United States
tf-fr j-WJ, Environmental Protection
mmmM mm Agency
EPA/690/R-17/010
FINAL
09-28-2017
Provisional Peer-Reviewed Toxicity Values for
4-Methyl-2-pentanol
(CASRN 108-11-2)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jon B. Reid, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Lucina E. Lizarraga, PhD
National Center for Environmental Assessment, Cincinnati, OH
Q. Jay Zhao, PhD, MPH, DABT
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the content of this PPRTV assessment should be directed to the EPA Office
of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical Support
Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 6
HUMAN STUDIES 9
ANIMAL STUDIES 9
Oral Exposures 9
Inhalation Exposures 9
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 10
Genotoxicity 10
Absorption, Distribution, Metabolism, and Elimination Studies 10
Acute Irritation Study in Humans 11
Acute Exposure Studies in Animals 11
Sub chronic-Duration Animal Studies with Principal Metabolite 12
DERIVATION 01 PROVISIONAL VALUES 12
DERIVATION OF ORAL REFERENCE DOSES 14
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 14
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 14
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 14
APPENDIX A. SCREENING PROVISIONAL VALUES 15
APPENDIX B. REFERENCES 45
in
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COMMONLY USED ABBREVIATIONS AND ACRONYMS1
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic
Industrial Hygienists
erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
7V-acetyl-P-D-glucosaminidase
AR
androgen receptor
NCEA
National Center for Environmental
AST
aspartate aminotransferase
Assessment
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NOAEL
no-observed-adverse-effect level
Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity
number
relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPN
chronic progressive nephropathy
RGDR
regional gas dose ratio
CYP450
cytochrome P450
RNA
ribonucleic acid
DAF
dosimetric adjustment factor
SAR
structure activity relationship
DEN
diethylnitrosamine
SCE
sister chromatid exchange
DMSO
dimethylsulfoxide
SD
standard deviation
DNA
deoxyribonucleic acid
SDH
sorbitol dehydrogenase
EPA
Environmental Protection Agency
SE
standard error
ER
estrogen receptor
SGOT
serum glutamic oxaloacetic
FDA
Food and Drug Administration
transaminase, also known as AST
FEVi
forced expiratory volume of 1 second
SGPT
serum glutamic pyruvic transaminase,
GD
gestation day
also known as ALT
GDH
glutamate dehydrogenase
SSD
systemic scleroderma
GGT
y-glutamyl transferase
TCA
trichloroacetic acid
GSH
glutathione
TCE
trichloroethylene
GST
glutathione-S-transferase
TWA
time-weighted average
Hb/g-A
animal blood-gas partition coefficient
UF
uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFa
interspecies uncertainty factor
HEC
human equivalent concentration
UFc
composite uncertainty factor
HED
human equivalent dose
UFd
database uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFl
LOAEL-to-NOAEL uncertainty factor
IVF
in vitro fertilization
UFS
subchronic-to-chronic uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level
Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV document.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
4-METHYL-2-PENTANOL (CASRN 108-11-2)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by at least two National Center for
Environment Assessment (NCEA) scientists and an independent external peer review by at least
three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data
or methodologies that might impact the toxicity values or characterization of potential for
adverse human-health effects and are revised as appropriate. Questions regarding nomination of
chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency
(EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-reeional-
science).
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. EPA programs or external parties who may choose to use PPRTVs are
advised that Superfund resources will not generally be used to respond to challenges, if any, of
PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the EPA
Office of Research and Development's (ORD's) NCEA, Superfund Health Risk Technical
Support Center (513-569-7300).
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INTRODUCTION
4-Methyl-2-pentanol, CASRN 108-11-2, also known as methyl isobutyl carbinol (MIBC),
belongs to the class of compounds known as secondary aliphatic alcohols. MIBC is used as a
solvent in the paint industry, a brake fluid, a cleaning agent for semiconductors, a flotation aid, a
fungicide, and an intermediate in the production of plasticizers (Palbe et al.. 2013). It is listed on
U.S. EPA's Toxic Substances Control Act's public inventory (U.S. EPA. 2016) and registered
with Europe's Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH)
program (ECU A, 2017). MIBC is formed as a byproduct in the production of methyl isobutyl
ketone (MIBK) (Falbe et al.. 2013).
The empirical formula for MIBC is C6H14O, and the chemical structure is shown in
Figure 1. Table 1 summarizes the physicochemical properties of MIBC. MIBC is a colorless
liquid at room temperature (HSI)B. 2015). Its high vapor pressure and moderate Henry's law
constant indicate that it is likely to exist solely as a vapor in the atmosphere and volatilize from
either dry or moist surfaces. The estimated half-life of MIBC in the atmosphere is 0.8 days. The
high water solubility and low estimated soil adsorption coefficient indicate that any MIBC in the
environment that has not volatilized may leach to groundwater or undergo runoff after a rain
event. MIBC was found to be readily biodegradable in screening tests, and it is not expected to
persist in the environment (ECUA. 2016; HSDB, 2015).
Ou ru
Ms On ^
Figure 1. 4-Methyl-2-pentanol (MIBC) Structure
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Table 1. Physicochemical Properties of 4-Methyl-2-pentanol (CASRN 108-11-2)
Property (unit)
Value
Physical state
Liquid
Boiling point (°C)
132a
Melting point (°C)
-90a
Density (g/cm3)
0.8b
Vapor pressure (mm Hg at 25 °C)
5.3a
pH (unitless)
NA
pKa (unitless)
NA
Solubility in water (mg/L at 25 °C)
1.64 x 104a
Octanol-water partition coefficient (log Kow)
1.43°
Henry's law constant (atm-m3/mol at 25°C)
4.45 x 10-5a
Soil adsorption coefficient Koc (L/kg)
8 (estimated)3
Atmospheric OH rate constant (cm3/molecule-sec at 25°C)
1.3 x io~n (estimated)3
Atmospheric half-life (d)
0.8 (estimated)3
Relative vapor density (air = 1)
NV
Molecular weight (g/mol)
1023
Flash point (closed cup in °C)
NV
aU.S. EPA (2012b).
''Falbc etal. (2013).
°HSDB (2015).
NA = not applicable; NV = not available.
A summary of available toxicity values for MIBC from EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for
4-Methyl-2-pentanol (CASRN 108-11-2)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2017)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2017)
IPCS
NV
NA
IPCS (2017);
WHO (2017)
Cal/EPA
NV
NA
Cal/EPA (2014);
Cal/EPA (2017a);
Cal/EPA (2017b)
OSHA (PEL)
25 ppm (100 mg/m3)
The PEL is an 8-hr TWA; based on skin
and eye irritation and CNS depression (skin
designation)
OSHA (2006a);
OSHA (2006b);
OSHA (2011)
NIOSH (REL)
25 ppm (100 mg/m3)
Based on skin and eye irritation and CNS
depression; skin designation indicates the
potential for dermal absorption
NIOSH (2016)
NIOSH (STEL)
40 ppm (165 mg/m3)
Based on skin and eye irritation and CNS
depression; skin designation indicates the
potential for dermal absorption
NIOSH (2015)
NIOSH (IDLH)
400 ppm (1,650 mg/m3)
Based on acute inhalation lethality studies
in animals; this may be a conservative
value due to the lack of relevant acute
toxicity data for workers exposed to
concentrations >50 ppm
NIOSH (1994)
ACGIH (TLV-TWA)
25 ppm (104 mg/m3)
Based on irritation of skin and mucous
membranes; skin notation assigned based
on systemic toxicity in rabbits following
dermal application
ACGIH (2016)
ACGIH (TLV-STEL)
40 ppm (167 mg/m3)
Based on irritation of skin and mucous
membranes; skin notation assigned based
on systemic toxicity in rabbits following
topical application
ACGIH (2016)
Cancer
IRIS
NV
NA
U.S. EPA (2017)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2017)
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Table 2. Summary of Available Toxicity Values for
4-Methyl-2-pentanol (CASRN 108-11-2)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Cal/EPA
NV
NA
Cal/EPA (2011):
Cal/EPA (2017a):
Cal/EPA (2017b)
ACGIH
NV
Sufficient data not available
ACGIH (2016)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration.
Parameters: IDLH = immediately dangerous to life or health; PEL = permissible exposure level;
REL = recommended exposure limit; STEL = short-term exposure limit; TLV = threshold limit value;
TWA = time-weighted average.
CNS = central nervous system; NA = not applicable; NV = not available.
Non-date-limited literature searches were conducted in June 2015 for studies relevant to
the derivation of provisional toxicity values for MIBC (CASRN 108-11-2). Searches were
updated in August 2017 for MIBC and all identified potential surrogate chemicals
(see Table A-l.). Searches were conducted using U.S. EPA's Health and Environmental
Research Online (HERO) database of scientific literature. HERO searches the following
databases: PubMed, ToxLine (including TSCATS1), and Web of Science. The following
databases were searched outside of HERO for health-related data: American Conference of
Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease
Registry (ATSDR), California Environmental Protection Agency (Cal/EPA), European Centre
for Ecotoxicology and Toxicology of Chemicals (ECETOC), European Chemicals Agency
(ECHA), U.S. EPA Integrated Risk Information System (IRIS), U.S. EPA Health Effects
Assessments and Related Activities (HEAST), U.S. EPA Office of Water (OW), U.S. EPA
TSCATS2/TSCATS8e, U.S. EPA High Production Volume Information System (HPVIS),
International Agency for Research on Cancer (IARC), International Programme on Chemical
Safety (IPCS/INCHEM), Japan Existing Chemical Data Base (JECDB), National Institute for
Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), Organisation
for Economic Co-operation and Development Screening Information Dataset (OECD SIDS),
International Uniform Chemical Information Database (IUCLID), and HPV, Occupational Safety
and Health Administration (OSHA), and World Health Organization (WHO).
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REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the noncancer and cancer data, respectively, for
MIBC and include all potentially relevant short-term-, subchronic-, and chronic-duration studies.
The phrase "statistical significance" and term "significant(ly)," used throughout the document,
indicate ap-walue of < 0.05 unless otherwise noted.
