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Updated 21 November 2022
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This publication is available at https://www.gov.uk/government/publications/methyl-ethyl-ketone-properties-and-incident-management/methyl-ethyl-ketone-toxicological-overview
Methyl Ethyl Ketone (MEK) is well absorbed through all routes of exposure.
Following absorption, MEK is distributed throughout the body.
MEK main metabolites are:
MEK can be excreted unchanged through exhalation; however, the majority is excreted as metabolites (3H2B and 2,3-BD) in the urine or enters the general metabolism and is excreted as single compounds such as carbon dioxide or water, mostly via exhalation.
MEK is an irritant by all routes of exposure and potentially toxic following inhalation, ingestion or dermal contact.
Symptoms of systemic toxicity include gastrointestinal upset, headache, dizziness, fainting, tremor, incoordination, hypothermia, respiratory depression, bradycardia, tachycardia, dyspnoea, convulsions and coma. Hyperglycaemia, ketosis and metabolic acidosis may also occur alongside hepatic and renal toxicity.
Exposure to MEK may cause dryness, erythema, dermatitis, defatting of the skin and paraesthesia. Prolonged exposure may result in systemic toxicity.
Chronic exposure to low levels of MEK results in neurological effects.
MEK is not considered a reproductive or developmental toxicant. It has not been shown to be genotoxic, mutagenic or carcinogenic.
The physicochemical properties of MEK, low molecular weight, 72.11 g/mol and Logkow  of 0.3 indicating lipophilicity, suggest it is rapidly absorbed following oral, dermal and inhalation routes of exposure (2). Liira and others (1988), found in humans that 53% of inhaled MEK was absorbed over a 4-hour exposure period at 200ppm (590 mg/m3) (3). Pulmonary uptake of MEK has been found to be higher in children than adults due to increased ventilatory rate increasing the likelihood of adverse response due to higher dose absorbed. Case reports of MEK poisoning provide evidence of MEK absorption by the gastrointestinal (GI) tract following oral exposure in humans (4). MEK is rapidly absorbed following dermal absorption. It is detectable in expired air just 2.5 to 3 minutes following application to normal skin of the forearm, and within 30 seconds post-application to moist skin (5).
Following absorption, MEK is rapidly transferred into the blood and distributed to various tissues around the body (2). In vitro assessment shows similar solubility in water, blood and oil, with distribution coefficients of 254, 202 and 264 respectively (3). Studies have shown MEK to deposit in human kidney, liver, muscle, lung, heart, fat, blood and brain with no preferential distribution noted. (5, 6).
MEK has an elimination half-life of 10 hours (7). Metabolites 2,3-BD and 3H2B account for 2.4% to 38% conversion of the exposure dose (1, 8). One study suggests unchanged MEK is primarily excreted via the lungs (2), although other sources find only 3% of the administered dose is excreted as such (3). Generally, it is believed the bulk of MEK enters the general metabolism and is excreted as carbon dioxide or water, mostly via exhalation (1).
Few studies exist for MEK metabolism in humans. Two metabolites, 3-hydroxy-2-butanone (3H2B) and 2,3-butanediol (2,3-BD) have been detected in human urine following inhalation exposure, but collectively only represented 0.1 to 2% of the absorbed dose. A small proportion of MEK is converted back to its endogenous metabolic precursor 2-butanol, which was found (alongside 2,3-BD) in the blood of male volunteers exposed to 200 ppm (590 mg/m3) for 4 hours (2, 5). Studies in rats confirm the major metabolic pathway to follow oxidation to 3H2B and to progress as:
Figure 1 shows the metabolic flow of MEK in humans. Oxidative metabolism to the 3H2B intermediate predominates and results in the production of 2,3-BD. This pathway includes small reverse flow through each intermediate (1).
