TECHNICAL REPORT DATA
ffteme irtd Instructions on the rtvtrte btfort completing)
1. R6PORT NO.
EPA/60Q/8-89/093
3. RECIPIENT'S ACCESSION NO
PB90-142456/AS
4. TITLE ANDSUmTLE
Updated Health Effects Assessment for Methyl Ethyl
Ketone
S. REPORT DATE
t. PERFORMING ORGANIZATION CODE
. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT7GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
15 SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order J2991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient .evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
C. COSATI Field/Croup
•. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (Thu Report I
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS
Unclassified
22. PRICE
IP4 Pan* 2220.1 (IU*. 4-77) PHCVIOUI COITION i* OMOkKTK
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EPA/600/8-89/093
February, 1989
HEALTH EFFECTS ASSESSMENT
FOR METHYL ETHYL KETONE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with methyl
ethyl ketone. All estimates of acceptable Intakes and carcinogenic potency
presented 1n this document should be considered as preliminary and reflect
limited resources allocated to this project. Pertinent toxlcologlc and
environmental data were located through on-Hne literature searches of the
TOXLINE, CANCERLINE and the CHEMFATE/OATALOG data bases. The basic litera-
ture searched supporting this document 1s current up to May, 1985. Secon-
dary sources of Information have also been relied upon In the preparation of
this report and represent large-scale health assessment efforts that entail
extensive peer and Agency review. The following Office of Health and
Environmental Assessment (OHEA) sources have been extensively utilized:
U.S. EPA. 1983. Reportable Quantity Document for 2-Butanone
(Methyl Ethyl Ketone). Prepared by the Office of Health and
Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Emergency and Remedial
Response, Washington, DC.
U.S. EPA. 1985a. Health and Environmental Effects Profile for
Methyl Ethyl Ketone. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited in
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemical(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD$ (formerly AIS) or subchronic reference dose, 1s
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
interval that does not constitute a significant portion of the lifespan).
This type of exposure estimate has not been extensively used, or rigorously
defined, as previous risk assessment efforts have been primarily directed
towards exposures from toxicants in ambient air or water where lifetime
exposure is assumed. Animal data used for RFD§ estimates generally
include exposures with durations of 30-90 days. Subchronic human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfDgj) and oral
exposures.
111
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate Inter-
pretation and use of the quantitative estimates presented.
A number of subchronlc Inhalation studies using experimental animals are
available, which suggest threshold exposure levels for liver damage, neuro-
logical Impairment and fetotoxldty. An RfDg of 3.0 mg/day was based on a
NOAEL of 235 ppm from a subchronlc Inhalation study and was verified by the
U.S. EPA (1985b). No chronic exposure data and no oral data were available;
however, an RfD$o of 32 mg/day, an RfD$i of 64 mg/day and an RfDj of 6
mg/day were estimated based on the subchronlc Inhalation data. These
estimates should be reviewed when adequate chronic data become available. A
CS of 9.6 was calculated for methyl ethyl ketone based on decreased body
weight gain In rats exposed by Inhalation.
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ACKNOWLEDGEMENTS
.The Initial draft of this report was prepared by. Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and Helen Ball was the Project
Officer. The final documents In this series were prepared for the Office of
Emergency and Remedial Response, Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Pat Daunt, Karen Mann and Jacky Bohanon
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE.
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL ....
2.2 INHALATION ..........
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS . .
3.1. SUBCHRONIC ..............
3.1.1. Oral
3.1.2. Inhalation. .........
3.2. CHRONIC
3.2.1. Oral.
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral. ...................
