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3 Methyl Ethyl Ketone1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P. L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Sylvia Talmage (Summitec Corporation) and Jim Holler and William Bress (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 140

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141 Methyl Ethyl Ketone effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the correspond- ing AEGL. SUMMARY Methyl ethyl ketone (MEK) is a volatile solvent with a sweet and sharp acetone-like odor. MEK is widely used as a solvent in common household prod- ucts, such as inks, paints, cleaning fluids, varnishes, and glues. In most industrial applications, it is used as a component of a mixture of organic solvents. It has also been detected in a wide variety of natural products and may be a minor product of normal mammalian metabolism. In 1999, U.S. production capacity was 675 million pounds. The inhalation toxicity of MEK is low. In clinical studies, a constant con- centration of 200 ppm and short exposures at 380 ppm were judged nonirritat- ing. At high concentrations of several thousand parts per million, MEK causes reversible central nervous system (CNS) depression as evidenced by neurobe- havioral effects in animals. Data on human exposures were available from clini- cal studies and workplace monitoring. Animal studies with a variety of species (baboon, rat, mouse, and guinea pig) addressed irritation, neurotoxicity, devel- opmental toxicity, and lethality. Exposure durations ranged from acute to chronic. MEK is not teratogenic, but at high concentrations, it is mildly fetotoxic to rats and mice. Genotoxicity was also addressed. No information on a concen- tration-exposure duration relationship for a defined end point was found. In clinical studies of 4-h duration, uptake was rapid during the first hour of expo-

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142 Acute Exposure Guideline Levels sure at 200 ppm, approaching steady state in the blood by the end of the expo- sure (Liira et al. 1988a,b). Four well-conducted clinical studies indicated that MEK is not a sensory irritant, nor does it induce neurobehavioral changes at concentrations up to 200 ppm for 2 or 4 h (Dick et al 1992; Muttray et al 2002; Shibata et al. 2002) or at variable concentrations ranging from 10 to 380 ppm over 4 h (five 8-min peaks to 380 ppm) (Seeber et al. 2002). Seeber et al. (2002) tested healthy subjects as well as subjects with self-reported multiple chemical sensitivity (sMCS). Sub- jects with sMCS reported no adverse symptoms during the 8-min exposures to 380 ppm. Additional metabolism studies were conducted at concentrations of 25 to 400 ppm for 4 h, but these studies did not address sensory irritation or neuro- toxic effects. In a clinical study with 24 male and female subjects, a concentra- tion of 200 ppm was judged unobjectionable for an 8-h exposure (Dick et al. 1992). Therefore, 200 ppm was selected as the threshold for sensory irritation and was used to derive the AEGL-1. The selection of this value is supported by numerous clinical studies in which volunteers were routinely exposed to MEK at 200-400 ppm for up to 4 h and by the exposure of sMCS subjects to it at 380 ppm for short periods of time. Because effects were not different in sensitive subjects at the higher concentration of 380 ppm, an intraspecies uncertainty fac- tor of 1 was applied. Because steady-state would be approached within 4 h at the 200-ppm concentration (Liira et al. 1988a,b) and because MEK is rapidly me- tabolized, the 200-ppm concentration was used across all AEGL-1 exposure durations. The AEGL-2 was based on an exposure concentration that did not result in neurobehavioral effects on the first day of the subchronic study by Cavendar et al. (1983). Rats were exposed to MEK at 5,000 ppm for 6 h/day, 5 days/week, for 90 days. No lesions were reported in this study (specific neuropathologic studies were conducted on the medulla and peripheral nerves), and there were no neurofunctional deficits. Narcosis was not observed on the first day of exposure or on subsequent days. The concentration may be close to the threshold for nar- cosis, as evidenced by mild somnolence in a repeated exposure study in which rats were exposed at 6,000 ppm for several weeks (Altenkirch et al. 1978). Be- cause uptake is dependent on the ventilatory rate and cardiac output, which are higher in rodents than in humans, an interspecies uncertainty factor of 1 was applied (at similar exposure concentrations, blood levels of MEK are higher in rats than in humans [Liira et al. 1990a]). Because the threshold for narcosis dif- fers by no more than 2- to 3-fold among the general population (see Section 4.4.2), an intraspecies uncertainty factor of 3 was applied to protect sensitive individuals. At the 5,000-ppm concentration, steady-state in the blood is pre- dicted to occur sometime after 4 h. Therefore, the 4- and 8-h AEGL-2 values were set equal to 1,700 ppm. The data show that for a common end point, higher concentrations can be tolerated at the shorter exposure durations. Therefore, the values for the shorter exposure durations were time-scaled from the 4-h time using the default n value of 3.