Following oral and intraperitoneal administration of MEK in rats and guinea pigs, metabolism yielded the same key metabolites as in humans: 3H2B, 2,3-BD and 2-butanol. These findings suggest these models share a similar route of metabolism to man (9, 10). These models confirmed MEK metabolism was mediated by cytochrome P450 enzymes. However, MEK metabolism was found to differ slightly in guinea pigs, where it is initially reduced to 2-butanol, only a minor metabolite in man, instead of being oxidised to 3H2B. These metabolites in guinea pigs were excreted in urine as O-glucuronides or O-sulfates following CYP mediated glucuronidation and sulfonation respectively. However, there is evidence of both oxidation and reductive pathways provided by Thrall and others (2002), who used inhibition of oxidative microsomal enzymes with pyrazole to demonstrate continued metabolism of MEK following inhalation exposure (6).
MEK has an inductive effect on several, predominately hepatic, enzymes. Acute oral exposure of rats to MEK at doses of 1,080 to 1,500 mg/kg/day for 1 to 7 days results in increased levels of CYP protein, increased activities of CYP-dependent monooxygenases (2). In addition, repeated daily doses of MEK at 1.87 ml/kg by gavage to male rats increases activity of 7-ethoxy coumarin- O-deethylase up to 500% after 1 to 7 days of MEK treatment. MEK increases liver cytochrome P450 content (33 to 86%) and glutathione-S-transferase (GST) activity (42 to 64%). Pre-treatment with MEK in rats also led to elevated total microsomal cytochrome P-450 and NADPH-dependent cytochrome-c-reductase. This was evidenced by increased rates of oxidation of N-nitrosodimethylamine, benzphetamine and pentoxyresorufin, and increased levels of immunoreactive protein for both P-450 isozymes. These induction effects may potentiate toxicity from metabolism of other compounds following exposure (1), although conflicting studies found MEK not to induce activation of CYP isoforms, such as 1A2 or 2E1, following MEK inhalation (2).
MEK exists naturally in the human body from isoleucine catabolism (1), but also a metabolism product of endogenous 2-butanol which is present at low levels in the body (5, 11). MEK can also be detected in environmental media, though usually at low levels. For example, MEK has been detected at concentrations of 200 ppb, 550 ppb and 15.0 ppb (200, 550 and 15 µg/kg) in water, soil and air samples respectively (2).
MEK is used as a solvent often found in mixtures with acetone, ethyl acetate, n-hexane, toluene, or alcohols. It has applications in the surface coating industry and in the dewaxing of lubricating oils. Other uses include the manufacture of colourless synthetic resins and leather treatment products, rubbers, lacquers, varnishes, glues, adhesives and sealants. MEK is also present in common household products, such as biocidal products, anti-freeze and de-icing products, glues, cleaning fluid, cosmetics and perfumes (10, 12).
Exposure to a small amount of MEK can result from its natural presence in foods such as raw chicken breast, milk, nuts and cheese amongst others, where it has been found at concentrations ranging from 0.3 to 19 ppm (0.3 to 19 mg/kg) and is listed as a food flavouring by the UN (13). Additionally, MEK exposure can result from contaminated drinking water but at low concentrations this may have little effect. MEK can be inhaled from tobacco smoke and household use of coating products following use (2, 14).
Occupational exposure to MEK may occur by inhalation and dermal contact during the loading and unloading of large quantities of commercial coating materials during shipment. The application of commercial coatings containing MEK without adequate protection may lead to high levels of exposure, primarily by inhalation (2). Workplace exposure limits (WELs) are enforced to protect workers from the harmful effects of MEK; in the UK there is no established long-term WEL (8 hour) and the short-term WEL (15 minute reference period) is 1.5 mg/m3 (15).
MEK is an irritant by all routes of exposure and potentially toxic following inhalation, ingestion or dermal contact. Symptoms of systemic toxicity include gastrointestinal upset, headache, dizziness, fainting, tremor, incoordination, hypothermia, respiratory depression, bradycardia, tachycardia, dyspnoea, convulsions and coma. Hyperglycaemia, ketosis and metabolic acidosis may also occur, as well as hepatic and renal toxicity (7).
