of bromosulphthalein MacEwen et al. 1971 100 equivalent 24 h/d for 90 d Monkey (n=2), dog, and rat (all male) No significant changes in hematology and clinical chemistry Increased ratios of liver weight/body weight and kidney weight/body weight; hyaline droplet degeneration of proximal tubules in rats MacEwen et al. 1971 500 6 h/d, 5 d/w for 2 w Rat, mouse No lacrimation of changes in body weight Phillips et al. 1987 662 or 803 4 h Mouse Reduction in duration of immobility during first 3 min of swimming De Ceaurriz et al. 1983

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Concentration, ppm Exposure Duration Species Effects Reference 1000 6 h/d, 5 d/w for 14 w Rat, mouse Male rats: Increased serum cholesterol; hyalin droplets in kidneys; increased urinary glucose and protein; normal serum concentrations of alkaline phosphatase, aspartate aminotransaminase, lactate dehydrogenase, and bilirubin; normal liver histology Phillips et al. 1987       Female rats: decreased eosinophils   1000-28000 5 h Rat Signs of mucosal irritation in 1 min; salivation in 2 min; death in 85 min to 5 h; loss of auditory and corneal reflexes Specht 1938 2000 6 h/d, 5 d/w for 2 w Rat, mouse Lacrimation; no change in growth; increased relative kidney weight; hyalin droplets and epithelial regeneration in proximal tubular cells in male rats Phillips et al. 1987 3200 5 min Mouse Mucosal irritation (the respiratory rate declined 50%) De Ceaurriz et al. 1983 10,300-24,000 0.25 to 22.6 h Mouse Signs of mucosal irritation; some deaths at 19,500 ppm or higher McOmie and Anderson 1949

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RATIONALE FOR ACCEPTABLE CONCENTRATIONS Table 12-4 presents exposure limits for MIBK set by other organizations and Table 12-5 presents the SMACs established by NASA. The SMACs are derived with the assistance of guidelines from the Committee of Toxicology, National Research Council (NRC 1992). Briefly, the procedure involves an identification of pertinent toxic end points for MIBK. For each toxic end point, an acceptable concentration (AC) is derived for each exposure duration of interest (i.e., 1 h, 24 h, 7 d, 30 d, and 180 d). The lowest AC for an exposure duration of interest is selected as the SMAC for that duration (Table 12-6). The toxic end points chosen for AC derivation are mucosal irritation and CNS depression. Hypercholesterolemia reported by Phillips et al. (1987) in rats exposed to MIBK at 250 or 1000 ppm, 6 h/d, 5 d/w for 14 w, is not included in AC derivation because the 23-35% increases in serum cholesterol are not considered TABLE 12-4 Exposure Limits Set by Other Organizations Organization Exposure Limit, ppm Reference ACGIH's TLV 50 (TWA) ACGIH 1991a ACGIH's STEL 75 ACGIH 1991a OSHA's PEL 50 (TWA) ACGIH 1991b NIOSH's REL 50 (TWA) ACGIH 1991b TLV, Theshold Limit Value; TWA, time-weighted average; STEL, short-term exposure limit; PEL, permissible exposure limit; REL, recommended exposure limit. TABLE 12-5 Spacecraft Maximum Allowable Concentrations Duration Concentration, ppm Concentration, mg/m3 Target Toxicity 1 h 35 143 CNS depression 24 h 35 143 CNS depression 7 da 35 143 Irritation, CNS depression 30 d 35 143 Irritation, CNS depression 180 d 35 143 Irritation, CNS depression a Current 7-d SMAC is 20 ppm.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 clinically important. It should also be noted that MacEwen et al. (1971) failed to find hypercholesterolemia in rats, dogs, and monkeys exposed continuously to MIBK at a concentration equivalent to 100 ppm for 90 d. According to MacEwen et al. (1971) and Phillips et al. (1987), continuous or repetitive MIBK exposures have been shown to lead to an increased liver-weight-to-body-weight ratio in rats. The histology of the liver, however, was normal in these animals. The increased relative liver weight was probably an adaptive change rather than an adverse effect. Lapadula et al. (1991) showed that MIBK is an inducer of cytochrome P-450 isozymes in chicken. Phillips et al. (1987) theorized that the increased relative liver weight might be a