3.3.2. Inhalation. ................
3:4. TOXICANT INTERACTIONS
CARCINOGENICITY
4.1. HUMAN DATA
4.2. BIOASSAYS
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDSi)
6.2. REFERENCE DOSE (RfD). .....
6.2.1. Oral (RfD0)
6.2.2. Inhalation (RfDi)
Page
. . . 1
. . . 3
. . . 3
. . . 3
. . . 4
4
. . . 4
4
. . . 6
. . . 6
6
. . . 6
. . . 6
. . . 6
. . . 8
9
. . . 9
. . . 9
. . . 9
. . . 9
. . . 11
. . . 12
. . . 12
. . . 12
12
, , . 13
... 13
... 14
6.3. CARCINOGENIC POTENCY (q-|*) ................ 14
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TABLE OF CONTENTS (cont.)
Page
7. REFERENCES 15
APPENDIX: Summary Table for Methyl Ethyl Ketone 21
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LIST OF ABBREVIATIONS
ADI . Acceptable dally Intake
CAS Chemical Abstract Service
CS Composite score
Koc Soil sorptlon coefficient
Kow Log octanol/water partition coefficient
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
ppm Parts per million
RfD Reference dose
RfDi Inhalation reference dose
RfDn, Oral reference dose
RFD$ Subchronlc reference dose
RFD$i Subchronlc Inhalation reference dose
Subchronlc oral reference dose
Dose-rating value
RVe Effect-rating value
STEL Short-term exposure limit
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
methyl ethyl ketone (CAS No. 78-93-3) are summarized below.
Chemical class: aliphatic ketone
Molecular weight: 72.1 Verschueren, 1983
Vapor pressure at 20°C: 77.5 mm Hg Verschueren, 1983
Water solubility at 20°C: 268 g/8, Papa and Sherman, 1981
Log Kow: 0.29 Hansch and Leo, 1985
Koc: 4.5-50 (estimated) U.S. EPA, 1985a
Bloconcentratlon factor 0.5-1 (estimated) U.S. EPA, 1985a
Half-life 1n air: 14-15 hours Graedel, 1978;
U.S. EPA, 1985a
1n water: few days U.S. EPA, 1985a
The primary removal mechanism for atmospheric methyl ethyl ketone will
be direct photolysis (U.S. EPA, 1985a). Detection of methyl ethyl ketone In
rain, cloudwater and airborne partlculate matter suggests that small amounts
of this compound may also be removed from the atmosphere by wet and dry
deposition (U.S. EPA, 1985a).
In water, methyl ethyl ketone 1s expected to be removed by evaporation
(half-life of 3-12 days) and blodegradatlon (half-life >3 days) (NLM,
1987). Direct photolysis near water surfaces may also be possible (U.S.
EPA, 1985a). Bloconcentratlon In aquatic organisms and adsorption to
sediments are not expected to be Important fate processes (U.S. EPA, 1985a).
0003H -1- 03/01/89
-------
The half-life of methyl ethyl ketone 1n soil could not be located In the
literature searched. By analogy to aquatic media, the dominant fate
processes 1n soil are expected to be volatilization and blodegradatlon (NLM,
1987; U.S. EPA, 1985a). Methyl ethyl ketone residue may be susceptible to
significant leaching (NLM, 1987; U.S. EPA, 1985a). It has been speculated
that the half-life of methyl ethyl ketone In soil would be on the order of a
few days.
0003H -2- 03/01/89
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative data on the oral absorption of methyl ethyl ketone are not
available, but absorption from the gastrointestinal (GI) tract can be
Inferred from systemic toxic effects observed after acute oral
administration (Lande et al., 1976). In male rats, the peak blood level of
methyl ethyl ketone (0.95 rag/ml) was reached within 4 hours following oral
administration of a 1690 mg/kg dose of the compound 1n water, Indicating
rapid absorption from the GI tract (D1etz et al., 1981; D1etz and Tralger,
1979).
