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5
Methyl Ethyl Ketone

Héctor D. García, Ph.D.

Toxicology Group

Habitability and Environmental Factors Division

Johnson Space Center

National Aeronautics and Space Administration

Houston, Texas


NASA previously established spacecraft maximum allowable concentrations (SMACs) for methyl ethyl ketone (MEK) vapors in spacecraft air in Volume 2 of the series Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (Wong 1996). This document establishes spacecraft water exposure guidelines (SWEGs) for MEK in spacecraft potable water.

PHYSICAL AND CHEMICAL PROPERTIES

MEK is a clear, colorless, volatile, flammable liquid with excellent solvent properties and an aroma that has been variously described as mild, fragrant, sharp, irritating, minty, acetone-like, sweet, and unpleasant (odor threshold = 16 parts per million [ppm], but a wide range of values have been reported) (Table 5-1). It forms explosive mixtures with air or oxygen at concentrations between 1.4% and 11.4%.

OCCURRENCE AND USE

MEK is a widely used solvent. It is used in the manufacture of paints, paint removers, lacquers, varnishes, glues, resins, rubbers, plastics, cellulose acetate, nitrocellulose, and artificial leather. MEK is a naturally occurring human metabolite, is present naturally in foods across all food groups, and is produced by microbes, algae, plants, and other organisms. The fragrance industry uses it at recommended concentrations up to 270 ppm in food flavorings for banana, white bread, carrot, cheddar and Swiss cheese, coffee, cream, dairy,



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5 Methyl Ethyl Ketone Héctor D. García, Ph.D. Toxicology Group Habitability and Environmental Factors Division Johnson Space Center National Aeronautics and Space Administration Houston, Texas NASA previously established spacecraft maximum allowable concentra- tions (SMACs) for methyl ethyl ketone (MEK) vapors in spacecraft air in Vol- ume 2 of the series Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants (Wong 1996). This document establishes spacecraft water exposure guidelines (SWEGs) for MEK in spacecraft potable water. PHYSICAL AND CHEMICAL PROPERTIES MEK is a clear, colorless, volatile, flammable liquid with excellent solvent properties and an aroma that has been variously described as mild, fragrant, sharp, irritating, minty, acetone-like, sweet, and unpleasant (odor threshold = 16 parts per million [ppm], but a wide range of values have been reported) (Table 5-1). It forms explosive mixtures with air or oxygen at concentrations between 1.4% and 11.4%. OCCURRENCE AND USE MEK is a widely used solvent. It is used in the manufacture of paints, paint removers, lacquers, varnishes, glues, resins, rubbers, plastics, cellulose acetate, nitrocellulose, and artificial leather. MEK is a naturally occurring hu- man metabolite, is present naturally in foods across all food groups, and is pro- duced by microbes, algae, plants, and other organisms. The fragrance industry uses it at recommended concentrations up to 270 ppm in food flavorings for banana, white bread, carrot, cheddar and Swiss cheese, coffee, cream, dairy, 147

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148 Spacecraft Water Exposure Guidelines TABLE 5-1 Physical and Chemical Properties of MEK C4H8O Formula Chemical name Methyl ethyl ketone Synonyms MEK, 2-butanone, methyl acetone, ethyl methyl ketone, methyl propanone CAS no. 78-93-3 O Molecular weight 72.1 C Boiling point 79.6°C CH2CH3 H3C Melting point –86.3°C 0.805 g/cm3 at 20°C Liquid density (15°C) Vapor pressure (at 20°C) 77.5 mm Hg Vapor pressure (at 25°C) 90.7 mm Hg Vapor density 2.00 Solubility Soluble in water, ether, acetone, benzene 1 ppm = 2.94 mg/m3 at 25°C Conversion factors 1 mg/m3 = 0.340 ppm Abbreviations: g/cm , gram per cubic centimeter; mg/m3, milligrams per cubic meter; 3 mm Hg, millimeters of mercury. fish, grape, black tea, tomato, and yogurt; its taste has been described as “chemical-like and slightly fruity green.” Average daily per capita intake in the United States via food is estimated to be 1.6 milligrams (mg), mostly from white bread, tomatoes, and cheddar cheese (IPCS 1993). MEK is not routinely used in spacecraft during flight but could potentially be part of some future payload or a component of utility chemicals, such as ad- hesives or an off-gassing product from nonmetallic materials. MEK has been found occasionally in trace concentrations (up to 21 micrograms/liter [µg/L]) in potable water on the International Space Station. TOXICOKINETICS AND METABOLISM Most of the MEK toxicokinetic and metabolism data in the literature in- volve exposure by inhalation, but many of the toxicokinetic results should hold true for MEK exposures by ingestion as well. Absorption No quantitative data on the extent of absorption of ingested MEK in hu- mans were identified, but case reports indicate that humans absorb enough MEK after ingestion of unknown quantities to cause systemic toxicity, including un- consciousness and metabolic acidosis (Kopelman and Kalfayan 1983). Nine