response to an increased metabolic load on the liver. Therefore, no ACs are established for the hepatic effects of MIBK. The investigations by MacEwen et al. and Phillips et al. showed that continuous or repetitive MIBK exposures could increase the incidence of hyalin droplet degeneration in proximal tubules in the kidney of male rats (MacEwen et al. 1971; Phillips et al. 1987). Similar lesions, which were thought to be due to α-2-µ-globulin found only in rats, have been demonstrated in male rats exposed to other hydrocarbons (NRC 1992). This type of lesions in male rats is not considered a good model for humans (Alden 1986; NRC 1992). As a result, it is not used as a toxic end point in AC derivation. Mucosal Irritation Silverman et al. (1946) reported that a 15-min exposure to MIBK at 200 ppm produced nose or throat irritation in the majority of 12 human volunteers. Dick et al. (1992) showed that a 4-h exposure to MIBK at 88 ppm was not irritating to 17 human subjects. The ACs for mucosal irritation are derived without any time adjustment, because mucosal irritation is not believed to be time dependent. Because less than 100 human subjects were used in the study of Dick et al. (1992), an adjustment for the small number of test subjects is done in setting the long-term ACs in order to prevent mucosal irritation. However, no such adjustment is needed for 1-h and 24-h ACs, because a small degree of irritation is acceptable in contingencies. 1-h and 24-h ACs for mucosal irritation = 4-h NOAEL = 88 ppm (rounded up to 90 ppm)

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 7-d, 30-d, and 180-d ACs for mucosal irritation = 4-h NOAEL × 1/small "n" factor = 88 ppm × (square root of "n")/10 = 88 ppm × (square root of 17)/10 = 35 ppm. CNS Depression The studies of McOmie and Anderson (1949), Specht (1938), and Phillips et al. (1987) found that MIBK exposures at >1000 ppm could result in the loss of reflexes or lethargy in rats or mice. Dick et al. (1992), however, showed that a 45-min or 2.75-h exposure to MIBK at 88 ppm produced no CNS impairment in 17 human subjects. Because 88 ppm is a NOAEL for 45 min or 2.75 h, it should also be a NOAEL for a 1-h exposure. The CNS depressive effects of organic solvents are believed to be dependent on the CNS concentration of the chemical, which is directly dependent on the blood concentration. Because Dick et al. (1992) showed that the blood concentration of MIBK reached equilibrium as early as 2 h into the 4-h exposure in humans, the NOAEL of 88 ppm can be used to derive the ACs for 24 h and beyond. 1-h, 24-h, 7-d, 30-d, and 180-d ACs for CNS depression = 2.75-h NOAEL × 1/small "n" factor = 88 ppm × (square root of "n")/10 = 88 ppm × (square root of 17)/10 = 35 ppm. Establishment of SMAC Values The ACs for CNS depression and mucosal irritation are tabulated below. The 1-h, 24-h, 7-d, 30-d, and 180-d SMACs are all set at 35 ppm. Because these toxic end points are not expected to be potentiated by physiological changes induced by microgravity, no adjustments are needed for these SMACs.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 TABLE 12-6 Acceptable Concentrations End Point, Exposure Data, Reference   Uncertainty Factors Acceptable Concentrations, ppm Species Time Species Small n 1 h 24 h 7 d 30 d 180 d Mucosal irritation Human — — 10/(Sq. Rt. 17) 90 90 35 35 35 NOAEL, 88 ppm for 4 h (Dick et al. 1992)   CNS Depresion Human — — 10/(Sq. Rt. 17) 35 35 35 35 35 NOAEL, 88 ppm for 2.75 h (Dick et al. 1992)   SMACs         35 35 35 35 35 —, not applicable.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 RECOMMENDATIONS The excess cancer deaths found by Capurro in residents around a chemical plant exposed to MIBK and other compounds suggest that the carcinogenicity of MIBK needs to be studied further. More epidemiological studies and a chronic animal bioassay should be conducted. REFERENCES Abou-Donia, M.B., D.M. Lapadula, G. Campbell, and P.R. Timmons. 1985. The synergism of n-hexane-induced neurotoxicity by methyl isobutyl ketone following subchronic (90 days) inhalation in hens: Induction of hepatic microsomal cytochrome P-450. Toxicol. Appl. Pharmacol. 