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Table 3A. Summary of Potentially Relevant Noncancer Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
Category
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetry3
Critical Effects
NOAEL
LOAEL
Reference (comments)
Notesb
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
Subchronic
12 Mill F, Wistar rat, whole-body
chamber; 0, 211, 825, 3,700 mg/m3;
6 hr/d, 5 d/wk, 6 wk
0, 37.8, 147,
660.7
No toxicologically relevant changes in
survival, clinical signs, body weight,
hematology, clinical chemistry,
urinalysis, or organ weight or histology
660.7
NDr
Blair et al. (1982) as cited in
OECD (2005)
(primary report not available;
data cannot be independently
reviewed)
NPR
"Dosimetry: HECexresp = (ppm x MW ^ 24.45) x (hours/day exposed ^ 24) x (days/week exposed ^ 7) x ratio of blood-gas partition coefficients (animal: human). For
MIBC, the values for the human, rat, and mouse blood-air partition coefficients are unknown, so the default ratio of 1 was applied (U.S. EPA. 19941.
bNotes: NPR = not peer reviewed.
EXRESP = extrarespiratory; F = female(s); HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level; M = male(s); MIBC = methyl
isobutyl carbinol or 4-methyl-2-pentanol; MW = molecular weight; ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level.
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Table 3B. Summary of Potentially Relevant Cancer Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
Category
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
NOAEL
LOAEL
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level.
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HUMAN STUDIES
No repeated-exposure human studies have been identified.
ANIMAL STUDIES
The repeated-exposure toxicity data for MIBC are limited to an unpublished 6-week
inhalation study in rats available only from secondary sources [Blair et al. (1982) as cited in
01X I) (2005)1.
Oral Exposures
No repeated-dose oral exposure studies in laboratory animals have been identified.
Inhalation Exposures
Blair et al. (1982) as cited in OECD (2005)
In an unpublished study available only from secondary sources, groups of Wistar rats
were exposed whole-body to MIBC at concentrations of 0, 211, 825, or 3,700 mg/m3 for
6 hours/day, 5 days/week for 6 weeks. Rats were examined twice daily for mortality and clinical
signs of toxicity. Body weights were recorded weekly. Blood and urine were collected at
sacrifice for hematology, clinical chemistry, and urinalysis (the endpoints examined were not
available). The brain, heart, kidney, liver, spleen, and testes were weighed at sacrifice and
histology was conducted on a complete set of 31 tissues.
No deaths, clinical signs of toxicity, or body-weight effects were reported. No
exposure-related changes were observed in hematological parameters. Serum alkaline
phosphatase (ALP) was significantly increased in females from the high-exposure group by 18%,
compared with controls; no other clinical chemistry changes were reported. Exposure-related
changes in urinalysis parameters included increased levels of ketone bodies in the urine of all
exposed females and males at >825 mg/m3 and proteinuria in males at 3,700 mg/m3 (magnitude
and statistics not reported). Kidney weights were significantly elevated in males from the
high-exposure group by 9%, compared with controls; it is unclear from the secondary report
whether these data are for absolute and/or relative kidney weights. No other organ-weight
changes were attributable to exposure. No histopathological lesions were associated with
exposure to MIBC. The clinical chemistry, urinalysis, and kidney-weight findings were not
considered toxicologically significant by the study authors.
For this study, the reported concentrations 0, 211, 825, and 3,700 mg/m3 have been
converted to human equivalent concentrations (HECs) of 0, 37.8, 147, and 660.7 mg/m3,
respectively, for extrarespiratory effects from a Category 3 gas, based on the following equation:
Concentration (HEC) = Concentration x (hours exposed ^ 24 hours) x (days
exposed ^ 7 days) x blood-air partition coefficient ratio (U.S. EPA, 1994). The values for the
human and rat blood-air partition coefficients for MIBC are unknown, so the default ratio of 1
has been applied. The highest exposure of 660.7 mg/m3 is a no-observed-adverse-effect level
(NOAEL) (HEC) based on a lack of toxicologically relevant findings associated with MIBC
exposure; however, these findings cannot be independently reviewed due to unavailability of the
primary report.
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Chronic-Duration/Carcinogenicity Studies
No chronic-duration inhalation studies have been identified in laboratory animals.
Reproductive/Developmental Studies
No reproductive/developmental inhalation studies have been identified in laboratory
animals.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Genotoxicity
Genotoxicity data for MIBC are limited to a single study, which found the chemical to be
nonmutagenic in Salmonella typhimurium and Escherichia coli bacteria with metabolic
activation (Shimizu et al., 1985).
Absorption, Distribution, Metabolism, and Elimination Studies
Information regarding the pharmacokinetics of MIBC is meager. The compound is
metabolized to MIRK and then to 4-hydroxy-4-methyl-2-pentanone (HMP) following exposure.
Gingell et al. (2003) evaluated the extent of metabolism of MIBC to MIBK after
administering a single dose of either compound (approximately 500 mg/kg) to male rats by
gavage in corn oil. Plasma levels of MIBK, MIBC, and HMP were determined up to 8 hours
after dosing. There were no deaths or clinical signs of toxicity in the study. HMP was the
predominant metabolite in the plasma following dosing with MIBK or MIBC, with similar areas
under the curve (AUCs) and both compounds achieving maximum concentration at 9 hours after
dosing. At 9 hours the plasma levels of MIBK and AUC were also comparable after MIBK or
MIBC administration. By comparing combined AUCs for MIBK and HMP, the study authors
estimated that the extent of metabolism of MIBC to MIBK was at least 73%, and proposed that
MIBC is metabolized to MIBK via alcohol dehydrogenase and further oxidized to HMP via
mixed function oxidase (01X I). 2005).
Granvil et al. (1994) examined the metabolism of MIBC in mice. Groups of eight male
Charles River CD-I mice were administered a single intraperitoneal (i.p.) injection of
2.5 mmol/kg (255.5 mg/kg) of MIBC, and the concentrations of metabolites were measured in
the blood and brain 15, 30, 60, and 90 minutes after dosing. Parent compound, MIBK, and HMP
were detected in the blood and brain. Levels of MIBC were highest (-82 |ig/mL and -73 jug/g,
respectively) at 15 minutes; levels of MIBK were also highest (-28 jag/m L and -23 jug/g,
respectively) at 15 minutes and subsequently rapidly decreased at similar rates. In contrast,
HMP peaked at -34 |ig/mL and -30 jug/g, respectively after 30-60 minutes and only gradually
decreased.
A study in rabbits indicated that MIBC metabolites may undergo glucuronic acid
conjugation prior to excretion (Kamil et al.. 1953). Following a single gavage exposure of
25 mmol MIBC/rabbit (850 mg/kg), 33.7% of the administered dose was recovered as glucuronic
acid in the urine. Urinary glucuronide levels returned to baseline within 48 hours. The study
authors also reported a "small amount" of methyl ketone (which they presumed to be MIBK) in
the urine.
Divincen/.o et al. (1976) identified metabolites from serum of guinea pigs treated with
MIBK via i.p. administration. The study authors noted that the concentration of MIBC was too
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low to quantify. The study authors determined that the half-life for MIBK is 66 minutes with a
clearance time of 6 hours. The major metabolite (HMP) had a clearance time of 16 hours.
Acute Irritation Study in Humans
Human studies are limited to a single acute controlled-exposure irritation-threshold study
by Silverman et al. (1946). In this study, a group of 12 subjects (both sexes, number per sex not
reported) were exposed to various concentrations of MIBC for 15 minutes. A majority of
subjects reported eye irritation at 50 ppm (200 mg/m3), with nose and throat irritation at
>50 ppm. The highest concentration that the majority of subjects estimated to be acceptable for
an 8-hour exposure was 25 ppm (100 mg/m3).
Acute Exposure Studies in Animals
Oral Exposure
Groups of mice (five/group; sex and strain not reported) were exposed to MIBC at doses
of 1.0, 1.5, or 2.0 mL/kg via gavage as temporary emulsion (10-40%) in 1% aqueous Tergitol
(McOmie and Anderson. 1949). The authors indicate that the chemicals in the study are "closely
approximate to, but not necessarily the equivalent of, the pure compounds." Mice were observed
for 7 days. Anesthesia (observed as loss of righting reflex) was observed in 2/5, 5/5, and
5/5 mice from the 1.0-, 1.5-, and 2.0-mL/kg dose groups, respectively. Mortality was observed
in 1/5, 4/5, and 5/5 mice from the 1.0-, 1.5-, and 2.0-mL/kg dose groups, respectively. Based on
the mortality data, a median lethal dose (LD50) value of 1.5 mL/kg (1,200 mg/kg) was estimated
for MIBC (McOmie and Anderson. 1949). Hyperemia of the stomach wall and duodenum was a
common gross pathology finding in the mice that died from treatment with the chemical. In
another acute lethality study, an LD50 value of 2.50 g/kg (95% confidence interval [CI]:
2.26-2.97 g/kg) was reported for male Wistar rats exposed to MIBC via gavage in water. The
rats were observed for 14 days after dosing (Smvth et al.. 1951). No gross pathology data for the
rats were presented.
The effect of oral administration of MIBC on the cholestasis induced by
manganese-bilirubin or manganese alone was studied in rats (Ve/.ina and Plaa. 1988). The
experimental design involved single and repeated (once daily for 3 days) gavage treatment prior
to administration of the cholestatic agent. Significant increases in manganese-bilirubin-induced
cholestasis were observed following a single exposure to >3.75 mmol/kg MIBC or repeated
exposures to >1.88 mmol/kg MIBC, compared with exposure to the cholestatic agent alone.
MIBC pretreatment also caused small, but significant, increases in manganese-induced
cholestasis at a dose of 7.5 mmol/kg. The study authors proposed that MIBC potentiated
cholestasis via metabolic transformation to MIBK because many ketogenic substances have been
shown to potentiate cholestatic liver injury. MIBC did not induce cholestasis when administered
without the cholestasis inducers. Similarly, a single gavage exposure of MIBC prior to the
administration of chloroform potentiated chloroform-induced liver injury in rats at doses
>5 mmol/kg (Ve/.ina et al.. 1990). None of the animal groups received MIBC alone in the
chloroform study.
Inhalation Exposure
Groups of mice (10/group, strain and sex not reported) were exposed to air saturated with
commercial-grade MIBC for 4, 8.5, 10, or 15 hours. The mice were observed during exposure
and for 7 days thereafter. The study authors estimated air concentrations of 20 mg/L at 20°C
(20,000 mg/m3) (McOmie and Anderson, 1949). Irritation, somnolence, and anesthesia were
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observed as early as 5 minutes, 1 hour, and 4 hours after exposure, respectively. Anesthesia
(observed as loss of righting reflex) was observed in 7/10 animals in the 4-hour exposure group
and 10/10 animals in each of the longer duration exposure groups. Deaths occurred in the
10-hour (6/10) and 15-hour (8/10) exposure groups only. Repeated 4-hour exposures to air
saturated with MIBC vapor also caused deep anesthesia in mice, with full recovery after
exposure cessation; no cumulative effects or deaths were noted (12 total exposures, and the time
between exposures was not reported) (McOmie and Anderson. 1949).