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143 Methyl Ethyl Ketone The AEGL-3 values were derived using different studies. The 10- and 30- min time periods were derived using the studies by Klimisch (1988) and Zakhari et al. (1977) with support from Hansen et al. (1992). The 1-, 4-, and 8-h values were derived from the study by Fowles et al. (1999) using data from La Belle and Brieger (1955). No deaths occurred in rats after a 30-min exposure to MEK at 92,239 ppm (Klimisch 1988), and no deaths occurred in mice after a 45-min exposure at 50,000 ppm (Zakhari et al. 1977). A projected value of 32 or 145 ppm for 30 min would decrease the respiratory rate of mice by 50% (Hansen et al. 1992). The highest tested concentration in the Hansen et al. (1992) study was 26,000 ppm. On the basis of these data it is thought that nearly all individuals could be exposed at 10,000 ppm for up to 30 min without developing life- threatening effects. Inter- and intraspecies uncertainty factors of 1 and 3, respec- tively, were applied for the AEGL-2. Additional studies support the 10,000-ppm value as being nonlethal: 10,000 ppm for 10 or 30 min was narcotic to mice in one study (Glowa and Dews 1987) but not in another (Hansen et al. 1992), 10,000 ppm was tolerated by rats for 8 h/day for several days (Altenkirch et al. 1978), and no deaths occurred in guinea pigs inhaling 10,000 ppm for 13.5 h (Patty et al. 1935). The longer-term AEGL-3 values were based on a maximum likelihood es- timate, with a 1% response (MLE01), of 7,500 ppm calculated by Fowles et al. (1999) from a 4-h study with rats exposed at several concentrations for 4 h (La Belle and Brieger 1955). In this study, the 4-h LC50 (concentration lethal to 50% of the exposed population) was 11,700 ppm, and the highest concentration re- sulting in no deaths was 7,850 ppm for 4 h. The 7,500-ppm MLE01 concentra- tion was divided by an interspecies uncertainty factor of 1 and an intraspecies uncertainty factor of 3, using the same rationale as that for AEGL-1. The result- ing value of 2,500 ppm was used for both the 4-h and 8-h AEGL-3 values. MEK may approach steady state in the blood by the end of 8 h. The 4-h 2,500 ppm value was time-scaled to the 1-h time using the default n value of 3 for scaling to shorter time intervals. The 8-h AEGL-3 of 2,500 ppm is low compared with 8-h nonlethal concentrations in animal studies cited above. The calculated values are listed in Table 3-1 below. 1. INTRODUCTION MEK is a volatile solvent with a sweet and sharp acetone-like odor. It is commercially manufactured from n-butenes in a metal-catalyzed hydrogena- tion reaction that proceeds through the intermediate formation of 2-butanol. MEK is widely used as a solvent in industrial settings and common household products, such as protective coatings, adhesives, inks, paints, cleaning fluids, and dewaxing agents. It is a common ingredient in consumer products, such as varnishes and glues. In most applications, it is used as a component of a mix- ture of organic solvents. It has also been detected in a wide variety of natural

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144 Acute Exposure Guideline Levels products and may be a minor product of normal mammalian metabolism (WHO 1993; Morgott et al. 2001). In 1999, U.S. production capacity was 675 million pounds (ChemExpo 2001). Global capacity in 2002 was about 1.3 mil- lion metric tons (Greiner and Funada 2009). Chemical and physical properties are listed in Table 3-2. 2. HUMAN TOXICITY DATA 2.1. Acute Lethality The relative toxicity of ketones is low (Morgott et al. 2001), and no stud- ies were located regarding deaths of humans following inhalation, oral, or der- mal exposure to MEK (ATSDR 1992; WHO 1993). TABLE 3-1 Summary of AEGL Values for Methyl Ethyl Ketone End Point (Reference) Classification 10 min 30 min 1h 4h 8h AEGL-1 200 ppm 200 ppm 200 ppm 200 ppm 200 ppm NOAEL for (nondisabling) (586 (586 (586 (586 (586 subjective mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) symptoms in humans (Dick et al. 1992; Muttray et al. 2002; Seeber et al. 2002 Shibata et al. 2002) 4,900 ppma 3,400 ppma 2,700 ppma AEGL-2 1,700 ppm 1,700 ppm Threshold for (disabling) (14,357 (9,962 (7,911 (4,980 (4,980 narcosis in rats mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (Cavender et al. 1983) b b 4,000 ppma 2,500 ppma 2,500 ppma AEGL-3 Threshold for (lethal) (11,720 (7,325 (7,325 lethality, mouse, mg/m3) mg/m3) mg/m3) rat (La Belle and Brieger 1955; Zakhari et al. 1977; Klimisch 1988; Hansen et al. 1992) a The 10- and 30-min and the 1-h AEGL-2 values and the 1-, 4-, and 8-h AEGL-3 values are higher than one-tenth of the lower explosive limit (LEL) of methyl ethyl ketone in air (LEL = 18,000 ppm). Therefore, safety considerations against the hazard of explosion must be taken into account. b The 10- and 30-min AEGL-3 value of 10,000 ppm (29,300 mg/m3) is higher than 50% of the LEL of methyl ethyl ketone in air (LEL = 18,000 ppm). Therefore, extreme safety considerations against the hazard of explosion must be taken into account. Abbreviation: NOAEL, no-observed-adverse-effect level.

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145 Methyl Ethyl Ketone TABLE 3-2 Chemical and Physical Data for Methyl Ethyl Ketone Parameter Data Reference Synonyms MEK, 2-butanone, ethyl ATSDR 1992; methyl ketone, methyl acetone, O’Neil et al. 2001 2-oxobutane CAS registry no. 78-93-3 ATSDR 1992 Chemical formula CH3COCH2CH3 O’Neil et al. 2001 Molecular weight 72.10 O’Neil et al. 2001 Physical state Liquid O’Neil et al. 2001 Boiling point 79.6°C O’Neil et al. 2001 Melting point −86°C O’Neil et al. 2001 Solubility in water 275,000 mg/L O’Neil et al. 2001 353,000 mg/L HSDB 2008 Vapor pressure 90.6 mmHg at 25°C ATSDR 1992 Vapor density (air =1) 1.3814 O’Neil et al. 2001 2.41 HSDB 2008 Liquid density (water =1) 0.805 O’Neil et al. 2001 Flash point 6°C (closed cup) O’Neil et al. 2001 Explosive limits ACGIH 2006 Upper 12% by volume Lower 1.8% by volume 1 ppm = 2.93 mg/m3 Conversion factors ATSDR 1992 1 mg/m3 = 0.341 ppm 2.2. Nonlethal Toxicity 2.2.1. Odor Threshold The odor of MEK has been described as sweet and sharp with the hedonic tone described as neutral to unpleasant (Leonardos et al. 1969; Hellman and Small 1974). The odor threshold has variously been reported as 0.25 to 147 ppm (Billings and Jonas 1981; Amoore and Hautala 1983; Ruth 1986); following standardization of results from different threshold studies, an odor detection threshold of 7.8 ppm was reported (Devos et al. 1990). In the Devos et al. (1990) study, odor thresholds were similar for male and female control subjects, 8.2 and 8.1 ppm, and for male and female subjects with multiple chemical sensitivities, 5.7 and 7.6 ppm. The odor recognition thresholds for trained panels of experts were similar, 6 ppm (Hellman and Small 1974) and 10 ppm (Leonardos et al. 1969). The threshold for irritation as reported by Ruth (1986) was 200 ppm. No data were provided for this value.