81:1-16. ACGIH. 1991a. Methylisobutylketone. Pp. 1019-1021 in Documentation of the Threshold Limit Values and Biologic Exposure Indices , Vol. 2, 6th Ed. American Conference of Governmental Industrial Hygienists, Cincinnati, OH. ACGIH. 1991b. P. 74 in Guide to Occupational Exposure Values–1991. American Conference of Industrial Hygienists, Cincinnati, OH. Alden, C.L. 1986. A review of unique male rat hydrocarbon nephropathy. Toxicol. Pathol. 14:109-111. 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. Capurro, P.U. 1979. Cancer in a community subject to air pollution by solvent vapors. Clin. Toxicol. 14:285-294. Chen, J.-D., J.-D. Wang, J.-P. Jang, and Y.-Y. Chen. 1991. Exposure to mixtures of solvents among paint workers and biochemical alterations of liver function. Br. J. Ind. Med. 48:696-701. de Ceaurriz, J., P. Desiles, P. Bonnet, B. Marignac, J. Muller, and J.P. Guenier. 1983. Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents. Toxicol. Appl. Pharmacol. 67:383-389. de Ceaurritz, J., C. Micillino, P. Bonnet, and J.P. Guenier. 1981. Sensory irritation caused by various industrial airborne chemicals. Toxicol. Lett. 9:137-143. de Ceaurriz, J., C. Micillino, P. Bonnet, B. Marignac, J. Muller, and J.P. Guenier. 1984. Qualitative evaluation of sensory irritating and neurobehavioral properties of aliphatic ketones in mice. Food Chem. Toxicol. 22:545-549. Dick, R.B., E.F. Krieg, Jr., J. Setzer, and B. Taylor. 1992. Neurobehavioral effects from acute exposures to methyl isobutyl ketone and methyl ethyl ketone. Fundam. Appl. Toxicol. 19:453-473. DiVincenzo, G.D., C.J. Kaplan, and J. Dedinas. 1976. Characterization of the metabo-

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 lites of methyl n-butyl ketone, methyl iso-butyl ketone, and methyl ethyl ketone in guinea pig serum and their clearance. Toxicol. Appl. Pharmacol. 36:511-522. Duguay, A.B., and G.L. Plaa. 1993. Plasma concentrations in methyl isobutyl ketone-potentiated experimental chloestasis after inhalation or oral administration. Fundam. Appl. Toxicol. 21:222-227. Gad, S., and C.S. Weil. 1988. Statistics and Experimental Design for Toxicologists. Caldwell, NJ: Telford Press. Garcia, C.R., I. Geller, and H.L. Kaplan. 1978. Effects of ketones on lever-pressing behavior of rats. Proc. West. Pharmacol. Soc. 21:433-438. Geller, I., E. Gause, R.J. Hartmann, and H. Kaplan. 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., E. Gause, R.J. Hartmann, and J. Seifer. 1979b. Use of discrimination behavior for the evaluation of toxicants. Neurobehav. Toxicol. Suppl. 1:9-13. Hirota, N. 1991. The metabolism of methyl isobutyl ketone and its biological monitoring. Part 1. Qualitative and quantitative studies of methyl isobutyl ketone exhaled from the lungs and excreted in the urine, and the metabolites in the urine of rats injected with methyl isobutyl ketone. Okayama Igakkai Zasshi 103:315-325. Hjelm, E.W., A. Boman, P. Fernstrom, M. Hagberg, and G. Johanson. 1991. Percutaneous uptake and kinetics of methyl isobutyl ketone (MIBK) in the guinea pig. Toxicol. Lett. 56:79-86. Hjelm, E.W., M. Hagberg, A. Iregen, and A. Lof. 1990. Exposure to methyl butyl ketone: Toxicokinetics and occurrence of irritative and CNS symptoms in man. Int. Arch. Occup. Environ. Health 62:19-26. Huang, J., H. Tanii, T. Ohyashiki, and K. Hashimoto. 1993. Structure-toxicity relationship of monoketones: In vitro effects on beta-adrenergic receptor binding and Na+, K+-ATPase activity in mouse synaptosomes. Neurotoxicol. Teratol. 15:345-352. Huntoon, C.L. 1990. Toxicological Analysis of STS-32 Atmosphere. Memorandum No. SD4/90-111. National Aeronautics and Space Administration, Johnson Space Center, Houston, TX. Huntoon, C.L. 1991. Toxicological Analysis of STS-40 Atmosphere. Memorandum No. SD4/91-362. National Aeronautics and Space Administration, Johnson Space Center, Houston, TX. Huntoon, C.L. 1992a. Toxicological Analysis of STS-42 Atmosphere. Memorandum No. SD4/92-165. National Aeronautics and Space Administration, Johnson Space Center. Houston, TX. Huntoon, C.L. 1992b. Toxicological Analysis of STS-45 Atmosphere. Memorandum No. SD4/92-259. National Aeronautics and Space Administration, Johnson Space Center. Houston, TX. Huntoon, C.L. 1992c. Toxicological Analysis of STS-49 Atmosphere. Memorandum No. SD4/92-260. National Aeronautics and Space Administration, Johnson Space Center. Houston, TX.