Carpenter et al. (1949) exposed a total of six Sherman albino rats (mixed male and
female, number/sex not given) to MIBC for 4 hours at a concentration of 2,000 ppm
(8,300 mg/m3). The study authors reported MIBC within a group of other compounds that killed
between two and four rats at this concentration; no further details were provided. Smvth et al.
(1951) exposed six male albino rats (strain not given) for 8 hours to 2,000 ppm (8,300 mg/m3)
with a 2-week observation period. Death occurred in 5/6 animals.
Dermal Exposure
Dermal application of undiluted MIBC to three rabbits (sex and strain not reported)
caused slight erythema within 15 minutes, with moderate erythema and drying developing
postexposure (McOmie and Anderson. 1949). Severe drying of the skin, with some cracking and
sloughing, was reported in three rabbits (sex and strain not reported) following five dermal
applications of MIBC at a concentration of 3 mL/kg (2,400 mg/kg); no systemic effects were
noted (McOmie and Anderson. 1949). Smvth et al. (1951) reported an acute dermal LD50 in
rabbits of 3.56 mL/kg (2,850 mg/kg).
Subchronic-Duration Animal Studies with Principal Metabolite
Nephropathy was observed in male and female Sprague-Dawley (S-D) rats following oral
exposure to HMP for 45 days (premating, mating, gestation, and 3 days lactation) at gavage
doses of >100 and >300 mg/kg-day, respectively [Ministry of Health and Welfare: Japan (1997)
as cited in OECD (2005)1. In males, but not females, nephropathy was associated with hyaline
droplets. Additional adverse effects at >300 mg/kg-day included decreased locomotor activity in
both sexes. At 1,000 mg/kg-day, additional effects included decreased body-weight gain in
females, altered blood parameters in males (increased platelet count, aspartate aminotransferase
[AST], total protein, total cholesterol, total bilirubin, blood urea nitrogen [BUN], creatinine,
calcium, and decreased glucose; magnitudes not reported), hepatocellular hypertrophy in both
sexes, and vacuolization in zona fasciculate of adrenals in males. No adverse reproductive or
developmental effects were reported.
DERIVATION OF PROVISIONAL VALUES
Tables 4 and 5 present summaries of noncancer and cancer reference values, respectively.
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Table 4. Summary of Noncancer Reference Values for
4-Methyl-2-pentanol (CASRN 108-11-2)
Toxicity Type
(units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFc
Principal
Study
Subchronic
p-RfD (mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
NDr
Screening
subchronic p-RfC
(mg/m3)a
Rat and
mouse/both
Reduced fetal body
weight, skeletal
variations, and increased
fetal death in mice; and
skeletal variations in
rats
3 x 10°
NOAEL
(HEC)
1,026
(based on
surrogate
POD)
300
Tyl et al.
(1987) as
cited in U.S.
EPA (2003c)
Screening
chronic p-RfC
(mg/m3)a
Rat and
mouse/both
Reduced fetal body
weight, skeletal
variations, and increased
fetal death in mice; and
skeletal variations in
rats.
3 x 10°
NOAEL
(HEC)
1,026
(based on
surrogate
POD)
300
Tyl et al.
(1987) as
cited in U.S.
EPA (2003c)
aBased on MIBK as a surrogate.
HEC = human equivalent concentration; MIBK = 4-methyl-2-pentanone or methyl isobutyl ketone; NDr = not
determined; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference
concentration; p-RfD = provisional reference dose; UFC = composite uncertainty factor.
Table 5. Summary of Cancer Reference Values for
4-Methyl-2-pentanol (CASRN 108-11-2)
Toxicity Type (units)
Species/Sex
Tumor Type Cancer Value Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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DERIVATION OF ORAL REFERENCE DOSES
No studies have been located regarding the toxicity of MIBC to humans by oral exposure.
Animal studies of oral exposure to MIBC are limited to acute lethality studies, which are of
inadequate duration and scope to support derivation of a subchronic or chronic provisional
reference dose (p-RfD). As a result of the limitations of the available oral toxicity data for
MIBC, subchronic and chronic p-RfDs are not derived. Lack of a satisfactory surrogate with an
independent peer-reviewed published toxicity assessment for oral exposure precludes
development of a screening subchronic or chronic p-RfD. See discussion in Appendix A.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Human studies of inhalation exposure to MIBC are limited to a single, acute irritation
study (Silverman et aL 1946). Available repeated-dose animal studies of MIBC are inadequate
to support derivation of a subchronic or chronic provisional reference concentration (p-RfC) due
to limited reporting or unavailability of the primary report (Blair, 1982). Available acute
lethality studies are of inadequate duration and scope to support derivation of a subchronic or
chronic p-RfC. As a result of the limitations of the available inhalation toxicity data for MIBC,
subchronic and chronic p-RfCs are not derived directly. Instead, screening p-RfCs are derived in
Appendix A using an alternative surrogate approach.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
No relevant data are available for MIBC. Under the U.S. EPA Guidelines for
Carcinogen Risk Assessment (U.S. EPA. 2005). there is "Inadequate Information to Assess
Carcinogenic Potential" of MIBC following both oral and inhalation exposure as shown in
Table 6.
Table 6. Cancer WOE Descriptor for 4-Methyl-2-pentanol (CASRN 108-11-2)
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation, or both)
Comments
"Carcinogenic to Humans "
NS
NA
There are no human data to support this.
"Likely to Be Carcinogenic
to Humans "
NS
NA
There are no suitable animal studies to
support this.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no suitable animal studies to
support this.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
No adequate studies evaluating
carcinogenicity effects in humans or
animals exposed to MIBC are
available.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
The available data do not support this
descriptor.
MIBC = methyl isobutyl carbinol or 4-methyl-2-pentanol; NA = not applicable; NS = not selected; WOE = weight
of evidence.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The absence of suitable data precludes development of cancer potency values for MIBC.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main provisional peer-reviewed toxicity value (PPRTV)
document, it is inappropriate to directly derive provisional toxicity values for
4-methyl-2-pentanol (methyl isobutyl carbinol [MIBC]). However, information is available for a
surrogate chemical which, although insufficient to support derivation of a provisional toxicity
value under current guidelines, may be of limited use to risk assessors. In such cases, the
Superfund Health Risk Technical Support Center summarizes available information for potential
surrogate chemicals in an appendix and develops a "screening value" based on dose-response
data (e.g., point of departure [POD]) from the single best surrogate. Appendices receive the
same level of internal and external scientific peer review as the PPRTV documents to ensure
their appropriateness within the limitations detailed in the document. Users of screening toxicity
values in an appendix to a PPRTV assessment should understand that there is considerably more
uncertainty associated with the derivation of an appendix screening toxicity value than for a
value presented in the body of the assessment. Questions or concerns about the appropriate use
of screening values should be directed to the Superfund Health Risk Technical Support Center.
APPLICATION OF AN ALTERNATIVE SURROGATE APPROACH
The surrogate approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for surrogate analysis are presented in Wang et al. (2012).
Three types of potential surrogates (structural, metabolic, and toxicity-like) are identified to
facilitate the final surrogate selection. The surrogate approach may or may not be applicable to
multiple routes of exposure. All information is considered together as part of the final
weight-of-evidence (WOE) approach to select the most suitable surrogate.
Structural Surrogates (Structural Analogs)
An initial surrogate search focused on identifying structurally similar chemicals with
toxicity values from the Integrated Risk Information System (IRIS), PPRTV, Agency for Toxic
Substances and Disease Registry (ATSDR), or California Environmental Protection Agency
(Cal/EPA) databases to take advantage of the well-characterized chemical-class information.
Under Wang et al. (20121 structural similarity for analogs is typically evaluated using
U.S. EPA's DSSTox database (DSSTox. 2016) and the National Library of Medicine's (NLM's)
ChemlDplus database (ChemlDplus. 2017). However, at the time of preparation of this
document, DSSTox was not available. In lieu of DSSTox scores, the Organisation for Economic
Co-operation and Development (OECD) Toolbox was used to calculate structural similarity
using the Tanimoto method (the same quantitative method used by ChemlDplus and DSSTox).
Five structural analogs to MIBC that have oral and/or inhalation noncancer toxicity values were
identified: 4-methyl-2-pentanone (methyl isobutyl ketone [MIBK]) (U.S. EPA. 2003c).
2-propanol (isopropanol) (U.S. EPA. 2014). 2-propanone (acetone) (U.S. EPA. 2003a; ATSDR.
1994). 2-butanone (methyl ethyl ketone [MEK]) (U.S. EPA. 2003b). and 2-hexanone (methyl
butyl ketone [MBK]) (U.S. EPA. 2009). MIBC and isopropanol are secondary alcohols
(i.e., aliphatic C2 alcohols). The other identified potential surrogates are aliphatic C2 ketones.
Table A-l summarizes the analogs' physicochemical properties and similarity scores. The
ChemlDplus similarity score for MIRK was 66%; there was no information on the other
potential surrogates in ChemlDplus. The OECD Toolbox similarity scores were 30% for MIBK,
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27% for isopropanol, and <5% for the remaining potential surrogates. Under the current tiered
surrogate approach (Wane et al.. 2012). similarity scores >50% are preferential in identification
of structural analogs. The low similarity scores for potential structural analogs of MIBC in
OECD's toolbox are likely related to the limited number of structural descriptors available for
this target compound. Structural similarity metrics use a variety of structural descriptors to
calculate similarity (although the nature of the descriptors may vary across different tools).
Similarity scores calculated for compounds with few structural descriptors will be
disproportionately influenced by changes in, or absence of, a single descriptor, while these same
changes have relatively lower impact on similarity scores for compounds with many descriptors.
Thus, similarity scores may be of limited use when comparing surrogates with relatively simple
structures such as those evaluated in this assessment. Physicochemical properties of the potential
surrogates suggest that MIBC, MIBK, and MBK are less hydrophilic and less volatile than
isopropanol, acetone, and MEK; however, all compounds are expected to be bioavailable
following oral and inhalation exposure. Based primarily on the highest similarity score across
two separate structural platforms (i.e., OECD Toolbox and ChemlDplus), MIBK is identified as
a candidate surrogate chemical for MIBC.
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Table A-l. Physicochemical Properties of 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates"
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Structure
OH CH,
1 1
H,C CH,
0 CH,
1 i
OH
H3C^CH3
O
J!