MEK is a metabolite of isobutanol, and therefore exposure to either may potentiate toxicity as it results in higher exposure to MEK. It can potentiate the neurotoxic effects of n-hexane and methyl butyl ketone. MEK may also potentiate the hepatotoxic effects of carbon tetrachloride. In addition, pulmonary uptake of MEK has been found to be higher in children than adults increasing the likelihood of adverse responses due to higher dose absorbed (12).
The effects of MEK in humans following inhalation include neurological symptoms (headache, fatigue, feeling of intoxication) and mucous membrane irritation of the eyes, nose, and throat (2).
In a volunteer study, nose and throat irritation was recorded in both male and females exposed to 100 ppm (295 mg/m3) for 6 hours, becoming objectionable at 350 ppm (1032 mg/m3). It concluded females were more sensitive to irritant effects of MEK but offered no reason for the findings (2, 11, 14). Another study notes 200 ppm (590 mg/m3) to be the irritation threshold (16).
In contrast, other studies have not reported an effect at an exposure level of 200 ppm (590 mg/m3). The National Institute for Occupational Studies (NIOSH) completed an inhalation study involving 4-hour exposure to 590 mg/m3 (200 ppm) in humans and found no statistically significant increase in reported symptoms of mucous membrane irritation or indications of neurotoxicity suggesting acute inhalation toxicity is only observed at higher concentrations (17, 18). In support of this, it has been reported that exposure to MEK concentrations greater than several thousand ppm is required for reversible central nervous system (CNS) depression to occur (11). Additionally, volunteer studies have shown exposure to a constant concentration of 200 ppm (590 mg/m3) for up to 8 hours with short exposures at 380 ppm (1121 mg/m3) to be non-irritant (11).
More significantly, a 38-year-old male worker exhibited neurological symptoms following exposure to paint containing MEK and toluene in an enclosed, unventilated garage. Exposure occurred at an unknown concentration of MEK for an acute, but unspecified, period. Initial symptoms included nausea, headache, dizziness, and respiratory distress. Over the next several days, the subject experienced impaired concentration, memory loss, tremor, gait ataxia, and dysarthria. Subsequent MRI evaluation revealed fluid accumulation in the left parietal area of the brain. The condition was diagnosed as toxic encephalopathy with dementia and cerebellar ataxia. Some neurological deficits persisted for more than 30 months following acute exposure to the mixture. It is important to note that it is not clear from this report whether the neurological effects were due to exposure to MEK or toluene exclusively, or the combination of solvents (5).
Ingestion of MEK may cause nausea, vomiting, haematemesis and inflammation and pain of the oral mucosa with hypersalivation (7).
Acute toxicity can occur at high doses, for example accidental ingestion of an unknown quantity of MEK by a 47-year-old woman inadvertently resulted in a loss of consciousness, hyperventilation, and onset of severe metabolic acidosis upon hospital admission. Her plasma concentration for MEK was 950 mg/L (4). After a complete and uneventful recovery, she was discharged from the hospital (4). This evidence shows substantial acute oral exposure can result in serious toxicity, although this level of exposure is rare.
Exposure to MEK may cause dryness, erythema, dermatitis, defatting of the skin and paraesthesia. Dermatitis and paraesthesia can also occur following exposure to MEK vapour. Prolonged skin contact may lead to systemic toxicity (7).
One study found increased skin irritation following occupational exposure to 51 to 177 ppm (150 to 522 mg/m3) MEK fumes over an 8-hour shift. However, concerns were raised over the study design and therefore it was concluded these findings should not be used to influence health guidance values (2).
Ocular exposure to MEK vapour in humans has been reported to result in mild eye irritation at concentrations of 200 ppm (590 mg/m3) after 3 to 5 minutes (2, 11).
Effects observed in animals include death, irritation of respiratory tissue, eyes, and skin, liver congestion, kidney congestion, corneal opacity, narcosis and incoordination. It has also been shown in animals that renal toxicity is the most sensitive endpoint following oral exposure, but the supporting evidence is generally lacking to suggest the same in humans (6).