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146 Acute Exposure Guideline Levels 2.2.2. Clinical Studies Five clinical studies addressed subjective symptoms during MEK expo- sure. These studies are summarized in Table 3-3 and discussed in the text below. Clinical studies that addressed neurotoxic end points are discussed in Section 2.3 (neurotoxicity) and are also summarized in Table 3-3. During metabolism stud- ies, groups of healthy subjects were exposed to MEK at 200 ppm (Liira et al. 1988a,b; 1990a,b; Shibata et al. 2002), 300 ppm (Tada et al. 1972; van Engelen et al. 1997), or 400 ppm (Liira et al. 1990a) for 2-4 h. A series of studies by Dick et al. (1984; 1988; 1989; 1992) and a study by Shibata et al. (2002) ad- dressed sensory irritation and neurotoxicity as well as metabolism. Two studies involved coexposures to MEK and n-hexane (van Engelen et al. 1997; Shibata et al. 2002). No adverse symptoms were reported in these studies. In some cases exercise was incorporated into the study protocol. Nelson et al. (1943) exposed 10 male and female volunteers to several concentrations of MEK for 3 to 5 min to determine a concentration that would be satisfactory for industrial exposures and a concentration that would be “un- pleasant” or objectionable. Atmospheres were generated by adding a known quantity of vapor saturated air to the measured flow of air being forced into the chamber; there were no analytic measurements. The volunteers found that nose and throat irritation were slight at 100 ppm. Mild eye irritation was reported by some subjects at 200 ppm, and 350 ppm was considered objectionable for an 8-h exposure. The majority of subjects considered 200 ppm satisfactory for an 8-h exposure. In a combined metabolism and sensory irritation study, four healthy male subjects with no prior exposure to organic solvents inhaled MEK at 100 or 200 ppm for 2 h, both in combination with hexane at 50 ppm (Shibata et al. 2002). The subjects exercised on a ergometer bicycle at a constant workload of 50 watts. The subjects rated the severity of the following symptoms: discomfort in eye, running nose, discomfort in throat or airways, headache, fatigue, nausea, dizziness, feeling of intoxication, difficulty in breathing, and odor of solvents. The rating system ranged from “no effect at all” to “almost unbearable.” Except for odor, all symptoms were rated between “not at all” and “hardly at all” by the subjects. Solvent odor ratings increased with increasing exposure to MEK (rat- ing not stated). Combined exposure to MEK and n-hexane depressed the me- tabolism of n-hexane. There were no differences in heart rate or performed workload among the different exposure conditions. Metabolism results are summarized in Section 4.1.2. In a double-blind study, Dick et al. (1992) exposed 13 male and 11 female subjects, ages 18-32, to 200 ppm for 4 h in a test of neurobehavioral perform- ance (summarized in Section 2.3) and sensory and irritant effects. The 4-h expo- sure session was composed of two 2-h periods. Additional subjects were ex- posed to methyl isobutyl ketone, a combination of MEK and methyl isobutyl

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147 Methyl Ethyl Ketone TABLE 3-3 Summary of Human Studies for Methyl Ethyl Ketone Concentration Exposure (ppm) Duration Effect and Type of Study Reference 90-270 4h Concentrations not held constant; underestimation of Nakaaki 1974 (average 150) times of 5 to 30 s by men and expansion of variation of time estimation in women; questionable results 100 3-5 min Slight nose and throat irritation Nelson et al. 200 3-5 min Mild eye irritation in some subjects; 1943 judged satisfactory for 8-h exposure 350 3-5 min Judged objectionable for 8-h exposure 100, 200 2h Metabolism study; exposures in combination with Shibata et al. n-hexane; constant workload of 50 watts; odor 2002 noticeable; no irritation and no subjective symptoms 200 4h No significant difference in choice reaction time, Dick et al. 1984 visual vigilance, or pattern recognition tests 200 4h No significant difference in psychomotor tests of Dick et al. 1988; choice reaction time, visual vigilance, dual task of 1989 auditory tone discrimination and tracking, memory scanning, postural sway, profile of moods states 200 4h Noticeable strong, unobjectionable odor; subjective Dick et al. 1992 symptoms similar to control responses 200 4h No irritation; no subjective symptoms; strong odor; Muttray et al. increase in mucociliary transport time; nonsignificant 2002 changes in proinflammatory cytokines 10 4h No effect Seeber et al. 10-380 (five 4h Intense odor; irritation rated “hardly at all”; subjects 2002; van Thriel 8-min peaks with self-reported multiple chemical sensitivity et al. 2003a to 380 ppm; included in the study time-weighted average ≈188) 25, 200, 400 4h Metabolism studies; exercise incorporated into some Liira et al. protocols 1988a,b; 1990a,b 300 2-4 h Metabolism study; sensory and neurobehavioral Tada et al. 1972 effects not addressed 300-600 Occupational Central-nervous-system effects, possibly attributable Smith and to concurrent dermal exposure Mayers 1944 33,000, 100,000 Few breaths Intolerable, irritation to eyes and nose Patty et al. 1935 10,000 Few breaths Almost intolerable, irritation to eyes and nose 3,300 Not given Strong odor, moderately irritating to eyes and nose