HjC CH3
O
A -CH,
H3C 3
O
h3c^^ch>
CASRN
108-11-2
108-10-1
67-63-0
67-64-1
78-93-3
591-78-6
Molecular weight
102
100
60
58
72
100
ChemlDplus similarity score (%)b
100
66
NV
NV
NV
NV
OECD Toolbox similarity score (%)°
100
30
27
3
2
4
Melting point (°C)
-90
-84
-90
-94.8
-87
-56
Boiling point (°C)
132
117
82
56
80
128
Vapor pressure (mm Hg at 25°C)
5.3
19.9
45.4
232
90.6
11.6
Henry's law constant (atm-m3/mole at 25°C)
4.45 x 10 5
1.4 x 10 4 (estimated)3
8.1 x 10-6
3.5 x 10-5
5.69 x 10-5
9.3 x 10-5
Water solubility (mg/L)
1.64 x 104
1.9 x 104
1 x 106
1 x 106
2.23 x 105
1.72 x 104
Log Kow
1.43d
1.31
0.05
-0.24
0.29
1.38
pKa
NA
NA
17.1
20
14.7
NA
'Data were gathered from PHYSPROP database for each respective compound unless otherwise specified (U.S. EPA. 2012b').
'ChemlDplus Advanced, similarity scores (CfaemlDpliis. 20171.
"OECD (2017).
MBK = methyl butyl ketone; MEK = methyl ethyl ketone; MIBC = methyl isobutyl carbinol or 4-methyl-2-pentanol; MIBK = 4-methyl-2-pentanone or methyl isobutyl
ketone; NA = not applicable; NV = not available; OECD = Organisation for Economic Co-operation and Development.
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Metabolic Surrogates
Table A-2 summarizes available toxicokinetic data for MIBC and the structurally similar
compounds identified as potential surrogates.
MIBK is considered a metabolic surrogate for MIBC based on bidirectional metabolism
between MIBC and MIBK and common downstream metabolites (OECD. 2005; Gingell et al..
2003; U.S. EPA. 2003c; Duuuav and Plaa. 1995; Granvil et aL 1994). Figure A-1 shows the
metabolic bidirectional metabolism of MIBC and MIBK, modified from Divincen/.o et al.
(1976). Following oral exposure, MIBK and MIBC can be metabolized into each other, and
ultimately produce a common downstream oxidation metabolite, 4-methyl-4-hydroxy-
2-pentanone (HMP), with similar kinetics. Available data indicate that both compounds are
rapidly absorbed, distributed, and metabolized, but data are inadequate to characterize excretion
patterns following exposure. Similar bidirectional metabolism has been described for other
C2 alcohol/C2 ketone pairs including potential surrogates for MIBC (MBK, MEK, isopropanol,
and acetone) (U.S. EPA, 2014, 2009; Clark et al, 2004; U.S. EPA, 2003a, b; Clewell et al,
2001; ATSDR, 1994). Additionally, bidirectional metabolism between isopropanol and acetone
has been used to develop connected physiologically based pharmacokinetic (PBPK) models
(Clark et al.. 2004; Clewell et al.. 2001). These precedents support that C2 alcohol/C2 ketone
pairs, including MIBC and MIBK, are metabolic surrogates for one another.
Isopropanol, acetone, and MEK, along with MIBK and MIBC, are all metabolized via
common oxidative metabolic pathways leading to carbon dioxide (CO:) (U.S. EPA. 2014; Clark
et al.. 2004; U.S. EPA. 2003a. b; Clewell et al.. 2001; ATSDR. 1994); however, oxidation to
CO2 is too general a pathway to use in selecting a surrogate because many small organic
compounds share this ultimate product. In addition, isopropanol, acetone, and MEK do not show
the bidirectional metabolic relationship with MIBC as observed between MIBC and MIBK.
Further, MBK and MEK are also rejected as applicable metabolic surrogates for MIBC due to
the metabolic formation of 2,5-hexanedione as the primary metabolite (U.S. EPA. 2009; Duuuav
and Plaa. 1995; ATSDR. 1992a). which is a known potent peripheral nerve toxicant. Metabolic
production of a similarly arranged dione is not possible for MIBC (Duguay and Plaa, 1995).
Therefore, only MIBK is considered an appropriate metabolic surrogate for MIBC.
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Table A-2. Comparison of Available ADME Data for 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
CASRN 108-11-2
CASRN 108-10-1
CASRN 67-63-0
CASRN 67-64-1
CASRN 78-93-3
CASRN 591-78-6
Absorption after oral exposure
Rapid absorption:
• In rats, MIBC and
metabolites were
detected in blood within
8-9 hr after single
gavage doses.
• Extent of absorption was
not measured.
Rapid absorption:
• In rats, dose-related
increase in MIBK blood
levels occurred 1 hr after
3 daily gavage doses.
• Extent of absorption was
not measured.
Rapid and extensive
absorption:
• In humans or rats given
oral doses of
isopropanol, peak blood
levels were attained for
isopropanol within
1-2 hr and for acetone
within 4-10 hr.
Rapid and extensive
absorption based on
elimination in urine and
expired air (see below).
Rapid absorption:
• In rats given single oral
doses, MEK was rapidly
detected in blood; peak
levels at 1-4 hr,
depending on dose.
• Extent of absorption was
not measured.
Extensive absorption:
• In humans, 66% of a
single oral dose was
absorbed.
• In rats given single oral
doses, 98% of the
administered dose was
absorbed.
• Rate of absorption was
not measured.
Distribution after oral exposure
No data for oral exposure,
but similar appearance and
clearance of the common
metabolite, HMP, occurred
in blood and brain after i.p.
injection of MIBC or
MIBK in mice.
Rapid distribution:
• In rats, 1 hr after 3 doses,
MIBK and principal
metabolite (HMP) were
detected in blood, liver,
and lung.
• Levels in other tissues
were not measured.
ND
No data for oral exposure,
but wide distribution
expected based on mouse
inhalation data.
No data for oral exposure,
but wide distribution
expected based on human
inhalation data.
Wide distribution and
rapid postexposure
clearance:
• Radiolabel was detected
in most rat tissues at 4 hr
with highest counts in
liver > kidney > brain.
• At 24 hr, radioactivity in
tissues was decreased by
about 50% of 4-hr
values.
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Table A-2. Comparison of Available ADME Data for 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Metabolism after oral exposure
Rapid bidirectional
metabolism between
MIBC and MIBK and
metabolic production of
common downstream
oxidation products:
• In rats after oral dose,
MIBK and HMP were
detected in blood.
• Combined MIBK and
HMP AUCs indicated
73% metabolism within
8-9 hr.
• 9-hr AUCs for HMP in
blood were similar in
rats after oral dose of
MIBC or MIBK.
Rapid bidirectional
metabolism between
MIBK and MIBC and
metabolic production of
common downstream
oxidation products:
• In rats after oral dose,
HMP was detected in
blood, liver, and lung;
MIBC was a minor
component in blood, but
was detected after i.p.
and inhalation exposure.
• 9-hr AUCs for HMP in
blood were similar in
rats after oral dose of
MIBC or MIBK.
Rapid bidirectional
metabolism between
isopropanol and acetone
and entry into intermediary
metabolism:
• Studies of humans and
rodents indicate that
absorbed isopropanol,
regardless of route, can
be metabolically
converted to acetone.
• Oxidative metabolism to
methylglyoxal and
1,2-propanediol, then
rapidly converted to
C02.
Rapid bidirectional
metabolism between
acetone and isopropanol:
• Studies of humans and
rodents indicate that
absorbed acetone,
regardless of route, can
be metabolically
converted to 2-propanol.
• Oxidative metabolism to
methylglyoxal and
1,2-propanediol, then
rapidly converted to
C02.
Rapid bidirectional
metabolism between MEK
and 2-butanol and
metabolic production of
common downstream
oxidation products:
• In rats, common
metabolites
(3 -hydroxy-2-butanone
and 2,3-butanediol) were
formed and eliminated
with similar kinetics
after oral dose of
2-butanol or MEK.
• Metabolic
interconversion between
MEK and 2-butanol
occurs in humans
following inhalation
exposure.
Rapid bidirectional
metabolism between MBK
and 2-hexanol and
metabolic production of
common downstream
oxidation products:
• In rats after oral dose,
2-hexanol,
5-hydroxy-2-hexanone,
and 2,5-hexanedione
were detected in blood;
2,5-hexanedione was the
predominant metabolite.
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Table A-2. Comparison of Available ADME Data for 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Excretion after oral exposure
Excretion in urine:
• In rabbits exposed to
MIBC via gavage,
33.7% of the
administered dose was
recovered as glucuronic
acid in the urine. "Small
amounts" of MIBK were
also detected.
ND
Minor excretion of parent
compound in exhaled air
and urine; formation of
CO2 through
gluconeogenesis:
• PBPK model
development indicates
that pathways of
excretion are expected to
be the same as acetone.
Minor excretion of parent
compound in exhaled air
and urine; formation of
CO2 through
gluconeogenesis:
• In humans, 65-93% of
oral dose was
metabolized to CO2 and
remainder was
eliminated unchanged in
urine and expired air.
• In rats, 47% of single
doses of acetone in water
was excreted as CO2 in
exhaled air in 13.5 hr.
ND
Excretion in urine and in
exhaled air as CO2:
• In humans, -40% of
14C-labeled dose was
excreted in breath (as
CO2) and 26% in urine
(chemical form
unidentified) after 8 d.
• In rats, 1% of
14C-labeled dose was in
feces, 44% in exhaled
breath, 38% in urine, and
15% remained in carcass
after 48 hr.
• In dogs given i.v.
14C-MBK, breath
contained ~1% of dose
as MBK and -10% as
CO2; urine contained
6-7% after 8 hr.
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Table A-2. Comparison of Available ADME Data for 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Absorption after inhalation exposure
ND
Rapid and extensive
absorption:
• In humans breathing
MIBK,
-56-62% absorption
was measured.
• In rats, dose-related
elevated MIBK blood
levels were noted after
the last of 3 daily 4-hr
exposures.
• Measured human
blood-air and oil/air
coefficients = 9 and 926.
Rapid and extensive
absorption:
• In rats breathing
isopropanol, blood levels
of isopropanol and
acetone rose quickly.
• Blood-air partition
coefficients were 1,290
in rats and 848 in
humans.
Rapid and extensive
absorption:
• In humans breathing
acetone, fractional
uptakes were 39-52 and
53%.
• Blood-air partition
coefficients for rats or
humans ranged from
210-301.
Rapid and extensive
absorption:
• In humans breathing
MEK, -70 and
-50% retentions were
measured.
• Blood-air partition
coefficients were -140
for rats and 125-202 for
humans. Oil/air
coefficient was 131.