2.2. INHALATION
PerbelUnl et al. (1984) reported a mean blood concentration of methyl
ethyl ketone of 2630+2450 yg/1 (range: 842-9573 yg/l) 1n workers
exposed to methyl ethyl ketone and several other compounds and that 70% of
the Inhaled methyl ethyl ketone was retained 1n the alveolar space. The
environmental concentration correlated significantly with the alveolar con-
centration of methyl ethyl ketone, which 1n turn correlated significantly
with blood levels. At the end of an 8-hour work shift, the urine of workers
exposed to a mean concentration of methyl ethyl ketone In the air of 10H67
vg/2, contained a mean concentration of 487+277 ^g/a (PerbelUnl et
al., 1984). Mlyasaka et al. (1982) reported that the urinary levels of
methyl ethyl ketone rose rapidly during the first 2 hours of an 8-hour work
shift 1n occupatlonally exposed workers and the levels correlated with the
measured levels 1n the air. Therefore, pulmonary absorption of methyl ethyl
ketone appears to occur rapidly during occupational exposure.
0003H -3- 11/22/88
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Pertinent data regarding the effects of oral exposure to
methyl ethyl ketone on humans or experimental animals were not located In
the available literature.
3.1.2. Inhalation. The subchronlc Inhalation studies on methyl ethyl
ketone are summarized In Table 3-1. Cavender et al. (1983) exposed both
sexes of Fischer 344 rats to methyl ethyl ketone at concentrations of 0,
1250, 2500 or 5000 ppm (0, 3687, 7373 or 14,746 mg/m3), 6 hours/day, 5
days/week for 90 days. There were no treatment-related effects at the 1250
ppm level; SGPT activity 1n female rats was elevated at the 2500 ppm level.
At the 5000 ppm level, effects were more severe: these Included depressed
mean body weight; slight but significant Increases In liver weight,
I1ver-to-body weight ratio, and I1ver-to-bra1n weight ratio; significantly
decreased SGPT activity; and Increased alkaline phosphatase, potassium and
glucose values 1n treated females.
Exposure of Wlstar rats to methyl ethyl ketone at a level of 0 or 200
ppm (0 or 590 mg/m3), 12 hours/day, 7 days/week for 24 weeks reportedly
resulted In slight neurological effects of unknown biologic significance
measurable only at 4 months of treatment (Takeuchl et al., 1983), but In
another study using rats exposed to 1125 ppm (3318 mg/m3) continuously for
5 months did not result 1n neuropathy, as Indicated by absence of paral-
ysis (Salda et al., 1976). In both studies, only a single toxlcological
endpoint was examined, such as motor nerve conduction velocity, mixed nerve
conduction velocities, or distal motor latency (Takeuchl et al., 1983) or
paralysis (Salda et al., 1976).
0003H -4- 11/21/88
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LaBelle and Brleger (1955) observed no effects of exposure to 0 or 235
ppm (0 or 693 mg/m3) of methyl ethyl ketone, 7 hours/day, 5 days/week, for
12 weeks, on growth, hematologlcal or pathological parameters of a group of
25 rats. Although the growth of the rats In the exposed group was less than
the controls, no statistical analysis was provided. Information on the
specific organs evaluated pathologically was not provided. Guinea pigs
presumably exposed to the same level exhibited no adverse effects on growth,
hematology or hlstopathology from the treatment. Similarly, exposure to 0,
125, 250, 500 or 1000 ppm of the compound for 30 days had no effect on rats
and guinea pigs (Mellon Institute, 1950); however, details of exposure were
not provided.
3.2. CHRONIC
3.2.1. Oral. Pertinent data regarding the chronic oral toxlclty of
methyl ethyl ketone to humans or experimental animals were not located In
the available literature.
3.2.2. Inhalation. Pertinent data regarding the chronic Inhalation
toxlclty of methyl ethyl ketone to humans or experimental animals were not
located In the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Pertinent data regarding the teratogenlclty of methyl ethyl
ketone following oral administration were not located In the available
literature.
3.3.2. Inhalation. Schwetz et al. (1974) exposed groups of 21-47 preg-
nant Sprague-Dawley rats to methyl ethyl ketone by Inhalation at levels of
0, 1000 or 3000 ppm (0, 2949 or 8848 mg/m3) for 7 hours/day on days 6-15
of gestation. There was no maternal toxlclty at either exposure level.
