Methyl ethyl ketone

Methyl ethyl ketone Toxic Tips INTRODUCTION Chemical and Physical Description

Methyl ethyl ketone, C4H8O, also known as 2-butanone, methyl acetone, ethyl methyl ketone, and MEK, is a ketone that has both a methyl group and an adjacent ethyl group.1 It is a colorless liquid with a minty or acetone-like odor.2 MEK is soluble in water and miscible in alcohol, ether, and benzene.3 It is highly volatile and flammable.4 MEK vapor is heavier than air, having a density of 0.805 g/cm3 at 20 8C.1,4 The CAS registry number for methyl ethyl ketone is 78-93-3. Its molecular weight is 72.11.5

3-hydroxy-2-butanone, which is then reduced to 2,3-butanediol and a small portion is reversibly converted to 2-butanol.6 2,3-butanediol is eventually metabolized to carbon dioxide and water.9 The majority of MEK is eliminated as carbon dioxide and water, primarily through the lungs.7 MEK is quickly removed from the blood, having a plasma half-life ranging from 46 to 96 minutes in humans.7 2-3% of MEK absorbed into the body is eliminated unchanged via exhalation.9 Another 3% on average is eliminated in the urine as metabolites 2,3-butanediol and 3-hydroxy-2-butanone.8,9 There is insufficient evidence to support that MEK accumulates in body tissues.4

Uses and Typical Exposure Situations

Methyl ethyl ketone is used as a solvent in the manufacture and application of paints and paint removers, acrylic coatings, varnishes, and adhesives. It is used in food and pharmaceutical production and processing. MEK is also used as a sterilizing agent for bacterial spores on surgical instruments, dental instruments, and hypodermic needles. According to the National Occupational Exposure Survey (NOES) conducted by the National Institute for Occupational Safety and Health (NIOSH) from 1981 to 1983, an estimated 1,400,000 workers are potentially exposed to MEK in the U.S. MEK can enter the water supply via cement at the joint connections of PVC pipe. MEK can also be found in tobacco smoke.6,7 MEK is a natural component of various foods including milk, cheese, raw chicken breast, and nectarines. It is released into the atmosphere by plants and animals as a metabolic byproduct. It is also emitted by volcanoes and forest fires.6,7 Metabolism and Pharmacokinetics

Methyl ethyl ketone is absorbed rapidly by respiratory and dermal routes.8 Due to its solubility in water, MEK is more rapidly absorbed by moist skin than dry skin.6,7 When applied to dry skin, a plateau for the concentration of MEK in exhaled air is reached in 4–5 hours. But when MEK is applied to moist skin, it can be detected in expired air within 30 seconds and reaches maximum concentration around 10-15 minutes after application.6 Because MEK is water soluble, it is easily distributed in the blood throughout the body. Because it is lipid soluble, MEK is evenly distributed among the tissues.9 MEK is metabolized to

1871-5532 http://dx.doi.org/10.1016/j.jchas.2015.06.007

PATHOPHYSIOLOGY Determinants of Toxicity

The airborne concentration of methyl ethyl ketone, the respiratory rate of the individual, and the time of exposure to the contaminated air determine the amount of toxicant absorbed through the respiratory system. The area of skin exposed, the concentration of the MEK, the moisture of the skin, and the length of time of skin contact determine the amount of MEK absorbed through the skin.6 Mechanisms of Action

MEK is known to potentiate the neurotoxicity of unbranched aliphatic hexacarbons, such as nhexane. MEK also potentiates hepatic and renal toxicity of haloalkanes.7 In one study, the effects of n-hexane, MEK, and a combination of both solvents were studied in rats. The solvents caused axon swelling by dramatically multiplying the number of neurofilaments. Other nonspecific alterations also occurred, including accumulation of clusters of phospholipids in the cytoplasm of Schwann cells and the accumulation of both phospholipids and glycogen in the axoplasm of nerve fibers. Schwann cells also underwent degenerative changes.7 Additionally, MEK induces microsomal P450 activity. So repeated exposures may enhance the metabolism of future exposures to MEK.6 CLINICAL PRESENTATION Effects Following Inhalation

MEK is known to cause irritation to the respiratory tract. Breathing MEK vapors can cause

ß Division of Chemical Health and Safety of the American Chemical Society Elsevier Inc. All rights reserved.