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149 Methyl Ethyl Ketone male volunteers exposed for 4 h to MEK vapors at 200 ppm had a constant rela- tive pulmonary uptake of 53% ± 2% throughout the exposure period, with or without exercise (Liira et al. 1988). Blood MEK concentrations increased rap- idly during the first hour and then rose slowly and linearly until the end of the exposure. Repeated bicycle exercise increased the overall blood MEK concen- tration steeply compared with sedentary activity (Liira et al. 1988). Distribution MEK is nearly equally soluble in water, blood, and oil. Distribution coef- ficients between water/air, blood/air, and oil/air are 254, 202, and 263, respec- tively (Sato and Nakajima 1979), implying that MEK distributes uniformly to the various soft tissue compartments. Metabolism Most inhaled MEK is believed to be metabolized in the liver by intermedi- ary metabolism (Liira et al. 1988). In mammals, MEK and its metabolites are essentially completely cleared in 24 h (IPCS 1993). Only about 0.1% of the ab- sorbed dose of inhaled MEK in humans is excreted in urine as the combined total of MEK and 3-hydroxy-2-butanone (Miyasaka et al.1982; Perbellini et al. 1984). Because approximately 3% of inhaled MEK is excreted unchanged in expired air, the main part is believed to be metabolized by uncharacterized pathways, probably by intermediary metabolism to acetate or acetoacetate, as suggested by Dawson and Hullin (Dawson and Hullin 1954). A well-known metabolite of MEK, 2,3-butanediol, was detected in small amounts (2% to 3% of inhaled dose) in the urine of volunteers inhaling 200 ppm of MEK for 4 h, with maximum rates of excretion at 6 to 12 h from the beginning of exposure and with large interindividual variation in excretion (Liira et al. 1988). In guinea pigs, metabolites found in the serum included 2-butanol, 3-hydroxy-2-butanone, and 2,3-butanediol (see Figure 5-1) after an intraperitoneal dose of MEK at 450 mg per kilogram of body weight (mg/kg) (DiVincenzo et al. 1976). In rats, the main identified biotransformation pathway led to 2,3-butanediol, representing 30% of the orally administered dose of 1,690 mg/kg (Dietz et al. 1981). Excretion After exposure, Liira et al. (1988) reported two elimination phases for MEK in blood. There was a more rapid elimination during the initial 0- to 45- min postexposure with a half-life of 30 min, followed by a slower elimination