0003H -6- 04/18/88
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Somewhat decreased fetal body measurements (body weight and crown-to-rump
length) were seen at the lower but not at the higher exposure level. At the
1000 ppm level, there was a significant Increase In the percentage of
Utters having at least one fetus with a skeletal abnormality; however,
there was no significant Increase 1n gross, soft-tissue or specific skeletal
anomalies. At the 3000 ppm level, a significant Increase In Utters having
fetuses with gross external anomalies or Internal soft-tissue anomalies was
seen. Schwetz et al. (1974) concluded that methyl ethyl ketone was feto-
toxlc and potentially teratogenlc, but not maternotoxlc to rats exposed at
levels of 1000 or 3000 ppm during days 6-15 of gestation.
Deacon et al. (1981) conducted an experiment to clarify the results of
the study reported by Schwetz et al. (1974). Groups of 25 pregnant Sprague-
Dawley rats were exposed to methyl ethyl ketone by Inhalation at levels of
400, 1000 or 3000 ppm (1180, 2949 or 8848 mg/m3), 7 hours/day on days 6-15
of gestation. A control group of 35 pregnant rats was maintained. No
maternal effects of toxldty were noted at the two lower concentrations and
only a decrease In body weight gain of the dams was reported at the high
exposure level. Five fetuses among all the groups, Including controls, had
at least one malformation upon examination for external and soft tissue
malformation. Details of these malformations are discussed In U.S. EPA
(1985a). Deacon et al. (1981) concluded that methyl ethyl ketone was not
teratogenlc 1n rats, because of the low Incidence and the distribution of
the malformations observed 1n the pups. Fetotoxldty was, however, mani-
fested as an Increased Incidence of extra ribs and of delayed ossification
In the cervical centra at the high exposure level only.
0003H -7- 03/01/89
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3.4. TOXICANT INTERACTIONS
Combined exposure to TOO ppm of n-hexane and 200 ppm of methyl ethyl
ketone for 24 weeks resulted 1n neurotoxk effects (defined as changes In
motor nerve conduction velocity, distal motor latency and mixed nerve con-
duction velocities) In rats that were not observed when either chemical was
tested by Itself (Takeuchl et al., 1983). Methyl ethyl ketone has also been
shown to potentiate the effect of n-hexane on the alveolar epithelium of
rats exposed to the mixture for 8 hours/day for <89 days (Schnoy et al.,
1982). Although lesions were not demonstrable by light microscopy, ultra-
structural examination revealed the presence of fatty deposits 1n Type I and
II pneumocyte cells.
Hewitt et al. (1983, 1986) found that methyl ethyl ketone potentiated
the ftepatotoxlc action of chloroform In rats. In the earlier study, a
significant positive correlation was shown between the carbon chain length
of ketones and the severity of the potentiated chloroform-Induced liver
damage. In the later study, 1t was determined that choleotasls resulted
from potentlatlon of chloroform-Induced alterations 1n canallcular membrane
permeability.
0003H -8- 04/19/88
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding the carcinogenic effects of exposure to methyl
ethyl ketone on humans were not 'located In the available literature.
4.2. BIOASSAYS
Pertinent data regarding the carcinogenic effects of oral or Inhalation
exposure to methyl ethyl ketone on experimental animals were not located In
the available literature. No tumors were observed on the skin of mice after
dermal application of 50 mg of methyl ethyl ketone twice weekly for 1 year
(U.S. EPA, 1985a). Methyl ethyl ketone 1s not scheduled for carcinogenldty
testing by the National Toxicology Program (NTP, 1987).