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148 Acute Exposure Guideline Levels ketone, or an alcoholic drink, which served as a positive control for the neuro- behavioral tests. Two control groups were also used: a chemical-control group and an alcohol-control group. The chemical control group was exposed to a combination of MEK and methyl isobutyl ketone at 25 ppm for 5 min at the be- ginning of the control session. For the subjective part of the study, two ques- tionnaires were used. The “Subjective I” questionnaire consisted of a yes/no format in response to the following items: (1) presence of odor, (2) strong odor, (3) objectionable odor, (4) headache, (5) nausea, (6) throat dryness or coughing, (7) tearing, and (8) unpleasant exposure. The “Subjective II” questionnaire also required yes/no responses to indicate whether the subjects had been exposed to a chemical or to the control atmosphere. The percentages of exposed subjects re- porting yes to the eight items above involving odor and irritation were 96%, 48%, 48%, 7%, 19%, 50%, 17%, and 44%, respectively. Except for strong odor, similar numbers of positive responses were recorded for the chemical-control group: 94%, 22%, 40%, 12%, 6%, 34%, 24%, and 34%. As noted, 48% of sub- jects exposed to MEK reported a strong odor and 22% of the subjects in the chemical-control group reported a strong odor (p < 0.05). The authors, in com- paring the headache response between the chemical-control and chemically ex- posed groups, suggested that test-taking for 4 h accounted for the headache ef- fect. In response to the Subjective II questionnaire, 96% of the subjects exposed to MEK correctly reported that they had been exposed to a chemical. Muttray et al. (2002) exposed 19 healthy nonsmoking males, ages 22-41, to MEK at 0 or 200 ppm for 4 h. The study was not blind in that subjects were aware of a chemical odor during the exposure to MEK. A questionnaire of 17 items relating to irritation of the mucous membranes, difficulties in breathing, and prenarcotic symptoms was administered before, after 2 h, and after 4 h of exposure. The nasal mucosa was examined. There was no subjective irritation of nasal mucosa. On a scale of 0 to 5, all median scores were 0 (no symptoms). Mucociliary transport time was statistically significantly higher, 660 vs. 600 s. Some cytokines were slightly, nonsignificantly increased, whereas others were unaffected. The authors considered any changes subclinical. Seeber et al. (2002, see also van Thriel et al. 2002, 2003b) evaluated psy- chologicl reactions related to chemosensory irritation. Specifically, the authors focused on relationships between irritation, odor, and annoyance in response to acute solvent exposure. They conducted 14 inhalation studies with 4-h expo- sures to each of eight chemicals. The subjects rated odor (scale of 0 [“not at all”] to 5 [“very strong”]), annoyance or well-being (scale of 1 [“not annoying”] to 7 [“very annoying”]), and eye and nose irritation (same scale as for odor) every half hour. For MEK, 24 paid naive subjects were exposed at a constant concen- tration of 10 ppm (near the odor threshold) or at five peaks of 380 ppm (initial exposure) with decreases to 10 ppm. The low and high concentrations were held for 8 min; they were linked by periods of increasing or decreasing concentra- tions for 22 min. The time-weighted average (TWA) in a similar study reported by van Thriel et al. (2003a) was 188 ppm. Rating surveys were taken during the maximum and minimum exposures and during the control exposure, and muco-

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149 Methyl Ethyl Ketone sal swelling as measured by anterior active rhinomenometry was measured. The study was single blind because the subjects were unaware of the exposures, but the staff had little interaction with the subjects. The exposure chamber was 28 m3, and concentrations were measured. Irritation, odor, and annoyance scores during exposure to clean air were 0.1, 0.1, and 1.3, respectively. The eye irrita- tion score was 0.4 for the constant 10-ppm MEK concentration. For the chang- ing conditions, odor ratings followed the peaks and valleys of the exposure con- centrations, ratings of ≥ 3 ranging from 0-9% of respondents at 10 ppm to 55-91% of respondents at 380 ppm. The averaged ratings for eye and nose irrita- tion were similar and were verbally scored “hardly at all.” Statistically, odor had the strongest effect, followed by annoyance and irritation. The authors (Seeber et al. 2002) concluded that there was no evidence of sensory irritation on a sub- jective level. When subjects in the Seeber et al. (2002) study were divided into those with “self-reported multiple chemical sensitivity” (sMCS), measured by re- sponse to items on a questionnaire, and subjects who were not sensitive to chemicals (controls), the scores for the sMCS increased with time, whereas those for the controls did not. Each of the nine ratings for the sMCS subjects, taken during the 4-h exposure, was ≤ 1 (“hardly at all”) for nose and eye irrita- tion, and the scores for the controls were all ≤ 0.25 (close to “not at all”). The 95% confidence interval for nose and eye irritation never rose above a score of 1.5. Inflammatory biomarkers—eosinophil cationic protein, myeloperoxidase, interleukin 1β, substance P, and neurokinin—were not affected by either expo- sure in either the control or the sMCS groups (van Thriel et al. 2003a). A weak dose-response increase in nasal symptoms was reported by the sMCS group; however, mean scores for nasal and eye irritation were never greater than 1 on a scale of 0-5; controls scored 0.2. There was no effect on nasal flow. (Compared with the controls, sMCS subjects had a significant decrease in the flow value in anterior rhinomanometry independent of dose [Wiesmuller et al. 2002]). Breath- ing rate and heart rate of the two groups of subjects reported in another paper (Haumann et al. 2003) were not changed appreciably by the exposures. Patty et al. (1935) stated that 33,000 and 100,000 ppm were intolerable to humans because of irritation of the eyes and nasal passages. A concentration of 10,000 ppm was intolerable after a few inhalations because of irritation to the eyes and nose, and 3300 ppm had a moderate-to-strong odor and was moder- ately irritating to the eyes and nose (no exposure durations given). The raw data or the source of the data were not provided, but the exposures presumably took place during the authors’ exposure of guinea pigs to the same concentrations. 2.2.3. Monitoring Studies Monitoring studies indicated that workers were routinely exposed to MEK at ≤ 100 ppm, as taken by instantaneous and 4-h passive samplers (Miyasaka et al. 1982; Brugnone et al. 1983; Perbellini et al. 1984), and to TWA exposures up