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150 Spacecraft Water Exposure Guidelines OH H3C-C-CH2-CH3 Conjugation/Excretion H 2-butanol O H3C-C-CH2-CH3 MEK O OH OH OH H3C-C-CH-CH3 H3C-CH-CH-CH3 3-hydroxy-2-butanone 2,3-butanediol FIGURE 5-1 Proposed pathways for metabolism of MEK in guinea pigs. Source: Adapted from DiVincenzo et al. 1976. Printed with permission; copyright 1976, Toxi- cology and Applied Pharmacology. phase with a calculated half-life of 81 min (Liira et al. 1988). As even the slower elimination rate is quite rapid, it is unlikely that MEK will accumulate in the body. Only 3% of the absorbed dose in volunteers inhaling 200 ppm of MEK for 4 h was excreted by exhalation (Liira et al. 1988). About 2% of the MEK dose taken up by the lungs was excreted in the urine as 2,3-butanediol (Liira et al. 1988). TOXICITY SUMMARY Exposure to MEK vapors can cause irritation of the eyes, nose, and throat as well as lacrimation and sneezing (Nelson et al. 1943; Nakaaki 1974). There are no reports of human deaths due to inhalation of MEK. In rats and mice, ex- posure to MEK at 3,000 ppm for 7 h/d during gestation days 6-15 was a lowest- observed-adverse-effect level (LOAEL) for fetal toxicity, consisting of in- creased incidences of gross and skeletal anomalies and delayed sternebral ossifi- cation in rats and decreased fetal weight in mice (Deacon et al. 1981; Schwetz et al. 1991). No data are available on developmental toxicity in humans. In 1996, the American Chemistry Council ketones panel submitted a petition to the U.S. Environmental Protection Agency (EPA) requesting that MEK be removed from the list of hazardous air pollutants (HAPs) under Section 112 of the Clean Air Act. On May 30, 2003, EPA issued a proposal to delist MEK as a HAP (68 Fed. Reg. 32605[2003]). The proposal is “based on the results of a risk assessment demonstrating that emissions of MEK may not reasonably be anticipated to re- sult in adverse human health or environmental effects” (68 Fed. Reg. 32605 [2003]). In December 2005, after an extensive, multiyear scientific and technical review, EPA removed MEK from the Clean Air Act list of HAPs.

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151 Methyl Ethyl Ketone Acute and Short-Term Toxicity Lethality There are no reports of human fatalities due to exposure to MEK, either by inhalation or by ingestion. MEK has a low order of toxicity after single oral ex- posure in rodents. Estimates of the acute oral median lethal dose in rats range from ≈2.5 to 5.6 g/kg (Smith et al. 1962; Kimura et al. 1971). For a 70-kg hu- man, these doses would represent 175-392 g of MEK. Neurobehavioral Toxicity A woman who ingested an unknown amount of MEK that had been stored in a rum bottle was rendered unconscious and had severe metabolic acidosis and a blood MEK concentration of 95 mg/deciliter (Kopelman and Kalfayan 1983). She reportedly had an uneventful recovery with no delayed effects. In tests of subclinical neurobehavioral performance and biochemical indi- cators during and after a 4-h exposure of volunteers to either 200 ppm of MEK (n = 25), 250 ppm of acetone (n = 22), a mixture of 100 ppm of MEK and 125 ppm of acetone (n = 19), 95% ethanol at 0.84 mL/kg (positive control) (n = 20), or a placebo (n = 21), no consistent statistically significant results that could be attributed to MEK exposure were seen in the volunteers (Dick et al. 1988). In similar tests of subclinical neurobehavioral performance, statistically significant effects were observed in only 4 of 32 measures in 68 male and 75 female volunteers exposed for 4 h to 200 ppm of MEK vapors, 100 ppm of methyl isobutyl ketone (MIBK), a mixture of 100 ppm of MEK and 50 ppm of MIBK, or a placebo, but the magnitude of the effects was not substantial and could not be attributed directly to the chemical exposures (Dick et al. 1992). The tests included five psychomotor tests (choice reaction time, simple reaction time, visual vigilance, dual task [auditory tone discrimination and tracking], and memory scanning), one sensorimotor test, and a test of mood. Significant odor sensations and irritant effects were reported during the exposures. Subchronic and Chronic Toxicity No studies were identified that examined the subchronic or chronic effects of oral exposure to MEK in humans or other animals. Subchronic MEK inhala- tion studies reporting liver effects (possibly adaptive rather than adverse) in animals were found, but none were identified in humans and no chronic inhala- tion studies in humans or other animals were identified. A two-generation repro- ductive and developmental toxicity study of 2-butanol in rats reported no repro- ductive effects. Although some developmental toxicity was reported, effects on