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 Huntoon, C.L. 1992d. Toxicological Analysis of STS-50 Atmosphere. Memorandum No. SD4/92-316. National Aeronautics and Space Administration, Johnson Space Center. Houston, TX. Huntoon, C.L. 1994. Toxicological Analysis of STS-58 Atmosphere. Memorandum No. SD4/94-001. National Aeronautics and Space Administration, Johnson Space Center. Houston, TX. Iregren, A., M. Tesarz, and E. Wigaeus-Hjelm. 1993. Human experimental MIBK exposure: Effects on heart rate, performance, and symptoms. Environ. Res. 63:101-108. James, J.T., T.F. Limero, H.J. Leaño, 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. Lam, C.-W., T.J. Galen, J.F. Boyd, and D.L. Pierson. 1990. Mechanism of transport and distribution of organic solvents in blood. Toxicol. Appl. Pharmacol. 104:117-129. Lapadula, D.M., C. Habig, R.P. Gupta, and M.B. Adou-Donia. 1991. Induction of cytochrome P-450 isozymes by simultaneous inhalation exposure of hens to n-hexane and methyl iso-butyl ketone (MIBK). Biochem. Pharmacol. 41:877-883. MacEwen, J.D., E.H. Vernot, and C.C. Haun. 1971. Pp. 1-23 in Effect of 90-Day Continuous Exposure to Methylisobutylketone on Dogs, Monkeys and Rats. Report No. AMRL-TR-71-65. Armstrong Medical Research Laboratory, Aerospace Medical Division, Air Force Systems Command, Wright-Patterson Air Force, OH. McOmie, W.A., and H.H. Anderson. 1949. Comparative toxicologic effects of some isobutyl carbinols and ketones. Univ. Calif. Berkley Pub. Pharmacol. 2:217-230. Microbiological Associates. 1984a. Salmonella/Mammalian Microsome Preincubation Mutagenicity Assay. EPA/OTS document No. 40-8444072. Report prepared for the Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. Microbiological Associates. 1984b. Unscheduled DNA Synthesis in Rat Primary Hepatocytes. EPA/OTS Doc. No. 40-8444072. Report prepared for the Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. Microbiological Associates. 1984c. Activity of MethylIsobutylKetone (T1827) in the Micronucleus Cytogenicity Assay in Mice. Report No. EPA/OTS Document No. 40-8444072. Report prepared for the Office of Toxic Substances, U.S. Environmental Protection Agency, Washington DC. NRC. 1992. Guidelines for Developing Spacecraft Maximum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. O'Donoghue, J.L., S.R. Haworth, R.D. Curren, P.E. Kirby, T. Lawlor, E.J. Moran, R.D. Phillips, D.L. Putnam, A.M. Rogers-Back, and R.S. Slesinski. 1988. Mutagenicity studies on ketone solvents: Methyl ethylketone, methyl isobutyl ketone, and isophorone. Mutat. Res. 189:357-362. Phillips, R.D., E.J. Moran, D.E. Dodd, E.H. Fowler, C.D. Kary, and J. O'Donoghue.

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Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants: Volume 4 1987. A 14-week vapor inhalation toxicity study of methyl isobutyl ketone. Fundam. Appl. Toxicol. 9:380-388. Silverman, L., H.F. Schulte, and M.W. First. 1946. Further studies on sensory response to certain industrial solvent vapors. J. Ind. Hyg. Toxocol. 28:262-266. Souza, V., and M. Puig. 1987. Cytogenic study of a group of workers exposed to thinner. Mutat. Res. 189:357-362. Specht, H. 1938. Acute response of guinea pigs to inhalation of methyl isobutyl ketone. Public Health Rep. 53:292-300. Swenberg, J.A., B. Short, S. Borghoff, J. Strasser, and M. Charbonneau. 1989. The comparative pathobiology of α-2µ-globulin nephropathy. Toxicol. Appl. Pharmacol. 97:35-46. Tyl, R.W., K.A. France, L.C. Fisher, I.M. Pritts, T.R. Tyler, R.D. Phillips, and E.J. Moran. 1987. Developmental toxicity evaluation of inhaled methyl isobutyl ketone in Fischer 344 rats and CD-1 mice. Fundam. Appl. Toxicol. 8:310-327.