*>EPA
United States
Environmental Protection
Agency
EPA/690/R-23/002F | February 2023 | FINAL
Provisional Peer-Reviewed Toxicity Values for
Isobutyl Alcohol
(CASRN 78-83-1)
U.S. EPA Office of Research and Development
Center for Public Health and Environmental Assessment
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A United $ta»s
Environmental Protection
%#UI r% Agency
EPA/690/R-23/002F
February 2023
https://www.epa.gov/pprtv
Provisional Peer-Reviewed Toxicity Values for
Isobutyl Alcohol
(CASRN 78-83-1)
Center for Public Health and 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
Jeffry L. Dean II, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Paul G. Reinhart, PhD, DABT
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
CONTRIBUTOR
Channa Keshava, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
Ingrid L. Druwe, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Deborah Segal, MHS
Center for Public Health and Environmental Assessment, Washington, DC
Shana White, PhD
Center for Public Health and Environmental Assessment, Cincinnati, OH
Michelle M. Angrish, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
John Stanek, PhD
Center for Public Health and Environmental Assessment, Research Triangle Park, NC
PRIMARY EXTERNAL REVIEWERS
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
PPRTV PROGRAM MANAGEMENT
Teresa L. Shannon
Center for Public Health and Environmental Assessment, Cincinnati, OH
J. Phillip Kaiser, PhD, DABT
Center for Public Health and Environmental Assessment, Cincinnati, OH
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Questions regarding the content of this PPRTV assessment should be directed to the U.S. EPA
Office of Research and Development (ORD) Center for Public Health and Environmental
Assessment (CPHEA) website at https://ecomments.epa.gov/pprtv.
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS v
BACKGROUND 1
QUALITY ASSURANCE 1
DISCLAIMERS 2
QUESTIONS REGARDING PPRTVs 2
1. INTRODUCTION 3
2. REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 7
2.1. HUMAN STUDIES 12
2.2. ANIMAL STUDIES 12
2.2.1. Oral Exposures (Cancer Studies Only) 12
2.2.2. Inhalation Exposures 12
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 22
2.3.1. Genotoxi city 22
2.3.2. Supporting Human Toxicity Studies 26
2.3.3. Supporting Animal Toxicity Studies 33
2.3.4. Metabolism/Toxicokinetic Studies 35
3. DERIVATION 01 PROVISIONAL VALUES 38
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES 38
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS 38
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES 38
3.4. CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR 39
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES 40
APPENDIX A. SCREENING PROVISIONAL VALUES 41
APPENDIX B. SYSTEMATIC LITERATURE SEARCH METHODS AND RESULTS 44
APPENDIX C. DATA EVALUATION METHODS AND RESULTS 50
APPENDIX D. REFERENCES 66
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
IVF
in vitro fertilization
ACGIH
American Conference of Governmental
LC50
median lethal concentration
Industrial Hygienists
LD50
median lethal dose
AIC
Akaike's information criterion
LOAEL
lowest-observed-adverse-effect level
ALD
approximate lethal dosage
MN
micronuclei
ALT
alanine aminotransferase
MNPCE
micronucleated polychromatic
AR
androgen receptor
erythrocyte
AST
aspartate aminotransferase
MOA
mode of action
atm
atmosphere
MTD
maximum tolerated dose
ATSDR
Agency for Toxic Substances and
NAG
7V-acetyl-P-D-glucosaminidase
Disease Registry
NCI
National Cancer Institute
BMC
benchmark concentration
NOAEL
no-observed-adverse-effect level
BMCL
benchmark concentration lower
NTP
National Toxicology Program
confidence limit
NZW
New Zealand White (rabbit breed)
BMD
benchmark dose
OCT
ornithine carbamoyl transferase
BMDL
benchmark dose lower confidence limit
ORD
Office of Research and Development
BMDS
Benchmark Dose Software
PBPK
physiologically based pharmacokinetic
BMR
benchmark response
PCNA
proliferating cell nuclear antigen
BUN
blood urea nitrogen
PND
postnatal day
BW
body weight
POD
point of departure
CA
chromosomal aberration
PODadj
duration-adjusted POD
CAS
Chemical Abstracts Service
QSAR
quantitative structure-activity
CASRN
Chemical Abstracts Service registry
relationship
number
RBC
red blood cell
CBI
covalent binding index
RDS
replicative DNA synthesis
CHO
