TECHNICAL REPORT DATA
(Heat read instructions on the reverie before comptenngj
1. REPORT NO.
EPA/600/8-88/045
2.
3. RECIPIENT'S ACCESSION NO
PB88-179924/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for Methyl Isobutyl Ketone
S, REPORT DATE
6. PERFORMING ORGANIZATION COOE
7. AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NC
PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
13. TYPE OF REPORT AND PERIOD COVERED
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
14. SPONSORING AGENCY CODE
EPA/600/22
5. SUPPLEMENTARY NOTES
6. 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 (toxicc.nts for which cancer is not the endpoint of
concern). The first, RfDg 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 Of CUM6NT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Croup
8. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This KeportI
Unclassified
21. NO. Of PAGES
SO. SECURITY CLASS (Thispage)
Unclassified
22. PRICE
EPA Farm 2220-1 (ft««. 4-77) pncyious COITION i>
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EPA/600/8-88/045
April, 1987
HEALTH EFFECTS ASSESSMENT
FOR METHYL ISOBUTYL 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
U.S. teTlronteatal Protection 'Agency
Ration 5, Library (5PL-13) '
2SC C. D«arborn Street, Room, 1670
Chicago, IL 60604
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental 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
Isobutyl ketone. 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. Pertinent toxlcologlc
and environmental data were located through on-line literature searches of
the TOXLINE, CANCERUNE and the CHEMFATE/DATALOG data bases. The basic
literature searched supporting this document 1s current up to May, 1986.
Secondary sources of Information have also been relied upon 1n the prepara-
tion 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. 1980a. Hazard Profile for Methyl Isobutyl Ketone.
Prepared by the Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste, Washington, DC.
U.S. EPA. 1986a. Integrated Risk Information System (IRIS).
Reference Dose (RfO) for Oral Exposure for Methyl Isobutyl Ketone.
Online (verification date 5/30/86, data Input pending). Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncarclnogens 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 chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc 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 Hfespan).
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. Subchronlc 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 (RfD$Q)
exposures.
111
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The RfD (formerly AIC) Is similar In concept and addresses chronic
exposure. It 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 llfespan [see U.S. EPA (1980b) for a discussion of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfOrj) or Inhalation (RfDi) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1983).
For compounds for which there Is sufficient evidence of carclnogenldty
RfOg and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer Is a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed. If appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation 1n 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
Interpretation and use of the quantitative estimates presented.
Chronic toxlclty and carclnogenldty data for MIBK by both oral and
Inhalation exposures are lacking. A 13-week rat gavage study (Microbio-
logical Associates, 1986) provides the only available subchronlc oral
toxlclty data for MIBK and defines a NOAEL of 50 mg/kg/day. Higher doses
caused Increased relative kidney and liver weights and general nephropathy.
Using this NOAEL, RfDgg and RfOn, values of 0.5 and 0.05 mg/kg/day (35
and 3.5 mg/day for a 70 kg human), respectively, were calculated.
An RfD$i of 14 mg/day and an RfOj of 1.4 mg/day were calculated from
a NOAEL In rats exposed 6 hours/day, 5 days/week at 50 ppm (205 mg/m3) for
14 weeks (Union Carbide Corp., 1983b). At a higher exposure level, 250 ppm
(1024 mg/ma), hyaline droplets In the proximal tubules of the kidneys were
observed. A CS of 11.5 was calculated for the occurrence of hyaline
droplets 1n kidneys of rats exposed at this higher level.
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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. Or. Christopher OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) 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, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
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 (RfOs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfD$i)
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfD0)
6.2.2. Inhalation (RfDj)
6.3. CARCINOGENIC POTENCY (q-|*)
REFERENCES
Page
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3
4
4
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. 13
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13
14
. . . 14
14
17
. . . 18
APPENDIX: Summary Table for MIBK 24
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LIST OF ABBREVIATIONS
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
LOAEl Lowest-observed-adverse-effect level
MED Minimum effect dose
MIBK Methyl Isobutyl ketone
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfO Reference dose
RfDj Inhalation reference dose
RfD0 Oral reference dose
RfOs Subchronlc reference dose
RfD$i Subchronlc Inhalation reference dose
RfD$Q Subchronlc oral reference dose
RVjj Dose-rating value
RVe Effect-rating Value
STEL Short-term exposed level
TLC Taurollthocholate
TLV Threshold limit value
TWA Time-weighted average
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1. ENVIRONMENTAL CHEMISTRY AND FATE
The relevant physical and chemical properties and environmental fate of
MIBK are presented In Table 1-1.