In rats an LC50 of 40,000 ppm (13,559 mg/m3) was determined for a 2-hour exposure, whilst an 8-hour exposure showed an LC50 of 23.5 mg/L (23,500 mg/m3) (11).
The effects of MEK include neurological symptoms and mucous membrane irritation of the eyes, nose, and throat. From laboratory animal studies, the following potential associations between MEK exposure and onset of health outcomes were made (2) eurobehavioral effects, eye and respiratory irritation (100 to 200 ppm/295 to 590 mg/m3); liver and kidney congestion, increased organ weight and mild renal necrosis (6,000 to 10,000 ppm/17,700 to 29,500 mg/m3); and fetotoxicity in rats (3,000 to 4,000 ppm/8,850 to 11,800 mg/m3).
Earlier studies determining time-to-incapacitation and time-to-death found exposure to 10,000 ppm (29,500 mg/m3) MEK produced incoordination in guinea pigs within 90 minutes, with unconsciousness following between 240 to 280 minutes. At higher concentrations (33,000 ppm/97,350 mg/m3), incoordination occurred at 18 to 30 minutes into exposure, and unconsciousness within 48 to 90 minutes. Death was due to narcosis and followed at 200 to 260 minutes; lung oedema was cited as secondary to narcosis. This shows the onset of neurological toxicity is more rapid at higher concentrations, and when sufficiently prolonged can result in lethal toxicity. However, there was no delayed deaths for guinea pigs that survived the exposures and shows removal from exposure may result in full if not partial recovery. It is important to note that likely exposure to residual environmental concentrations is typically lower than the concentrations used in these animal studies (2).
LD50 values for oral toxicity in adult rats and mice range from 2 to 6 g/kg (2).
Renal tubule damage has been reported in rats following an oral dose of 1 g/kg. An oral dose of 1.5 g/kg to rats resulted in a 63% increase in liver triglycerides after 16 to 23h, but did not alter liver histology or increase either of 2 enzymes, serum glutamic-pyruvic transaminase (alanine transferase (ALT)) and hepatic glucose-6-phosphatase. These results suggest that this dose caused metabolic disturbances to the liver of rats. In addition, a graded series of single doses of MEK to guinea pigs revealed high sensitivity to small changes in dosage. The low dose (0.75 g/kg) appeared to produce no liver damage, whereas 1.5 g/kg produced slight liver damage and 2.0 g/kg produced major liver damage. These results also suggest that guinea pigs and rats may be equally sensitive to MEK in terms of liver damage following oral exposure (2).
Guinea pigs exposed (via the eye) to ≥10,000 ppm (29,500 mg/m3) experienced eye irritation and lacrimation, when exposure reached 100,000 ppm (295,000 mg/m3) corneal opacity was reported. In the surviving guinea pigs, corneal opacity gradually recovered in 8 days.
MEK instilled into the conjunctival sac of rabbits caused irritation, corneal opacity, and conjunctivitis. However, these effects were generally reversible within 7 to 14 days (2).
Typically, chronic exposure to low levels of MEK results in neurological effects over mucous membrane irritation. This is typically because irritation occurs at higher concentrations than required to induce neurological effects. Therefore, it is possible for effects to occur at concentrations that go undetected by human sensory organs.
A case study describing occupational exposure of one individual via inhalation and dermal routes showed evidence of severe cerebellar and brainstem atrophy causing slurred speech, cerebral ataxia and sensory loss in arms and the left side of his face. A survey of his work area revealed peak MEK concentrations in excess of 5,000 mg/m3 in some operations and 10-minute concentrations of 900 mg/m3 (5).
Another case study in a 31-year old male engineer who had been occupationally exposed to MEK fumes at unreported concentrations over 7 months developed severe chronic headache, dizziness, loss of balance, memory loss, fatigue, tremors, muscle twitches, visual disturbances, throat irritation, and tachycardia. He had been working without the provision of personal protective equipment (PPE) and subsequent medical assessment diagnosed the individual with chronic toxic encephalopathy, peripheral neuropathy, vestibular dysfunction, and nasosinusitis. Further clarification of the predominant exposure route, exposure concentration, and progression of these medical conditions were not provided (5).