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152 Spacecraft Water Exposure Guidelines embryos are not considered in setting exposure limits for contaminants in space- craft water and air because pregnant astronauts are not permitted to fly. Headaches, Nausea, and Vomiting Elkins reported an investigation of industrial exposure to MEK before 1950 (Elkins 1959). In certain processes in Massachusetts, exposures reportedly were as high as 700 ppm. Concentrations above 300 ppm reportedly resulted in complaints of headaches and throat irritation; in one plant, nausea and vomiting were reported with concentrations averaging 500 ppm. However, no permanent effects were noted. The study by Elkins should be interpreted with caution be- cause of the reliance on subjective complaints and incomplete information about peak exposures, exposures to other compounds, and other aspects of the work conditions. Hepatotoxicity Increased liver weights and liver-to-body-weight ratios were observed in Sprague-Dawley rats exposed by inhalation to 800 ppm of MEK for 4 wk (Toft- gard et al. 1981). The concentration of in vitro microsomal cytochrome P-450 was not altered, but the formation of two metabolites of androstenedione was depressed. A 90-d study in weanling F344 rats exposed for 6 h/d, 5 d/wk to MEK va- por at 0, 1,250, 2,500, or 5,000 ppm observed similar increases in liver weights and liver-to-body-weight ratios as well as liver-to-brain-weight ratios at 5,000 ppm (Cavender et al. 1983). No pathological effects attributable to MEK expo- sure were observed at any MEK concentration up to 5,000 ppm. In females, the highest dose increased alkaline phosphatase, potassium, and glucose values. Serum glutamate pyruvate transaminase activity increased at the 2,500-ppm dose but decreased at 5,000 ppm in females. The authors concluded that the or- gan weight changes and altered serum enzyme values may indicate damage but also may be due to the development of an adaptive response, as no pathology was observed in routine histopathology studies (Cavender et al. 1983). Neurotoxicity Male rats exposed 22 h/d for 180 d to 500 ppm of MEK via inhalation showed no clinical signs of neurologic effects (Egan et al. 1980). Histopa- thologic examination of the lumbar cord, dorsal and ventral spinal roots, spinal ganglia, sciatic notch, and tibial nerve showed no evidence of neurologic effects.

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153 Methyl Ethyl Ketone Carcinogenicity There is no evidence that occupational exposure to MEK is associated with an increased incidence of cancer in humans (Alderson and Rattan 1980). Genotoxicity MEK has been shown to lack genotoxic activity in a variety of short-term tests. MEK and the metabolically related 2-butanol were not mutagenic to the bacteria Salmonella typhimurium and Escherichia coli, with and without meta- bolic activation. MEK did not induce mitotic gene conversion in the yeast Sac- charomyces cerevisiae nor did it cause chromosome damage in mammalian cells (cultured rat liver cells) (Brooks et al. 1988). MEK had no effect in the Salmo- nella microsome assay, mouse lymphoma assay, BALB/3T3 mouse embryo cell transformation assay, unscheduled DNA synthesis in rat primary hepatocytes, and the in vivo mouse micronucleus assay (O’Donoghue et al. 1988). MEK also did not produce chromosomal aberration in rat liver cells (in vitro) or mouse bone marrow (in vivo) or DNA damage (unscheduled DNA synthesis in rat hepatocytes) (Shirasu 1976; Florin et al. 1980; Nestmann et al. 1980; Perocco et al. 1983; Marnett et al. 1985). MEK, at a concentration of 3.54%, induced chromosomal malsegregation, characterized as aneuploidy, in S. cerevisiae but did not induce mitotic recombi- nations or point mutations (Zimmermann et al. 1985). However, the protocol involved cold storage on ice for up to 17 h after treatment for 4 h, and ane- uploidy was observed only after incubation on ice. This storage at ice-cold tem- perature may have been associated with the response. A number of chemicals have been shown to induce aneuploidy, many of which do not induce other de- tectable genetic effects (e.g., mutation or recombination). Thus, chemically in- duced chromosomal malsegregation might be the result of damage or alteration to different targets than those leading to mutation (that is, the primary targets were not DNA or the DNA metabolizing systems). Microtubules are candidate targets for induction of aneuploidy. Other investigators have reported negative genotoxicity studies of MEK in bacteria (Shimizu et al. 1985; Zeiger et al. 1992). The clastogenicity of MEK was investigated in the in vivo micronucleus assay by administering MEK at 10 mL/kg to male and female Chinese hamsters (intraperitoneally) and failed to show any mutagenic effect (Basler 1986). Reproductive Effects There are no reports of reproductive toxicity in humans or other animals due to exposure to MEK, but reproductive studies have not been conducted with MEK. In the subchronic inhalation study by Cavender et al. (1983), histologic examination of the testes, epididymides, seminal vesicles, vagina, cervix, uterus,