Rapid and extensive
absorption:
• In humans breathing
MBK,
75-92% absorption was
measured.
• In dogs,
65-68% absorption was
measured.
• Blood-air coefficient of
127 was measured with
human blood.
Distribution after inhalation exposure
No data for inhalation
exposure, but similar
appearance and clearance
of the common metabolite,
HMP, occurred in blood
and brain after i.p.
injection of MIBC or
MIBK in mice.
Wide distribution:
• In rats, dose-related
increases in MIBK and
metabolites were found
in plasma, liver, and
lungs after inhalation
exposure; no other
tissues examined.
ND
Rapid and wide
distribution with some
preference for
water-enriched tissues:
• In mice breathing
acetone, highest levels
were in water-enriched
tissues.
• Acetone levels in all
tissues returned to
background levels within
24 hr postexposure.
Wide tissue distribution,
but fat preference not
expected:
• In two cases of
MEK-exposed workers,
postmortem MEK
tissue/air solubility ratios
for kidney, liver, muscle,
lung, heart, fat, and brain
were similar.
• Air partition coefficients
(in vitro) were
equivalent in various rat
tissues and blood.
Wide distribution:
• In rats, dose-related
increases in MBK and
metabolites (2-hexanol
and 2,5-hexanedione)
were found in plasma,
liver, and lungs after
inhalation exposure; no
other tissues were
examined.
22
4-Methyl-2-pentanol
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Table A-2. Comparison of Available ADME Data for 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Metabolism after inhalation exposure
ND
Rapid bidirectional
metabolism between
MIBK and MIBC, and
metabolic production of
common downstream
oxidation products.
Rapid bidirectional
metabolism between
isopropanol and acetone
and entry into intermediary
metabolism, regardless of
exposure route (see "Oral
Section" above).
Rapid bidirectional
metabolism between
acetone and isopropanol
and entry into intermediary
metabolism, regardless of
exposure route (see "Oral
Section" above).
Rapid bidirectional
metabolism between MEK
and 2-butanol and
metabolic production of
common downstream
oxidation products:
• In humans breathing
MEK, 2-butanol and
2,3-butanediol were
detected in serum and
3 -hydroxy-2-butanone
and 2,3-butanediol were
detected in urine.
Rapid bidirectional
metabolism between MBK
and 2-hexanol and
metabolic production of
common downstream
oxidation products:
• In humans breathing
MBK, 2,5-hexandione
was detected in serum
postexposure.
• In rats after oral or
inhalation exposure,
2-hexanol,
5-hydroxy-2-hexanone,
and 2,5-hexanedione
were identified as
metabolites in serum,
liver, and lungs.
23
4-Methyl-2-pentanol
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Table A-2. Comparison of Available ADME Data for 4-Methyl-2-pentanol (CASRN 108-11-2) and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Excretion after inhalation exposure
ND
No data characterizing
excretion pathways after
inhalation:
• In humans after
breathing MIBK,
2-phase elimination of
MIBK in blood was
seen, but body-excretion
pathways were not
characterized.
• MIBK, HMP, and MIBC
were not detected in 3-hr
postexposure urine.
Minor excretion of parent
compound in exhaled air
and urine and primary
elimination by
intermediary metabolism
to C02:
• PBPK model
development indicates
that pathways of
excretion are expected to
be the same as for
acetone.
Minor excretion of parent
compound in exhaled air
and urine and primary
elimination by
intermediary metabolism
to CO2, regardless of
route:
• In humans after
breathing acetone for
2 hr, 16-27% of
absorbed acetone was in
4-hr expired air as
nonmetabolized acetone,
<1% was in urine, and
remainder was assumed
to have been
metabolized through
intermediary
metabolism.
Minor excretion in exhaled
air and urine and primary
elimination by
intermediary metabolism
to C02:
• In humans, urinary
excretion of MEK and
metabolites and
exhalation of MEK only
accounted for 0.1-3% of
the absorbed dose. The
remainder was expected
to be converted to CO2
via intermediary
metabolism.
Excretion in exhaled air as
parent material and CO2
and as other metabolites in
urine:
• In humans breathing
MBK for 4-7.5 hr, MBK
was detected in expired
air during and after
exposure, but
metabolites were not
detected. MBK and
metabolites were not
detected in urine.
• In dogs given i.v.
14C-MBK, breath
contained ~1% of dose
as MBK and -10% as
CO2; urine contained
6-7% after 8 hr.
OECD (2005); Ginaell et
al. (2003); Granvil et al.
U.S. EPA (2003c):
Duauav and Plaa (1995);
U.S. EPA (2014): Clark et
al. (2004); Clewell et al.
U.S. EPA (2003a):
ATSDR (1994)
U.S. EPA (2003b):
ATSDR (1992a)
U.S. EPA (2009); Duauav
and Plaa (1995): ATSDR
(1994); Kamil et al. (1953)
Granvil et al. (1994);
Duauav and Plaa (1993)
(2001)
(1992b)
ADME = absorption, distribution, metabolism, and excretion; AUC = area under the curve; CO2 = carbon dioxide; HMP = 4-hydroxy-4-methyl-2-pentanone;
i.p. = intraperitoneal; i.v. = intravenous; MBK = methyl butyl ketone; MEK = methyl ethyl ketone; MIBC = methyl isobutyl carbinol or 4-methyl-2-pentanol;
MIBK = 4-methyl-2-pentanone or methyl isobutyl ketone; ND = no data; PBPK = physiologically based pharmacokinetic.
24
4-Methyl-2-pentanol
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09-28-2017
MIBC
r\o
vjll
CH-
lj po r^T-T——rH—rR
.A- Ji- ^ JL .1a JL A X ^Wil.*' JL. JL jL JL <•»
2 2 3
O
CTJ
Crl-,
upu _ r ^tt ptt nTi
ttK^n — v_ "vn^vn^vii^
MIBK
0
CM,
ITPfT p pi I p PIT
,IjL JljL^, Vw^1 V^y X Vw** 1.1 ^
HMP OH
Figure A-l. MIBK Metabolism: 4-Methyl-2-pentanol (MIBC), Methyl Isobutyl
Ketone (MIBK), 4-Methyl-4-hydroxy-2-pentanone (HMP) ("Divincenzo et al., 1976)
25
4-Methyl-2-pentanol
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09-28-2017
Toxicity-Like Surrogates (Oral)
Table A-3 summarizes available oral and inhalation toxicity values for MIBC and the
compounds identified as potential structural surrogates.
MIBC and all potential surrogates exhibit relatively low acute oral toxicity. Although
there are no repeated-dose oral toxicity data for MIBC, HMP (the common metabolite for MIBC
and MIBK) has been studied in a 45-day gavage study in rats; this study was published in
Japanese and was only available from a secondary source [Ministry of Health and Welfare: Japan
(1997) as cited in OECD (2005)1. The critical effect was nephropathy in males at
1,000 mg/kg-day and females at >300 mg/kg-day (male nephropathy was identified to include
hyaline droplets suggesting the potential involvement of an alpha 2u-mediated pathway, bringing
into question the biological relevance of the kidney effect in this sex). Additional effects in
males and females included general central nervous system (CNS) depression (>300 mg/kg-day)
and liver and adrenal damage (1,000 mg/kg-day). Whereas the oral toxicity database for HMP
can provide insight to the potential toxic effects of MIBC, HMP was not identified as a structural
surrogate and it is therefore unclear if the oral toxicity data for HMP are directly relevant to
MIBC.
There are limited oral toxicity data for MIBK, however increased liver and kidney
weights were observed in rats at >250 mg/kg-day (U.S. EPA. 2003c). Effects of oral exposure to
isopropanol include developmental effects in rabbits (240 mg/kg-day) and rats
(>596-mg/kg-day). Multiple organ weights, including liver and kidney, were increased in rats at
>71 1 mg/kg-day isopropanol coupled with decreased body weight at >1,605 mg/kg-day (U.S.
EPA, 2014). The kidney is a target organ for oral exposure to acetone as nephropathy was
observed in rats at >500 mg/kg-day. Hematological changes were also observed in rats at
>1,700 mg/kg-day acetone as well as reproductive effects at 3,400 mg/kg-day. CNS effects
(i.e., decreased motor nerve conduction velocity) were observed in rats at 650 mg/kg-day acetone
(U.S. EPA. 2003a). There are no oral toxicity data available for MEK; however, oral data are
available for 2-butanol which is considered an appropriate surrogate for MEK. Developmental
effects were observed after treatment with 2-butanol at >1,771 mg/kg-day as well as renal effects
(i.e., nephropathy) at >3,122 mg/kg-day (U.S. EPA. 2003b). MBK.-induced peripheral nerve
toxicity was observed in rats at >143 mg/kg-day and in chickens and guinea pigs at various doses
(U.S. EPA. 2009). As discussed in the "Metabolic Surrogates" section, peripheral nerve toxicity
caused by MBK is due to the metabolic formation of 2,5-hexanedione, a product not expected to
be produced by the metabolism of MIBC.
In conclusion, MBK and MEK are not considered ideal toxicity-like surrogates for MIBC
due to 2,5-hexanedione-dependent peripheral neuropathy. As discussed earlier in the "Metabolic
Surrogates" section of this Appendix, it is not possible to form the metabolite responsible for
peripheral neuropathy following exposure to MIBC. The remaining surrogates (i.e., MIBK,
isopropanol, and acetone) appear to all share the kidneys as a target organ for oral toxicity, but
the relevance of these effects to the potential toxicity of MIBC remains uncertain (e.g., hyaline
droplet nephropathy following HMP exposure in male rats; complete lack of repeat-dose toxicity
information for MIBC). In the complete absence of repeated-dose oral toxicity data for MIBC,
there is no basis for identification of a single best toxicity-like surrogate for the oral route of
exposure.
26
4-Methyl-2-pentanol
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Toxicity-Like Surrogates (Inhalation)
As described above, MBK and MEK were not considered as applicable toxicity like
surrogates for MIBC due to 2,5-hexanedione dependent peripheral neuropathy. Because this
information also pertains to the inhalation route, the potential of MBK and MEK as applicable
inhalation toxicity-like surrogates for MIBC is not further discussed.
No acute inhalation toxicity data were available for MIBC; acute inhalation toxicity is
low for all surrogates. Repeated-exposure toxicity data available for MIBC are limited to an
unpublished 6-week rat inhalation study available only from a secondary source [Blair et al.
(1982) as cited in OECD (2005)1. Although the biological relevance of these effects are
unknown, Blair et al. (1982) observed renal effects denoted as ketone bodies in the urine in
males (>147 mg/m3 [HEC]) and females (>37.8 mg/m3 [HEC]) and proteinuria in males at
660.7 mg/m3 (HEC). Additionally, kidney weights were statistically significantly elevated (9%)
in males at 660.7 mg/m3 (HEC), approaching the 10% criteria for biological significance.