The atmospheric half-life of MIBK Is based on Us reaction with photo-
chemlcally generated HO radical. The atmospheric half-life was calculated
using measured hydroxyl reaction rate constants of (1.24-1.52)xlO~ai
cmVmolecule-sec and an ambient HO radical concentration of 8xlOs
molecules/cm3. B1odegradat1on, photolysis and volatilization are possible
mechanisms by which MIBK may be removed from aqueous systems (Lande et a!.,
1976); however, the overall rate of removal could not be located In the
available literature. The volatilization half-life from agitated water 1 m
deep was calculated to be 16.8 hours using the measured mass transfer
coefficient for MIBK and 02 at 25°C (Rathbun and Ta1, 1982). Based on Us
relatively high water solubility and low soil adsorption coefficient, MIBK
Is predicted to be highly mobile In soil (Swann et al., 1984). Monitoring
data reveal that this compound has been Identified 1n leachates from land-
fills and could potentially contaminate groundwater (Francis et al., 1980;
Sawhney and KozlosM, 1984).
0081h -1- 02/03/87
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TABLE 1-1
Selected Physical and Chemical Properties and Half-Lives for MI8K
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
or
B1oconcentrat1on factor:
Soil adsorption
coefficient:
Half-life 1n air:
108-10-1
saturated aliphatic
ketone
100.16
15 mm Hg at 20°C
2.04x10* l at 20'C
1.09 (estimated)
2 (estimated)
19 (estimated)
<1 day
Lande et al., 1976
Lande et al., 1976
Hansch et al., 1968
Lyman et al., 1S82
Lyman et al., 1982
Cox et al., 1S80;
Daman et al., 1976
0081 h
-2-
02/03/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Acute toxldty studies 1n animals Indicate that MIBK Is absorbed from
the gastrointestinal tract (U.S. EPA, 1980a). OWIncenzo and Krasavage
(1974) have shown that MIBK 1s metabolized 1n guinea pigs arvd 1s excreted In
the urine.
2.2. INHALATION
Acute toxlclty studies In animals Indicate that MIBK Is absorbed from
the respiratory tract (U.S. EPA, 1980a). MacEwen et al. (1971) exposed
rats, dogs, monkeys and mice by Inhalation to 100 or 200 ppm MIBK for 2-week
periods. The results of these studies Indicated that MIBK 1s absorbed from
the respiratory tract and excreted primarily through the kidney.
0081h -3- 02/03/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. Microbiological Associates (1986) conducted a 13-week study
In which groups of 30 male and 30 female Sprague-Dawley rats received gavage
doses of 0, 50, 250 or 1000 mg/kg/day MIBK In conn oil. Extensive analyses
of hematologlcal parameters, clinical chemistry and urine chemistry were
performed on 10 rats/sex from each treatment, along with hlstopathologlcal
examination of all major tissues. The only clinical sign of toxclty was
lethargy which occurred only 1n high-dose rats of both sexes. Two high-dose
females and one control female died during the study. There was a slight
(9%) reduction In body weight gain among high-dose males. Slight hemocon-
centratlon occurred In females given 250 or 1000 mg/kg/day. Hypoglycemla
and hypercholesterolemla occurred In females given 250 mg/kg/day and to a
greater extent 1n both sexes at 1000 mg/kg/day. No other hematologlcal or
clinical chemistry parameters were affected. Generalized nephropathy and
Increased relative kidney weights occurred In both sexes at 1000 mg/kg/day.
Relative kidney weights were also Increased, but to a lesser extent, 1n the
250 mg/kg/day groups. Hepatomegaly occurred In both sexes at 1000 mg/kg/day
and possibly In males at 250 mg/kg/day. No treatment-related hlstopatho-
loglcal lesions were found 1n the liver or any other tissue. The authors
concluded that 50 mg/kg/day for 13 weeks was a NOEL for rats 1n this study.
