INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY
ENVIRONMENTAL HEALTH CRITERIA 143
METHYL ETHYL KETONE
This report contains the collective views of an international group of
experts and does not necessarily represent the decisions or the stated
policy of the United Nations Environment Programme, the International
Labour Organisation, or the World Health Organization.
Published under the joint sponsorship of
the United Nations Environment Programme,
the International Labour Organisation,
and the World Health Organization
First draft prepared by Dr R.B. Williams,
United States Environmental Protection Agency
World Health Orgnization
Geneva, 1993
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WHO Library Cataloguing in Publication Data
Methyl ethyl ketone.
(Environmental health criteria ; 143)
1.Butanones - adverse effects 2.Butanones - toxicity
3.Occupational exposure I.Series
ISBN 92 4 157143 8 (NLM Classification: QV 633)
ISSN 0250-863X
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CONTENTS
ENVIRONMENTAL HEALTH CRITERIA FOR METHYL ETHYL KETONE
1. SUMMARY
1.1. Properties and analytical methods
1.2. Sources of exposure and uses
1.2.1. Production and other sources
1.2.2. Uses and loss to the environment
1.3. Environmental transport and distribution
1.4. Environmental levels and human exposure
1.5. Kinetics and metabolism
1.6. Effects on experimental species
1.7. Effects on humans
1.7.1. MEK alone
1.7.2. MEK in solvent mixtures
1.8. Enhancement of the toxicity of other solvents
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES AND ANALYTICAL METHODS
2.1. Identity
2.2. Chemical and physical properties
2.3. Conversion factors
2.4. Sampling and analytical methods
2.4.1. General considerations
2.4.2. Air
2.4.3. Water
2.4.4. Solids
2.4.5. Biological materials
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1. Natural occurrence
3.2. Production levels, processes and uses
3.2.1. World production
3.2.2. Production processes
3.2.3. Other sources
3.2.4. Uses
3.3. Release into the environment
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1. Transport in the environment
4.2. Bioaccumulation and biodegradation
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1. Environmental levels
5.1.1. Air
5.1.2. Water
5.1.3. Foodstuffs
5.2. General population exposure
5.3. Occupational exposure
5.4. Peri-occupational exposure
6. KINETICS AND METABOLISM
6.1. Absorption
6.1.1. Percutaneous absorption
6.1.2. Inhalation absorption
6.1.3. Ingestion absorption
6.1.4. Intraperitoneal absorption
6.2. Distribution
6.3. Metabolic transformation
6.3.1. Animal studies
6.3.2. Human studies
6.4. Elimination and excretion
6.5. Turnover
6.6. Metabolic interactions
6.7. Mechanisms of action
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1. Acute exposure
7.1.1. Lethal doses
7.1.2. Non-lethal doses
7.1.3. Skin and eye irritation
7.2. Repeated exposures
7.3. Neurotoxicity
7.3.1. Behavioural testing
7.3.2. Histopathology
7.4. Developmental toxicity
7.5. Mutagenicity and related end-points
7.6. Carcinogenicity
8. EFFECTS ON HUMANS
8.1. General population exposure
8.2. Effects of short-term exposure
8.3. Skin irritation and sensitization
8.4. Occupational exposure
8.4.1. MEK alone
8.4.2. MEK in solvent mixtures
8.5. Carcinogenicity
9. EFFECTS ON OTHER ORGANISMS IN THE LABORATORY AND FIELD
9.1. Microorganisms
9.2. Aquatic organisms
9.3. Terrestrial organisms
9.3.1. Animals
9.3.2. Plants
10. ENHANCEMENT OF THE TOXICITY OF OTHER SOLVENTS BY MEK
10.1. Hexacarbon neuropathy
10.1.1. Introduction
10.1.2. Animal studies
10.1.3. Human studies
10.1.3.1 Solvent abuse
10.1.3.2 Occupational exposure
10.2. Haloalkane solvents
10.2.1. Studies in animals
10.2.2. Potentiation of haloalkane toxicity in humans
11. EVALUATION OF HUMAN HEALTH RISKS AND EFFECTS ON THE ENVIRONMENT
11.1. Human health risks
11.1.1. Non-occupational exposure
11.1.2. Occupational exposure
11.1.3. Relevant animals studies
11.2. Effects on the environment
12. RECOMMENDATIONS FOR THE PROTECTION OF HUMAN HEALTH AND THE
ENVIRONMENT
12.1. Human heath protection
12.2. Environmental protection
13. FURTHER RESEARCH
REFERENCES
APPENDIX 1. Conversion factors for various solvents
RESUME
RESUMEN
WHO TASK GROUP ON ENVIRONMENTAL HEALTH CRITERIA FOR METHYL ETHYL
KETONE
Members
Professor E.A. Bababunmi, Postgraduate Institute for Medical Research
and Training, College of Medicine, Ibadan, Nigeria
Dr P.E.T. Douben, Department of Ecotoxicology, Institute for Forestry
and Nature Research, Arnhem, The Netherlands
Professor C.L. Galli, Toxicology Laboratory, Institute of
Pharmacological Sciences, University of Milan, Milan, Italy
(Chairman)
Dr R.F. Hertel, Fraunhofer Institute of Toxicology and Aerosol
Research, Hanover, Germany
Dr H.P.A. Illing, Head of Toxicology, Health and Safety Executive,
Bootle, United Kingdom
Professor A. Massoud, Department of Community, Environmental &
Occupational Health, Faculty of Medicine, Ain Shams University,
Abbassia, Egypt (Joint Rapporteur)
Dr K. Morimoto, Division of Chem-Bio Informatics, National Institute
of Hygienic Sciences, Setagaya-ku, Tokyo, Japan
Dr V. Riihimäki, Institute of Occupational Health, Helsinki, Finland
Dr E. de Souza Nascimento, University of Sao Paulo, Sao Paulo, Brazil
Dr H. Tilson, Neurotoxicology Division, Health Effects Research
Laboratory, US Environmental Protection Agency, Research Triangle
Park, USA
Dr R.B. Williams, Office of Research and Development, US Environmental
Protection Agency, Washington D.C., USA (Joint Rapporteur)
Secretariat
Dr P.G. Jenkins, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr E. Smith, International Programme on Chemical Safety, World Health
Organization, Geneva, Switzerland
NOTE TO READERS OF THE CRITERIA MONOGRAPHS
Every effort has been made to present information in the criteria
monographs as accurately as possible without unduly delaying their
publication. In the interest of all users of the Environmental Health
Criteria monographs, readers are kindly requested to communicate any
errors that may have occurred to the Director of the International
Programme on Chemical Safety, World Health Organization, Geneva,
Switzerland, in order that they may be included in corrigenda.
* * *
A detailed data profile and a legal file can be obtained from the
International Register of Potentially Toxic Chemicals, Palais des
Nations, 1211 Geneva 10, Switzerland (Telephone No. 7988400 or
7985850).
ENVIRONMENTAL HEALTH CRITERIA FOR METHYL ETHYL KETONE
A WHO Task Group on Environmental Health Criteria for Methyl
Ethyl Ketone (MEK) met at the World Health Organization, Geneva, from
9 to 13 September 1991. Dr E. Smith welcomed the participants on
behalf of Dr M. Mercier, Director, IPCS, and on behalf of the heads of
the three IPCS cooperating organizations (UNEP/ILO/WHO). The Task
Group reviewed and revised the draft monograph and made an evaluation
of the risks for human health and the environment from exposure to
MEK.
The first draft of this monograph was prepared by Dr R.B.
Williams, Office of Research and Development, US Environmental
Protection Agency. Dr E. Smith and Dr P.G. Jenkins, both members of
the IPCS Central Unit, were responsible for the scientific content and
technical editing, respectively.
The efforts of all who helped in the preparation and finalization
of the monograph are gratefully acknowledged.
ABBREVIATIONS
ALT alanine transferase
BEI biological exposure index
DCB dichlorobenzene
DMA dimethylamine
DMF dimethylformamide
DNPH 2,4-dinitrophenyl hydrazine
EBK ethyl n-butyl ketone
ECD electron-capture detection
FID flame ionization detection
FT-IR Fourier transform infrared
GC gas chromatography
GLDH glutamate dehydrogenase
GPT glutamic-pyruvic transaminase
GST glutathione-S-transferase
2,5-HD 2,5-hexanedione
2,5-Hpdn 2,5-heptanedione
HPLC high-performance liquid chromatography
HS headspace
IR infrared
LC50 median lethal concentration
LDQ lowest detectable quantity
MAC maximum allowable concentration
MBK methyl n-butyl ketone
MEK methyl ethyl ketone
MIBK methyl isobutyl ketone
MS mass spectrometry
NADPH reduced nicotinamide adenine dinucleotide phosphate
OCT ornithine carbamyl transferase
PID photo-ionization detection
SRT simple reaction time
STEL short-term exposure limit
TLV threshold limit value
TWA time-weighted average
UV ultraviolet
1. SUMMARY
1.1 Properties and analytical methods
Methyl ethyl ketone (MEK) is a clear, colourless, volatile,
highly flammable liquid with an acetone-like odour. It is stable under
ordinary conditions but can form peroxides on prolonged storage; these
may be explosive. MEK can also form explosive mixtures with air. It is
very soluble in water, miscible with many organic solvents, and forms
azeotropes with water and many organic liquids. In the atmosphere MEK
produces free radicals, which may lead to the formation of
photochemical smog.
Several analytical methods exist for the measurement of MEK at
environmental levels in air, water, biological samples, waste and
other materials. In the more sensitive methods, MEK is trapped and
concentrated either on a solid sorbant or as a derivative of
2,4-dinitrophenylhydrazine (DNPH). Absorbed MEK and other volatile
organic compounds are desorbed, separated by gas chromatography and
measured with a mass spectrometer or flame ionization detector.
Derivatized MEK is separated from related compounds by high
performance liquid chromatography and measured by ultraviolet
absorption. In media such as solid waste and biological materials, MEK
must first be separated from the substrate by methods such as solvent
extraction or steam distillation. High concentrations of MEK in air
can be monitored continuously by infrared absorption. Detection limits
are 3 µg/m3 in air, 0.05 µg/litre in drinking-water, 1.0 µg/litre in
other types of water, 20 µg/litre in whole blood and 100 µg/litre in
urine.
1.2 Sources of exposure and uses
1.2.1 Production and other sources
Recent values for annual industrial manufacture (in thousands of
tonnes) are: USA, 212 to 305; western Europe, 215; Japan, 139. In
addition to its manufacture, sources of MEK in the environment are
exhaust from jet and internal combustion engines, and industrial
activities such as gasification of coal. It is found in substantial
amounts in tobacco smoke. In the USA, production of MEK by engines is
no more than 1% of its deliberate manufacture. In smog episodes,
photochemical production of MEK and other carbonyls from free radicals
can be far greater than direct anthropogenic emission. MEK is produced
biologically and has been identified as a product of microbial
metabolism. It has also been detected in a wide diversity of natural
products including higher plants, insect pheromones, animal tissues,
and human blood, urine and exhaled air. It is probably a minor product
of normal mammalian metabolism.
1.2.2 Uses and loss to the environment
The major use of MEK, application of protective coatings and
adhesives, reflects its excellent characteristics as a solvent. It
also is used as a chemical intermediate, as a solvent in magnetic tape
production and the dewaxing of lubricating oil, and in food
processing. In addition to industrial applications, it is a common
ingredient in consumer products such as varnishes and glues. In most
applications MEK is a component of a mixture of organic solvents.