Similar effects have also been observed after inhalation exposure to MIBK and isopropanol.
MIBK inhalation exposure caused the following renal effects: increased kidney weights in mice
and rats at >367 mg/m3 (HEC) and increased urine protein was also observed in male rats at 733
mg/m3 (HEC). In addition, MIBK caused nephropathy in male and female rats at >2045 mg/m3
(HEC) (U.S. EPA. 2003c). For isopropanol, the renal effects were observed following inhalation
exposure including increased relative kidney weight and histopathological lesions in male and
female rats at >1,101 mg/m3 (HEC) (U.S. EPA, 2014). No kidney effects were observed
following inhalation exposure to acetone (ATSDR, 1994). Taken together, these data suggest
that the kidneys are a shared site of toxicity between MIBC, MIBK, and isopropanol but not
acetone.
In addition to renal effects, developmental effects were also observed in rats following
inhalation exposure to MIRK at 3,073 mg/m3 (HEC). Additional inhalation effects for MIRK
include: histopathological changes in the liver, increases in various relative organ weights (liver,
testis, cauda epididymis, seminal vesicle, and adrenal weights), and reduced startle reflex at
>2045 mg/m3 (HEC) (U.S. EPA, 2003c). Reproductive effects were reported in mice following
inhalation exposure to isopropanol at >221 mg/m3 (HEC). Further inhalation effects for
isopropanol include neurotoxicity, increased liver weight, adrenal gland congestion, stomach and
splenic lesions, clinical signs of toxicity, and mortality. The inhalation toxicity information for
acetone was limited to neurological effects in humans.
In summary, inhalation exposure studies of MIBC, MIBK, and isopropanol suggest that
the kidneys are a shared site of toxicity. The available data suggest that acetone does not affect
the kidneys. Therefore, MIBK and isopropanol are both considered inhalation toxicity-like
surrogate compounds for MIBC.
27
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Structure
OH CH,
1 T
h3c
0 CH,
1 X
OH
h3c^ch3
0
1
HjC CHj
O
A .CH,
HjC 3
O
H3C'jl^-/CH3
CASRN
108-11-2
108-10-1
67-63-0
67-64-1
78-93-3
591-78-6
Repeated-dose toxicity—oral, subchronic
POD (mg/kg-d)
NA
NA
55.2
NA
NA
NA
POD type
NA
NA
BMDLos (HED)
NA
NA
NA
Chronic UFC
NA
NA
30 (3 UFa, 10 UFh)
NA
NA
NA
p-RfD/MRL
(mg/kg-d)
NA
NA
2 x 10°
NA
NA
NA
Critical effects
NA
NA
Decreased fetal body
weight at 240 mg/kg-d
NA
NA
NA
Other effects
(in principal
study)
NA
NA
Maternal toxicity was
observed at 480 mg/kg-d
(decreased maternal food
consumption and increased
mortality).
NA
NA
NA
Species
NA
NA
Rabbit
NA
NA
NA
Duration
NA
NA
GDs 6-18
NA
NA
NA
Route
NA
NA
Gavage
NA
NA
NA
28
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Additional
toxicity data
(from other
studies)
NA
NA
Preimplantation loss,
decreased fetal body
weight, and skeletal
anomalies were also
observed at >596 mg/kg-d
in developmental rat
studies.
Several relative organ
weights were increased in
12-wk and one- or
two-generation
reproductive studies in rats
(liver, kidney, adrenal,
spleen, and/or testes) at
doses as low as
711 mg/kg-d. Decreased
body weights were reported
at >1,605 mg/kg-d.
NA
NA
NA
Source
NA
NA
U.S. EPA (2014)
NA
NA
NA
Repeated-dose toxicity—oral, chronic
POD (mg/kg-d)
NA
NA
55.2
900
639
5
POD type
NA
NA
BMDLos (HED)
NOAEL
BMDLos
BMDLio
Chronic UFC
NA
NA
30 (3 UFa, 10 UFh)
1,000 (3 UFa,
10 UFh, 3 UFS,
10 UFd)
1,000 (10 UFa,
10 UFh, 10 UFd)
1,000 (10 UFa,
10 UFh, 10 UFd)
p-RfD/RfD
(mg/kg-d)
NA
NA
2 x 10°
9 x 10-1
6 x 10-1
5 x 10-3
29
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Critical effects
NA
NA
Decreased fetal body
weight at 240 mg/kg-d
Mild nephropathy
Decreased fetal body
weight at
1,771 mg/kg-d
Axonal swelling of
the peripheral nerve at
143 mg/kg-d
Other effects
(in principal
study)
NA
NA
Maternal toxicity was
observed at 480 mg/kg-d
(decreased maternal food
consumption and increased
mortality).
Increased severity of
nephropathy,
macrocytic and
normochromic
anemia in males at
1,700 mg/kg-d
Increased relative
testes weight,
decreased sperm
motility, caudal and
epididymal weights,
and increased
incidence of abnormal
sperm at
3,400 mg/kg-d
Parental toxicity
(decreased male
mating index,
decreased male and
female body weight),
decreased pup
survival, and
nephropathy in
F1 males (potentially
a2u-g associated)
were noted at
>3,122 mg/kg-d.
Note: The principal
study evaluated the
toxicity of 2-butanol,
which was considered
an appropriate
surrogate for
2-butanone (2-butanol
is a metabolic
precursor of
2-butanone).
Axonal swelling in
the brain and spinal
cord, and myofibrillar
atrophy of quadriceps
and calf muscles at
>266 mg/kg-d
Species
NA
NA
Rabbit
Rat
Rat
Rat
Duration
NA
NA
GDs 6-18
13 wk
Multigenerational
study (~23 wk)
13 mo
Route
NA
NA
Gavage
Drinking water
Drinking water
Drinking water
30
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
4-Methyl-2-pentanone
2-Propanol
2-Propanone
2-Butanone
2-Hexanone
(MIBC)
(MIBK)
(isopropanol)
(acetone)
(MEK)
(MBK)
Additional
NA
A previous IRIS
See "Repeated-dose
No chronic-duration
No oral toxicity data
Several additional
toxicity data
RfD (1991) based on liver
toxicity—oral, subchronic"
or multigenerational
were available for
studies also reported
(from other
and kidney effects was
section above.
studies were
2-butanone, and no
neurotoxicity
studies)
withdrawn in 2003
identified:
additional oral
(swelling/
because the observed
• Nephropathy was
toxicity data were
degeneration of
effects were not
not observed in the
reported for
peripheral axons,
considered clearly
companion mouse
2-butanol.
neuropathy, ataxia,
biologically relevant.
13-wk drinking
water study at doses
up to 4,900 mg/kg-d
(M) or
11,000 mg/kg-d (F).
• Decreased motor
nerve conduction
velocity was
observed in rats
exposed to
650 mg/kg-d for
6 wk in drinking
water.
hind-limb paralysis),
including a 90-d
gavage study in hens,
90-d and 40-wk
gavage study in rats,
120-d drinking water
study in rats, and
24-wk drinking water
study in guinea pigs.
Peripheral toxicity is
attributed to the
principal metabolite,
2,5-hexanedione.
31
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Continued:
Continued:
Continued:
Continued:
Continued:
• Increased severity
of nephropathy in
male and female
rats was observed in
a 90-d gavage study
at >500 mg/kg-d;
nephropathy in
males was
associated with
hyaline droplet
formation.
Additional effects
noted in rats
following subchronic
gavage exposure at
2,500 mg/kg-d
included excessive
salivation,
hematological
alterations in males
(increased Hb, Hct,
and mean cell count),
increased ALT, and
decreased absolute
brain weight. No
body-weight effects
were noted.
Continued:
Continued:
Source
NA
U.S. EPA (2003c)
U.S. EPA (2014)
U.S. EPA (2003a)
U.S. EPA (2003b)
U.S. EPA (2009)
32
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Repeated-dose toxicity—inhalation, subchronic
POD (mg/m3)
NA
NA
661.8
3,000
NA
NA
POD type
NA
NA
NOAEL (HEC)
LOAEL
NA
NA
Subchronic UFC
NA
NA
100 (3 UFa, 10 UFh,
3 UFd)
100 (10 UFh, 10 UFl)
NA
NA
Subchronic
p-RfC/
intermediate
MRL (mg/m3)
NA
NA
7 x 10°
3 x 101
NA
NA
Critical effects
NA
NA
Increased mean cumulative
motor activity at
2,198 mg/m3 (HEC)
Increased visual
evoked responses
NA
NA
Other effects
(in principal
study)
NA
NA
Clinical signs of
neurotoxicity (ataxia,
transient narcosis, lack of
startle reflex), and transient
mild anemia were also
observed at 2,198 mg/m3
(HEC). No toxicologically
significant changes in body
weight, FOB (performed
~42 hr after most recent
exposure at Wk 1, 2, 4, 9,
and 13), clinical chemistry,
or organ weight or
histology.
No changes in
respiratory or cardiac
function,
hematological
parameters, serum
liver or kidney
enzymes, or urinalysis
parameters.
NA
NA
Species
NA
NA
Rat
Human
NA
NA
Duration
NA
NA
13 wk
6 wk
NA
NA
Route
NA
NA
Inhalation
Inhalation
NA
NA
33
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Additional
toxicity data
(from other
studies)
Significantly increased
kidney weight and
proteinuria were
observed in male rats
at 660.7 mg/m3 (HEC).
Increased levels of
ketone bodies in the
urine of all exposed
females and males at
>14.7 mg/m3 (HEC).
NA
Clinical signs of
neurotoxicity and increased
relative liver weight (in the
absence of histological
effects) were observed at
>661.8 mg/m3 (HEC) in
mice in a 13-wk study. No
toxicologically significant
changes in body weight,
hematology, clinical
chemistry, organ weight, or
histology.
In a developmental rat
study, decreased implants,
increased resorptions, fetal
growth retardation, and
malformations were noted
at >5,048 mg/m3 (HEC).
Various other
neurological effects
have been reported in
exposed volunteers or
workers (weakness,
tiredness, headache,
dizziness,
unsteadiness,
confusion, delayed
reaction time, tension,
narcosis).