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sufficient irritation of the mucous membranes of the nose and throat leading to coughing and wheezing. When sufficient concentrations are inhaled, dizziness, lightheadedness, headache, nausea, vomiting, and unconsciousness can occur.1,10 Exposures to high levels of MEK can potentially cause damage to both the peripheral nervous system (PNS) and central nervous system (CNS).11 Effects Following Skin Exposure

MEK is a known skin irritant. Exposure can cause a rash or burning feeling.10 Repeated exposure can cause inflammation and defatting of the skin.4 Effects Following Eye Exposure

Direct contact of the eyes with MEK can cause irritation, burning, and cornea damage.4 Carcinogenicity

Since there are no human carcinogenicity data and inadequate animal data, the carcinogenicity of MEK cannot be determined at this time.7 However, mechanism-based structure-activity relationship (SAR) analysis determined that MEK is not likely to be carcinogenic. This type of analysis involves comparing a compound with unknown carcinogenic activity to compounds with a similar structure and known carcinogenic activity. Specifically, the structural features, functional properties, and probable mechanism(s) of action are evaluated.12 Reproductive Effects

Although it has been reported that MEK can cross the placenta and enter the human fetus, there is insufficient data to determine if MEK is a teratogen in humans.7 One study in mice showed a statistically significant increase in the incidence of misaligned sternebrae in fetuses whose mothers were exposed to MEK for ten days at a concentration of 3,000 ppm during gestation (sternebrae are segments of bone in fetuses that fuse later in development to form the sternum).13 The authors of this study concluded that MEK vapors at such levels cause mild developmental toxicity. MEK should be treated as a

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possible teratogen until more data is available.10 FIRST AID AND CLINICAL MANAGEMENT

In the case of high exposure by inhalation, move the individual to fresh air. Monitor the individual for breathing difficulties and administer oxygen if necessary. Mouth to mouth resuscitation should only be used if absolutely necessary. If MEK is ingested, the mouth of the individual should be rinsed with water and the contents spit out. Vomiting should not be induced. If eye exposure occurs, the eyes of the individual should be rinsed thoroughly with water for ten minutes. If skin exposure occurs, any contaminated clothing should be removed and the exposed skin should be thoroughly cleaned with soap and water. In severe exposure cases, further medical treatment should be provided as quickly as possible.4

HANDLING AND EXPOSURE Accidental Release Measures

If a spill occurs, all sources of ignition should be immediately shut off and the area evacuated.4 The spilled liquid should be absorbed with an inert absorbent such as diatomite, vermiculite, or sand. Dispose of the absorbent using methods approved by your Environmental Protection office.1,4 Respiratory, eye and hand protection should be worn during clean up. The area where the spill occurred should be well ventilated and decontaminated .4 MEK fires should be extinguished with alcohol foam, carbon dioxide, or dry chemicals.11 Storage Guidelines

MEK should be stored in tightly closed containers in cool, well-ventilated areas. It should be stored away from sources of ignition and heat.4,10 MEK should be kept away from strong oxidizers.1 Containers of MEK should be clearly and permanently labeled. Use original containers as much as possible.4

alkali chromium trioxide. It will ignite on contact with potassium tert-butoxide. MEK can form an explosive mixture with air.4,11 MEK produces explosive peroxides when reacted with hydrogen peroxide and hydrogen ion. Hydrogen ions (H+) can originate from acid solutions, such as nitric acid or sulfuric acid.4 Seven of these peroxides have been identified: 1,4,7-Trimethyl-1,4,7-triethyl-1,4,7cyclononatriperoxane (I); 1,4,7,10,13, 16-Hexamethy1-1,4,7,10,13,16-hexaethyl-1,4,7,10,13-pentaperoxy-l,16dihydroperoxide (II); 1,4,7,10,13-Pentamethyl-l,4,7,10,13-pentaethyl-l,4,7, 10-tetraperoxy-1,13-dihydroperoxide (III); 1,4,7,10-Tetramethy1-1,4,7,l0-tetraethyl-l,4,7-triperoxy-1,l0-dihydroperoxide; 2,20 -dihydroperoxy-2,20 -dibutyl peroxide (VI); 2,2-dihydroperoxybutane;1,4,7-Trimethyl-l,4,7-triethyl-l,4diperoxy-l,7-dihydroperoxide (V); and 2,2-Dihydroperoxybutane (VII). The most abundant product is 2,20 -dihydroperoxy-2,20 -dibutyl peroxide (VI). The reaction mechanism of this product is shown in Figure 1, which is entitled Synthesis of a Peroxide From Methyl Ethyl Ketone and Hydrogen Peroxide. In reaction 1 of the mechanism, MEK, hydrogen peroxide, and H+ react reversibly and form 2-hydroperoxy-2-butanol. This intermediate reacts with hydrogen peroxide and H+ in reaction 2, forming 2,2-dihydroperoxybutane and water. The 2,2-dihydroperoxybutane then reacts with 2-hydroperoxy2-butanol and H+ in reaction 3, producing 2,2 0 -dihydroperoxy-2,2 0 -dibutyl peroxide and water. The other, less abundant products are formed by 2,20 dihydroperoxy-2,20 -dibutyl peroxide continuing to react with the intermediate 2-hydroperoxy-2-butanol.14,15 Mixing MEK with 2-propanol will also produce explosive peroxides. MEK reacts vigorously with chloroform and alkali. Other incompatibilities of MEK include oleum, chlorosulfonic acid, isocyanates, pyridines, amines, ammonia, and inorganic acids.4,11