Losses to the environment are mainly to the air and result principally
from solvent evaporation from coated surfaces. MEK is released into
water as a component of the waste from its manufacture and from a
variety of industrial operations. It has been detected in natural
waters and could have originated from microbial activities and from
atmospheric input, as well as from anthropogenic pollution.
1.3 Environmental transport and distribution
MEK is highly mobile in the natural environment and subject to
rapid turnover. It is very soluble in water and evaporates readily
into the atmosphere. In air MEK is subject to rapid photochemical
decomposition and is also synthesized by photochemical processes. In
water containing free halogens or hypohalites, it reacts to form a
haloform that is more toxic than the original compound. MEK is
distributed by both air and water, but does not accumulate in any
individual compartment, and does not persist long where there is
microbial activity. It is rapidly metabolized by microbes and mammals.
There is no evidence of bioaccumulation. MEK occurs naturally in some
clover species and is produced by fungi to concentrations that affect
the germination of some plants.
1.4 Environmental levels and human exposure
General population exposure to low levels of MEK is widespread.
In minimally polluted air, the concentration is less than 3 µg/m3
(< 1 ppb), but a level of 131 µg/m3 (44.5 ppb) has been measured
under conditions of heavy air pollution. Away from industrial areas
where MEK is manufactured or used, major sources may be vehicle
exhaust and photochemical reactions in the atmosphere. Cigarettes and
other tobacco products that are burned contribute to individual
exposure (20 cigarettes contain up to 1.6 mg). Volatilization of MEK
from building materials and consumer products can pollute indoor air
to levels far above adjacent outdoor air. MEK concentrations in
exposed natural waters are rarely above 100 µg/litre (100 ppb) and are
usually below a detectable level. Trace amounts of MEK, however, have
been detected widely in drinking-water (approximately 2 µg/litre) and
presumably originated as solvent leached from cemented joints of
plastic pipe. Although MEK is a normal component of many foods,
concentrations are low and food consumption cannot be considered a
significant source of population exposure. Average daily per capita
intake in the USA via foodstuffs is estimated to be 1.6 mg, most
coming from white bread, tomatoes and Cheddar cheese. In addition to
MEK present naturally, foods may contain MEK from cheese ripening,
aging of poultry meat, cooking or food processing, or by absorption
from plastic packaging materials.
Industrial exposure to moderate levels of MEK is widespread.
However, in some regions workers in small factories (e.g., shoe
factories, printing plants and painting operations) are exposed to
much higher concentrations due to inadequate ventilation. In these
factories, exposure is usually to a mixture of solvents including
n-hexane.
1.5 Kinetics and metabolism
Absorption of MEK is rapid via dermal contact, inhalation,
ingestion and intraperitoneal injection. It is rapidly transferred
into the blood and thence to other tissues. The solubility of MEK
appears similar for all tissues. The clearance of MEK and its
metabolites in mammals is essentially complete in 24 h. It is
metabolized in the liver where it is mainly oxidized to
3-hydroxy-2-butanone and subsequently reduced to 2,3-butanediol. A
small portion may be reduced to 2-butanol, but 2-butanol is rapidly
oxidized back to MEK. The bulk of MEK taken into the mammalian body
enters the general metabolism and/or is eliminated as simple compounds
such as carbon dioxide and water. Excretion of MEK and its
recognizable metabolites is mainly through the lungs, although small
amounts are excreted via the kidneys.
MEK increases microsomal cytochrome P-450 enzyme activities. This
enhancement of enzymatic activity and thus of the body's potential for
metabolic transformation may well be the mechanism by which MEK
potentiates the toxicity of haloalkane and aliphatic hexacarbon
solvents.
1.6 Effects on experimental species
MEK has low to moderate acute, short-term and chronic toxicity
for mammals. LD50 values for adult mice and rats are 2 to 6 g/kg
body weight, death occurring within 1 to 14 days following a single
oral dose. Average vapour concentrations producing lethality in rats
following a single exposure are around 29 400 mg/m3 (10 000 ppm),
although guinea-pigs survived a 4-h exposure to this concentration.
The lowest acute oral dose modifying body structure is 1 g/kg body
weight, which damaged kidney tubules in the rat. Inhalation by rats of
74 mg/m3 (25 ppm) for 6 h produced measurable changes in behaviour
which persisted for several days. Repeated exposure of rats to 14 750
mg/m3 (5000 ppm) (6 h/day, 5 days/week) produced no lethality, had
only minor effects on growth and structure, and there were no
neuropathological changes. There was no evidence that MEK produced
neuropathological changes in chickens, cats or mice exposed to 3975
mg/m3 (1500 ppm) for periods of up to 12 weeks. Transient effects on
behaviour or neurophysiology were detected following repeated exposure
of rats and baboons to concentrations as low as 295-590 mg/m3 (100
to 200 ppm).
There is evidence for a low level of fetotoxicity without any
maternal toxicity at 8825 mg/m3 (3000 ppm), but no evidence for
embryotoxic or teratogenic effects at lower exposure levels. Repeated
exposure of pregnant rats to 8825 mg/m3 induced in their offspring
a small but significant increase in skeletal abnormalities of types
that occurred at low incidences among the unexposed population.
Although examined in a number of conventional mutagenicity test
systems, the only evidence of mutagenicity was provided by a study on
aneuploidy in the yeast Saccharomyces cerevisiae.
MEK is not acutely toxic to fish or aquatic invertebrates and
LC50 values range from 1382 to 8890 mg/litre.
MEK has an inhibiting effect on the germination of several plant
species, even at levels occurring naturally. The growth of aquatic
algae is inhibited.
Compared with natural background levels, relatively high
concentrations of MEK have been used for fumigation under experimental
conditions. It is moderately effective as a fumigant against the
Caribbean fruit fly and is a very effective attractant for tsetse
flies. Levels of MEK up to 20 mg/litre retard biodegradation but do
not stop the process entirely. At levels of up to 100 mg/litre, MEK is
biostatic to a variety of bacteria. At higher concentrations (1000
mg/litre or more) inhibition of the growth of bacteria and protozoa
occurs.
1.7 Effects on humans
1.7.1 MEK alone
Exposure to 590 mg/m3 (200 ppm) had no significant effect in a
variety of behavioural and psychological tests. Short-term exposure to
MEK alone does not appear to be a significant hazard, either
occupationally or for the general public. Experimental exposure to a
concentration of 794 mg/m3 (270 ppm) for 4 h/day had little or no
effect on behaviour, and a 5-min contact with liquid MEK produced no
more than a temporary whitening of the skin. There is only one
non-occupational report of acute toxicity to MEK. This resulted from
accidental ingestion and appeared to produce no lasting harm. There is
no evidence that occupational MEK exposure has resulted in death.
There have been two reports of chronic occupational poisoning and one
questionable report of acute occupational poisoning. In one of the
chronic cases, exposure to 880-1770 mg/m3 (300-600 ppm) resulted in
dermatoses, numbness of fingers and arms, and various symptoms such as
headache, dizziness, gastrointestinal upset, and loss of appetite and
weight. This paucity of incidents of reputed poisoning by MEK alone
reflects both the low toxicity of MEK and the fact that it is most
commonly used not on its own but as a component of solvent mixtures.
1.7.2 MEK in solvent mixtures
Exposure to solvent mixtures containing MEK has been associated
with some reduction in nerve conduction velocity, memory and motor
alterations, dermatoses and vomiting. In one longitudinal study,
consecutive measurements of simple reaction time showed an improvement
in performance in parallel with decreasing concentrations of MEK to
one tenth the original values (which were up to 4000 mg/m3 for
certain routine tasks).
1.8 Enhancement of the toxicity of other
solvents
MEK potentiates the neurotoxicity of hexacarbon compounds
( n-hexane, methyl- n-butylketone and 2,5-hexanedione) and the liver
and kidney toxicity of haloalkane (carbon tetrachloride and
trichloromethane) solvents.
The potentiation of the neurotoxic effects of hexacarbons has
been demonstrated for all three hexacarbons in animals. The peripheral
neuropathies observed in humans followed changes in the formulations
of solvents to which they had been exposed, either voluntarily or
occupationally. The mechanism by which this potentiation occurs is
unclear.
Evidence for potentiation of the liver and kidney toxicity of
haloalkanes comes from animal studies. MEK probably activates the
haloalkane metabolism to tissue-damaging species as a result of
induction of the relevant oxidation enzymes.
2. IDENTITY, PHYSICAL AND CHEMICAL PROPERTIES AND ANALYTICAL METHODS
2.1 Identity
H H O H
| | || |
Chemical structure: H - C - C - C - C - H
| | |
H H H
Chemical formula: C4H8O
Synonyms: Butanone, 2-butanone, butane-2-one,
ethyl methyl ketone, MEK, MEETCO,
methyl acetone, methylpropanone
CAS registry number: 78-93-3
RTECS registry number: EL 6475000
UN registry number: 1193
EC registry number: 606-002-00-3
Relative molecular mass: 72.10
2.2 Chemical and physical properties
Methyl ethyl ketone (MEK) is an important synthetic organic
chemical. The physical properties of MEK are summarized in Table 1. It
is a highly flammable, volatile, clear, colourless liquid that is
stable under ordinary conditions. The vapour forms explosive mixtures
with air over a range of approximately 2% to 12% (vol./vol.). The
odour is acetone-like and variously described as sharp, fresh or
sweet. The odour threshold appears to be around 5.9 mg/m3 (2 ppm)
although a range between 0.74 and 147.5 mg/m3 has been reported
(Ruth, 1986). MEK is moderately soluble in water; the solubility
decreases with increasing temperature. It is miscible with organic
solvents such as alcohol, ether and benzene, and forms azeotropes with
water and many organic liquids.
The value in Table 1 for log Po/w (logarithm of the octanol/
water partition ratio) of 0.26 is taken from Verschuren (1983).
Banergee & Howard (1988) quoted a slightly higher value of 0.29. Other
partition values for MEK (at 37 °C) are: water/air = 254; blood/air =
202; olive oil/air = 263; olive oil/water = 1.0; and olive oil/blood
= 1.3 (Sato & Nakajima, 1979). Perbellini et al. (1984), however,
determined partition values for saline solution/air and olive oil/air
of 193 and 191 respectively.
Table 1. Physical properties of MEK
Reference
Appearance colourless liquid
Relative molecular mass 72.10 Papa & Sherman (1978)
Specific gravity (liquid density)
(at 20 °/4 °C)a 0.805 Krasavage et al. (1982)
Vapour density (air = 1.00) 2.41 Verschuren (1983)
Vapour pressure at 20 °C (torr) 77.5 Weast (1986)
Boiling point (°C) 79.6 Weast (1986)
Melting point (°C) -86 Weast (1986)
Water solubility at 20 °C (g/litre) 275 Windholz (1983)
Refractive index 1.3788 Krasavage et al. (1982)
Flash point (closed cup) (°C) -6 Papa & Sherman (1978)
Log Po/w 0.26 Verschuren (1983)
0.29 Banergee & Howard (1988)
Saturation concentration in
air (g/m3 at 20 °C) 301 Krasavage et al. (1982)
a Specific gravity at 20 °C relative to the density of water at 4 °C
The physical and chemical properties of MEK are determined
largely by its carbonyl group. MEK engages in reactions typical of
saturated aliphatic ketones. These include condensations with amines,
aldehydes and many other organic compounds, hydrolysis (catalysed with
acid or base), oxidation via concentrated oxidizing acids or acidic
peroxides, and reduction with hydrogen and metal catalysts. None of
these reactions is likely to be important in nature. On the other
hand, MEK and other methyl ketones will react with halogens and
hypohalides in aqueous solution to form a carboxylic acid and a
haloform. The reaction provides a specific test for methyl ketones,
and may produce chloroform in chlorinated water supplies contaminated
with methyl ketones. MEK and other ketones are photochemically
reactive when excited by wavelengths occurring in the atmosphere and
produce free radicals which lead to the formation of photochemical
smog (Grosjean et al., 1983).