NA
NA
Source
OECD (2005)
NA
U.S. EPA (2014)
ATSDR (1994)
NA
NA
Repeated-dose toxicity—inhalation, chronic
POD (mg/m3)
NA
1,026
221
3,000
1,517
90
POD type
NA
NOAEL (HEC)
LOAEL (HEC)
LOAEL
BMCLio (HEC)
BMCLos (HEC)
Chronic UFC
NA
300 (3 UFa, 10 UFh,
10 UFd)
1,000 (3 UFa, 10 UFH,
10 UFl, 3 UFd)
100 (10 UFh, 10 UFl)
300 (3 UFa, 10 UFH,
10 UFd)
3,000 (3 UFa,
10 UFh, 10 UFS,
10 UFd)
p-RfC/RfC
(mg/m3)
NA
3
2 x 10-1
3 x 101
5
3 x 10-2
34
4-Methyl-2-pentanol
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Critical effects
NA
Decreased fetal body
weight, delayed skeletal
ossification, increased
fetal death at 3,073 mg/m3
(HEC)
Decreased absolute and
relative testes weight at
221 mg/m3 (HEC)
Increased visual
evoked responses at
3,000 mg/m3 (HEC)
Developmental
toxicity (skeletal
variations) at
2,980 mg/m3 (HEC)
Decreased MCV of
the sciatic tibial nerve
at 73 mg/m3 (HEC)
Other effects
(in principal
study)
NA
Maternal toxicity was
observed at 3,073 mg/m3
(HEC), including clinical
signs of toxicity, and
reduced maternal body
weight, and body-weight
gain.
Increased relative liver
weight, seminal vesicle
enlargement, increased
incidences of adrenal gland
congestion, mucosal cell
hyperplasia in the stomach,
splenic hematopoiesis, and
hemosiderosis at
>1,101 mg/m3 (HEC).
Body weights remained
within 10% of control in all
treated groups (up to
2,211 mg/m3 [HEC]).
No changes in
respiratory or cardiac
function,
hematological
parameters, serum
liver or kidney
enzymes, or urinalysis
parameters
Decreased fetal body
weight and a slight
(7%) increase in
maternal relative liver
weight were observed
at 8,909 mg/m3
(HEC). No maternal
body-weight effects
were noted. No
treatment-related
increases in
intrauterine death or
number of
malformations were
observed.
Decreased MCV of
the ulnar nerve,
hind-limb paralysis
Species
NA
Rat
Mouse
Human
Mouse
Monkey
Duration
NA
GDs 6-15 (6 hr/d)
78 wk
6 wk
GDs 6-15 (7 hr/d)
10 mo (6 hr/d,
5 d/wk)
Route
NA
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
35
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Additional
toxicity data
(from other
studies)
NA
Histopathological changes
in liver and kidney,
increases in various
relative organ weights
(liver, kidney, testis, cauda
epididymis, seminal
vesicle, adrenal weights),
and reduced startle reflex
were observed at higher
concentrations in a
multigenerational
reproductive study.
Transient body-weight
effects were observed in
F0 and F1 parental
animals during premating
and mating exposure, but
not gestation or lactation.
Survival was decreased in
male rats at the high
concentration. The kidney
in rats and the liver in
mice were the main targets
of MIBK toxicity and
carcinogenicity.
Hepatocellular adenomas,
and adenoma of carcinoma
(combined) were
increased in male and
female mice exposed to
the high concentration.
In the companion rat study,
effects noted at
>1,101 mg/m3 (HEC)
included increased relative
liver weight, kidney
lesions, and clinical signs
of toxicity (hypoactivity,
ataxia, prostration, and
narcosis) and mortality
(males only). Body
weights remained within
10% of control in all treated
groups (up to 2,211 mg/m3
[HEC]).
See "Subchronic
p-RfC/intermediate
MRL" row in the
"Repeated-dose
toxicity—inhalation,
subchronic" section
above.
Limited to equivocal
evidence of
neurological effects in
humans following
long-term
occupational
exposure.
Skeletal variations
and maternal toxicity
were also observed in
rats at 2,950 mg/m3
(HEC).
Altered MCV and
hind-limb paralysis
were also observed in
rats in the same
study.
Human occupational
exposure to «-hexane
(parent compound for
«-hexanone) also
causes decreased
MCV and
polyneuropathy.
Peripheral toxicity is
attributed to the
principal metabolite,
2,5-hexanedione.
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Continued:
Continued:
Continued:
There were also
treatment-related increases
in multiple adenomas in
both sexes.
Continued:
Continued:
Continued:
Transient decreases in
body-weight gain,
increased absolute
and relative liver
weight, altered liver
enzyme levels,
increased relative
kidney weight, and
decreased absolute
and relative brain
weight were observed
in rats exposed to
14,870 mg/m3
(HEC = 2,655 mg/m3)
for 90 d. No
hematological or
histopathological
effects were noted.
No peripheral
neurotoxicity was
observed in rats
exposed to
3,318 mg/m3 (HEC)
for up to 55 d or
590 mg/m3 (HEC) for
24 wk.
Continued:
Source
NA
U.S. EPA (2003c): Stout
et al. (2008)
U.S. EPA (2014)
ATSDR (1994)
U.S. EPA (2003b)
U.S. EPA (2009)
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Acute toxicity
Rat oral LD5o
(mg/kg)
2,590
2,080
5,045
5,800
2,737
2,590
Toxicity at rat
oral LD5o
NA
NA
Somnolence, altered sleep
time, and righting reflex
Tremors, altered sleep
time, and righting
reflex
NA
NA
Mouse oral
LD50 (mg/kg)
1,000 (LDlo)
1,900
3,600
3,000
4,050
2,430
Toxicity at
mouse oral LD50
GI changes (no further
information provided)
NA
Somnolence, altered sleep
time, and righting reflex
NA
NA
NA
Rat inhalation
LC50 (mg/m3)
NA
100,000
39,000
50,100
23,500
8,000
Toxicity at rat
inhalation LC50
NA
NA
NA
NA
NA
NA
Mouse
inhalation LC50
(mg/m3)
NA
23,300
31,500 (LClo)
44,000
32,000
NA
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Table A-3. Comparison of Available Assessment Health Values and Acute Toxicity Data for 4-Methyl-2-pentanol (CASRN 108-11-2)
and Candidate Surrogates
4-Methyl-2-pentanol
(MIBC)
4-Methyl-2-pentanone
(MIBK)
2-Propanol
(isopropanol)
2-Propanone
(acetone)
2-Butanone
(MEK)
2-Hexanone
(MBK)
Toxicity at
mouse
inhalation LC50
NA
NA
NA
NA
NA
NA
Source
GiemlDplus (2017)
GiemlDplus (2017)
GiemlDplus (2017)
GiemlDplus (2017)
GiemlDplus (2017)
GiemlDplus (2017)
a2u-g = alpha 2u-globulin; ALT = alanine aminotransferase; BMCL05 = 5% benchmark concentration lower confidence limit; BMCL10 = 10% benchmark concentration
lower confidence limit; BMDL05 = 5% benchmark dose lower confidence limit; BMDL10 = 10% benchmark dose lower confidence limit; F = female(s);
FOB = functional observational battery; GD = gestation day; GI = gastrointestinal; Hb = hemoglobin; Hct = hematocrit; HEC = human equivalent concentration;
HF.D = human equivalent dose; IRIS = Integrated Risk Information System; LC50 = median lethal concentration; LClo = lowest lethal concentration; LD50 = median
lethal dose; LDlo = lowest lethal dose; LOAEL = lowest-observed-adverse-effect level; M = male(s); MBK = methyl butyl ketone; MCV = motor conduction velocity;
MEK = methyl ethyl ketone; MIBC = methyl isobutyl carbinol or 4-methyl-2-pentanol; MIBK = 4-methyl-2-pentanone or methyl isobutyl ketone; MRL = minimal risk
level; NA = not applicable; NOAEL = no-observed-adverse-effect level; POD = point of departure; p-RfC = provisional reference concentration; p-RfD = provisional
reference dose; RfC = inhalation reference concentration; RfD = oral reference dose; UFa = interspecies uncertainty factor; UFC = composite uncertainty factor;
UFd = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
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Weight-of-Evidence Approach
A WOE approach is used to evaluate information from potential candidate surrogates as
described by Wang et al. (2012). Commonalities in structural/physicochemical properties,
toxicokinetics, metabolism, toxicity, or mode of action (MOA) between potential surrogates and
chemical(s) of concern are identified. Emphasis is given to toxicological and/or toxicokinetic
similarity over structural similarity. Surrogate candidates are excluded if they do not have
commonality or demonstrate significantly different physicochemical properties, and
toxicokinetic profiles that set them apart from the pool of potential surrogates and/or chemical(s)
of concern. From the remaining potential surrogates, the most appropriate surrogate (most
biologically or toxicologically relevant analog chemical) with the highest structural similarity
and/or most conservative toxicity value is selected.
Oral Exposure
Based on structural analog analysis, MIBK provided the highest similarity scores to
MIBC among potential surrogates. Based primarily on the available metabolism information,
only MIBK is identified as a suitable metabolic surrogate compound for MIBC. Specifically,
MIBC and MIBK are involved in a rapid bidirectional metabolic relationship that includes the
shared production of common downstream metabolites including HMP. MBK and MEK are not
considered suitable metabolic surrogates due to the formation of 2,5-hexanedione, a known
potent peripheral nerve toxicant that cannot be formed during MIBC metabolism. Whereas
MIBC, MIBK, isopropanol, and acetone are all metabolized via a common oxidative metabolic
pathway leading to CO2, isopropanol and acetone do not demonstrate the close bidirectional
metabolic relationship with MIBC as observed between MIBC and MIBK. Furthermore, a
terminal metabolic product of CO2 should not be considered a common metabolite because many
small organic compounds can be metabolized to CO2. MIBK, isopropanol, and acetone via the
oral route have all been shown to induce kidney effects suggesting the potential for MIBC to
share in a common target organ of toxicity. However, kidney effects observed following oral
isopropanol or acetone exposure occurred at higher doses than those that induced other systemic
toxicity effects. In addition, although HMP, a shared downstream metabolite of MIBC and
MIBK, was shown to induce kidney toxicity following oral exposure in rats for 45 days, the
study authors identified hyaline droplets in males suggesting the potential involvement of an
alpha 2u-globulin-mediated pathway. Lastly, the complete lack of oral repeated-dose toxicity
information for the target compound, MIBC, limits toxicity comparisons to the surrogate
population.
Based primarily on metabolic considerations, MIBK is selected as the most appropriate
surrogate compound for MIBC for the oral route of exposure. Support for MIBK as the chosen
surrogate compound is provided by the fact that MIBK displays the highest structural similarity
to MIBC. Isopropanol and acetone are not selected as the surrogate compound for MIBC due to
the disparities in metabolism (CO2 is the only shared metabolite) and because neither chemical
could be identified as an oral toxicity-like surrogate compound for MIBC.