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154 Spacecraft Water Exposure Guidelines oviducts, ovaries, and mammary glands of rats exposed to MEK at concentra- tions up to 5,000 ppm for 90 d revealed no exposure-related lesions. Developmental Toxicity in Humans There are no reports of developmental or fetal toxicity in humans due to exposure to MEK. Developmental Toxicity in Animals Schwetz et al. (1991) reported developmental toxicity (reduction in mean fetal body weight) and no overt maternal toxicity in Swiss CD-1 mice exposed to 3,000 ppm of MEK for 7 h/d, during days 6-15 of gestation but not at 1,000 or 400 ppm, although there was a slight (7%), treatment-related increase in relative liver weight, which achieved statistical significance only in the 3,000-ppm group (Dow Chemical Corporation 1979; Deacon et al. 1981; Mast et al. 1989; NTP 1990; Schwetz et al. 1991). Each group consisted of about 30 bred females. Among mice exposed to MEK, there were no decreases in the incidences of pregnancy or in the average number of implantations or live fetuses per dam, nor were there increases in resorption. There was no significant increase in the inci- dence of any single malformation, but several malformations that were not ob- served in the concurrent control group or in the controls of contemporary studies were present at a low incidence only at the 3,000-ppm dose: cleft palate, fused ribs, missing vertebrae, and syndactyly. There was also a trend for increased incidence of misaligned sternebrae, a developmental variation. Interaction with Other Chemicals Data from studies in rats (Saida et al. 1976; Altenkirch et al. 1978; Takeu- chi et al. 1983; Ralston et al. 1985) show that continuous inhalation exposure to MEK concentrations ranging from 200 to 1,000 ppm for 25 d to 8 wk can de- crease the time to effect and increase the extent and severity of neurotoxicity produced by coexposure to six-carbon compounds that are, or can be, metabo- lized to γ-diketones—including 2,5-hexanedione, n-hexane, and methyl n-butyl ketone—and can potentiate the hepatotoxic effects of carbon tetrachloride and chloroform (Hewitt et al. 1986, 1987). Evidence from studies in exposed humans, however, is less clear, because of confounding exposures to multiple solvents, low concentrations (e.g., 100 ppm) of MEK, or weak and inconclusive evidence of neurotoxicity. No evidence of neurotoxic interactions was found in human volunteers exposed to MEK ei- ther alone at 200 ppm or at 100 ppm in combination with approximately 50 ppm of either acetone, MIBK, or toluene for 4 h (Dick et al. 1984, 1988, 1992). Stud-

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155 Methyl Ethyl Ketone ies of occupational exposures, however, report possible interactions from expo- sures to mixtures of organic solvents that contain MEK, but the studies cannot establish causation because of the nature of the exposures (Arlien-Søborg 1992). Exposure to 2-butanol can increase sensitivity to the effects of MEK because MEK is a metabolite of 2-butanol. MEK can reduce the elimination rate of etha- nol in CD-1 mice (Cunningham et al. 1989). In a case report involving coinges- tion of unknown amounts of MEK and methanol that induced a hyperosmolar coma, the authors suggested that MEK may have inhibited methanol metabo- lism, contributing to the low observed serum formate concentration (1.3 mmol/L) and normal anion gap despite a blood methanol concentration of 67 mmol/L (Price et al. 1994). Table 5-2 presents a summary of selected studies on the toxicity of MEK. Table 5-3 presents a list of exposure limits for MEK that have been set by other organizations. RATIONALE FOR ACCEPTABLE CONCENTRATIONS Calculation using the guidelines established by the National Research Council-Committee on Toxicology (NRC 1992) to determine the highest ac- ceptable concentration (AC) for each major end point and exposure duration is documented below. The resulting ACs for the various end points are compiled in Table 5-4 and compared. SWEG values are set at each duration on the basis of the end point that yielded the lowest AC at that exposure duration. Because of the short half-life of MEK in humans and because long-term exposures of ani- mals to relatively high concentrations have revealed no organ histopathology, a dose that is nontoxic for 1 d would be expected to remain nontoxic for all expo- sure durations. Sensory Irritation Although exposure to vapors of MEK can irritate the eyes and respiratory tract, ingestion of MEK would not be expected to affect the eyes or respiratory tract. No data are available concerning potential irritant effects (e.g., nausea) caused by ingestion of MEK; therefore, no AC can be set for this end point. Central Nervous System Effects Published studies indicate that neither acute nor chronic exposures to MEK are neurotoxic as measured by neurobehavioral testing or histopathology of the nervous system.