Chinese hamster ovary (cell line cells)
RfC
inhalation reference concentration
CL
confidence limit
RfD
oral reference dose
CNS
central nervous system
RGDR
regional gas dose ratio
CPHEA
Center for Public Health and
RNA
ribonucleic acid
Environmental Assessment
SAR
structure-activity relationship
CPN
chronic progressive nephropathy
SCE
sister chromatid exchange
CYP450
cytochrome P450
SD
standard deviation
DAF
dosimetric adjustment factor
SDH
sorbitol dehydrogenase
DEN
diethylnitrosamine
SE
standard error
DMSO
dimethylsulfoxide
SGOT
serum glutamic oxaloacetic
DNA
deoxyribonucleic acid
transaminase, also known as AST
EPA
Environmental Protection Agency
SGPT
serum glutamic pyruvic transaminase,
ER
estrogen receptor
also known as ALT
FDA
Food and Drug Administration
SSD
systemic scleroderma
FEVi
forced expiratory volume of 1 second
TCA
trichloroacetic acid
GD
gestation day
TCE
trichloroethylene
GDH
glutamate dehydrogenase
TWA
time-weighted average
GGT
y-glutamyl transferase
UF
uncertainty factor
GSH
glutathione
UFa
interspecies uncertainty factor
GST
g 1 ut a t h i o nc - V-1 ra n s fc ra sc
UFC
composite uncertainty factor
Hb/g-A
animal blood-gas partition coefficient
UFd
database uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFh
intraspecies uncertainty factor
HEC
human equivalent concentration
UFl
LOAEL-to-NOAEL uncertainty factor
HED
human equivalent dose
UFS
subchronic-to-chronic uncertainty factor
i.p.
intraperitoneal
U.S.
United States of America
IRIS
Integrated Risk Information System
WBC
white blood cell
Abbreviations and acronyms not listed on this page are defined upon first use in the
PPRTV assessment.
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
ISOBUTYL ALCOHOL (CASRN 78-83-1)
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 U.S. Environmental Protection Agency (U.S. EPA)
guidance on human health toxicity value derivations.
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.
Currently available PPRTV assessments can be accessed on the U.S. EPA's PPRTV
website at https://www.epa.gov/pprtv. PPRTV assessments are eligible to be updated on a 5-year
cycle and revised as appropriate to incorporate new data or methodologies that might impact the
toxicity values or affect the characterization of the chemical's potential for causing adverse
human-health effects. Questions regarding nomination of chemicals for update can be sent to the
appropriate U.S. EPA eComments Chemical Safety website at
https://ecomments.epa.gov/chemicalsafetv/.
QUALITY ASSURANCE
This work was conducted under the U.S. EPA Quality Assurance (QA) program to ensure
data are of known and acceptable quality to support their intended use. Surveillance of the work
by the assessment managers and programmatic scientific leads ensured adherence to QA
processes and criteria, as well as quick and effective resolution of any problems. The QA
manager, assessment managers, and programmatic scientific leads have determined under the
QA program that this work meets all U.S. EPA quality requirements. This PPRTV assessment
was written with guidance from the CPHEA Program Quality Assurance Project Plan (PQAPP),
the QAPP titled Program Quality Assurance Project Plan (PQAPP) for the Provisional Peer-
Reviewed Toxicity Values (PPRTVs) and Related Assessments/Documents
(L-CPAD-0032718-QP), and the PPRTV development contractor QAPP titled Quality Assurance
Project Plan—Preparation of Provisional Toxicity Value (PTV) Documents
(L-CPAD-0031971-QP). As part of the QA system, a quality product review is done prior to
management clearance. A Technical Systems Audit may be performed at the discretion of the
QA staff.
All PPRTV assessments receive internal peer review by at least two CPHEA scientists
and an independent external peer review by at least three scientific experts. The reviews focus on
whether all studies have been correctly selected, interpreted, and adequately described for the
purposes of deriving a provisional reference value. The reviews also cover quantitative and
qualitative aspects of the provisional value development and address whether uncertainties
associated with the assessment have been adequately characterized.
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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
U.S. EPA ORD CPHEA website at https://ecomments.epa.gov/pprtv.