2.3 Conversion factors
1 ppm = 2.95 mg/m3; 1 mg/m3 = 0.34 ppm
(at 25 °C and 101.3 kPa)
2.4 Sampling and analytical methods
2.4.1 General considerations
Analytical methods for MEK depend on the matrix. They are
summarized in Table 2.
Where MEK is present in a substantial concentration and is known
to be the only or the dominant organic contaminant, simplified
methodology is feasible. The occupational atmospheric exposure limits,
currently in the range 295-590 mg/m3 (100-200 ppm), permit
monitoring in the workplace with less sensitive procedures.
The precise determination of MEK when present in the environment
at low concentrations is a complex task because of the wide variety of
other organic compounds that may be present and the many possibilities
for error, interference and contamination. MEK, other ketones and
other interfering substances are so prevalent in laboratory and
industrial air that care must be taken in all determinations to
minimize the possibility of contamination of samples, equipment and
reagents. Care must be taken to avoid contamination in sampling since,
for example, easily unnoticed sources like PVC (polyvinyl chloride)
glue in collection equipment may leach a significant amount of MEK
into water samples (Kent et al., 1985).
Table 2. Some analytical techniques for determining MEK concentrations in environmental media and biological materialsa
Methods Detection Comments Reference
limits
Air
Trapping in solid sorbant tube (Tenax(R)); 200 µg/m3 working range is 0.2-100 mg/m3; analysis can Brown & Purnell
thermal desorption: separation-detection; be automated (1979)
GC-FID
Trapping in DNPH; separation: HPLC 3-6 µg/m3 general method for aldehydes and ketones in Riggin (1984)
(reverse phase); detection: UV air; some isomeric aldehydes and ketones are
absorption not well separated
Trapping in solid sorbant tube 0.15 mg per working range is 50-1500 mg/m3; acetone and US NIOSH (1984a)
(Ambersorb XE-347(R)); desorption: sample isopropanol interfere
CS2; separation-detection: GC-FID
Absorption of specific IR wavelengths 3 mg/m3 can measure several different pollutant Persson et al.
from CO2 laser; automated, computer- vapours simultaneously and continuously (1984)
controlled system
Trapping in DNPH; colour matching 300 mg/m3 working range is 300-1200 mg/m3; other Smith & Wood
against standards aldehydes and ketones interfere; method (1972)
requires no specialized equipment
Water
Separation from water sample by heated 0.05-1.0 water samples must be preserved from bacterial Pellizzari et al.
gas purge; trapping on Tenax(R); thermal µg/litreb action with methylene chloride, and free chlorine (1985)
desorption; separation-detection: GC/MS removed with thiosulfate; achieving lower limit
of detection requires concentration by
distillation; no interference reported
Table 2 (contd.)
Methods Detection Comments Reference
limits
Concentration on zeolite (ZSM-5); 2 µg/litre developed for drinking-water analysis; no Ogawa & Fritz
elution with acetonitrile; derivatization interference reported (1985)
with DNPH; separation-detection: HPLC/UV
Direct injection of aqueous sample; 40 µg/litre developed for industrial waste-water analysis; Middleditch et al.
separation-detection: GC/FID no interference reported (1987)
Solids
Solvent extraction with tetraethylene 0.5-5 µg/g tetraglyme must be purified and stabilized to Gurka et al.
glycoldimethyl ether (tetraglyme); purge (wet weight) prevent peroxide formation; no interference (1984)
and trap; separation-detection: GC/MS reported
Heated purge of sample/water slurry or 10 µg/kg method developed for volatile organic compounds Fisk (1986)
of methanol extract of sample; trap; (wet weight) at concentrations of < 1 mg/kg; no interference
desorption; separation-detection: GC/MS reported
Biological Materials
Mixture with dextrose and heating; 20 µg/litre method developed for simultaneous determination US NIOSH (1984b)
HS analysis; GC/FID of MEK, toluene and ethenol in blood; recovery
rates 90-98%
Incubation in sealed vial; HS 100 µg/litre method developed for blood; uses 200-µl sample; Ramsey & Flanagan
analysis; separation-detection: applicable to urine and tissue; no interference (1982)
GC/FID and ECD reported
Concentration by reverse-phase 100-150 method developed for MEK and its metabolites Kezic & Monster
extraction column; separation- µg/litre in urine; no interference reported (1988)
detection: GC/FID
Table 2 (contd.)
Methods Detection Comments Reference
limits
Derivatized with o-nitrophenylhydrazine 100 µg/litre method developed for the determination of MEK Van Doorn et al.
and reacted with cyclohexane; in human urine (1989)
centrifuge separation; reversed-
phase HPLC; UV (254 nm)
Steam distillation of slurry; HS 20 µg/litre method developed for cheese, but probably Lin & Jeon (1985)
analysis; separation-detection: widely applicable; no interference reported
GC/FID
Homogenization; HS analysis; 6 mg/litre method developed for the identification of Deveaux & Huvenne
GC/FT-IR solvents of abuse in biological fluids (1987)
a Abbreviations used in the table
DNPH 2,4-dinitrophenylhydrazine
ECD electron-capture detector
FID flame ionization detector
FT Fourier transformed
GC gas chromatograph
HPLC high performance liquid chromatograph
HS headspace
IR infrared
MS mass spectrometer
UV ultraviolet
b 0.05 µg/litre for drinking-water; 1.0 µg/litre for all other types of water
The general procedure for analysis of MEK is summarized below:
a) collect the sample, and if necessary, chemically stabilize it;
b) separate MEK (and other volatile organic compounds) from the
substrate;
c) trap and concentrate MEK (plus other organic compounds);
d) recover the trapped material;
e) separate MEK and other organic compounds;
f) detect and identify MEK;
g) determine the quantity recovered;
h) calculate the concentration present in the sample.
In actual practice the procedure may be simplified by combining or
omitting certain steps, or it may contain an additional step, i.e. the
preparation of 2,4-dinitrophenylhydrazine (DNPH) derivatives of MEK
and other aldehydes and ketones. The formation of DNPH derivatives
quantitatively captures both aldehydes and ketones, and facilitates
their subsequent separation with either gas or liquid chromatography.
The preparation of DNPH derivatives also forms the basis for a
simplified, non-specific method for roughly measuring high levels of
ketones and aldehydes without the use of sophisticated laboratory
equipment (Smith & Wood, 1972). The use of other derivatives, such as
imines via phenylmethylamine (Hoshika et al., 1976), azines via
3-methyl-2-benzothiazolone (Chiavari et al., 1987), and
O-(2,3,4,5,6-pentafluorobenzyl) oximes via
pentafluorophenylhydrazine and pentafluorobenzyloxyamine (Kobayashi et
al., 1980) has also been proposed.
2.4.2 Air
A general methodology for determining MEK in air consists of
trapping and concentrating MEK and other volatile organic compounds in
sampling devices containing an absorbent material, charcoal
(carbopack) or an artificial resin (Tenax GC(R), Ambersorb XE(R),
Amberlites XAD(R)), followed by desorption and analysis.
MEK decomposes when absorbed on charcoal and sample loss may
occur after a few days (Elskamp & Schultz, 1983; Levin & Carleborg,
1987). Ambersorb XE(R) showed good capacity, and decomposition was
insignificant (Levin & Carleborg, 1987). Kenny & Stratton (1989)
evaluated various mixtures to find a solvent that would provide
optimum desorption efficiency. For samples of MEK collected on
charcoal tubes, a mixture of carbon disulfide with 10% amyl alcohol
was found to be an effective desorption solvent. The substitution of
hexyl for amyl alcohol gave comparable recovery but slower GC/FID
analysis. Both thermal desorption and solvent desorption have been
used to release the MEK from the trapping column.
Collectors may be passive and dependent on diffusion or a packed
tube through which a known volume of air is drawn. Passive collectors,
often in the form of badges, avoid the need for specialized sampling
equipment and are convenient for monitoring individual exposure.
However, the results of several studies suggest that passive
(diffusive) collectors not only show significant individual and brand
variability but also variability in their speed of uptake of different
solvent vapours (Hickey & Bishop, 1981; Feigley & Chastain, 1982), and
thus may require calibration against a more quantitative method. The
trapped organic compounds are desorbed either thermally by application
of heat or microwave radiation, or by solution in carbon disulfide,
and are separated with gas chromatography. A wide diversity of columns
and packings have been found satisfactory for this separation.
Using gas chromatography with a flame ionization detector, an
overall precision (Sr) of 0.069 with a limit of detection of 0.004
mg/sample was achieved (US NIOSH, 1984a).
Methodology for analysing air samples recommended by the United
States Environmental Protection Agency (US EPA) can detect MEK and
most other mono-functional aldehydes and ketones at the 3-6 µg/m3
(1-2 ppb) level (Riggin, 1984). Air is drawn through a mixture of
isooctane and an acidified solution of 2,4-dinitrophenylhydrazine
(DNPH), which reacts chemically with MEK. DNPH derivatives of
aldehydes and ketones are extracted from the aqueous layer, separated
with high performance liquid chromatography (HPLC) and detected by
ultraviolet absorption.
MEK vapour can also be detected and measured directly and
instantaneously by absorption of infrared light. The method (detection
limit, 3 mg/m3) appears suitable for use in the workplace where only
a limited number of solvent vapours are present (Persson et al., 1984)
but may not reliably detect MEK in the presence of a diverse mixture
of organic vapours, due to overlapping of infrared absorption peaks
(Puskar et al., 1986). Ying & Levine (1989) used Fourier
transform-infrared spectrometry (FT-IR) to determine the concentration
of MEK in mixtures of vapours in ambient air and obtained a detection
limit of 1 mg/m3. Surface acoustic wave devices have been tested
experimentally for the detection of MEK and other vapours
(Rose-Pehrsson et al., 1988) and show promise for the development of
electronic devices that can continuously monitor and analyse vapour
mixtures at concentrations likely to be present in the work
environment.
2.4.3 Water
Water samples containing high levels of MEK (e.g., industrial
waste water) can be analysed by direct injection of the sample into a
gas chromatograph; the detection limit is 40 µg/litre (Middleditch et
al., 1987). Samples with low levels of MEK (e.g., drinking-water)
require some form of concentration such as distillation (Pellizzari et
al., 1985) or adsorption on a hydrophobic zeolite (Ogawa & Fritz,
1985). GC/MS analysis gives a detection limit of 0.05 µg/litre
(Pellizzari et al., 1985) whereas HPLC with UV detection has a
detection limit of 2 µg/litre (Ogawa & Fritz, 1985).
2.4.4 Solids
Analysis of solid and semisolid materials such as industrial
wastes for MEK presents special difficulties in terms of both sampling
and analysis. The sample must be representative and of adequate size,
since substrates such as waste tend to be very non-homogeneous and MEK
must be completely removed from both solid and liquid components. One
method accomplishes this by extracting the sample with an appropriate
solvent (tetraglyme) and purging MEK and other volatile organics from
the tetraglyme with an inert gas (Gurka et al., 1984). Another method
(Fisk, 1986) either directly purges MEK and other organic compounds
from a water/solid material slurry held at an elevated temperature or
purges a methanol extract of the solid material at an elevated
temperature.