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156 TABLE 5-2 Toxicity Summary Exposure Concentration Duration Species Effects Reference Effects in Humans 200-ppm inhalation 4h Human NOAEL for neurobehavioral performance and biochemical Dick et al. 1988 N = 137 indicators. 200-ppm inhalation 4h Human Significant odor sensations and irritant effects. NOAEL for Dick et al. 1992 N = 68 M + 75 neurobehavioral performance and biochemical indicators. F Unknown amount Case report Human, F, age Unconsciousness, hyperventilation, severe metabolic acidosis. Kopelman and ingested; serum: 950 47 Uneventful recovery. Kalfayan 1983 mg/L Effects in Animals and Microbes 5,000-ppm inhalation 6 h/d, 5 F344/N rats Increased liver weight, liver:body-wt ratio, and liver:brain-wt Cavender et al. d/wk, 90 d ratio. No pathological effects but increased alkaline phosphatase, 1983 potassium, and glucose in females. Decreased SPGT activity at 5,000 ppm but increased at 2,500 ppm. 800-ppm inhalation 4 wk S-D rats Increased liver weight and liver:body-wt ratio. No change in Toftgard et al. microsomal P-450 concentration but depressed formation of two 1981 metabolites of androstenedione. 100-ppm 2-hexanone, 6 mo Rats No clinical signs of neuropathy; histologically, scattered fiber Egan et al. 1980 96.7% pure, inhalation degeneration in the gracile tract of the spinal cord. 100-ppm 2-hexanone, 4 mo Rats Giant axonal swelling and demyelination in fibers of tibia1 nerves, Egan et al. 1980 96.7% pure, inhalation medulla oblongata, and cerebellum. 10 mL/kg, i.p. Once Chinese No clastogenicity/mutagenicity in the in vivo micronucleus assay. Basler 1986 hamsters, M and F

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1,000-ppm inhalation 7 h/d, days Swiss CD-1 NOAEL for developmental toxicity. NOAEL for maternal Schwetz et al. 6-15 of mice toxicity. 1991 gestation 3,000-ppm inhalation 7 h/d, days Swiss CD-1 Developmental toxicity (low incidence of malformations). Schwetz et al. 6-15 of mice NOAEL for maternal toxicity. 1991 gestation 3.54% wt/vol in water S. cerevisiae Chromosomal malsegregation, characterized as aneuploidy. Zimmermann et al. 1985 Abbreviations: i.p., intraperitoneally; NOAEL, no-observed-adverse-effect level; SPGT, serum glutamate pyruvate transaminase. 157