In a study by Union Carbide Corporation (1983a), groups of five female
Wlstar rais were exposed to drinking water containing 0 or. 1.354 MIBK (1.04
g/kg/day) for 120 days. Rats were examined for neurological effects and
body welqhts were recorded at regular Intervals throughout the study.
0081h -4- 02/03/87
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Necropsies were performed after terminal sacrifice and animals were examined
for neuropathy and muscle atrophy. The only effect noted In MIBK-treated
rats was a significant (p
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evidenced by hematologlcal and clinical chemistry measurements and hlsto-
pathologlcal examinations. The growth rate of rats appeared to be unaffect-
ed by treatment. Control and treated rats appeared to average 0.35 kg
during the experiment (estimated from graphic presentation of growth curve).
Rats exposed to MIBK had Increased relative liver and kidney weights. All
exposed rats had hyaline droplet degeneration of the proximal tubules with
occasional tubular necrosis. These results suggest that rats are more
sensitive to MIBK than dogs and monkeys; however, these results are of ques-
tionable relevance to environmental exposures and risk assessment because of
the specialized conditions under which this experiment was conducted.
Union Carbide Corporation (1983b) exposed groups of 14 males and 14
female Fischer 344 rats and B6C3F1 mice to 0, 50, 250 or 1000 ppm (0, 205,
1024 or 4097 mg/m3) 6 hours/day, 5 days/week for 14 weeks. The parameters
examined were clinical observation, body weight, organ weights (heart,
kidney, liver, lungs and testes), urlnalysls (rats only), serum chemistry
(rats only) and hematologlc, ophthalmologlc, gross pathologic and hlstologlc
evaluations.
The results of the study showed significantly Increased absolute and
relative l^r weights In male mice and rats exposed at 1000 ppm MIBK. Male
mice exposed at 250 ppm MIBK had an Increase 1n absolute liver weight
(p<0.05). No effects on liver weights were noted 1n female mice or rats.
An Increase 1n the Incidence of hyaline droplets 1n the proximal tubules 1n
male rats exposed at 250 and 1300 ppm was also noted. This effect was not
observed 1n female rats or mal<.« and female mice. No other chemical-related
changes were noted 1n either MIBK-exposed rats or mice.
0081h -6- 02/03/87
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Spencer et al. (1975) exposed a group of six rats to 1500 ppm (6140
mg/m3) MIBK, 6 hours/day, 5 days/week, for up to 5 months and compared
them with a control group of three rats. No effects on body weight gain or
neurological function occurred. H1stopatholog1cal examination, limited to
selected peripheral nerves, revealed 1nvag1nat1ons of the Schwann cells,
focal swelling and dilated mltochondrlal remnants 1n the adaxonal segments
of the t1t>1al and ulnar nerves. The authors attributed these findings to
contamination of the MIBK with methyl n-butyl ketone, which caused similar
effects 1n a companion study.
Geller et al. (1979) conducted behavioral experiments with four juvenile
male baboons exposed to 50 ppm (205 mg/m3) MIBK 24 hours/day for 7 days.
The baboons were exposed to other ketones as well, but at least 1 month
elapsed between the exposures to different chemicals. Effects were
evaluated using a delayed match-to-sample discrimination task. Accuracy of
performance was minimally affected, but response time was slowed by MIBK.
Abou-Don1a et al. (1985) conducted Inhalation experiments with groups of
five hens exposed to 1000 (4090 mg/ma) MIBK for 90 days followed by a
30-day observation period. MIBK exposure resulted In leg weakness with
subsequent recovery.
3.2. CHRONIC
3.2.1. Oral. Chronic oral toxlclty studies with MIBK could not be
located 1n the available literature.
3.2.2. Inhalation. There are several reports of humans occupatlonally
exposed to. MIBK vapors. L1nar1 et al. .(1964) reported that 19 workers near
a centrifuge were exposed to 500 ppm (2050 mg/m3) MIBK for 20-30 minutes/
day, while concentrations elsewhere In the room were 80 ppm (330 mg/m3).