In a third case, a 27-year-old man developed multifocal myoclonus, ataxia, and postural tremor after occupational exposure (through dermal and inhalation pathways) over a 2-year period to solvents containing 100% MEK (Orti-Pareja and others, 1996). The actual exposure levels are unknown. The patient reported symptoms of dizziness, anorexia, and involuntary muscle movement, beginning about one month prior to admission. Symptoms of solvent toxicity disappeared one month after cessation of exposure (5).
In addition to neurotoxic symptoms, other occupational studies have reported ocular irritation, upper respiratory tract irritation and various types of bone, muscle, or joint pain (5). These case studies described above suggest development of chronic neurological toxicity may occur below an objectionable threshold of MEK exposure.
There is insufficient data on the effects of chronic ingestion of MEK in humans.
There are no studies in the literature addressing the genotoxicity of MEK in humans (2, 14).
There is limited data available to assess the carcinogenicity of MEK in humans.
Retrospective cohort studies of worker populations exposed to MEK provide no clear evidence of MEK posing a hazard for cancer. For example, in a historical prospective mortality study of 446 male workers exposed to MEK in a dewaxing plant with an average follow-up of 13.9 years, the observed deaths (46) were below the expected (55.51). There was a slight deficiency of deaths from neoplasms (13 observed; 14.26 expected) but there was a significant increase of deaths from tumours of the buccal cavity and pharynx (2 observed; 0.13 expected), which the authors considered to be due to chance. However, there were significantly fewer deaths from lung cancer (1 observed; 6.02 expected). In addition, the use of tobacco was not considered in this study. In view of the small numbers, it was concluded that there was no clear evidence of cancer hazard in the workers from this dewaxing plant (2, 5). In an additional retrospective cohort study of 1,008 male workers exposed to MEK in a dewaxing-lubricating oil plant the overall cancer mortality was lower than expected (2).
There are no studies available on the reproductive or developmental effects following inhalation, oral or dermal exposure to MEK alone. An increase in the incidence of congenital CNS defects was observed in the offspring of women exposed to a mixture of organic solvents during the first trimester of pregnancy, which was not thought to be associated specifically with MEK (12). One occupational study of 50 males exposed to a mixture of solvents (including MEK) and jet fuel at an aircraft maintenance facility found some subjects experienced a significant decline in sperm motility (19.5%) at 30 weeks (5).
No chronic MEK inhalation studies in animals are noted in the literature (5). In a sub-chronic inhalation study, 15 rats were exposed to MEK at vapour concentrations of 1,254, 2,518 and 5,041 ppm (3,699, 7,428 and 14,870 mg/m3) for 6 hours a day, 5 days a week for 90 days, to simulate occupational exposure (10). Effects included body weight changes, significantly elevated corpuscular haemoglobin in high-dose male and females, the liver weight, liver:body weight ratio, and liver:brain weight ratio were significantly elevated in high-dose male rats as well as the kidney:body weight ratio. In female rats, a significant dose response was observed in increased liver weight. In high-dose female rats, significantly depressed spleen and brain weights were also observed. The liver:body weight ratio was significantly elevated, and the brain:body weight ratio was significantly depressed in high-dose female rats. Also in this group, the liver:brain and kidney:brain weight ratios were significantly elevated (10).
No sub-chronic or chronic oral toxicity studies of MEK in experimental animals were located (5).
MEK produced negative results for gene mutation in the Ames assay in various strains of Salmonella typhimurium (TA97, TA98, TA100, TA1535, TA1537), with and without metabolic activation. Negative results were reported in the in vitro micronucleus assay using V79 Chinese hamster fibroblasts. Several other in vitro assays have also produced negative results including tests for chromosomal aberrations, unscheduled DNA synthesis and DNA damage (2, 5).
There is limited in vivo data available on the genotoxicity of MEK.