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150 Acute Exposure Guideline Levels to 224 ppm (Yoshikawa et al. 1995) and 270 ppm (median value, 26 ppm) (Im- briani et al. 1989); in one case, 4-h TWA exposures ranged up to 950 ppm (Ghittori et al. 1987). Samples were taken by several methods, including instan- taneous samples via glass tubes and 2- and 4-h passive samplers. In some cases, workers were exposed to a mixture of solvents. Health effects were not ad- dressed in these studies. 2.2.4. Case Reports In occupational settings, the primary routes of exposure are inhalation and skin contact. Symptoms incurred by workers during occupational exposures have been described. MEK is a strong degreasing agent, and contact with the skin might result in dermatitis. Workers handling MEK while manufacturing raincoat water-proofing material developed severe dermatosis with a complete lack of sensation in the digits and limbs (Smith and Mayers 1944). Workroom concentrations ranged from 300 to 600 ppm. Dermal contact with liquid MEK during the processes was highly likely because it was reported that workers tended to wash their hands in the solvent. Two workers in a similar plant where exposures were at 1,000 ppm measured as ketone vapors (acetone at 330-495 ppm plus MEK at 398-561 ppm) suffered episodes of CNS depression, and loss of consciousness (Smith and Mayers 1944). 2.2.5. Epidemiologic Studies Available epidemiology studies involved a mixture of solvents and gener- ally addressed neurotoxicity (Arlien-Soberg 1991). Adverse effects could not clearly be related to exposure to MEK alone and therefore are not discussed in this report. Epidemiology studies that addressed the potential carcinogenicity of MEK are discussed in Section 2.6 (Carcinogenicity). 2.3. Neurotoxicity During 4-h exposures of male and female human subjects to MEK at 90 to 270 ppm, the subjects participated in time-estimation tests (Nakaaki 1974). The concentration increased over the 4-h periods; the average concentration for each exposure was 150 ppm. There were nine morning and nine afternoon sessions, and two males and two females participated in each session. Males tended to underestimate times of 5 to 30 s, and females showed more variable results compared with control estimates of time. The time-estimation values from this study were highly variable, and no statistical differences were presented be- tween or among the exposure groups. The subjects reported a strong odor at 90 ppm. This study differs from recent well-conducted clinical studies in that symp- toms of tears and sneezes were reported (see Table 3-3 for results of recent stud-

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187 Methyl Ethyl Ketone Stoltenburg-Didinger, G., H. Altenkirch, and M. Wagner. 1990. Neurotoxicity of organic solvent mixtures: Embryotoxicity and fetotoxicity. Neurotoxicol. Teratol. 12(6):585-589. Stone, L.C., G.T. Lawhorn, J.C. McKinney, and M.S. McCracken. 1981. Upper respira- tory tract sensory responses to volatile chemicals. Toxicologist 1:134 [Abstract 288]. Tada, O., K. Nakaaki, and S. Fukabori. 1972. An experimental study on acetone and methyl ethyl ketone concentrations in urine and expired air after exposure to those vapors. J. Sci. Labour 48:305-336. 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. ten Berge, W.F., A. Zwart, and L.M. Appleman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309. ToxiGenics, Inc. 1981. 90-Day Vapor Inhalation Toxicity Study of Methyl Ethyl Ketone in Albino Rats. Study 420-0305. EPA 560/1981/CIIT/004. Prepared by ToxiGen- ics, Inc., Decatur, IL, for the Chemical Industry Institute of Toxicology, Research Triangle Park, NC. Traiger, G.J., and J.V. Bruckner. 1976. The participation of 2-butanone in 2-butanol- induced potentiation of carbon tetrachloride hepatotoxicity. J. Pharmacol. Exp. Ther. 196(2):493-500. van Engelen, J.G., W. Rebel-de Haan, J.J. Opdam, and G.J. Mulder. 1997. Effect of co- exposure to methyl ethyl ketone (MEK) on n-hexane toxicokinetics in human vol- unteers. Toxicol. Appl. Pharmacol. 144(2):385-395. van Thriel, C., K. Haumann, E. Kiesswetter, M. Blaszkewicz, and A. Seeber. 2002. Time courses of sensory irritations due to 2-butanone and ethyl benzene exposure: Influ- ences of self-reported multiple chemical sensitivity (sMCS). Int. J. Hyg. Environ. Health 204(5-6):367-369. van Thriel, C., G.A. Wiesmuller, M. Blaszkewicz, K. Golka, E. Kiesswetter, A. Seeber, and C. Bachert. 2003a. Intranasal effects in chemically sensitive volunteers: an ex- perimental exposure study. Environ. Toxicol. Pharmacol. 14(3):129-137. van Thriel, C., A. Seeber, E. Kiesswetter, M. Blaszkewicz, K. Golka, and G.A. Wiesmul- ler. 2003b. Physiological and psychological approaches to chemosensory effects of solvents. Toxicol. Lett. 140-141:261-271. Walter, G., M. Berg, J.G. Filser, and H. Greim. 1986. Toxicokinetics of the inhaled sol- vents n-hexane, 2-butanone, and toluene in the rat: Alone and in combination. N-S. Arch. Pharmacol. 334 (Suppl.1) R22 [Abstract 87]. Wen, C.P., S.P. Tsai, N.S. Weiss, R.L. Gibson, O. Wong, and W.A. McClellan. 1985. Long-term mortality study of oil refinery workers. IV. Exposure to the lubricating- dewaxing process. J. Natl. Cancer Inst. 74(1):11-18. WHO (World Health Organization). 1993. Methyl Ethyl Ketone. Environmental Health Criteria 143. Geneva, Switzerland: World Health Organization [online]. Available: http://www.inchem.org/documents/ehc/ehc/ehc143.htm [accessed Nov. 5, 2010]. Wiesmuller, G.A., C. van Thriel, A. Steup, C. Bachert, M. Blaszkewicz, K. Golka, E. Kiesswetter, and A. Seeber. 2002. Nasal function in self-reported chemically intol- erant individuals. Arch. Environ. Health 57(3):247-254. Witschi, H.R., and J.A. Last. 2001. Toxic responses of the respiratory system. P. 519-534 in Casarett & Doull’s Toxicology: The Basic Science of Poisons, C.D. Klaassen, ed. New York: McGraw-Hill.