2.4.5 Biological materials
Biological materials offer the same analytical problems as solid
waste: MEK must be completely removed from both solid and liquid
components of the sample. This can be accomplished by headspace
analysis (Ramsey & Flanagan, 1982; US NIOSH, 1984b), steam
distillation of a sample slurry followed by headspace analysis
(Bassette & Ward, 1975; Lin & Jeon, 1985), derivation with
o-nitrophenylhydrazine (Van Doorn et al., 1989) and, in the case of
an entirely liquid substrate, separation and concentration by
reverse-phase extraction (Kezic & Monster, 1988).
For MEK in blood the United States National Institute of
Occupational Safety and Health method (US NIOSH, 1984b), using GC/FID,
has a detection limit of 20 µg/litre and the Ramsey & Flanagan (1982)
method has a detection limit of 100 µg/litre. The latter method can
also be used for the analysis of MEK in urine with the same limit of
detection. Other methods for analysis in urine are those of Kezic &
Monster (1988), using GC/FID, and Van Doorn et al. (1989) using
HPLC/UV; both methods have limits of detection of 100 µg/litre.
3. SOURCES OF HUMAN AND ENVIRONMENTAL EXPOSURE
3.1 Natural occurrence
MEK occurs naturally at low concentrations. It has been
identified in cigarette smoke (Osborne et al., 1956; Hoshika et al.,
1976; Higgins et al., 1983). It also has been reported in chicken
breast muscle (Grey & Shrimpton, 1967), weed residues (Bradow &
Connick, 1988), southern pea seeds (Fisher et al., 1979), insect
pheromones (Cammaerts et al., 1978; Attygalle et al., 1983), juniper
leaves (Khasanov et al., 1982); marine macroalgae (seaweeds) (Whelan
et al., 1982) and as a product of microbial metabolism (Patel et al.,
1982; Mohren & Juttner, 1983; Zechman et al., 1986), including
cultures isolated from fresh water and soil (Hou et al., 1983; Patel
et al., 1983). Berseem clover, hairy vetch and crimson clover emitted
volatile compounds including MEK (Bradow & Connick, 1990). Six
amaranth species emit MEK which has been shown to cause significant
inhibition of tomato and onion seed germination (Connick et al.,
1989). Some bacteria (e.g., thermophilic obligate methane-oxidizing
bacteria) can oxidise 2-butanol to produce MEK (Imai et al., 1986).
Studies have shown that MEK is a normal component of flavour and odour
in a wide range of foods, especially cheese and other fermented
products (Zakhari et al., 1977), often as a result of bacterial
activity (Lin & Jeon, 1985). Seven types of fish contain MEK, although
reported levels were low relative to other compounds (Sakakibara et
al., 1990). MEK has been detected in coyote urine (Schultz et al.,
1988), in the urine of non-occupationally exposed humans (Tsao &
Pfeiffer, 1957; Mabuchi, 1969), in human blood (Mabuchi, 1969) and in
exhaled air (Conkle et al., 1975). The MEK in exhaled air may have
been derived from food, but the observations of Poli et al. (1985) and
other researchers (see section 6) strongly suggest that MEK and
similar carbonyl compounds are minor products of normal mammalian
metabolism.
3.2 Production levels, processes and uses
3.2.1 World production
Although MEK is an important industrial chemical, world
production figures are not available. Annual production in the USA,
reported by the US International Trade Commission, ranged from 212 to
305 thousand tonnes over the period 1980-1987 and averaged 258
thousand tonnes (USITC, 1981-1988). Current (1987) annual capacity and
production values for western Europe are 308 and 215 thousand tonnes,
respectively (Chemical Business Newsbase, 1988). Japanese annual
capacity and production figures in 1986 were 180 and 139 thousand
tonnes, respectively (Chemical Business Newsbase, 1987). Argentinean
annual capacity was 15 thousand tonnes in 1985 (Chemical Business
Newsbase, 1986). A production plant opened in Brazil in 1991 but
information on capacity and production is not available (personal
communication from E. de S. Nascimento).
3.2.2 Production processes
MEK is produced mainly by dehydrogenation of sec-butyl alcohol
(Liepins et al., 1977; SRI International, 1985, 1988). In the USA, one
process uses sec-butyl alcohol vapour at 400 to 550 °C oxidized with
a zinc oxide catalyst. Reaction gases are condensed and the condensate
fractionated in a distillation column. The yield of MEK is 85 to 90%
(Lowenheim & Moran, 1975). Any uncondensed reaction gases are scrubbed
with water or a non-aqueous solvent and the waste stream from the
scrubber, which contains MEK and reaction by-products, is either
recycled or discarded (Liepins et al., 1977). In Europe, sec-butyl
alcohol is dehydrogenated over Rainey nickel or copper chromite
catalyst at 150 °C (Papa & Sherman, 1978)
MEK is also produced by the oxidation of n-butane, either as
the main product or as a by-product in the manufacture of acetic acid
(Liepins et al., 1977; Papa & Sherman, 1978). Liquid butane reacts
with compressed air in the presence of a transition metal acetate
catalyst, normally cobalt acetate, and the reaction product phase is
separated. The hydrocarbon-rich phase is recycled to the reactor and
the aqueous phase with MEK is withdrawn and purified. MEK and other
organic compounds with low boiling points are separated from acetic
acid by distillation. Reaction conditions determine whether MEK or
acetic acid is the principal product (Lowenheim & Moran, 1975). Butane
oxidation accounted for about 13% of the 1987 MEK production capacity
in the USA (SRI International, 1988) but for none of the 1984
production capacity in western Europe (SRI International, 1985). Other
methods exist for the commercial manufacture of MEK (Papa & Sherman,
1978), but there is no evidence that any of these alternatives are of
current importance.
3.2.3 Other sources
In addition to manufacture by the chemical industry, MEK and
other carbonyls are incidentally produced as components of exhaust
from jet (Miyamoto, 1986) and internal combustion engines (Seizinger
& Dimitriades, 1972; Creech et al., 1982; Hampton et al., 1982) and
from industrial activities such as retort distillation of oil shale
(Hawthorne et al., 1985) and gasification of coal (Pellizzari et al.,
1979). MEK comprises about 0.05% of the hydrocarbon exhaust gases of
motor vehicles, and in 1987 the vehicle emission of MEK in the USA was
estimated to be 1909 tonnes (Somers, 1989). Thus its anthropogenic
production by vehicles plus an additional amount by stationary engines
was no more than 0.1% of the industrial production in the USA.
Grosjean et al. (1983) concluded, however, that during smog episodes
in the Los Angeles basin much of the ambient level of MEK was produced
photochemically.
3.2.4 Uses
The major uses of MEK reflect its excellent characteristics as a
solvent (Table 3). Its high solvency for gums, resins and many
synthetic polymers permits formulations with high solid content and
low viscosity. It is also inert to metal, evaporates rapidly, and is
relatively low in toxicity compared with solvents like benzene which
MEK replaced (Zakhari et al., 1977; Basu et al., 1981).
Table 3. Major uses of MEK in the USAa
End use %
Solvent - protective coatings 65
Solvent - adhesives 15
Solvent - magnetic tape production 8
Lubricating oil dewaxing 5
Chemical intermediate 4
Miscellaneous 3
a From: Manville Chemical Products Corp. (1988)
The largest single use of MEK is as a solvent for vinyl plastic
used in coatings and moulded articles. Other important uses are as a
solvent for lacquers and for cellulose nitrate, cellulose acetate,
acrylics, and adhesive coatings. Its properties as a selective solvent
make it ideal for dewaxing lubricating oils. MEK is also used for
degreasing metals, in the manufacture of magnetic tapes, inks and
smokeless powder, and as a chemical intermediate in the production of
methyl ethyl ketoxime, MEK peroxide, methyl isopropyl ketone and many
other compounds.
In addition to industrial uses, MEK is an ingredient in a variety
of consumer products such as lacquers, varnishes, spray paints, paint
removers, sealers and glues (Zakhari et al., 1977). In both consumer
products and industrial applications, MEK is frequently only one of
several components in a mixture of organic solvents.
MEK is also used as an extraction solvent in the processing of
foodstuffs and food ingredients, e.g., in fractionation of fats and
oils, decaffeination of tea and coffee, and extraction of flavourings.
3.3 Release into the environment
Releases of MEK are mainly into the atmosphere (Reilly, 1988).
These can result from: spillage; venting of gases and fugitive
emissions during manufacture, transfer and use; solvent evaporation
from coated surfaces; loss from landfills and waste dumps; and engine
exhaust (Basu et al., 1981; LaRegina & Bozzelli, 1986). Relatively
little MEK is lost during manufacture when the process is enclosed.
The average annual release from four manufacturing plants in the USA
was estimated to be 82 tonnes per site, equal to a total of 328 tonnes
or about 0.1% of their annual production (Reilly, 1988).
The bulk of MEK eventually evaporates to the atmosphere, since
the major use of MEK is as a solvent for coatings and adhesives. In
industry, some of the MEK evaporated from surface coatings or lost
during cooking and thinning of resin is removed from the ventilation
exhaust by absorption on charcoal filters or by incineration of the
exhaust stream. The latter method can reduce emission by up to 97%
(Gadomski et al., 1974), and removal is accomplished in a single step
without generating a residue for subsequent disposal (DiGiacomo,
1973).
The waste stream from MEK production contains acetic acid and a
variety of alcohols, aldehydes, ketones and other organic compounds.
It is likely that butane and other organic compounds are discharged
into the atmosphere from the reaction section, but no specific
information is available (Liepins et al., 1977).
MEK is released from other industrial operations involving its
use, and from activities such as retort distillation of oil shale and
gasification of coal (Pellizzari et al., 1979; Hawthorne et al.,
1985).
It has been detected in drinking-water (Ogawa & Fritz, 1985), in
well water (Jacot, 1983), in ground water (Botta et al., 1984) and in
leachate from a hazardous waste site (Jacot, 1983). MEK occurs in
water often as a result of natural processes (section 3.1).
Atmospheric input and direct anthropogenic pollution contribute
significantly to elevated levels (Grosjean & Wright, 1983).
4. ENVIRONMENTAL TRANSPORT, DISTRIBUTION AND TRANSFORMATION
4.1 Transport in the environment
MEK appears to be highly mobile in the natural environment (Lande
et al., 1976). It is water soluble (Windholz, 1983) and evaporates
rapidly in air. The generally low values for MEK in outdoor air
probably stem mainly from its rapid removal by photodecompo-sition.
Scavenging by aqueous droplets and dry deposition, which also
represent potential routes of loss from the atmosphere, are balanced
to an unknown extent by evaporation of MEK from water and soil. There
is no specific information on partitioning of MEK in the environment.
Although Basu et al. (1981) estimated from its physical properties
that MEK will "exhibit low sediment-water and soil-water partitioning
and be susceptible to substantial leaching from soils to which it is
not extensively chemically bound", there is no information on chemical
binding of MEK to sediment particles. As mentioned above, MEK has,
however, been detected in ground water and the leachate from hazardous
waste sites (section 3.3).