0081h -7- 02/03/87
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Over 50% of the workers experienced nausea, headache, burning 1n the eyes
and weakness; some also experienced somnolence, Insomnia and Intestinal
pain, and four appeared to have slightly enlarged Hvers. Armell et al.
(1968) conducted a similar study of this workplace 5 years later, when
hygiene Improvements resulted In MIBK concentrations of 100-105 ppm (410-430
mg/m3} near the centrifuge during Us 15-30 minutes of operation and 50
ppm (205 mg/m3) elsewhere 1n the room. A few workers still experienced
gastrointestinal and CNS symptoms, and slight liver enlargement was found 1n
two workers. Elklns (1959) reported that workers exposed to MIBK levels of
100 ppm (410 mg/m3) complained of headache, nausea and respiratory
Irritation.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.K Oral. Data concerning teratogenlclty or other reproductive
effects of MIBK could not be located 1n the available literature.
3.3.2. Inhalation. Union Carbide Corporation (1984) conducted terato-
genlclty studies using rats and mice following Inhalation exposure to MIBK.
Groups of 25 pregnant Fischer 344 rats and 25 CD-I mice were exposed to 0,
300, 1000 or 3000 ppm (0, 1229, 4097 or 12,290 mg/m3) MIBK vapors, 6
hours/day on gestation days 6 through 15. Rats were sacrificed on day 21
and mice on day .18 of gestation.
Maternal toxldty was observed 1n rats and mice. Rats exhibited
reduction In body weight, loss of coordination, negative tall and toe pinch,
partial paralysis, muscular weakness 1n hlndHmbs, pHoerectlon, Iacr1mat1on
and red peMoral encrustation.. At sacrifice, relative kidney weights of the
dams were also significantly Increased compared with controls. In mice, no
changes In body weight were noted; however, 3/25 mice died. Clinical signs
of toxldty Included Irregular gait, partial paralysis, hypoactWHy,
0081h . -8- 02/03/87
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ataxla, negative toe pinch, unkempt fur and lacrlmatlon. At sacrifice,
absolute and relative liver weights were significantly Increased.
Results of reproductive parameters showed no treatment-related effects
on the number of corpora lutea, total Implantations per Utter, percent
prelmplantatlonal loss, percent live fetuses or sex ratio In either rats or
mice. Fetal weight per Utter was significantly reduced In rats at 300 and
3000 ppm but not at the 1000 ppm exposure level. In mice, there was a
significant decrease In the number of live births and fetal body weights per
Utter at 3000 ppm. Teratogenlc examination revealed no statistically
significant Increases 1n malformations 1n either rats or mice. An Increased
Incidence of poorly ossified or unosslfled skeletal elements was observed In
rats and mice at 3000 ppm. Investigators concluded that Inhalation exposure
of pregnant rats and mice to MIBK at >3000 ppm was associated with maternal
and fetal toxldty but not teratogenldty.
3.4. TOXICANT INTERACTIONS
Plaa and Ayotte (1985) studied potentlalon of TLC toxldty In rats by
MIBK pretreatment. Pretreatment of male Sprague-Oawley rats with 3.75 or
7.5 mmol/kg for 3 or 7 days enhanced the cholestasls caused by Intravenous
Injections of TLC. Another study found MIBK to potentiate the hepatonecro.-
genlc properties of chloroform and carbon tetrachlorlde (Vezlna et al.,
1985).
The Inhalation studies by Abou-0on1a et al. (1985) and Geller et al.
(1979), also contained Information about the Interaction of MIBK with other
toxicants. In the Geller et al. (J979) baboon behavioral study, adminis-
tration of MIBK and methyl ethyl ketone together .caused an Increase In
responses and a decrease 1n response times, effects not seen when the
chemicals were administered Individually. Abou-Don1a et al. (1985) exposed
0081h -9- 02/03/87
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hens to mixtures of MI8K and n-hexane (1000 ppm) to study the effect of MIBK
on n-hexane-lnduced neurotoxldty. They found that exposure to the mixture
potentiated clinical signs of n-hexane-lnduced neurotoxldty, which were
MIBK-dose-related 1n Intensity. The ability of MIBK to potentiate n-hexane
neurotoxldty may have been due to Us ability to Induce liver mlcrosomal
enzymes resulting In Increased activation of n-hexane to more toxic
metabolites (Abou-0on1a et a!., 1985).