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188 Acute Exposure Guideline Levels Wurster, D.E., and R. Munies. 1965. Factors influencing percutaneous absorption II. Absorption of methyl ethyl ketone. J. Pharmaceut. Sci. 54(4):554-556. Yoshikawa, M., T. Kawamoto, K. Murata, K. Arashidani, T. Katoh, and Y. Kodama. 1995. Biological monitoring of occupational exposure to methyl ethyl ketone in Japanese workers. Arch. Environ. Contam. Toxicol. 29(1):135-139. Zakhari, S., M. Leibowitz, P. Levy, and D.M. Aviado. 1977. Acute, oral, intraperitoneal, and inhalational toxicity in the mouse. P. 67-69 in Isopropanol and Ketones in the Environment, L. Golberg, ed. Cleveland, OH: CRC Press.

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189 Methyl Ethyl Ketone APPENDIX A DERIVATION OF AEGL VALUES FOR METHYL ETHYL KETONE Derivation of AEGL-1 Values Key studies: Dick et al. (1992); Muttray et al. 2002; Seeber et al. 2002; Shibata et al. 2002 Toxicity end points: 200 for 4 h and 380 ppm for several 8-min exposure durations were NOAELs for sensory irritation and CNS effects; the lower number was chosen as the basis for the AEGL-1. Time-scaling: Not applied Uncertainty factors: 1 for intraspecies variability Modifying factor: Not applied Calculations: The 200-ppm concentration was used for all exposure durations. 10-min AEGL-1: 200 ppm 30-min AEGL-1: 200 ppm 1-h AEGL-1: 200 ppm 4-h AEGL-1: 200 ppm 8-h AEGL-1: 200 ppm Derivation of AEGL-2 Values Key studies: Altenkirch et al. (1978); Cavender et al. (1983) Toxicity end points: 5,000 ppm was a NOAEL for neurobehavioral effects (narcosis) on the first and subsequent days of a sub- chronic study with rats; exposures were for 6 h/day, 5 days/week, for 90 days. Time-scaling: Default value of n = 3 applied to shorter exposure durations

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190 Acute Exposure Guideline Levels Uncertainty factors: 1 for interspecies; rodents have higher respiratory rates and cardiac output than humans; metabolism differences will not be significant at high, acute exposures. 3 for intraspecies; differences among humans for CNS effects of anesthetics are not expected to vary greatly. Modifying factor: Not applied Calculations: 5,000 ppm/3 = 1,700 ppm C3 × 240 min = k (1,700)3 × 240 min = 1.179 × 1012 ppm3-min [(1.179 × 1012 ppm3-min)/10 min]1/3 10-min AEGL-2: C = 4,900 ppm [(1.179 × 1012 ppm3-min)/10 min] 1/3 30-min AEGL-2: C = 3400 ppm [(1.179 × 1012 ppm3-min)/60 min] 1/3 1-h AEGL-2: C = 2700 ppm 4-h AEGL-2: 1,700 ppm 8-h AEGL-2: 1,700 ppm Derivation of AEGL-3 Values Key studies: 10 and 30 min: Zakhari et al. 1977; Klimisch 1988; Hansen et al. 1992; 1, 4, and 8 h: La Belle and Brieger 1955 Toxicity end points: (1) Threshold for lethality—mouse, rat 30-min exposure of rats at 92,239 ppm (Klimisch 1988) 45-min exposure of mice at 50,000 ppm (Zakhari et al. 1977) Calculated 30-min RD50 of 31,246 ppm—mice (Hansen et al. 1992) (2) 4-h MLE01 of 7,500 ppm for rat calculated by Fowles et al. (1999) from data of La Belle and Brieger (1955)

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191 Methyl Ethyl Ketone Time-scaling None for 10- and 30-min values None for 4- and 8-h values 1-h value time-scaled from 4-h value using n = 3 (Cn × t = k) Uncertainty factors: 1 for interspecies; rodents have higher respiratory rates and cardiac output than humans; metabolism differences will not be significant at high, acute exposures. 3 for intraspecies; differences among humans for irritancy and CNS effects are not expected to vary greatly. Modifying factor: Not applied Calculations: (1) values adjusted to 10,000 ppm (2) 7,500 ppm/3 = 2,500 ppm 4-h value: (2,500 ppm)3 × 240 min = 3.75 × 1012 ppm3-min 10-min AEGL-3: 10,000 ppm 30-min AEGL-3: 10,000 ppm C3 × 60 min = 3.75 × 1012 ppm3-min 1-h AEGL-3: C = 4,000 ppm 4-h AEGL-3: 2,500 ppm 8-h AEGL-3: 2,500 ppm

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192 Acute Exposure Guideline Levels APPENDIX B CATEGORY GRAPH OF TOXICITY DATA AND AEGL VALUES 1000000 Human - No Effect Human - Discomfort 100000 Human - Disabling Animal - No Effect 10000 ppm AEGL-3 Animal - Discomfort 1000 AEGL-2 Animal - Disabling Animal - Some Lethality 100 AEGL-1 Animal - Lethal AEGL 10 0 60 120 180 240 300 360 420 480 Minutes FIGURE 3-2 Category graph of toxicity data and AEGL values. TABLE B-1 Data Used in Category Graph Categorya Source Species ppm Minutes NAC/AEGL-1 200 10 AEGL NAC/AEGL-1 200 30 AEGL NAC/AEGL-1 200 60 AEGL NAC/AEGL-1 200 240 AEGL NAC/AEGL-1 200 480 AEGL NAC/AEGL-2 4,900 10 AEGL NAC/AEGL-2 3,400 30 AEGL NAC/AEGL-2 2,700 60 AEGL NAC/AEGL-2 1,700 240 AEGL NAC/AEGL-2 1,700 480 AEGL NAC/AEGL-3 10,000 10 AEGL NAC/AEGL-3 10,000 30 AEGL NAC/AEGL-3 4,000 60 AEGL (Continued)