4.2 Bioaccumulation and biodegradation
On the basis of its octanol/water partition and water solubility,
bioconcentration factors (BCF) of approximately 1 and 0.5,
respectively, have been calculated for MEK (US EPA, 1985b). In view of
its high water solubility, ecosystem modelling (Metcalf et al., 1973;
Chiou et al., 1977) indicates that it is unlikely that MEK will
accumulate in food webs. It is absorbed and metabolized by organisms
present in the environment, e.g., in waste water (Dore et al., 1975;
Bridie et al., 1979a) and in soil (Perry, 1968). It is rapidly
metabolized by mammals (Di Vincenzo et al., 1976, 1978; Dietz et al.,
1981; Miyasaka et al., 1982) and by many microbes (Gerhold & Malaney,
1966; Dojlido, 1977; Urano & Kato, 1986). MEK is nearly completely
degradable at concentrations up to 800 mg/litre on the basis of
biochemical oxygen demand (BOD), and the rate of degradation decreases
with increasing concentration of MEK. Using activated sludge there was
complete degradation of MEK in 8 days at a concentration of 200
mg/litre (200 ppm) and in 9 days at a concentration of 400 mg/litre
(400 ppm) (Dojlido, 1979). At a concentration of 20 mg/litre in river
water containing preadapted microbes, MEK was completely degraded in
2.5 days (Dojlido, 1977). Delfino & Miles (1985) reported a slower
rate of decomposition in aerobic ground water; 1 mg/litre was fully
degraded in 14 days. However, a bacterial species (Alcaligenes
faecalis) found in sewage sludge metabolized MEK slowly if at all
(Marion & Malaney, 1963). The data on mammals and microbes suggest
that MEK is rapidly absorbed and metabolized by most living organisms
(Basu et al., 1981).
MEK in air is rapidly decomposed by photochemical processes,
mainly through oxidation by hydroxyl free radicals as well as some
decomposition by direct photolysis (Levy, 1973; Laity et al., 1973;
Dilling et al., 1976; Grosjean, 1982; Seinfeld, 1989). Basu et al.
(1981) estimated a half-life of 5.4 h for photochemical decomposition
in urban atmospheres. They further concluded that the lower
concentration of photochemically produced oxidants in rural air will
lead to a substantially lower rate of photochemical decomposition in
these areas. The concentration of MEK and other carbonyls is higher in
urban air (Grosjean & Wright, 1983; Snider & Dawson, 1985). Greater
anthropogenic emissions and photochemical synthesis of carbonyls from
free radicals (Grosjean et al., 1983) may overwhelm the more rapid
photochemical decomposition in urban atmospheres. Scavenging by
aqueous droplets and dry deposition may also be important processes in
the removal of atmospheric MEK (Grosjean & Wright, 1983).
MEK (and other saturated aliphatic carbonyls) is not chemically
reactive under conditions found in most natural waters and in general
will not degrade rapidly from physical causes once deposited in water
(US EPA, 1985b). The exception is water containing free halogens (such
as chlorine) or hypohalides. MEK reacts with these to form a haloform
and propionic acid (Basu et al., 1981). This can be a cause for
concern in chlorinated waste water and water supplies, since the
chloroform thus produced is more toxic than the original MEK (US EPA,
1985a).
5. ENVIRONMENTAL LEVELS AND HUMAN EXPOSURE
5.1 Environmental levels
5.1.1 Air
Although MEK is widely present in the natural environment,
concentrations are always low even under conditions of pollution
(Table 4). In minimally polluted outdoor air, the level is less than
3 µg/m3 (1 ppb), but 131 µg/m3 (44.5 ppb) has been measured under
conditions of heavy air pollution in the Los Angeles basin.
Volatilization of MEK from building materials and consumer products
can pollute indoor air to levels above adjacent outside air. In a
study of 15 Italian urban homes, De Bortoli et al. (1985, 1986)
reported 8 µg/m3 as a mean indoor air value and 38 µg/m3 as a
maximum value. Maximum and average values for MEK in outdoor air
adjacent to these homes were 12 and 3.8 µg/m3 respectively. Shah &
Singh (1988) reported four observations of MEK in indoor air in the
USA; the median and mean values were 21 and 27 µg/m3 (7.1 and 9.2
ppb), respectively. In a confined and tightly sealed space, however,
MEK concentrations can be much higher. Liebich et al. (1975) measured
1.9 to 4.4 mg/m3 (665 to 1505 ppb) in Space Lab IV.
Human activities, other than the deliberate manufacture and use
of MEK, may in some circumstances contribute significantly to
environmental levels. MEK is a minor component, < 2.95 mg/m3 (1.0
ppm), of gasoline engine exhaust and also has been detected in the
exhaust from diesel engines and jet aircraft. The US Environmental
Protection Agency estimated that 1909 tonnes of MEK was emitted in
motor vehicle exhaust in the USA in 1987 ("Mobile source estimates for
methyl ethyl ketone"; personal communication by J.H. Somers, 1989). In
addition, Grosjean et al. (1983) concluded that synthesis of MEK and
other carbonyls from hydrocarbons in vehicle exhaust by photochemical
reactions in the atmosphere may greatly exceed their direct production
by motor vehicles. Thus, away from industrial areas where MEK is
manufactured or used, it is likely that motor vehicles are an
important and possibly major source of atmospheric pollution by MEK.
Smoking cigarettes and other tobacco products contributes slightly to
individual exposure. Although the concentration of MEK in cigarette
smoke (Table 4) may exceed recommended levels of permissible
occupational exposure (Table 5) by several a Assuming a respiratory
volume of 20 m3 per day times, the total amount of MEK generated by
smoking a single cigarette is about 1/74th of the acceptable human
daily chronic intake in the USA (15.43 mg/day) (US EPA, 1986). MEK
also has been detected in the gases from structural (building) fires
(Lowry et al., 1981).
5.1.2 Water
MEK concentrations in exposed natural waters are less than 0.1
mg/litre (0.1 ppm) and are usually below the level of detection. Ewing
et al. (l977) analysed 204 samples from rivers with industrialized
basins; only one sample contained MEK (0.023 mg/litre). Jungclaus et
al. (1978) measured significant levels of MEK in waste water from a
chemical plant but could not detect it in either water or sediment of
the brackish Delaware River receiving this waste. Despite its rapid
disappearance from water, trace amounts of MEK have been detected
widely in drinking-water (US EPA, 1985b). A potential source is
solvent leached from the cemented joints of plastic pipe (Wang &
Bricker, 1979; Boettner et al., 1981). A single unexpectedly high
value of 0.47 mg/litre (0.47 ppm) in mist from the landward edge of
the Los Angeles basin probably resulted from scavenging of heavily
polluted air (Grosjean & Wright, 1983). Data on MEK in sediment (US
EPA, 1985b) were based on four samples and are difficult to interpret.
Sawhney & Kozloski (1984) studied organic pollution of leachates from
municipal landfill sites in Connecticut, USA. MEK concentrations
ranging between 4.8 and 8.2 mg/litre were measured over a two-year
period at one site. This high value may have resulted not only from a
substantial input but also from reduced microbial activity and no
evaporative loss to the air.
Environmental concentrations in a number of media are shown in
Table 4.
Table 4. Concentrations of MEK in the environment
Source Concentration Reference
Air (rural)
South-western USA 1.77 µg/m3 Snider & Dawson (1985)
(0.6 ppb)
Air (urban)
South-western USA, Tucson 7.1 µg/m3 Snider & Dawson (1985)
(2.4 ppb)
USA, Los Angeles basin 0-131.3 µg/m3 Grosjean et al. (1983)
(0-44.5 ppb)
Sweden, traffic areas 7.7-94 µg/m3 Jonsson et al. (1985)
(2.6-32 ppb)
Italy < 2.1-12.1 µg/m3 De Bortoli et al. (1985)
(< 0.7-4.1 ppb)
Japan (air pollution) 12.7 µg/m3 Anonymous (1978)
(4.3 ppb)
Air (indoor)
Italy (homes) < 2.1-38.1 µg/m3 De Bortoli et al. (1985)
(< 0.7-12.9 ppb)
USA (homes) detected in 3 out of Jarke et al. (1981)
87 samples
Space Lab IV 1.96-4.44 mg/m3 Liebich et al. (1975)
(0.665-1.505 ppm)
Water
Sea water (Gulf Stream) < 0.022 mg/litre Corwin (1969)
Sea water (Mediterranean) < 0.008 mg/litre Corwin (1969)
Mist (California, USA) < 0.47 mg/litre Grosjean & Wright (1983)
Drinking-water (USA) < 0.0016 mg/litre Ogawa & Fritz (1985)
Ground water (hazardous 4.8-8.2 mg/litre Sawhney & Kozloski (1984)
waste landfill sites, USA)
Table 4 (contd.)
Source Concentration Reference
Rivers (industrialized 0.023 mg/litrea Ewing et al. (1977)
areas, USA)
Waste water (oil well, USA) 1.5 mg/litre Sauer (1981)
Waste water (Chemical plant, 8-20 mg/litre Jungclaus et al. (1978)
USA)
Waste water (plant, Poland) > 100 mg/litre Dojlido (1977)
Sediment
USA 0.050-23 mg/kg US EPA (1985b)
Anthropogenic sources
Automobile exhaust < 0.3-2.95 mg/m3 Seizinger & Dimitriades
(0.1-1.0 ppm) (1972)
Cigarette smoke 80-207 µg/cigarette Higgins et al. (1983)
a MEK was detected in only one of 204 samples.
Table 5. Levels of estimated daily MEK intake from different
sources/routes of exposure
Type/route of exposure Daily intake
Foodstuffs 1590 µg
Drinking-water (2 litres) 3.2 µg
Ambient aira
outdoor, rural 36 µg
outdoor, urban < 2620 µg
indoor < 760 µg
Tobacco smoking (20 cigarettes) < 1620 µg
a Assuming a respiratory volume of 20 m3 per day
5.1.3 Foodstuffs
MEK is produced in small amounts by animals, higher plants, algae
and microbes, and is a widespread, although generally minor, component
of taste and odour in foods (Zakhari et al., 1977). It has been
identified in some foodstuffs and beverages. Using the DNPH method
with column or paper chromatography, it has been identified (but not
quantified) in white bread (Ng et al., 1960), tomatoes (Schormüller &
Grosch, 1964), cooked turkey meat (but not in raw meat and with more
MEK in roasted than in boiled meat, the level increasing with roasting
time) (Hrdlicka & Kuca, 1965), and in egg white (Sato et al., 1968).
Using gas chromatography, traces of MEK were found in fresh chicken
meat (pectoral muscle) with a marked increase in samples kept for 4
days at room temperature. It was not found in caecal gas from living
chickens but was detected in the gas 18 and 24 h after death (Grey &
Shrimpton, 1967). MEK has also been detected in cottonseed oil
(Dornseifer et al., 1965), honey (Cremer & Riedmann, 1964), coffee
(Gianturco et. al., 1966), roast barley (Shimizu et al., 1969), and in
the mushroom Agaricus bisporus (Staüble & Rast, 1971). By means of
GC/MS, Wong et al. (1967) detected MEK in codfish and Kahn et al.
(1968) reported its presence in a low-boiling distillation fraction of
Canadian whisky.
In a study of compounds related to milk flavour, Wong & Patton
(1962) determined MEK concentrations using the DNPH method with column
separation and paper chromatography. The concentrations in two samples
of untreated milk were 0.77 and 0.79 mg/litre and in two samples of
cream were 0.154 and 0.177 mg/litre. Gordon & Morgan (1972) examined
the influence of volatile compounds in milk on "feed" flavour and
reported MEK concentrations of 0.25-0.35 mg/litre in moderately "feed"
flavoured milk and 0.50-1.0 mg/litre in strongly flavoured milk, with
a highest concentration detection of 1.4 mg/litre. They concluded that
MEK is one of the compounds responsible for producing the unpleasant
"feed" flavour in milk. Using the DNPH method and paper
chromatography, Harvey & Walker (1960) detected MEK in New Zealand
cheddar cheese one day after manufacture. The concentration increased
during ripening, reaching 0.9 mg/kg at 40 weeks, and was related to
the development of typical Cheddar cheese flavour. In another study of
the chemical nature of USA Cheddar cheese flavour, Day et al. (1960)
analysed the volatile flavour fraction of cheeses over 1 year old
using DNPH and column partition chromatography, and reported
approximate MEK concentrations of 12.5 mg/kg. Keen et al. (1974)
postulated that the formation of MEK in New Zealand Cheddar cheese,
for which levels as high as 19 mg/kg had been reported, occurred in
steps carried out by different microbial species including
Streptococcus cremaris, Pediococcus cerevisiae, Lactobacillus
plantarum and Lactobacillus brevis. They considered that MEK was
an important flavour constituent in the cheese.