There is limited data available on the carcinogenicity of MEK in experimental animals. No tumours were observed in a chronic skin carcinogenicity study on mice, following dermal application of 50 mg/application MEK biweekly for one year (11).
Fetotoxicity, including skeletal variations, has been observed in the offspring of rats and mice exposed to MEK during gestation. In an inhalation developmental study pregnant rats were exposed to 0, 1,000 (2,950 mg/m3) or 3,000 ppm (8,850 mg/m3) MEK for 7 hours per day on 6 to 15 of gestation. No evidence of maternal toxicity was reported. A small but statistically significant reduction in fetal body weight and crown-rump length was observed in the 1,000 ppm (2,950 mg/m3) group but not in the 3,000 ppm (8,850 mg/m3) group. Rare gross malformations were observed in 4 of the 21 litters (2 fetuses with acaudia and imperforate anus and 2 with brachygnathous). A statistically significant increase in litters with sternebral skeletal variations was observed in the 3,000 ppm (8,850 mg/m3) group, as was a statistically significant increase in the number of litters with any soft tissue anomalies (2, 12, 19).
Further study by the same group assessed exposure to 0, 400 (885 mg/m3), 1,000 (2,950 mg/m3) and 3,000 ppm (8,850 mg/m3) MEK for 7 hours a day on days 6 to 15 of gestation. Signs of maternal toxicity including decreased body weight gain and an increase in water consumption were observed in the dams exposed to 3,000 ppm (8,850 mg/m3). A significant increase in the number of litters with extra ribs was observed in the 3,000 ppm group (8,850 mg/m3) (2, 12, 19).
Similar results were observed in a subsequent inhalation development study in pregnant Sprague-Dawley rats exposed to 0, 1,000, 2,000, 4,000 or 6,000 ppm (0, 2,950, 11,800, 17,700 mg/m3) MEK 6 hours per day on gestation days 6 to 20. Significant decreases in food consumption and maternal bodyweight gain were observed in the dams exposed to 4,000 and 6,000 ppm. Decreases in fetal body weight were reported in the offspring of dams exposed to ≥ 4,000 ppm. A statistically significant increase in the incidence of incomplete sternebrae ossification was observed in the groups exposed to 4,000 ppm and 6, 000 ppm (2).
A developmental study exposed pregnant mice to 0, 400, 1,000, or 3,000 ppm (0, 1,180, 8,850 mg/m3) MEK 7 hours per day on days 6 to 15 of gestation. There was a statistically significant increase in the relative liver weight (7%) of dams in the 3,000 ppm group. A small but statistically significant decrease in fetal bodyweight (5%) was overserved in male offspring of dams exposed to 3,000 ppm. In addition, a statistically significant trend in the incidence of fetuses with misaligned sternebrae was reported at doses > 400 ppm (2, 12, 19).
An increase in the incidence of dams with complete litter loss was reported in pregnant rats exposed to 800 and 1,000 – 1,500 ppm (2,360 and 2,950-4425 mg/m3 ) MEK 23 hours per day on gestation days 1 to 21. Delayed brain development was observed in the offspring of rats that did deliver pups (2).
MEK administered in drinking water to rats over two generations did not affect reproductive parameters or cause fetotoxicity at doses up to 1,644 mg/kg/day. A slight decrease in pup body weight was observed at 3,122 mg/kg/day alongside significant kidney histopathology as renal tubular degeneration/regeneration, renal tubular casts, and microcysts to the tip of the papilla in rat dams. At 4,571 mg/kg/day, pup viability was decreased (10).
 n-Octanol/Water Partition Coefficient (Kow) is defined as the ratio of the concentration of a chemical in n-octanol and water at equilibrium at a specified temperature. Substances with high LogKow values are more soluble in organic matter because of their low affinity for water. Chemicals with a high LogKow may bioaccumulate (ChemSafetyPro).
 1 ppb = 1ug/l and 1 ug/kg
 1 ppm = 2.95 mg/m3
1 mg/m3 = 0.399 ppm
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