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193 Methyl Ethyl Ketone TABLE B-1 Continued Categorya Source Species ppm Minutes NAC/AEGL-3 2,500 240 AEGL NAC/AEGL-3 2,500 480 AEGL Nelson et al. 1943 Human 100 5 0 Human 200 5 1 Human 350 5 1 Shibata et al. 2002 and Human 200 120 0 others Dick et al. 1992 and Human 200 240 0 others Seeber et al. 2002 Human 380 8 0 Patty et al. 1935 Human 3,300 1 2 Seeber et al. 2002 Human 10 480 0 Klimisch 1988 Rat 92,239 180 SL Rat 92,239 30 2 Pozzani et al. 1959 Rat 8,000 480 SL Smyth et al. 1962 Rat 2,000 120 0 LaBelle and Brieger 1955 Mouse 103,000 43 3 Mouse 9,090 240 SL Mouse 11,700 240 SL Mouse 7850 240 2 Zakhari et al. 1977 Mouse 69,500 45 SL Mouse 50,000 45 2 Patty et al. 1935 Guinea pig 100,000 45 3 Guinea pig 33,000 200 3 Guinea pig 10,000 480 2 Geller et al. 1979 Baboon 100 480 0 Altenkirch et al. 1978 Rat 10,000 480 2 Rat 6,000 480 0 Hansen et al. 1992 Mouse 26,000 30 2 Mouse 10,000 30 1 DeCeaurriz et al. 1981 Mouse 10,745 5 2 Stone et al. 1981 Mouse 5,000 10 1 Mouse 9,000 10 2 Glowa and Dews 1987 Mouse 10,000 9.5 2 Mouse 5600 9.5 2 Mouse 1,000 9.5 0 Mouse 300 9.5 0 Patty et al. 1935 Guinea pig 3,300 240 0 Guinea pig 10,000 40 2 a Categories: 0, no effect; 1, discomfort; 2, disabling; SL, some lethality; and 3, lethal.

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194 Acute Exposure Guideline Levels APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR METHYL ETHYL KETONE Derivation Summary for Methyl Ethyl Ketone AEGL-1 VALUES 10 min 30 min 1h 4h 8h 200 ppm 200 ppm 200 ppm 200 ppm 200 ppm Key references: 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(3):453-473. Muttray, A., D. Jung, L. Klimek, and C. Kreiner. 2002. Effects of an external exposure to 200 ppm methyl ethyl ketone on nasal mucosa in healthy volunteers. Int. Arch. Occup. Environ. Health 75(3):197-200. Seeber, A., C. van Thriel, K. Haumann, E. Kiesswetter, M. Blaszkewicz, and K. Golka. 2002. Psychological reactions related to chemosensory irritation. Int. Arch. Occup. Environ. Health 75(5):314-325. Shibata, E., G. Johanson, A. Lof, L. Ernstgard, E. Gullstrand, and K. Sigvardsson. 2002. Changes in n-hexane toxicokinetics in short-term single exposure due to co- exposure to methyl ethyl ketone in volunteers. Int. Arch. Occup. Environ. Health 75(6):399-405. Test species/Strain/Number: Human/24 subjects (Dick et al. 1992); 19 male subjects (Muttray et al. 2002); 24 subjects (Seeber et al. 2002); 4 male subjects (Shibata et al. 2002) Exposure route/Concentrations/Durations: 200 ppm for 4 h (Dick et al. 1992; Muttray et al. 2002); 200 ppm for 2 h (Shibata et al. 2002); 10-380 ppm (average 188 ppm) for over 4 h (Seeber et al. 2002) Effects: At 200 ppm, unobjectionable, no neurobehavioral effects, and no other effects reported in additional studies End point/Concentration/Rationale: NOAEL for irritation and neurobehavioral deficits Uncertainty factors/Rationale: Total uncertainty factor: 1 Interspecies: Not applicable Intraspecies: 1, no susceptible populations were located. The intensity of discomfort associated with 200 ppm is not expected to vary greatly among the general population. Modifying factor: Not applied Animal-to-human dosimetric adjustment: Not applicable (Continued)

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195 Methyl Ethyl Ketone AEGL-1 VALUES Continued 10 min 30 min 1h 4h 8h 200 ppm 200 ppm 200 ppm 200 ppm 200 ppm Time-scaling: Not applied; a tolerance develops to any irritation Data adequacy: The database on clinical and monitoring studies is extensive. MEK is rapidly metabolized. Short exposures of healthy subjects and subjects with sMCS at 380 ppm without apparent adverse effects supports the concentration of 200 ppm for the general population. AEGL-2 VALUES 10 min 30 min 1h 4h 8h a a a 4,900 ppm 3,400 ppm 2,700 ppm 1,700 ppm 1,700 ppm Key reference: Cavender, F.L., H.W. Casey, H. Salem, J.A. Swenberg, and E.J. Gralla. 1983. A 90- day vapor inhalation toxicity study of methyl ethyl ketone. Fundam. Appl. Toxicol. 3(4):264-270. Supporting reference: Altenkirch, H., G. Stoltenburg, and H.M. Wagner. 1978a. Experimental studies on hydrocarbon neuropathies induced by methyl-ethyl-ketone (MEK). J. Neurol. 219(3):159-170. Test species/Strain/Number: Rat/Fischer 344/15 males and 15 females (Cavender et al. 1983); Wistar/5 rats (Altenkirch et al. 1978) Exposure route/Concentrations/Durations: Inhalation/0, 1,250, 2,500, or 5,000 ppm for 6 h/day, 5 days/week, for 90 days (Cavender et al. 1983); 6,000 ppm for 8 h/day, 7 days/week, for several weeks (Altenkirch et al. 1978) Effects: At 5,000 ppm, no irritation, no narcosis, and transient weight loss (Cavender et al. 1983); at 6,000 ppm, hyperexcitability followed by somnolence within 5-10 min and gait disturbance after exposures, no neuropathies, animals died of bronchopneumonia in 7th week (Altenkirch et al. 1978). End point/Concentration/Rationale: NOAEL for neurobehavioral deficits at 5,000 ppm for 6 h Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, uptake is greater and faster in rodents compared with humans. Intraspecies: 3, no susceptible populations identified; metabolism is not expected to vary greatly among individuals; and susceptibility to CNS depression does not vary by more than a factor of 2- to 3-fold among the general population. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applied (Continued)