In another investigation of monocarbonyl compounds as flavour
components, Mookherjee et al. (1965) measured MEK in fresh and stale
(8 weeks old) potato chips with the DNPH method and liquid-liquid
chromatography. In fresh potato chips the concentration of MEK was 1.8
µmoles/kg, and this increased to 2.2 µmoles/kg in stale chips.
Amylomaize starches are heat treated in the production of films
and fibres to concentrate the amylose. Bryce & Greenwood (1963) used
gas chromatography to measure pyrolysis products (including MEK) of
potato starch, potato amylose and amylopectin, maltose, isomaltose and
glucose. MEK was not detected in untreated starch nor in starch
pyrolysed in vacuo for 20 min at 200 and 220 °C. With increasing
temperatures the concentration of MEK increased; at 230, 250, 300, 350
and 400 °C the MEK concentrations were 10, 15, 50, 65 and 70 moles x
107/g starch, respectively.
Small quantities (up to 2 ng/1.5 g bean) were found in soybeans
(Clycine max) and winged beans (Psophocarpus tetragonolobus) by
means of dynamic headspace GC/MS (Del Rosario et al., 1984).
However, the reported concentrations of MEK in foods are low and
food consumption is not considered a significant source of population
exposure.
5.2 General population exposure
Stofberg & Grundschober (1984) calculated the consumption ratio
between the quantity of a flavouring material consumed as an
ingredient of basic and traditional foods and the quantity of that
same flavouring material consumed as a component of added flavourings
by a certain population. If the consumption ratio is more than 1, this
substance is consumed predominantly as an ingredient of traditional
foods. For MEK, this ratio may be up to 411. The annual consumption in
the USA of MEK via apple juice is 85 kg, white bread 70 132 kg, butter
34 kg, carrot 154 kg, Cheddar cheese 30 139 kg, Swiss cheese 198 kg,
fish 81 kg, potato chips 31 kg, tomato 31 878 kg, and yoghurt 1104 kg.
Assuming a population of 230 millions, the estimated average daily
intake in the USA amounts to 1.59 mg/kg foodstuff. Some information on
the MEK contents of various foodstuffs is given in Table 6. The
European Economic Community regulates the level of MEK in certain
foodstuffs; these are given in Table 7.
In addition to the MEK that is naturally present, foods may also
contain MEK absorbed from plastic packaging materials. This can be
derived from solvent left in the plastic during manufacture
(Kontominas & Voudouris, 1982) or represent one of the many organic
compounds produced during extrusion (Fernandes et al., 1986). It can
also be produced by irradiation of polyethylene film during the
sterilization of packaged foods with an electron beam (Azuma et al.,
1983). Although the presence of MEK and associated organic compounds
from packaging materials may affect the flavour of foods, it probably
does not represent a significant source of population exposure.
Table 6. MEK concentrations of certain foodstuffs
Source Concentration Reference
Bean seeds (raw) 0.5 mg/kg Del Rosario et al. (1984)
Bean seeds (heated at 0.7-2.0 mg/kg Del Rosario et al. (1984)
190 °C)
Pea seeds 0.074-0.39 mg/kg Fisher et al. (1979)
Milk ("feed"-flavoured) 0.25-14 mg/litre Gordon & Morgan (1972)
Bread 3.06 mg/kg Sosulski & Mahmoud (1979)
Cheddar cheese 12.5 mg/kg Day et al. (1960)
19 mg/kg Bills et al. (1966)
Table 7. Food uses of MEK permitted in the European Economic Community
Conditions of use Maximum residue limits in the extracted
foodstuff, food or food-contact material
In manufactured or regenerated 0.6 mg/dm2 on the side in contact with
cellulose film that comes into foodstuffs
contact with fooda
Fractionation of fats/oilsb 5 mg/kg in the fat/oil
Decaffeination of, or removal of 20 mg/kg in the coffee or tea
irritants and bitterings from, (as granules, powder, leaves,
coffee and teab etc.)
Preparation of flavourings 1 mg/kg in the foodstuff
from natural flavouring materialsb
a Council Directive 83/229/EEC
b Council Directive 88/344/EEC
Higgins et al. (1983) analysed the gas phase organic compounds in
cigarette smoke. In cigarettes with high tar content (7-45 mg per
cigarette), the MEK level was 63-131 µg/cigarette, whereas in ultralow
tar delivery cigarettes (advertised value < 0.01-0.2 mg per
cigarette), it was 0.93-4 µg MEK/cigarette.
Levels of estimated daily MEK intake from different sources/
routes of exposure are given in Table 5.
5.3 Occupational exposure
Information on measured levels of occupational exposure is
summarized in Table 8. Some national occupational exposure limits for
MEK in workplace air are shown in Table 9. In a study of an electronic
parts plant in the USA, Lee & Parkinson (1982) reported that workers
were exposed to mixtures of solvent vapours containing MEK. Inoue et
al. (1983), in a nationwide survey of Japanese factories, found that
MEK was widely used as a component of solvent mixtures. A study by
Falla (1987) of 19 British plants manufacturing or applying surface
coatings reported that none had MEK concentrations in excess of 295
mg/m3 (100 ppm). The highest TWA value, 723 mg/m3 (245 ppm),
reported by Lee & Murphy (1982) represented a worker who entered the
highly polluted vinyl dip room (502-1785 mg/m3; 170-605 ppm) only
occasionally, but without always donning his respirator hood. A
co-worker stationed in the vinyl dip room who wore his respirator hood
constantly had TWA exposures of 307-617 mg/m3 (104-209 ppm). De Rosa
et al. (1985) examined 504 work stations in 81 Italian plants (shoe
factories, painting operations and printing plants) and found that the
TLV for MEK (590 mg/m3, 200 ppm) was rarely exceeded.
5.4 Peri-occupational exposure
Many small industries in the Netherlands are located in inner
city areas. The influence of such industries on the quality of indoor
air in adjacent houses was studied by Verhoeff et al. (1987), who
monitored the indoor air of a car-body repair shop, an offset printing
office and surrounding houses for organic solvents, including MEK.
Monitoring was carried out for one week, and the individual exposure
of workers and residents was investigated by biological monitoring of
the exhaled breath with additional personal air sampling of the
workers. Concentrations in both the factories were lower than 29.5
mg/m3, i.e. 5% of the Dutch MAC values (590 mg/m3). In the
personal air samples of the employees, MEK was at or below the
detection level. In the house located directly over the car-body
repair shop, the average concentrations of MEK were about 50% those in
the shop, while two floors above, MEK was detected only once.
Table 8. Occupational exposure to MEK via air
Activity Country Sampling Concentration Reference
details mg/m3 (ppm)
Printing and printing Japan personnel (62) 0-265 (0-90) Miyasaka et al. (1982)
machine manufacturing
Shoe factory Italy not given 0-300 (0-102) Brugnone et al. (1983)
Shoe factories, painting Italy personnel (1 h) 0-1110 (0-376)a De Rosa et al. (1985)
operations, printing plants (504)
Miscellaneous factories Italy personnel (4 h) (65) 10-953 (3.4-323) Ghittori et al. (1987)
Sheet metal shop Sweden area (continuous) approx. 3-44 Persson et al. (1984)
(approx. 1-15)
Organic chemical waste USA area (9) < 0.06 (< 0.02) Decker et al. (1983)
incinerator (vicinity)
personnel (7) < 0.06-189 (< 0.02-64)
(exposed workers)
Radio components USA personnel (range 0-38 (0-13) Lee & Parkinson (1982)
manufacturing of jobs)
Solvent recycling plant USA < LDQ-166 (< LDQ-38)b Kupferschmid & Perkins (1986)
Plastic items factory USA no details 0.07-0.16 Ahrenholz & Egilman (1983)
(0.024-0.054)
Surface coatings United area (59) < 295 (100) Falla (1987)
factories Kingdom
Table 8 (contd)
Activity Country Sampling Concentration Reference
details mg/m3 (ppm)
Lubricating oil USA personnel (38) 0.09-80 (> 0.029-27) Emmel et al. (1983)
refineries
Miscellaneous factories USA personnel (179) 0-0.59 (0-0.2) Whitehead et al. (1984)
with spray application (non-exposed
of glue and paint workers)
1.18-6.2 (0.4-2.1)
(exposed workers)
Aircraft maintenance USA personnel (9) 0-65 (0-22)c Thoburn & Gunter (1982)
Athletic equipment USA personnel (12) 307-723 Lee & Murphy (1982)
factory (104-245 TWA)d
(vinyl dip room)
0.89-534 (0.3-181)
TWA (elsewhere)
a MEK was found in 85/504 samples
b LDQ = lowest detectable quantity
c MEK was detected in only one of nine samples
d 8-h time-weighted average
Table 9. Some national occupational exposure limits for MEK in air
Country Exposure limit Category of limitb Reference
mg/m3 (ppm)
Argentina 590 (200) TWA IRPTC (1987, 1991)
885 (300) STEL
Brazil 460 (155) for 48 h/week IRPTC (1987, 1991)
Germany 590 (200) TWA IRPTC (1987, 1991)
1180 (400) 30 min. STEL
(average value,
4 x per shift)
Hungary 200 (68) TWA (8 h) IRPTC (1987, 1991)
1000 (2950) STEL (30 min)
Italy 590 (200) TWA Notified by country
Japan 590 (200) TWA IRPTC (1987, 1991)
Netherlands 590 (200) TWA a
Sweden 150 (50) TWA IRPTC (1987, 1991)
300 (100) STEL (15 min)
United Kingdom 590 (200) TWA (8 h), OES Notified by country
885 (300) STEL (10 min), OES
USA (NIOSH/OSHA) 590 (200) TWA (10 h) US NIOSH (1990)
885 (300) STEL (15 min)
8850 (3000) IDLH
USA (ACGIH) 590 (200) TLV (TWA) ACGIH (1991)
885 (300) STEL
2 mg/litre BEI
urine; end of
shift
Yugoslavia 295 (100) Notified by county
TWA and TLV are, with one exception, in the range of 295-590 mg/m3 (100-200 ppm). The
latter is stated to be the highest concentration which can be tolerated by humans without
discomfort (ACGIH, 1986). In addition a short-term exposure limit of 885-1180 mg/m3
(300-400 ppm) has been established by some nations.
a Dutch Expert Committee for Occupational Standards (1991)
b Abbreviations: BEI = biological exposure index (ACGIH); IDLH = concentration
immediately dangerous to life or health (US NIOSH); OES = occupational exposure
standard (UK); STEL = short-term exposure limit; TLV = threshold limit value
(ACGIH); TWA = time weighted average
6. KINETICS AND METABOLISM
6.1 Absorption
6.1.1 Percutaneous absorption
Percutaneous absorption of MEK appears to be rapid (Munies &
Wurster (1965) and Wurster & Munies (1965) reported that MEK was
present in the exhaled air of human subjects within 2.5-3.0 min after
it was applied to normal skin of the forearm, and the concentration of
MEK in exhaled air reached a plateau in 2-3 h. The rate of absorption
was controlled mainly by the moisture content of the skin. With dry
skin, absorption was slow, and it took 4-5 h for the concentration of
MEK in expired air to attain a plateau. With moist skin, absorption
was very rapid initially. MEK was detected in expired air in
measurable concentrations within 30 seconds after an application of
MEK to the forearm, and a maximum concentration in expired air,
averaging four times the plateau level for normal and dry skin, was
achieved in 10-15 min. The concentration of MEK in expired air, and
thus its absorption, subsequently declined to a plateau level somewhat
above that for normal and dry skin because the MEK partially
desiccated the moist skin with which it was in contact. Munies &
Wurster (1965) concluded that the rapid percutaneous absorption of MEK
reflected its olive oil-water partition coefficient, which is close to
unity. Their data have been used to calculate minimum rates of
percutaneous penetration of 0.46 µgÊcm-2Êmin-1 for dry or normal
skin and 0.59 µgÊcm-2Êmin-1 for moist skin (JRB Associates, Inc.,
1980). These rates are minimal because they are based solely on
exhalation from the lungs and ignore all other excretion processes for
MEK.