EXPOSURE CONTROLS

Reactivities and Incompatibilities

Sampling and Analysis

MEK is incompatible with strong oxidizers, such as trichloromethane/

The Occupational Safety and Health Administration (OSHA) calls for the

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[(Figure_1)TD$IG]

Figure 1. Synthesis of a peroxide from methyl ethyl ketone and hydrogen peroxide.

use of SKC Anasorb CMS (carbon molecular sieves) sampling tubes with calibrated personal air sampling pumps. Diffusive samples can be collected by exposing SKC 575-002 passive samplers or 3 M 3520 organic vapor monitors (OVMs) to workplace air. The MEK is desorbed with carbon disulfide containing 1% N,N-dimethylformamide. Analysis is performed by gas chromatography (GC) with a flame ionization detector.16 Exposure Guidelines

The American Conference of Governmental Industrial Hygienists (ACGIH) threshold limit value-time weighted average (TLV-TWA) for methyl ethyl ketone is 200 ppm averaged over an 8hour workshift. The short term exposure limit (STEL) is 300 ppm. The biological exposure index (BEI) for MEK is 2 mg MEK/L urine collected at the

end of a work shift.17 The NIOSH recommended exposure limit (REL) is 200 ppm averaged over a 10-hour workshift and 300 ppm, not to be exceeded during any 15 minute period.10 The OSHA permissible exposure limit (PEL) is 200 ppm averaged over an 8-hour workshift.11 The odor threshold range for MEK is 0.07339 ppm. Most sources reported the odor threshold to be well below the TLV-TWA and PEL values. Only one source reported an odor threshold range (34-339 ppm) that reached above the TLV-TWA and PEL values.18

should be worn. Butyl rubber is recommended for use as a protective material. Indirect-vent, impact and splash resistant goggles should also be worn. When there is potential for exposure over the TLV-TWA value, a MSHA/ NIOSH approved full facepiece respirator with an organic vapor cartridge should be worn. When there is potential for higher exposure, a NIOSH approved supplied-air respirator with a full facepiece should be worn and operated in a pressure-demand or other positive-pressure mode.10

REFERENCES PERSONAL PROTECTION

When working in an area where there is potential for exposure to MEK, solvent-resistant gloves and clothing

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1. National Institute for Occupational Safety and Health (NIOSH). [8_TD$IF]International Chemical Safety Cards (ICSC): Methyl Ethyl Ketone[8_TD$IF]. Accessed from http://www.cdc.gov/niosh/ipcsneng/ neng0179.html[9_TD$IF] on January 21, 2015.