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1. INTRODUCTION
2-Methyl-l-propanol (isobutyl alcohol), CASRN 78-83-1, is one of four possible
butanols of 4-carbon alcohol isomers. The other three butanols are 1-butanol, 2-butanol, and
A.'/7-butyl alcohol (Biliig. 2001). Isobutyl alcohol is used as a solvent or as an intermediate in the
flavor, fragrance, pharmaceutical, and pesticide industries. Other reported uses of isobutyl
alcohol are as a process solvent (replacement for 1-butanol); a diluent and additive for
nitrocellulose and synthetic resins and lacquers; a solvent in paint strippers, cleaners, hydraulic
fluids, and wetting agents; and a component of printing inks and related products (Nl.M. 2019;
Hahn et al.. 2013; Biliig. 2001). Isobutyl alcohol is listed on the U.S. EPA's Toxic Substances
Control Act (TSCA) public inventory (U.S. HP A. 2021). and it is registered with Europe's
Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) program
(HCHA. 2019).
The primary isobutyl alcohol production method is through propene hydroformylation, in
which carbon monoxide and hydrogen are added to propene in the presence of catalysts.
Selection of the catalyst and manufacturing processes determines the ratio of isobutyl alcohol
produced compared to other isomers. Rhodium has been found to be a more favorable catalyst
when optimizing the reaction for isobutyraldehyde, the isobutyl alcohol precursor. Another
commercial production method of isobutyl alcohol is the Reppe process in which olefins, carbon
monoxide, and water react in the presence of a catalyst. Isobutyl alcohol occurs in natural
products and can be isolated from fusel oils (Hahn et al.. 2013).
The empirical formula for isobutyl alcohol is C4H10O and its structure is shown in
Figure 1. Table 1 summarizes the physicochemical properties of isobutyl alcohol. Isobutyl
alcohol is a clear, colorless liquid at environmental temperatures with a high vapor pressure and
high water solubility. Volatilization of isobutyl alcohol from water and moist surfaces is
expected based on a measured Henry's law constant of 9.78 x 10 6 atm-m3/mol. Hydrolysis of
isobutyl alcohol in aqueous conditions is not expected based upon the chemical structure, which
lacks functional groups that hydrolyze under environmental conditions. Adsorption of isobutyl
alcohol to suspended solids and sediment in water is not expected based on its estimated soil
adsorption coefficient (Koc) of 10.3 L/kg. Volatilization of isobutyl alcohol from dry surfaces is
also expected based on its measured vapor pressure. In the atmosphere, isobutyl alcohol will
exist solely as a vapor, where it will be degraded by reaction with photochemically produced
hydroxyl radicals corresponding to a half-life of 1.7 days. Direct photolysis is not expected
because isobutyl alcohol does not contain chromophores that absorb at wavelengths >290 nm
(wavelengths necessary for sunlight photolysis). Isobutyl alcohol is expected to have high
mobility in soil based on its soil adsorption coefficient (estimated Koc of 10.3 L/kg), which
indicates that it may leach to groundwater.
HO
h3c
Figure 1. Isobutyl Alcohol (CASRN 78-83-1) Structure
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Table 1. Physicochemical Properties of Isobutyl Alcohol (CASRN 78-83-1)
Property (unit)
Value
Physical state
Liquid3
Boiling point (°C)
108b
Melting point (°C)
-108b
Density (g/cm3)
0.822b (predicted average)
Vapor pressure (mm Hg)
10.4b
pH (unitless)
NV
Acid dissociation constant (pKa) (unitless)
NV
Solubility in water (mol/L)
1.12b
Octanol-water partition coefficient (log Kow)
0.760b
Henry's law constant (atm-m3/mole)
9.78 x 10-6b
Soil adsorption coefficient (Koc) (L/kg)
10.3° (predicted average)
Atmospheric OH rate constant (cm3/molecule-sec)
1.17 x 10-llb
Atmospheric half-life (d)
1.7 (calculated based on the measured OH rate constant)13
Relative vapor density (air =1)
2.56°
Molecular weight (g/mol)
74.123b
Flash point (closed cup in °C)
28.6b (predicted average)
aO'Neil (2013).
bData were extracted from the U.S. EPA CompTox Chemicals Dashboard (2-methyl-l-propanol; CASRN 78-83-1;
https://comptox.epa.gov/dashboard/dsstoxdb/results?search=DTXSID0021759: accessed December 15, 2021). All
listed values represent experimentally determined averages unless otherwise noted.
°NLM (2019).
NV = not available; U.S. EPA = U.S. Environmental Protection Agency.
A summary of available toxicity values for isobutyl alcohol from the U.S. EPA and other
agencies/organizations is provided in Table 2.