As the elimination of MEK via inhalation constitutes only 5 to
10% of the total loss (Cushny, 1910), these rates should be multiplied
by factors of 10-20. This gives a percutaneous absorption of 5-10
µgÊcm-2Êmin-1, which is identical to the value measured for methyl
isobutyl ketone by DiVincenzo et al. (1978).
6.1.2 Inhalation absorption
The absorption of MEK via the lungs was examined by Perbellini et
al. (1984) in a study of workers exposed in industrial workplaces. The
MEK concentration in alveolar and expired air correlated significantly
with the environmental concentration, and averaged 30% of the latter.
In more recent studies (Liira et al., 1988a, 1988b), values for
pulmonary absorption ranging from 41.1% to 55.8% were obtained. Liira
et al. (1988b) suggested that differences in their values may have
reflected variations in breathing technique during the collection of
samples rather than actual changes in uptake. Deeper inhalation
increased the alveolar volume relative to the dead space (the
non-alveolar volume of the respiratory system), and thus increased the
apparent absorption (personal communication by J. Liira, 1989). When
the alveolar retention of MEK (about 70%) measured by Perbellini et
al. (1984/1985) is transformed to overall pulmonary retention, their
observations and those of Liira et al. (1988a,b) are in agreement,
showing that about 50% of inhaled MEK is taken up.
Results of studies by Liira et al. (1988a,b, 1990a,b) indicated
a rapid transfer of MEK vapour into the blood stream. Perbellini et
al. (1984, 1985), reported that the concentrations of MEK in the blood
and urine were significantly correlated with the environmental
concentration, indicating rapid transfer to the blood and thence to
other tissues. In human volunteer subjects, exercise during exposure
markedly increased the MEK level in blood in comparison with sedentary
behaviour (Liira et al., 1988b), indicating that the blood MEK level
also depended on the rate of uptake. Ghittori et al. (1987) and
Miyasaka et al. (1982) also found significant correlations between
environmental levels of MEK and amounts excreted in the urine of
exposed workers. The concentration of MEK in urine rose from
essentially zero to 70% of its maximum value during the first 2 h of
an 8-h shift (Miyasaka et al., 1982).
Ong et al. (1991) studied biological monitoring of occupational
exposure to MEK in 67 healthy male workers employed in plastic bag or
video-tape production. Their ages ranged between 18 and 52 years with
an average working experience of 8.6 years. For the majority of the
workers, atmospheric MEK concentrations were in the range 30-885
mg/m3 (10-300 ppm). MEK concentrations in urine, blood and exhaled
air were measured once weekly at the end of a shift. About 10% of
absorbed MEK was eliminated in the exhaled air. Following exposure to
590 mg/m3 (200 ppm), the urinary concentration was 5.1 µmol/litre or
4.11 mg/g creatinine. The correlation coefficients (tau) between
atmospheric MEK concentration and end-of-shift urine, blood and
exhaled air were 0.89, 0.85 and 0.79, respectively. The authors also
reported good correlation between blood and urinary MEK (tau = 0.86)
and between blood and exhaled air concentrations (tau = 0.8) but poor
correlation between exhaled air and urinary MEK concentrations.
6.1.3 Ingestion absorption
In male rats given a large MEK dose (1505 or 1690 mg/kg) in
water, blood concentrations reached maxima of 0.95 and 0.94 mg/ml 4 h
after ingestion and subsequently declined sharply, indicating
protracted absorption of this dose from the gastro-intestinal tract
(Traiger & Bruckner, 1976; Dietz & Traiger, 1979; Dietz et al., 1981).
6.1.4 Intraperitoneal absorption
The results of DiVincenzo et al. (1976) and Zakhari et al.
(1977), who used intraperitoneal injections of MEK in research on
metabolism and toxicity, suggest that absorption from the peritoneal
cavity is rapid.
6.2 Distribution
The distribution of MEK in human tissues was examined by
Perbellini et al. (1984) in two solvent-exposed workers who died
suddenly of heart attacks at the workplace. The results of this study
(Table 10) indicate that the solubility of MEK is similar for all
tissues. Brugnone (1985) calculated the uptake and distribution of MEK
from the lungs. With a blood/air partition coefficient of 202, MEK can
reach equilibrium concentration in a compartment in about 3 min.
Distribution volumes were 6.0 for vessel-rich tissues, 39.6 for muscle
and 12.8 for fat. Biological half-lives for the same tissues were 0.8,
21.8 and 23.3 min, respectively. The results of in vitro
measurements at 37 °C of human tissue-gas partition coefficients,
obtained by exposing samples of blood and tissue to a known
concentration of MEK (Fiserova-Bergerova & Diaz, 1986), differed from
the observations of Perbellini et al. (1984). The partition
coefficients ranged from 96 to 162, but did not exceed 111, with the
exceptions of whole blood (125), blood plasma (133) and fat (162).
Other blood-gas partition coefficients measurements for MEK are 202
(Sato & Nakajima, 1979) and 215 (Pezzagno et al., 1983). Traiger &
Bruckner (1976) and DiVincenzo & Krasavage (1974) provided evidence
that MEK can enter the liver of rats and guinea-pigs, and Dowty et al.
(1976) reported that it can cross the placenta and enter the human
fetus.
6.3 Metabolic transformation
MEK has been reported to be a metabolic end product of natural
gas (methane 88%, ethane 5%, propane 5%, isobutane 2% with traces of
tert-butyl mercaptan and methyl acrylate) inhaled for 2 h by ICR
mice (Tsukamoto et al., 1985a). In an in vivo study of the
metabolism of propane, n-butane and iso-butane inhaled for 1 h by
ICR mice, it was found that n-butane gave rise to sec-butanol and
MEK (Tsukamoto et al., 1985b). In vitro studies showed that mouse
liver microsomal preparations metabolized n-butane to sec-butanol,
the precursor of MEK (Tsukamoto et al., 1985b). Inhalation by male
Sprague-Dawley rats of sec-butanol at concentrations of 5900 mg/m3
(2000 ppm) for 3 days or 1475 mg/m3 (500 ppm) for 5 days caused
marked enzyme induction of cytochrome P-450 in liver and kidney but
other butanol isomers did not have this effect (Aarstad et al., 1985,
1986). The authors concluded that the mechanism of induction was via
the sec-butanol metabolite MEK.
Table 10. Solubility (partition coefficient) of MEK in human tissuesa
Tissues Tissue/air Tissue/blood
Blood 183 1.00
Kidney 197 1.08
Liver 180 0.98
Brain 168 0.92
Fat 161 0.88
Muscle 212 1.16
Heart 254 1.39
Lung 147 0.80
a From: Perbellini et al. (1984)
6.3.1 Animal studies
Traiger & Bruckner (1976) showed that the toxic effects of MEK
and 2-butanol were essentially identical in rats, and that 2-butanol
was rapidly oxidized to MEK. DiVincenzo et al. (1976) identified the
metabolites of MEK in guinea-pigs as 2-butanol, 3-hydroxy-2-butanone
and 2,3-butanediol. They hypothesized that the metabolism followed
both oxidative and reductive pathways, with the latter leading to the
production of 2-butanol. The former, employing microsomal omega-1
oxidization, oxidized MEK to 3-hydroxy-2-butanone, which was
subsequently reduced to 2,3 butanediol. Further research utilizing
rats (Dietz & Traiger, 1979; Dietz et al., 1981) clarified the
pathways of rat MEK metabolism and permitted a calculation of rate
constants for the elimination of MEK and its metabolites from the
blood as well as for the metabolic transformations (Fig. 1). The body
was divided into two compartments: (a) the liver, where metabolic
transformations took place; and (b) the blood, which was the site of
sampling. Experimental data and equations derived from this data
indicated that the major metabolic pathway is butanol -> MEK ->
3-hydroxy-2-butanone -> 2,3-butanediol, with small or non-existent
reverse flows. Dietz et al. (1981) estimated that an oral dose of
2-butanol or MEK resulted, on a molar basis, in the same blood
level-time curve for 2,3-butanediol as 28-30% of this amount given as
an intravenous dose of 2,3-butanediol. Their data indicated that
transformations of 2-butanol to MEK and of 3-hydroxy-2-butanone to
2,3-butanediol are rapid and that transformation of MEK to
3-hydroxy-2-butanone is much slower. It is likely that 2-butanol, like
ethanol (Mezey, 1976), inhibits oxidative pathways of drug metabolism
and thus inhibits the hydroxylation step leading to
3-hydroxy-2-butanone. This possibility is supported by the observation
of Dietz et al. (1981) that 2-butanol, at concentrations similar to
those achieved in the blood of rats in the above experiment,
significantly inhibited N-dealkylation of aminopyrine by rat liver
microsomes in vitro .
In rats exposed by inhalation to 1760 mg MEK/m3 (600 ppm),
there were only marginal effects on microsomal cytochrome P-450
activities (Liira et al., 1991). However, a daily dose of 1.4 ml MEK
per kg for 3 days increased the amounts of ethanol- and
phenobarbital-inducible cytochromes P-450 (P-450 IIEI and P-450 IIB)
(Raunio et al., 1990). In a study on male Sprague-Dawley rats,
pretreatment with MEK elevated total microsomal cytochrome P-450 and
NADPH-dependent cytochrome-c-reductase, the rates of oxidation of
N-nitrosodimethylamine, benzphetamine and pentoxyresorufin, and also
the levels of immunoreactive protein for both P-450 isozymes (Brady et
al., 1989). In a study of hepatotoxicity in rats, Brondeau et al.
(1989) found that MEK increased liver cytochrome P-450 content
(33-86%) and glutathione-S-transferase (GST) activity (42-64%) but had
no effect on serum glutamate dehydrogenase (GLDH) activity. Robertson
et al. (1989) studied the effects on hepatic cytochrome P-450
activities of repeated daily doses of 1.87 ml/kg given by gavage to
male Fischer-344 rats. The activity of 7-ethoxy
coumarin- O-deethylase was increased by up to 500% after 1 to 7 days
of MEK treatment, but there was practically no change in
benzphetamine- N-demethylase activity. In another study in male
Sprague-Dawley rats, administration of MEK by gavage caused an
increase in hepatic acetanilide hydroxylase and a marginal increase in
aminopyrine- N-demethylase activities (Traiger et al., 1989).