4.3. OTHER RELEVANT DATA
Methyl ethyl ketone was negative for reverse mutation when tested In
Salmonella typhlmurlum strains TA98, TA100, TA1535 or TA1537 with or without
metabolic activation (Florin et al., 1980; Douglas et al.t 1980). Methyl
ethyl ketone has been shown, however, to be a strong Inducer of aneuploldy
in the dlploid 061.M strain of Saccharomyces cerevlslae (Zlmmermann et al.,
1985). When Ineffective low levels of methyl ethyl ketone were combined
with Ineffective low levels of nocodazole, another Inducer of aneuploldy In
this system, significantly elevated levels of aneuploldy resulted (Mayer and
Coin, 1987).
4.4. WEIGHT OF EVIDENCE
Methyl ethyl ketone has not been tested for cardnogenlclty by the oral
or Inhalation routes. No tumors were observed 1n the only dermal exposure
study as seen 1n Section 4.2. (U.S. EPA, 1985a). IARC has not evaluated the
risk to humans associated with oral or Inhalation exposure to methyl ethyl
0003H -9- 03/01/89
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ketone. Because of lack of evidence, methyl ethyl ketone 1s classified as a
U.S. EPA Group 0 chemical; that 1s, not classifiable as to human
cardnogenldty.
0003H -10- 11/21/88
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5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1986a) set a TLV-TWA of 200 ppm (590 mg/m3) and a STEL of 300
ppm (885 mg/m3) for methyl ethyl ketone; the basis for these standards Is
the minimization of eye and nose Irritation, and systemic toxic effects are
not expected to develop at this exposure level (ACGIH, 19865).
The NIOSH (1978) recommendation and OSHA (1985) PEL for methyl ethyl
ketone are both 200 ppm (590 mg/m3).
ACGIH (1986b) summarized the occupational standards and their year of
establishment 1n other countries as follows: 200 ppm 1n West Germany (1974);
150 ppm 1n Sweden (1974); 100 ppm 1n East Germany (1973); and 100 ppm in
USSR (1966), Yugoslavia (1971) and Hungary (1974).
0003H -11- 11/21/88
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDg)
6.1.1. Oral (RfD.J. The lack of subchronlc oral toxlclty data pre-
wU
eludes the derivation of an RfDSQ for subchronlc exposure to methyl ethyl
ketone based on oral data. U.S. EPA (1985a) derived a chronic oral RfOQ
of 3 mg/day based on the subchronlc rat Inhalation study reported by LaBelle
and BMeger (1955). Derivation of the RfD will follow 1n Sections 6.1.2.
and 6.2.1. Therefore, 1t would be appropriate to use the subchronlc rat
NOAEL of 46 mg/kg/day, adjusted for oral route by multiplying the Inhalation
NOAEL by an absorption factor of 0.5, as the basis for an RfDSQ for methyl
ethyl ketone. Applying an uncertainty factor of 100 (10 for both Inter- and
Intraspecles variability) to the rat NOAEL of 235 ppm (693 mg/m3), con-
verted to 46 mg/kg/day, results 1n an RfDSQ of 0.5 mg/kg/day or 32 mg/day.
Medium confidence 1s placed 1n the RfD-Q as discussed In Section 6.2.1.
6.1.2. Inhalation (RfOSI). As reported In Section 3.1.2., several
subchronlc Inhalation studies have been performed with methyl ethyl ketone.
Two of these studies were considered not useful for risk assessment: the
study by Salda et al. (1976) 1n which only one toxlcologlcal endpoint was
evaluated and the study by Mellon Institute (1950) 1n which complete
exposure data were not available and a short duration of exposure (30 days)
was used.
A NOAEL of 235 ppm (693 mg/m3) for methyl ethyl ketone 1n rats can be
Identified from the LaBelle and BMeger (1955) study. For Identifying the
toxic threshold for methyl ethyl ketone, the studies by Cavender et al.
(1983) and Takeuchl et al. (1983) are useful, as both also define a NOAEL.