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196 Acute Exposure Guideline Levels AEGL-2 VALUES Continued 10 min 30 min 1h 4h 8h a a a 4,900 ppm 3,400 ppm 2,700 ppm 1,700 ppm 1,700 ppm Time-scaling: The 4- and 8-h exposures were set equal to 1,700 ppm; the 10- and 30- min and 1-h values were time-scaled with the default n value of 3. Data adequacy: Extensive database of human (irritation, neurotoxicity, and metabolism) and animal studies (baboon, rat, mouse, and guinea pig); animal studies addressed irritation, neurotoxicity, developmental toxicity, and subchronic toxicity; the Cavender et al. (1983) study is supported by a study with rats conducted at 6,000 ppm (Altenkirch et al. 1978); the key study utilized groups of 15 male and 15 female rats; and complete histologic examinations were performed at the end of exposure. a The 10- and 30-min and the 1-h AEGL-2 values are higher than one-tenth of the lower explosive limit (LEL) of MEK in air (LEL = 18,000 ppm). Therefore, safety considera- tions against the hazard of explosion must be taken into account. AEGL-3 VALUES 10 min 30 min 1h 4h 8h a a 4,000 ppmb 2,500 ppmb 2,500 ppmb Key references: Fowles, J.R., G.V. Alexeeff, and D. Dodge. 1999. The use of the benchmark dose methodology with acute inhalation lethality data. Regul. Toxicol. Pharmacol. 29(3):262-278. Hansen, L.F., A. Knudsen, and G.D. Nielsen. 1992. Sensory irritation effects of methyl ethyl ketone and its receptor activation mechanism. Pharmacol. Toxicol. 71(3 Pt. 1):201-208. Klimisch, H. 1988. The inhalation hazard test; principle and method. Arch. Toxicol. 61(5):411-416. La Belle, C.W., and H. Brieger. 1955. The vapor toxicity of a composite solvent and its principal components. Arch. Ind. Health 12(6):623-627. Zakhari, S., M. Leibowitz, P. Levy, and D.M. Aviado. 1977. Acute, oral, intraperitoneal, and inhalational toxicity in the mouse. P. 67-69 in Isopropanol and Ketones in the Environment, L. Golberg, ed. Cleveland, OH: CRC Press. Test species/Strain/Number: Rat/unspecified/6 rats (Klimisch 1988); mouse/CF-1/10 per group (Zakhari et al. 1977); mouse/CF-1/4 per group (Hansen et al. 1992); rat/strain not given/6 per group (La Belle and Brieger 1955) Exposure route/Concentrations/Durations: Inhalation/92,239 ppm for 30 min or 3 h (Klimisch 1988); 50,000, 60,000, 70,000, 80,000, or 100,000 ppm, for 45 min (Zakhari et al. 1977); 0, 3809, 9136, 12,771, 24,179, or 26,416 ppm, for30 min (Hansen et al. 1992); 7,850, 9,090, 9,260, 12,200, 13,750, 18,100, or 20,200 ppm, for 4 h (La Belle and Brieger 1955) (Continued)

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197 Methyl Ethyl Ketone AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h a a b b 2,500 ppmb 4,000 ppm 2,500 ppm Effects: No deaths at 96,239 ppm for 30 min (Klimisch 1988); no deaths at 50,000 ppm for 45 min (Zakhari et al. 1977); concentration-dependent decrease in respiratory rate and tidal volume; calculated RD50 of 31,246 ppm; no deaths at 26,000 ppm for 30 min (Hansen et al. 1992); and no deaths at 7,850 ppm (La Belle and Brieger 1955) End point/Concentration/Rationale: On the basis of the first three studies, 10,000 ppm would not be life-threatening to humans; at 7,500 ppm for 4-h, maximum likelihood estimate, with a 1% response (MLE01) calculated by Fowles et al. (1999) from data of La Belle and Brieger (1955) Uncertainty factors/Rationale: Total uncertainty factor: 3 Interspecies: 1, uptake is greater and faster in rodents than in humans. Intraspecies: 3, no susceptible populations identified; CNS depression does not vary by more than a factor of 2-3 among the general population. Modifying factor: Not applicable Animal-to-human dosimetric adjustment: Not applied Time-scaling: Cn × t = k. Default value of n = 3 used when scaling from longer to shorter time intervals; both 4- and 8-h values set equal to 2,500 ppm; 1-h value time-scaled from the 4-h value Data adequacy: Extensive database of human (irritation, neurotoxicity, and metabolism) and animal studies (baboon, rat, mouse, and guinea pig); animal studies addressed irritation, neurotoxicity, developmental toxicity, and subchronic toxicity; studies were supported by no deaths in rats exposed at 10,000 ppm for several days (Altenkirch et al. 1978) and no deaths in guinea pigs exposed at 10,000 ppm for 13.5 h (Patty et al. 1935). a The 10- and 30-min AEGL-3 value of 10,000 ppm (29,300 mg/m3) is higher than 50% of the lower explosive limit (LEL) of MEK in air (LEL = 18,000 ppm). Therefore, extreme safety considerations against the hazard of explosion must be taken into account. b The 1-, 4-, and 8-h AEGL-3 values are higher than one-tenth of the LEL of MEK in air (LEL = 18,000 ppm). Therefore, safety considerations against the hazard of explosion must be taken into account.