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158 Spacecraft Water Exposure Guidelines TABLE 5-3 Exposure Limits for MEK Vapors Set by Other Organizations Organization, Standard Exposure Limit Reference EPA EPA 2003 RfD 0.6 mg/kg/d ACGIH ACGIH 2001 200 ppm (590 mg/m3) TLV TWA 300 ppm (885 mg/m3) STEL OSHA NIOSH 2005 200 ppm (590 mg/m3) PEL TWA NIOSH NIOSH 2005 200 ppm (590 mg/m3) REL TWA 300 ppm (885 mg/m3) REL ST 3,000 ppm (8,850 mg/m3) IDLH Abbreviations: ACGIH, American Conference of Governmental Industrial Hygienists; EPA, U.S. Environmental Protection Agency; IDLH, immediately dangerous to life and health; NIOSH, National Institute of Occupational Safety and Health; OSHA, Occupa- tional Safety and Health Administration; PEL, permissible exposure limit; REL, recom- mended exposure limit; RfD, reference dose; STEL, short-term exposure limit; ST, short term; TLV, Threshold Limit Value; TWA, time-weighted average. Organoleptic Effects Although a concentration of 1,700 mg/L would be nontoxic, it has a defi- nite odor. The odor is not unpleasant, but crewmembers would likely avoid drinking water that had a significant odor, especially if they did not know what was causing it. Because this situation would likely lead to some dehydration, the AC should be set at a value that would not likely cause a crewmember to mini- mize drinking the water due to organoleptic considerations. “Sniff tests” of vari- ous dilutions of MEK in water showed large inter-individual variation in sensi- tivity to the odor of MEK; in general, 1,700 ppm had a definite odor that was objectionable to some of six test subjects (H. Garcia, unpublished material, 2007). A 3-fold lower concentration (540 ppm) was undetectable by several subjects and was objectionable to only one of the subjects who could detect the odor (H. Garcia, unpublished material, 2007). Because reduction of water consumption for 1 d would be acceptable for emergency situations, the AC for 1 d is set to the concentration that was objec- tionable to only a small percentage of subjects (Table 5-5). Thus, 1-d AC for organoleptic effects = 540 ppm. To set 10-, 100-, and 1,000-d ACs that would be unobjectionable to essen- tially all crewmembers and exposure durations, the LOAEL of 540 ppm was divided by 10. Thus, 10-, 100-, and 1,000-d AC for organoleptic effects = 540 ppm(LOAEL) × 1/10(safety factor) = 54 ppm.

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TABLE 5-4 Acceptable Concentrations for MEK Acceptable Concentration, Uncertainty Factors ppm or mg/L End Point Exposure Reference Species NOAEL Time Species Spaceflight 1 10 100 1,000 Odor aversion LOAEL = 540 Human NA 1 1 1 540 — — — H. Garcia, unpub- ppm lished material, 2007 Odor aversion LOAEL = 540 Human 10 1 1 1 — 54 54 54 H. Garcia, unpub- ppm lished material, 2007 SWEGs 540 54 54 54 Abbreviations: NA, not applicable; NOAEL, no-observed-adverse-effect level. 159

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160 Spacecraft Water Exposure Guidelines TABLE 5-5 Spacecraft Water Exposure Guidelines for MEK Duration, d Concentration, ppm (mg/L) Target Toxicity 1 540 Odor aversion 10 54 Odor aversion 100 54 Odor aversion 1,000 54 Odor aversion Developmental Effects Several studies have reported developmental toxicity (an increased inci- dence of skeletal variations and a decrease in weight in male fetuses) in off- spring of female rats exposed at an inhalation dose (about 3,000 ppm) that caused mild maternal toxicity (slightly decreased weight gain and increased ma- ternal liver-to-body-weight ratio) (Dow Chemical Corporation 1979; Deacon et al. 1981; Mast et al. 1989; NTP 1990; Schwetz et al. 1991). At lower concentra- tions (1,000 and 400 ppm) no developmental toxicity was observed. Neverthe- less, developmental effects will not be used to set an AC because NASA does not permit pregnant astronauts to fly. The SWEGs, which are based on or- ganoleptic effects, are 300-fold below the EPA calculated benchmark dose (set to protect against decreased pup weight) of 657 mg/kg/d for 2-butanol. The SWEGs assume water consumption by a 70-kg person of 2.8 L/d with 54 mg of MEK per liter of water to yield a daily dose of 2.2 mg/kg/d. This value is only about 1.4 times greater than the reported average daily per capita intake of MEK via food in the U.S. Spaceflight Considerations None of the end points induced by exposure to MEK is expected to be af- fected by launch, microgravity, or reentry. RECOMMENDATIONS Because of the low toxicity of MEK, experiments to obtain data on the rate of absorption of MEK by the gastrointestinal tract are not needed to protect the health of exposed populations but would be useful for academic reasons, such as improving the parameters used in physiologically based pharmacoki- netic models of the pharmacokinetics of ingested MEK. It would also be aca- demically interesting to determine the fate of the ~95% of absorbed MEK in humans that is believed to be processed by intermediary metabolism.