NOAELs of 2500 ppm (7373 mg/m3) for Increased SGPT activity In female rats
(Cavender et al., 1983) and 200 ppm (590 mg/m3) for temporary slight
neurological effects of unknown biological significance 1n rats (Takeuchl et
0003H -12- 03/01/89
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al., 1983) were Identified from these studies. According to the analysis
provided by the U.S. EPA (1985a,b), the NOAEL from the LaBelle and BMeger
(1955) study provides the lowest and most protective dose and Is therefore
the study of choice for deriving the RfD-. Additionally, methyl ethyl
ketone was also tested for teratogenUHy (Schwetz et al., 1974; Deacon et
al., 1981) and the observed LOAEL, estimated to be 130.5 mg/kg/day for
fetotoxlclty from the Schwetz et al. (1974) study (U.S. EPA, 1985b), was
higher than the NOAEL estimated from the data of LaBelle and Brleger (1955).
The NOAEL of 235 ppm (693 mg/m3) from the rat subchronlc Inhalation study
(LaBelle and Brleger, 1955) converts to 92 mg/kg/day by expanding to
continuous exposure and using 0.223 mVday as a reference Inhalation rate
for rats and a reference body weight for rats of 0.35 kg as follows: 693
mg/m3 x (7/24 hours/day) x (5/7 days/week) x 0.223 mVday/0.35 kg = 92
mg/kg/day. Applying an uncertainty factor of 100 (10 for both Intra- and
Interspedes extrapolation), results 1n an RfOSI of 0.9 mg/kg/day or 64
mg/day for a 70 kg man. Confidence 1n this RfDST is medium as discussed
1n Section 6.2.1.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). U.S. EPA (1985a) derived a chronic RfD of 3 mg/day
for methyl ethyl ketone from the rat subchronlc Inhalation study reported by
LaBelle and Brleger (1955). The NOAEL of 235 ppm (693 mg/m3) converts to
46 mg/kg/day by using the methodology presented 1n Section 6.1.2. and also
using an absorption factor of 0.5 to extrapolate from Inhalation to oral
exposure. Applying an uncertainty factor of 1000 (10 for both Intra- and
Interspedes variability and 10 to extrapolate from subchronlc to chronic
data), results In the chronic RfD_ of 0.05 mg/kg/day or 3 mg/day for a 70
kg man. This value Is verified and available on IRIS (U.S. EPA, 1985b).
0003H -13- 03/01/89
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Confidence In the study was rated medium because only 25 rats were exposed
to only one dose and the control group was not characterized. The data base
was given a medium rating because four other studies support the NOAEL.
Therefore, confidence 1n the RfD was rated medium (U.S. EPA, 1985b).
6.2.2. Inhalation (RfD.). Using the methodology discussed In Section
6.1.2. and applying an additional uncertainty factor of 10 to expand from
subchronlc to chronic exposure to the RfDSI of 0.9 mg/kg/day or 64 mg/day
results In a chronic RfD, of 0.09 mg/kg/day or 6 mg/day. This chronic
RfD, was derived for Interim purposes only and the Issue of the Inhalation
RfD for methyl ethyl ketone Is pending verification by the RfD Workgroup.
A CS of 9.6 was derived by the U.S. EPA (1985a) based on the decreased
weight gain effects reported 1n the LaBelle and Brleger (1955) study at 235
ppm (693 mg/m3). Discussion and details of the derivation are presented
1n the U.S. EPA (1985a) document. The human MED of 110 mg/day corresponds
to an RV. of 2.4 and the effects of decreased bo.dy weight warranted an
RV& of 4, resulting 1n a CS of 9.6.
6.3. CARCINOGENIC POTENCY (q^)
Methyl ethyl ketone Is classified as a U.S. EPA Group D chemical; that
1s, not classifiable as to human cardnogenlcHy because of lack of evidence
for cardnogenlcHy.
The lack of carclnogenldty data precludes the derivation of a carcino-
genic potency for exposure to methyl ethyl ketone.
0003H -14- 03/01/89
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7. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986a.
Threshold Limit Values for Chemical Substances 1n the Workroom Environment
adopted by ACGIH. Cincinnati, OH. p. 24.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986b.