0081n -10- 02/03/87
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4. CARCINOGENICITY
4.1. . HUMAN DATA
Pertinent data regarding the carcinogenic potential of MIBK by oral or
Inhalation exposure to humans could not be located In the available
literature.
4.2. BIOASSAYS
Studies regarding the cardnogenldty of MIBK to animals exposed by the
oral or Inhalation routes could not be located 1n the available literature.
4.3. OTHER RELEVANT DATA
In a report by the Chemical Manufacturers Association (1984), MIBK was
found to be negative for reverse mutation 1n Salmonella typhlmuMum strains
TA98, TA100, TA1535. TA1537 and TA1538 both with and without S-9 metabolic
activation. MIBK was also found to be negative for unscheduled DNA
synthesis and In the mouse mlcronucleus assay. The mouse lymphoma assay for
forward gene mutation was positive, however, only at a concentration that
produced 97% cell death. MIBK was also studied 1n a cell transformation
assay In the presence and absence of S-9 metabolic activation. This assay
showed positive results 1n the nonactlvated but not 1n the activated
cultures; however, a repeat assay Indicated that MIBK did not significantly
Increase the 'number of transformed fod In either the presence or absence
of S-9.
4.4. WEIGHT OF EVIDENCE
Data concerning potential cardnogenldty of MIBK could not be located
In the available literature.. MIBK has not been classified; however,
according to the U.S. EPA (1986b) Guidelines for Carcinogen Risk Assessment,
MIBK would most appropriately be classified as a Group D chemical, I.e., not
classifiable as to human cardnogenldty.
0081 h -11- 02/03/87
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5. REGULATORY STANDARDS AND CRITERIA
ACGIH (1986) recommended a TLV-TWA of 50 ppm (205 mg/m3) and a
TLV-STEL of 75 ppm (300 mg/m3) for occupational atmospheric exposure to
MIBK. This value was based on the animal data of MacEwen et al. (1971) and
the human data of Elklns (1959), which Indicated that adverse effects (head-
ache and nausea In humans and Increased kidney weight In animals) occurred
at 100 ppm (410 mg/m3). NIOSH (1978) also proposed a TWA limit of 50 ppm
(205 mg/m3). The OSHA (1983) standard for HIBK 1s 100 ppm (410 mg/m3).
0081h -12- 02/03/87
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6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RFD.)
6.1.1. Oral (RfOS()). The study by Microbiological Associates (1986)
provides the only suitable basis for deriving an RfOSQ- In this study,
MIBK was administered to groups of 30 male and 30 female Sprague-Dawley rats
by gavage In corn oil dally for 13 weeks. Nephrotoxlclty and Increased
liver and kidney weights occurred 1n males and females at 1000 mg/kg/day and
to a lesser extent at 250 mg/kg/day. No adverse effects occurred at 50
mg/kg/ day. By dividing this NOEL by an uncertainty factor of 100, to
account for Interspedes extrapolation and Intraspedes variations In
sensitivity, an RfDcn value of 0.5 mg/kg/day (35 mg/day) can be derived.
oU
6.1.2. Inhalation (RfD..). Subchronlc Inhalation studies available for
consideration 1n the derivation of an RfD-, are limited to the 90-day
continuous exposure study by MacEwen et al. (1971) In which rats were
exposed to 100 ppm (410 mg/m3) MIBK and a H-week Intermittent exposure
study by Union Carbide Corp. (1983b) 1n which rats and mice were exposed to
0, 50, 250 and 1000 ppm (0, 205, 1024 and 4097 mg/m3) MIBK. Because the
MacEwen et al. (1971) study was conducted under reduced atmospheric and
Increased oxygen concentration and because only one exposure level was
tested which did not define a NOAEL, the Union Carb1.de Corp. (1983b) study
was considered more appropriate for estimation of an RfOST- Exposure to
250 ppm (1024 mg/m3) MIBK for 6 hours/day, 5 days/week resulted In an
Increase 1n absolute liver weights In male mice and an Increase 1n hyaline
droplets of the proximal tubules of the kidney 1n male rats. No effect was
seen In either male or female rats or mice at 50 ppm (205 mg/m3).