Inhalation Exposure
As discussed above, MIBK is the only suitable metabolic surrogate for MIBC primarily
based on a bidirectional metabolic relationship, and, that they share HMP as a common major
metabolite. MIBK and isopropanol are considered toxicity-like surrogate compounds for MIBC
based on a demonstrated common target of toxicity (kidneys) following inhalation exposure. In
total, MIBK is identified as the most appropriate structural, metabolic, and toxicity-like surrogate
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for MIBC and is therefore selected as the surrogate compound for deriving the screening
subchronic and chronic p-RfCs.
ORAL TOXICITY VALUES
Derivation of Screening Subchronic and Chronic Provisional Reference Doses
Based on the overall surrogate approach presented in this PPRTV assessment, MIBK was
selected as an appropriate surrogate for MIBC for both oral and inhalation exposure. However,
because no oral toxicity value exists for MIBK, derivation of a screening subchronic or chronic
provisional reference dose (p-RfD) for MIBC is precluded.
INHALATION TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Concentration
Based on the overall surrogate approach presented in this PPRTV assessment, MIBK was
selected as the surrogate for MIBC for deriving a screening subchronic provisional reference
concentration (p-RfC). While the U.S. EPA's IRIS program does not have a subchronic
inhalation reference concentration (RfC) value for MIBK, the chronic RfC value is based on a
developmental study in rats and mice [Tyl et al. (1987) as cited in U.S. EPA (2003cYl. While
only a chronic RfC is available for MIBK, this value is applicable to the derivation of both a
screening subchronic and chronic p-RfC because it is based on a gestational exposure study.
The IRIS summary expresses doses as time adjusted (6 hours of exposure/24 hours in a
day). The IRIS summary report for MIBK described this study as follows:
Developmental and maternal toxicity were evaluated in groups of 35
pregnant Fischer 344 and 30 pregnant CD-I mice exposed by inhalation to 0,
300, 1000, or 3000 ppm (0, 30 7, 1026, 30 73 mg/m3) MIBK for 6 hrs/day on
gestation days 6 through 15 (Bushy Run Research Center, 1984; Tyl etal., 1987).
Animals were sacrificed on gestation day 21 (rats) or 18 (mice). Dams were
evaluatedfor exposure-related changes in clinical signs, body weight, food
consumption, organ weights (kidney, liver, and gravid uterus), and reproductive
parameters; fetuses were evaluatedfor exposure-related changes in body weight
and viability andfor external, skeletal, and thoracic and peritoneal visceral
alterations.
Maternal mean body weight, weight gain, andfood consumption were
significantly decreased in rats exposed to 30 73 mg/m3 (but not to <=1026 mg/m3)
MIBK during the exposure period, but they had recovered to control levels by the
day of sacrifice; maternal body weight was not affected in mice. Maternal
clinical signs observed in rats or mice included coordination loss, hindlimb
weakness, paresis, irregular gait, hypoactivity, ataxia, unkempt fur, negative tail
or toe pinch, piloerection, lacrimation, or red perioral encrustation; these clinical
signs were observed only during the exposure period and only at 30 73 mg/m3.
Three maternal deaths (12% of the animals in the group) occurred in mice
exposed to 30 73 mg/m3 after the first exposure on gestation day 6; no further
deaths occurred in that group, and no exposure-related deaths occurred in the
other mouse or rat exposure groups.
No exposure-related effects were observed in rats or mice with respect to
numbers of corpora lutea, total implants, percent implantation loss, live fetuses
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per litter, non-viable implants per litter, percent live fetuses, and sex ratio. In
mice, there was an increased mean number of deadfetuses per litter at
30 73 mg/m3 (0.6per litter as compared to 0.1 in controls). Fetal body weights
(litter weight, male weight per litter, andfemale weight per litter) were
significantly reduced in rats exposed to 307 (the mean by 3%) and 30 73 mg/m3
(the mean by 6%) (not at 1026 mg/m3), and in mice at 30 73 mg/m3 (the mean by
13%) (not at <=1026 mg/m3). The authors indicated that the reducedfetal body
weight in rats at 307 mg/m3 was confounded by litter size and was apparently not
treatment-related.
No exposure-related change in the incidence of malformations of any type
were observed in rat and mouse fetuses. The number of litters with observations
indicating retarded skeletal ossification was significantly increased to various
degrees in both rats and mice at 30 73 mg/m3 relative to controls for a variety of
skeletal endpoints, with scattered increases in litters with retarded ossification at
lower exposure levels that were not considered by the authors to be
exposure-related. The numbers of individuals with various manifestations of
retarded skeletal ossification were also apparently increased in rats and mice at
30 73 mg/m3 relative to controls, but no results of statistical comparisons were
indicated in the study report.
The critical effects for the developmental study included reduced fetal body weight,
skeletal variations, and fetal death in mice and skeletal variations in rats at a time adjusted
lowest-observed-adverse-effect level (LOAEL) of 3,073 mg/m3; the no-observed-adverse-effect
level (NOAEL) of 1,026 mg/m3 was used as the POD. Because the current practice is to only
adopt existing PODs, benchmark dose (BMD) modeling is not performed when applying the
alternative surrogate approach (Wang et al.. 2012) in PPRTV assessments. The U.S. EPA
(2003c) calculated an HEC according to U.S. EPA (1994) guidance for Category 3 gases by a
continuous exposure basis [per U.S. EPA (2002)1. and multiplying the result by a ratio of the
animal blood-gas partition coefficient for MIBK to the human blood-gas partition coefficient for
MIBK. Because blood-air partition coefficients for MIBK are unknown, a default value of 1 was
assigned.
Surrogate POD (NOAEL [HEC]) = NOAELadj (mg/m3) x (Hb/g-A) - (Hb/g-H)
= 1,026 x 1 = 1,026 mg/m3
In deriving a screening subchronic p-RfC for MIBC, a composite uncertainty factor
(UFc) of 300 is applied, based on a 3-fold uncertainty factor value for interspecies extrapolation
(interspecies uncertainty factor [UFa], reflecting use of a dosimetric adjustment) and 10-fold
uncertainty factor values for both intraspecies variability (UFh) and database deficiencies
(database uncertainty factor [UFd], reflecting lack of any repeated-exposure toxicity information
for MIBC). Using the NOAEL (HEC), the screening subchronic p-RfC for MIBC is derived as
follows:
Screening Subchronic p-RfC = Surrogate NOAEL (HEC) - UFc
1,026 mg/m3-300
= 3 x 10° mg/m3
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Table A-4 summarizes the uncertainty factors for the screening subchronic p-RfC for
MIBC.
Table A-4. Uncertainty Factors for the Screening Subchronic p-RfC for
4-Methyl-2-pentanol (CASRN 108-11-2)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following MIBC exposure. The toxicokinetic
uncertainty has been accounted for by calculating an HEC.
UFd
10
A UFd of 10 is applied to account for the absence of reliable repeated-dose inhalation toxicity data
for MIBC.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of MIBC in humans.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the critical effects (i.e., reduced fetal body weight, skeletal
variations, and increased fetal death in mice, and skeletal variations in rats) are developmental
effects. The developmental period is recognized as a susceptible life stage when exposure during a
time window of development is more relevant to the induction of developmental effects than
life-time exposure CU.S. EPA. 1991).
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level; MIBC = methyl isobutyl
carbinol or 4-methyl-2-pentanol; NOAEL = no-observed-adverse-effect level; POD = point of departure;
p-RfC = provisional reference concentration; UFA = interspecies uncertainty factor; UFC = composite uncertainty
factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL
uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Concentration
Based on the overall surrogate approach presented in this PPRTV assessment, MIBK was
selected as the surrogate for MIBC for derivation of a screening chronic p-RfC. The IRIS RfC
for MIBK was based on the developmental study in rats and mice described in the "Derivation of
a Screening Subchronic Provisional Reference Concentration" section [Tyl et al. (1987) as cited
in U.S. EPA (2003cYl. The study description, POD, and UFc are described above.
Using the POD (HEC), the screening chronic p-RfC for MIBC is derived as follows:
Screening Chronic p-RfC = Surrogate NOAEL (HEC) ^ UFc
1,026 mg/m3- 300
= 3 x 10° mg/m3
Table A-5 summarizes the uncertainty factors for the screening chronic p-RfC for MIBC.
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Table A-5. Uncertainty Factors for the Screening Chronic p-RfC for
4-Methyl-2-pentanol (CASRN 108-11-2)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty in characterizing the toxicokinetic or
toxicodynamic differences between rats and humans following MIBC exposure. The toxicokinetic
uncertainty has been accounted for by calculating an HEC.
UFd
10
A UFd of 10 is applied to account for the absence of reliable repeated-dose inhalation toxicity data
for MIBC.
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of MIBC in humans.
UFl
1
A UFl of 1 is applied because the POD is a NOAEL.
UFS
1
A UFS of 1 is applied because the critical effects (i.e., reduced fetal body weight, skeletal
variations, and increased fetal death in mice, and skeletal variations in rats) are developmental
effects. The developmental period is recognized as a susceptible life stage when exposure during a
time window of development is more relevant to the induction of developmental effects than
life-time exposure (U.S. EPA. 1991s).
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
HEC = human equivalent concentration; LOAEL = lowest-observed-adverse-effect level; MIBC = methyl isobutyl
carbinol or 4-methyl-2-pentanol; NOAEL = no-observed-adverse-effect level; POD = point of departure;
p-RfC = provisional reference concentration; UFA = interspecies uncertainty factor; UFC = composite uncertainty
factor; UFD = database uncertainty factor; UFH = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL
uncertainty factor; UFS = subchronic-to-chronic uncertainty factor.
Consideration of Potential Carcinogenicity
As discussed above, MIBK was selected as the surrogate for 4-methyl-2-pentanol for
derivation of a screening subchronic and chronic p-RfC using an alternative surrogate approach
(Wang et al.. 2012). MIBK was previously identified by the International Agency for Research
on Cancer (IARC) as being "Possibly Carcinogenic to Humans" (Kegley et al.. 2016) and is
currently listed as a carcinogen on the Pesticide Action Network (IARC. 2013). Furthermore,
MIBK is currently identified on the Cal/EPA's Proposition 65 List as a chemical that causes
cancer (Cal/EPA, 2017a). This information suggests that based on similarity to MIBK,
4-methyl-2-pentanol might have carcinogenic potential as well but does not preclude the
development of noncancer, surrogate-derived, screening provisional values within this document.
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