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2. National Institute for Occupational Safety and Health (NIOSH). NIOSH Pocket Guide to Chemical Hazards: 2-Butanone. Accessed from [10_TD$IF]http://www. cdc.gov/niosh/npg/npgd0069.html[9_TD$IF] on January 21, 2015. 3. O’Neil, M. J.; Heckelman, P. E.; Koch, C. B.; Roman, K. J. The Merck Index, 14th ed[1_TD$IF]. Merck & Co: Whitehouse Station, NJ, 2006, pp. 1047–1048. 4. Institut fur Arbeitsschutz der Deutschen Gesetzlichen Unfaliversicherung (IFA). [12_TD$IF]GESTIS Substance Database: Butanone[13_TD$IF]. Accessed from http:// gestis-en.itrust.de/nxt/gateway.dll/ gestis_en/000000.xml?f=templates$fn= default.htm$vid=gestiseng:sdbeng$3.0[14_TD$IF] on January 21, 2015. 5. American Conference of Governmental Industrial Hygienists (ACGIH). [16_TD$IF]Documentation of the Threshold Limit Values for Chemical Substances: Methyl Ethyl Ketone, [17_TD$IF]7th ed. ACGIH: Cincinnati, OH, 2001, Accessed from http://www.acgih.org on January 21, 2015. 6. U.S. Environmental Protection Agency (EPA). Toxicological Review of Methyl Ethyl Ketone, dated September 2003. Accessed from [10_TD$IF]http://www.epa.gov/iris[18_TD$IF] on January 21, 2015. 7. National Library of Medicine (NLM). Hazardous Substances Data Bank (HSDB): Methyl Ethyl Ketone. Accessed from [10_TD$ IF ]http://toxnet.nlm.nih.gov/

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cgibin/sis/search2/f?./temp/2aMfLZ:2[19_TD$IF] on January 22, 2015. Still, K.; Jederberg, W.; Luttrell, W. Derivation of [20_TD$IF]occupational exposure limits, In Luttrell, W. E.; Jederberg, W. W.; Still, K. R. (Eds.), Toxicology Principles for the Industrial Hygienist, American Industrial Hygiene Association (AIHA): Fairfax, VA, 2008, p. 347. Zenz, C.; Dickerson, O. B.; Horvath, E. P., Jr. Occupational Medicine, 3rd ed[1_TD$IF]. Mosby-Year Book, Inc.: St. Louis, MO, 1994, p. 149. New Jersey Department of Health and Senior Services. [2_TD$IF]Hazardous Substance Fact Sheet: Acetone[23_TD$IF]. Accessed from http://nj.gov/health/eoh/rtkweb/documents/ fs/0006.pdf[24_TD$IF] on January 25, 2014. Lewis, Sr., ; Richard, J. Sax’s Dangerous Properties of Industrial Materials, 8th ed[1_TD$IF]. Van Nostrand Reinhold: New York, NY, 1992, p. 2319. Woo, Y.-T., ; Lai, D.; McLain, J. L.; Manibusan, M. K.; Dellarco, V. Use of [25_TD$IF]mechanism-based structure–activity relationships analysis in carcinogenic potential ranking for drinking water disinfection by-products. Environ. Health Perspect. 2002, 110, 75–87. Bingham, E.; Cohrssen, B.; Powell, C. H. Patty’s Toxicology Volumes [26_TD$IF]1–9, 5th ed. John Wiley & Sons: New York, N.Y, 2001.

14. Milas, N. A.; Golubovic´, A. Studies in [27_TD$IF]organic peroxides. XXV. Preparation, [28_TD$IF]separation and identification of peroxides derived from methyl ethyl ketone and hydrogen peroxide. J. Am. Chem. Soc. 1959, 81(21), 5824–5826. 15. Zhang, J.; Wu, W.; Qian, G.; Zhou, X. Continuous synthesis of methyl ethyl ketone peroxide in a microreaction system with concentrated hydrogen peroxide. J. [29_TD$IF]Hazard. Mater. 2010, 181, 1024–1030. 16. Occupational Safety and Health Administration (OSHA). [30_TD$IF]Sampling and Analytical Methods: 2-butanone (MEK) and Hexone (MIBK)[31_TD$IF]. Accessed from https://www.osha.gov/dts/sltc/ methods/mdt/mdt1004/1004.html[9_TD$IF] on March 28, 2015. 17. American Conference of Governmental Industrial Hygienists (ACGIH). [3_TD$IF]TLVs and BEIs Based on the Documentation of the Threshold Limit Values for Chemical Substances and Physical Agents & Biological Exposure Indices; ACGIH: Cincinnati, OH, 2014, p. 41. 18. Murnane, S. S.; Lehocky, A. H.; Owens, P. D. Odor Thresholds for Chemicals with Established Occupational Health Standards, 2nd ed[35_TD$IF][6. American Industrial Hygiene Association (AIHA): Falls Church, VA, 2013, pp. 107–108.

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