Therefore, the 50 ppm dose was considered a NOEL and the 250 ppm dose a
LOAEL. An equivalent Inhalation dose for rats was calculated by multiplying
the NOEL exposure dose (205 20/m3) by the animal breathing rate (0.223),
0081h1 -13- 06/09/87
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dividing by the reference body weight for rats (0.35 kg) and multiplying by
the factors of 6 hours/24 hours and 5 day*/7days to expand to continuous
exposure. The resultant Inhalation dose 1s 23.3 mg/kg/day. An RfO.. of
0.23 mg/kg/day or 16 mg/day for a 70 kg man was derived by applying an
uncertainty factor of 100, 10 to account for Interspecles variation and 10
to provide greater protection for unusually sensitive Individuals.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral {RfOQ). Data regarding the chronic oral toxldty of MIBK
could not be located In the available literature. The 13-week rat study by
Microbiological Associates (1986) provides suitable oral subchronlc data for
deriving an RfDQ. The resulting RfDQ Is 0.05 mg/kg/day (3.5 mg/day),
which 1s the same as the RfD value calculated by U.S. EPA (1986a).
The data from the 13-week rat gavage study by Microbiological Associates
(1986) are the only bases suitable for deriving CSs for oral exposure.
These calculations are summarized In Table 6-1. Using standard methodology
and dividing by an uncertainty factor of 10 to account for use of subchronlc
data, a human MED of 261 mg/day and an RV. of 1.9 were calculated. An
RVg of 4 was assigned to the effect, resulting In a CS (RVd x RV&)
of 7.6.
6.2.2. Inhalation (RfD,). Data concerning the chronic Inhalation
toxlcity of MIBK could not be located 1n the available literature. An
RfDT for MIBK can be derived by the application of an additional
uncertainty factor of 10 to the RfDSI of 16 mg/day derived from the
subchronlc study by Union Carbide Corporation (1983b). The resultant RfDj
of 1.6 mg/day for 70 kg adult 1s recommended for Inhalation exposure to MIBK.
0081h -14- 06/09/87
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ACGIH (1986) cited an occupational exposure study reported by Elklns
(1959) In which workers Involved In the waterproofing of boots were exposed
to 100 ppm (410 mg/m3) MIBK and complained of headache and nausea. An
RfOT for MIBK could be derived using the TLV of 50 ppm based on the above
study by Elklns (1959) and animal studies by Geller et al. (1979). However,
because of the uncertainty associated with the estimation of concentrations
In the human studies, an RfDj derived from the RfDSI Is more appropriate
(Union Carbide Corp., 1983b).
CSs can be calculated for the effects of MIBK by Inhalation exposure.
Several reports (Llnarl et al.. 1964; Armell et al., 1968; Elklns, 1959)
associate exposure In the workplace to Irritation, nausea,, headache, dis-
turbed sleep and CNS symptoms. Elklns (1959) appears to be the only study
to quantify the effects of MIBK In humans; the author reported headache,
nausea and respiratory Irritation In workers exposed to 100 ppm. In the
90-day continuous Inhalation rat study at 410 mg/m3 (MacEwen et al., 1971)
and the 14-week rat study at 1024 mg/m3 (Union Carbide Corp., 1983b),
hlstopathologlcal changes were observed In the kidneys; 1n the 5-month rat
study by Spencer et al. (1975), 1500 ppm (6140 mg/m3) was associated with
hlstopathologlcal changes In the brain. Inhalation concentrations In
mg/m3 were expanded to continuous exposure, multiplied by reference
Inhalation rates and divided by appropriate measured or assumed animal body
weights (If appropriate) to estimate exposed dose In terms of mg/kg/day.