Methyl Ethyl Ketone. Documentation of the Threshold Limit Values and
Biological Exposure Indices, 5th ed. p. 395.
Cavender, F.L., H.W. Casey, H. Salem, J.A. Swenberg and E.J. Garalla. 1983.
A 90-day vapor Inhalation toxldty study of methyl ethyl ketone. Fund.
Appl. Toxlcol. 3(4): 264-270.
Deacon, H.M., M.D. Pliny, J.A. John, et al. 1981. Embryotox1c1ty and feto-
toxlclty of Inhaled methyl ethyl ketone In rats; Toxlcol. Appl. Pharmacol.
59(3): 620-622. (Cited 1n U.S. EPA, 1985a)
Dletz, F.K. and G.J. Tralger. 1979. Potent1at1on of carbon tetrachloride
hepatotoxldty 1n rats by a metabolite of 2-butanone: 2,3-Butanediol.
Toxicology. 14(3): 209-215. (Cited 1n U.S. EPA, 1985a)
Dletz, F.K., M. Rodrlguez-Glaxola, G.J. Tralger, V.J. Stella and K.J.
Hlmmelsteln. 1981. Pharmacok1net1cs of 2-butanol and Us metabolites In
the rat. J. Pharmacoklnet. Blopharm. 9(5): 553-576. (Cited In U.S. EPA,
1985a)
0003H -15- 03/01/89
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Qouglas, G.R., E.R. Nestmann, J.L. Belts, et al. 1980. Mutagenic activity
In pulp mill effluents. Water Chlorlnatlon: Environ. Impact Health Eff. 3:
865-880. (CHed In U.S. EPA, 1985a)
Florin, I., L. Rutberg, M. Curvall and C.R. Enzell. 1980. Screening of
tobacco smoke constituents for mutagenlclty using the Ames test. Toxicology.
15: 219-232. (CHed 1n U.S. EPA, 1985a)
Graedel, I.E. 1978. Chemical Compounds In the Atmosphere. Academic Press,
NY. p. 187.
Hansch, C. and A.J. Leo. 1985. MedChem Project Issue No. 26. Pomona
College, Claremont, CA.
HewHt, W.R., E.M. Brown and G.L. Plaa. 1983. Relationship between the
carbon skeleton length of ketonlc solvents and potentlatlon of chloroform-
Induced hepatotoxlclty In rats. Toxlcol. Lett. 16(3-4): 297-304. (CA
98:22111146)
Hewitt, L.A., P. Ayotte and G.L. Plaa. 1986. Modifications 1n rat hepato-
bHlary function following treatment with acetone, 2-butanone, 2-hexanone,
mlrex, or chlordecone and subsequently exposed to chloroform. Toxlcol.
Appl. Pharmacol. 83(3): 465-473. (Taken from MEDLINE Database File 154 on
Dialog, Accession No. 86209163)
LaBelle, C.W. and H. Brleger. 1955. Vapour toxlclty of a composite solvent
and Us principal components. Arch. Ind. Health. 12: 623-627. (CHed In
U.S. EPA, 1985a)
0003H -16- 03/01/89
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Lande, S.S., P.R. Durkin, D.H. Christopher, P.H. Howard and J. Saxena.
1976. Investigation of selected potential environmental contaminants:
Ketonlc solvents. Prepared under Contract No. 68-01-3100. Office of Toxic
Substances, U.S. EPA, Washington, DC. EPA 560/2-76-003.
Mayer, V.W. and C.J. Go1n. 1985. Effects of chemical combinations on the
Induction of aneuploldy In Saccharomyces cerevlslae. Mutat. Res. 187(1):
21-30. (Taken from MEOLINE Database File 154 on Dialog, Accession No.