6.3.2 Human studies
MEK has been identified as a minor but normal constituent of
urine (Tsao & Pfeiffer, 1957), serum and urine of diabetics (Mabuchi,
1969), and expired air (Conkle et al., 1975). Its production in the
body has been attributed to isoleucine catabolism (Tsao & Pfeiffer,
1957; Przyrembel et al., 1979). Although Smith (1981) mentioned MEK as
a product of autoxidation of cholesterol, no evidence was offered that
this process occurred in vivo . The studies of Perbellini et al.
(1984) and Liira et al. (1988a,b) indicate that the same metabolites
are produced and excreted in humans as in experimental animals. Liira
(personal communication by J. Liira, 1989) further indicated that in
an inhalation exposure to 590 mg MEK/m3 (200 ppm) the calculated
areas under the curves of blood solvent concentration versus time
(AUC) for MEK and 2,3-butanediol were equal, which suggests that MEK
is almost completely transformed to 2,3-butanediol. The bulk of MEK
absorbed thus enters the general metabolism and is transformed to
simple compounds like carbon dioxide and water.
6.4 Elimination and excretion
MEK and its metabolites are excreted by the lungs and kidneys.
Liira et al. (1988a) reported that only 3% of the calculated absorbed
dose during a 4-h exposure to 590 mg MEK/m3 (200 ppm) was secreted
unchanged in the exhaled air of volunteers after the exposure. The
fractional elimination of unchanged substance however depends on the
efficiency of metabolic clearance. Since metabolic saturation for MEK
in humans begins at relatively low levels (about 100 ppm) of exposure
(Liira et al., 1990a), proportionally greater amounts of MEK would be
expected to be excreted via the lungs (and kidneys) at high exposure
levels.
Relatively little of the absorbed MEK is excreted unchanged via
the kidneys; a study of occupationally exposed workers revealed that
it is less than 0.1% of the alveolar uptake (Miyasaka et al., 1982).
In a similar study of workers occupationally exposed to a mixture of
solvents, the excretion of MEK and a major recognizable metabolite,
3-hydroxy-2-butanone, was 0.1% of alveolar uptake (Perbellini et al.,
1984). The concentrations of both MEK and 3-hydroxy-2-butanone in
urine were significantly correlated with the environmental level of
MEK. Other metabolites of MEK, 2-butanol or 2,3-butanediol, which
DiVincenzo et al. (1976) identified in the serum of guinea-pigs, were
not detected in the urine of the exposed workers. Liira et al.
(1988a), however, reported that human excretion of 2,3-butanediol was
individually variable but averaged 2% of the absorbed MEK. The urinary
excretion of 2-butanol, a minor metabolite of MEK, was examined by
Kamil et al. (1953), who found that clearance of 2-butanol
administered by gavage in rabbits was about 14% of the administered
dose and in the form of a glucuronide.
Since MEK and 2,3-butanediol disappear from blood and urine and
there is no evidence for accumulation elsewhere in the body, the above
data suggest that the bulk of MEK absorbed by mammals enters the
general metabolism and is eliminated from the body as simple compounds
like carbon dioxide and water whose source is not readily
identifiable. The specific pathways by which MEK is metabolized have
not been identified. There also is no information on loss of MEK in
faeces.
6.5 Turnover
Both animal and human data indicate a rapid turnover of MEK. In
guinea-pigs receiving an intraperitoneal dose of 450 mg MEK per kg,
the half-life of MEK in blood serum was 4´ h and the clearance time
for MEK in serum was 12 h. For the metabolites 2-butanol,
3-hydroxy-2-butanone and 2,3-butanediol, the clearance time in serum
was 11 h (DiVincenzo et al., 1976). In rats given a 2.2-ml/kg oral
dose of 2-butanol, the butanol was largely cleared from the blood in
15 h and the 2-MEK derived from the butanol was cleared in 24 h
(Traiger & Bruckner, 1976). In a study by Dietz & Traiger (1979) on
rats given an oral dose of 2-butanone of 2.1 mg/kg, there was a
half-life of 3.6 h for MEK in blood if the rate of loss was assumed to
be constant between the two times of measurement (4 h and 18 h) after
dosing. Data from a study of Dietz et al. (1981) on rats receiving
oral doses of 2-butanol or MEK also indicate a half-life of about 4 h
for MEK. These authors reported that the clearance rate for
3-hydroxy-2-butanone and 2,3-butanediol was independent of dose for
the two doses used (0.4 and 0.8 g/kg) and that the half-lives for
these metabolites of MEK were 47 min and 3.45 h, respectively. Liira
et al. (1988a) reported a steady increase in blood concentrations
during 4-h exposures of human volunteer subjects to 590 mg/m3 (200
ppm) and observed a rapid elimination of MEK, with half-lives of 30
min during the first post-exposure hour and 81 min thereafter. An
inhalation study with two volunteer subjects exposed to MEK for 4 h at
concentrations of 74, 590 and 1180 mg/m3 (25, 200 and 400 ppm)
indicated that the kinetics of MEK were dose dependent at higher
exposure concentrations, i.e. much higher levels of MEK in blood were
reached relative to inhaled concentrations, and the post-exposure
elimination of MEK in blood was slower (zero-order kinetics).
Simulated exposure to MEK for 8 h suggests that saturation kinetics
are reached at about 295 mg/m3 (100 ppm) at rest and 148 mg/m3 (50
ppm) during light exercise (Liira et al., 1990a).
6.6 Metabolic interactions
Ingestion of ethanol (0.8 g/kg) combined with an inhalation
exposure to MEK (590 mg/m3, 200 ppm) inhibited the oxidative
metabolism of MEK and led to a marked increase in the blood
concentration of MEK (Liira et al., 1990b). There was a concurrent,
even more pronounced elevation of the blood 2-butanol concentration;
the most likely explanation is competitive inhibition by ethanol of
the oxidation of 2-butanol back to MEK. Ethanol also appeared to
interact with the further biotransformation of 2,3-butanediol as the
urinary excretion of the metabolite was increased. Co-exposure with
xylene, however, had no effect on the human metabolism or rate of
elimination of MEK (Liira et al., 1988b).
6.7 Mechanisms of action
There is very limited information on the mechanisms of toxic
action of MEK. Relatively high inhaled concentrations 1475-29 500
mg/m3 (500-10 000 ppm) caused pulmonary vasoconstriction and
hypertension in cats and dogs (Zakhari et al., 1977). From the
toxicological point of view, interactions leading to the potentiation
of effects, particularly neurotoxicity, by other intrinsically toxic
substances constitute the main hazard of MEK. The mechanisms
underlying these interactions are incompletely known (see section 10).
7. EFFECTS ON LABORATORY MAMMALS AND IN VITRO TEST SYSTEMS
7.1 Acute exposure
7.1.1 Lethal doses
Data on the acute toxicity of MEK to experimental animals are
summarized in Table 11. Oral toxicity is low with LD50 values
ranging from 2 to 6 g/kg for adult mice and rats. Intraperitoneal
LD50 values are lower (approximately 1.5 g/kg for 24 h and 0.6 g/kg
for 14 days). A larger dermal LD50 value for rabbits, i.e. > 8 g/kg
(contact time: 24 h; observation time: 14 days), may reflect slower
and less complete absorption via the skin, although it may also
reflect species differences in sensitivity to MEK. The lethal dose of
MEK given to rats in the only study using dosing by pulmonary
aspiration (Panson & Winek, 1980) was 0.8 g/kg. This is well below the
intraperitoneal 24-h LD50 for adult rats but similar to the 14-day
value (Lundberg et al., 1986). It cannot be excluded that the high and
rapid lethality of this aspirated dose to adult rats (5/6 deaths in
< 24 h, with 4/6 reported as dying "instantly") may reflect serious
damage to the lungs.
Studies examining the effects of acute inhalation of MEK are not
entirely comparable since they used not only different species but
also different concentrations of MEK, exposure times, and periods over
which survival was measured. For mice the LC50 (45-min exposure) was
about 200 000 mg/m3. The lowest concentration lethal to all rats
exposed by inhalation for 8 h was 47 200 mg/m3 and the lowest
concentration producing lethality in a 4-h exposure was 5900 mg/m3
(2000 ppm). Guinea-pigs survived exposure to 29 500 mg/m3 for 4 to
4.7 h and showed no abnormal signs at 9735 mg/m3. A concentration of
97 350 mg/m3 was lethal to all exposed guinea-pigs in 3.3 to 4.2 h,
whereas a slightly lower concentration, 73 750 mg/m3, although
ultimately lethal to all animals, permitted some guinea-pigs to
survive a 5.4-h exposure (Patty et al., 1935; Specht et al., 1940).
7.1.2 Non-lethal doses
Non-lethal acute doses of MEK produced a number of measurable
changes in experimental animals (Table 11). An oral dose of 1.5 g/kg
to rats resulted in a 63% increase in liver triglycerides after 16 to
23 h, but did not alter liver histology or increase either of two
enzymes, serum glutamic-pyruvic transaminase (alanine transferase
(ALT)) and hepatic glucose-6-phosphatase (Traiger & Bruckner, 1976).
These results suggest that this dose caused metabolic disturbances to
the liver of rats. Much smaller acute intraperitoneal doses (0.049 to
0.194 g/kg) to rats appeared not to damage the liver. A single oral
dose (15 mmol/kg) of MEK did not affect the hepatobiliary function of
rats over an observation period of 10 to 96 h (Hewitt et al., 1986).
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 even though guinea-pigs survive acute
exposure to higher concentrations of MEK vapour than do rats
(DiVincenzo & Krasavage, 1974).
Consistent increases in the frequency of food-reinforced lever
pressing by rats were detected at MEK exposures as low as 74 mg/m3
(25 ppm) for 2 h (Garcia et al., 1978). Vestibulo-ocular effects were
detected during continuous intravenous administration of MEK for 1 h
via the caudal vein at a dosage as low as 0.005 g/kg per min (Tham et
al., 1984). This dosage is roughly equivalent to inhalation of 2700
mg/m3 (900 ppm). Glowa & Dews (1987) reported that exposure of mice
to 885 mg/m3 (300 ppm) for 30 min did not significantly alter
schedule-controlled responses, whereas concentration-related
suppression of response occurred at consecutive increasing
concentrations (for 30 min) ranging from 2950 to 29 500 mg/m3 (1000
to 10 000 ppm) (see section 7.3.1).
It can be concluded from observations of their behaviour that
respiratory irritation occurred in guinea-pigs exposed to 29 500
mg/m3 or more within 2 min (Patty et al., 1935; Specht et al.,
1940). In survivors, post-exposure recovery from this effect was
rapid. Rats exposed for 8 h/day to 29 500 mg/m3 showed severe
irritation of the upper respiratory tract after a "few days"
(Altenkirch et al., 1979).
7.1.3 Skin and eye irritation
In skin irritation studies, a small dose (8 mg) applied to
clipped skin and covered by an impervious plastic film for 24 h (which
was followed by a 14-day observation period) produced only minor
irritation in male New Zealand albino rabbits (Smyth et al., 1962). A
dose of 400 mg applied to the clipped dorsal skin of restrained albino
rabbits in a gauze patch produced mild to moderate irritation in some
cases (Weil & Scala, 1971). Data from this latter study, however, were
highly variable and may reflect the fact that its purpose was
intercomparison of laboratories rather than the effects of MEK on test
animals. Neat MEK (0.1 ml) applied to the clipped skin of the flanks
of guinea-pigs and rabbits daily for 10 days and left uncovered caused
erythema and oedema after 24-72 h. These effects were more marked in
rabbits (Wahlberg, 1984a).
Table 11. Acute toxicity of MEK for mammalsa
Species Number and sex Exposure concentration Exposure Study Effects Reference
(strain)