From animal studies, human MEDs were calculated (see Section 6.2.1.). These
CSs are presented 1n Table 6-1. The highest CS (11.5) based on hlstopatho-
loglcal effects 1n the kidneys of rats exposed by Inhalation (Union Carbide
Corp., 1983b), Is appropriately chosen to represent the toxtdty of MIBK.
OOSlh -16- 06/09/87
-------
6.3. CARCINOGENIC POTENCY (q^)
Data concerning possible cardnogenlclty of MIBK could not be located In
the available literature.
0081h -17- 02/03/87
-------
7. REFERENCES
»
Abou-Donla, M.S., O.M. Lapadula, G. Campbell and P.R. Tlmmons. 1985. The
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ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1986.
Documentation of the Threshold Limit Values and Biological Exposure Indices,
5th ed. Cincinnati, OH. p. 402.
Armell, G., f. Unarl and G. Martovano. 1968. Rellevl Cllnld ed Emato-
chlmlcl In operal Espostl all'azlone d1 un Chetone Superlone (MIBK) R1petu1
a dlstanza d1 S annl. Lav. Urn. 20: 418. (Ital.) (Cited 1n ACGIH, 1986)
Chemical Manufacturers Association. 1984. Voluntary testing program under
Section 4. Toxic Substances Control Act. Submission of test data Vol. 1:
MIBK MutagenlcHy and Teratology Studies. U.S. EPA/OPTS Public Files OTS
0000355-0.
Cox, R.A., R.G. Dei went and M.R. Williams 1980. Atmospheric photooxldatlon
reactions rates, reactivity and mechanism for reaction of organic compound
with hydroxyl radicals. Environ. Scl. Technol. 14: 57-61.
Darnall, K.R., A.C. Lloyd, A.M. Winder and J.N. Pitts, Jr. 1976. Reactiv-
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radicals. Environ. Sc1. Technol. 10: 692-696.
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Q1V1ncenzo, G.D. and W.J. Krasavage. 1974. Serum ornlthlne carbamyl trans-
ferase as a liver response test for exposure to organic solvents. Am. 0.
Ind. Hyg. Assoc. 35: 21-29.
Elklns, H.B. 1959. The Chemistry of Industrial Toxicology, 2nd ed.
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Francis, A.J., C.R. Iden, 8.J. Nine and C.K. Chang. 1980. Characterization
of organlcs In leachates from low-level radioactive waste disposal sites.
Nuclear Techno!. 50: 158-163.
Geller, I.. E. Gause, H. Kaplan and R.J. Hartmann. 1979. Effects of
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task 1n the baboon. Pharmacol. Blochem. Behav. 11(4): 401-406.
Hansch, C., J.E. Qulnlan and G.L. Lawrence. 1968. The linear free-energy
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IARC (International Agency for Research on Cancer). 1979. Chemicals and
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Lande, S.S., P.R. Durkln, D.H. Christopher, P.M. Howard and J. Saxena.
1976. Investigation of selected potential environmental contaminants:
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0081h -19- 02/03/87
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LlnaM, F., G.C. Cosda, G. Martovano and G. Perrelli. 1964, AmlnoaclduMa
In occupational Intoxication. Arch. Scl. Med. 116(6): 336-347. (CHed In
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Property Estimation Methods. McGraw H111 Book Co., Mew York. p. 4-9, 5-5.
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Microbiological Associates. 1986. Subchronlc toxldty of methyl isobutyl
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Plaa, G.L. and P. Ayotte. 19ff5. Taurollthocholate-lnduced Intrahtpatlc
cholestasls: Potent1at1on by methyl Isobutyl ketone and methyl n-butyl
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0081H -20- 02/03/87
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Rathbun, R.E. and O.Y. Tal. 1982. Volatilization of ketones. Water Air
Soil Pollut. 17: 281-293.
Sadtler. n.d. Sadtler Standard UV Spectra No. 21. Sadtler Research
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n-butyl ketone. Arch. Neurol. 32: 219-222.
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Union Carbide Corporation. 1983a. Comparative toxlclty to rats of
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Union Carbide Corporation. 19835. Ninety-day Inhalation study 1n rats and
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U.S. EPA. 1986b. Guidelines for carcinogen risk assessment, request for
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