87090136)
Mellon Institute. 1950. Methyl Ethyl Ketone, Report 14-33, unpublished,
Union Carbide Corporation. (Cited 1n U.S. EPA, 1985a)
Mlyasaka, M., M. Kumal, A, Koizumi, et al. 1982. Biological monitoring of
occupational exposure to methyl ethyl ketone by means of urlnalysls for
methyl ethyl ketone Itself. Int. Arch. Occup. Environ. Health. 50(2):
131-137. (Cited 1n U.S. EPA, 1985a)
NIOSH (National Institute for Occupational Safety and Health). 1978.
Criteria for a Recommended Standard...Occupational Exposure to Ketones,
U.S. DHEH, PHS, CDC. Cincinnati, OH. Publ. No. 78-173. (Cited In U.S.
EPA, 1985a)
NLM (National Library of Medicine). 1987. Hazardous Substance Data Base.
Report No. 99. On-Llne.
0003H -17- 03/01/89
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NTP (National Toxicology Program). 1987. Management status report produced
from NTP Chemtrack System. Data received up to 01/09/87. NTP, Research
Triangle Park, NC.
OSHA (Occupational Safety and Health Administration). 1985. OSHA Occupa-
tional Standards, Permissible Exposure Limits. 29 CFR 1910.1000.
Papa, A.J. and P.O. Sherman, Jr. 1981. Ketones. ln_: K1rk-0thmer Encyclo-
pedia of Chemical Technology, Vol. 13, 3rd ed., M. Grayson and D. Eckroth,
Ed. John Wiley and Sons, Inc., New York. p. 894-941. (Cited In U.S. EPA,
1985a)
PerbelUnl, L., F. Brugnone, P. Mozzo, V. Cocheo and D. Caretta. 1984.
Methyl ethyl ketone exposure In Industrial workers: Uptake and kinetics.
Int. Arch. Occup. Environ. Health. 54(1): 73-81. (CUed 1n U.S. EPA, 1985a)
Salda, K., J.R. Mendel! and H.S. Weiss. 1976. Peripheral nerve changes
Induced by methyl n-butyl ketone and potentlatlon by methyl ethyl ketone.
3. Neuropathol. Exp. Neurol. 35: 207-225.
Schnoy, N., R. Schmidt, A. AHendlrch and A.M. Wagner. 1982. Ultra-
structural alteration of the alveolar epithelium after exposure to organic
solvents. Respiration. 43: 221-231. (Cited 1n U.S. EPA, 1985a)
Schwetz, B.A., 8.K.J. Leong and P.J. Gehrlng. 1974. Embryo- and feto-
toxldty of Inhaled carbon tetrachlorlde, 1 ,l-d1chloroethane and methyl
ethyl ketone 1n rats. Toxlcol. Appl. Pharmacol. 28(3): 452-464.
0003H -18- 03/01/89
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Takeuchl, Y., Y. Ono, N. Hlsanaga, et al. 1983. An experimental study of
the combined effects of n-hexane and methyl ethyl ketone. Br. 3. Ind. Med.
40(2): 199-203.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1983. Reportable Quantity Document for 2-Butanone (Methyl ethyl
ketone). Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals Based on
Chronic Tox1c1ty Data. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH for
the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985a. Health and Environmental Effects Profile for Methyl Ethyl
Ketone. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1985b. Integrated Risk Information Systems (IRIS). Reference
dose (RfD) for oral exposure for methyl ethyl ketone. On-line (Verification
date 7/8/85.) Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
0003H -19- 03/01/89
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Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemistry,
2nd ed. Van Nostrand Reynold Co., NY. p. 850-852.
Zlmmermann, F.K., V.W. Mayer, I. Scheel and M.A. Resnlck. 1985. Acetone,
methyl ethyl ketone, ethyl acetate, acetonUMle and other polar aprotlc
solvents are strong Inducers of aneuploldy 1n Saccharomyces cerevlslae.
Mutat. Res. 149(3): 339-351. (Taken from MEDLINE Database File 154 on
Dialog, Accession No. 85188025)
0003H -20- 11/21/88
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