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163 Methyl Ethyl Ketone NRC (National Research Council), 1992. Guidelines for Developing Spacecraft Maxi- mum Allowable Concentrations for Space Station Contaminants. Washington, DC: National Academy Press. NTP (National Toxicology Program). 1990. Inhalation Developmental Toxicology Stud- ies: Teratology Study of Methyl Ethyl Ketone. NTP Study TER88046. National Toxicology Program, Research Triangle Park, NC. 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. Rodgers-Back, R.S. Slesinski, and A. Thiligar. 1988. Mutagenicity studies on ketone solvents: Methyl ethyl ketone, methyl isobythyl ketone, and isophorone. Mutat. Res. 206(2):149-162. Perbellini, L., F. Brugnone, P. Mozzo, V. Cocheo, and D. Caretta. 1984. Methyl ethyl ketone exposure in industrial workers - uptake and kinetics. Int. Arch. Occup. En- viron. Health 54(1):73-81. Perocco, P., S. Bolognesi, and W. Alberghini. 1983. Toxic activity of seventeen industrial solvents and halogenated compounds on human lymphocytes cultured in vitro. Toxicol. Lett. 16(1-2):69-75. Price, E.A., A. D'Alessandro, T. Kearney, K.R. Olson, and P.D. Blanc. 1994. Osmolar gap with minimal acidosis in combined methanol and methyl ketone ingestion. J. Toxicol. Clin. Toxicol. 32(1):79-84. Ralston, W.H., R.L. Hilderbrand, D.E. Uddin, M.E. Anderson, and R.W. Gardier. 1985. Potentiation of 2,5-hexanedione neurotoxicity by methyl ethyl ketone. Toxicol. Appl. Pharmacol. 81(2):319-327. Saida, K., J.R. Mendell, and H.S. Weiss. 1976. Peripheral nerve changes induced by methyl n-bythyl ketone and potentiation by methyl ethyl ketone. J. Neuropathol. Exp. Neurol. 35(3):205-225. Sato, A., and T. Nakajima. 1979. Partition coefficients of some aromatic hydrocarbons and ketones in water, blood and oil. Br. J. Ind. Med. 36(3):231-234. Schwetz, B.A., T.J. Mast, R.J. Weigel, J.A. Dill, and R.E. Morrissey. 1991. Developmen- tal toxicity of inhaled methyl ethyl ketone in Swiss mice. Fundam. Appl. Toxicol. 16(4):742-748. Shimizu, H., Y. Suzuki, N. Takemura, S. Goto, and H. Matsushita. 1985. The results of microbial mutation test for forty-three industrial chemicals. Sangyo Igaku 27(6):400-419. Shirasu, Y. 1976. Mutagenicity testing of pesticides: Kogia to Taiaku. J. Environ. Pollut. Control 12:407-412. Smith Jr., H.F., C.P. Carpenter, C.S. Weill, U.C. Pozzani, and J.A. Striegel. 1962. Range finding toxicity data: List VI. Am. Ind. Hyg. Assoc. J. 23:95-107. Takeuchi, Y., Y. Ono, N. Hisanaga, M. Iwata, M. Aoyama, J.Kitoh, and Y. Sugiura. 1983. An experimental study of the combined effects of n-hexane and methyl ethyl ketone. Br. J. Ind. Med. 40(2):199-203. Toftgard, R., O.G. Nilsen, and J.A. Gustafsson. 1981. Changes in rat liver microsomal cytochrome P-450 and enzymatic activities after the inhalation of n-hexane, xy- lene, methyl ethyl ketone, and methylchloroform for four weeks. Scand. J. Work Environ. Health 7(1):31-37. Wong, K.L. 1996. Methyl ethyl ketone. Pp. 307-329 in Spacecraft Maximum Allowable Concentrations for Selected Airborne Contaminants, Vol. 2. Washington, DC: Na- tional Academy Press. Zeiger, E., B. Anderson, S. Haworth, T. Lawlor, and K. Mortelmans. 1992. Salmonella mutagenicity tests: V. Results from the testing 311 chemicals. Environ. Mol. Mutagen. 19(Suppl. 21):2-141.

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164 Spacecraft Water Exposure Guidelines Zimmermann, F.K., V.W. Mayer, I. Scheel, and M.A. Resnick. 1985. Acetone, methyl ethyl ketone, acetonitrile, and other polar aprotic solvents are strong inducers of aneuploidy in Saccharomyces cerevisiae. Mutat. Res. 149(3):339-351.