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Table 2. Summary of Available Toxicity Values for Isobutyl Alcohol
(CASRN 78-83-1)
Source
(parameter)3'b
Value
(applicability)
Notes
Reference0
Noncancer
IRIS (RfD)
0.3 mg/kg-d
Based on hypoactivity and
ataxia in rats exposed orally
for 13 wk
U.S. EPA (2002a)
HEAST (sRfD)
3 mg/kg-d
Based on hypoactivity and
ataxia in rats exposed orally
for 13 wk
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2018)
ATSDR
NV
NA
ATSDR (2019)
IPCS
NV
NA
IPCS (1987)
CalEPA
NV
NA
CalEPA (2020); CalEPA
(2019)
OSHA (PEL)
100 ppm (300 mg/m3)
8-h TWA for general
industry, construction, and
shipyard employment
OSHA (2020): OSHA (2018a):
OSHA (2018b)
NIOSH (REL)
50 ppm (150 mg/m3)
10-h TWA
NIOSH (2018)
NIOSH (IDLH)
1,600 ppm
Based on acute inhalation
toxicity data in rats
NIOSH (1994)
ACGIH (TLV)
50 ppm
8-h TWA based on skin and
eye irritation
ACGIH (2018): ACGIH
(2001)
USAPHC (air-MEG)
1-h critical: 5,000 mg/m3
1-h marginal: 5,000 mg/m3
1-h negligible: 3,500 mg/m3
8-h negligible: 150 mg/m3
14-d negligible: 52 mg/m3
1-yr negligible: 52 mg/m3
1-h values based on TEELs;
8-h, 14-d, and 1-yr values
based on ACGIH TLV for
eye and skin irritation
U.S. APHC (2013)
Cancer
IRIS
NV
NA
U.S. EPA (2002a)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2018)
NTP
NV
NA
NTP (2016)
IARC
NV
NA
IARC (2019)
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Table 2. Summary of Available Toxicity Values for Isobutyl Alcohol
(CASRN 78-83-1)
Source
(parameter)3'b
Value
(applicability)
Notes
Reference0
CalFPA
NV
NA
CalEPA (2020): CalEPA
(2019)
ACGIH
NV
NA
ACGIH (2018)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; CalEPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
I ARC = 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;
USAPHC = U.S. Army Public Health Command.
Parameters: IDLH = immediately dangerous to life or health concentrations; MEG = military exposure guideline;
PEL = permissible exposure level; REL = recommended exposure level; RfD = reference dose; sRfD = subchronic
reference dose; TEEL = temporary emergency exposure limit; TLV = threshold limit value; TWA = time-weighted
average.
°Reference date is the publication date for the database and not the date the online source was accessed.
NA = not applicable; NV = not available.
Systematic review methods were used to identify studies relevant to the derivation of
inhalation provisional toxicity values and oral and inhalation cancer weight of evidence (WOE)
for isobutyl alcohol, CASRN 78-83-1. Details and results of systematic literature review can be
found in Appendix B.
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2. REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide overviews of the relevant inhalation noncancer and inhalation
and oral cancer evidence bases, respectively, for isobutyl alcohol, and include all potentially
relevant repeated-dose subchronic, and chronic studies, as well as reproductive and
developmental toxicity studies, evaluated as medium or high confidence during systematic
review (see Appendix C for more details). Oral noncancer data were not reviewed or included in
this document because there is an existing Integrated Risk Information System (IRIS) oral
reference dose (RfD). Principal studies used in the PPRTV assessment for derivation of
provisional toxicity values are identified in bold. The phrase "statistical significance" and term
"significant," used throughout the document, indicate ap-value of < 0.05 unless otherwise
specified.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Isobutyl Alcohol (CASRN 78-83-1)
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Study
Reference
Category3
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
(comments)
Notes0
Human
1. Oral (mg/kg-d)
NV
2. Inhalation (mg/m3)
NV
Animal
1. Oral (mg/kg-d)
NV
2. Inhalation (mg/m3)
Subchronic
10-20 M/20 F, Sprague Dawley rat,
0, 140, 565.2, 1,379
No toxicologically
1,379
NDr
Lietal. (1999):
PR;
whole-body vapor inhalation, 6 h/d, 4-5 d/wk,
relevant effects
Li and Kaemofe
NPR,
3 mo (14 wk)
(1996)
GLP
Reported analytical concentrations: 0, 258,
1,044, 2,548 ppm
Subchronic
10 M, Sprague Dawley rat, whole-body vapor
0, 140, 565.7, 1,379
No toxicologically
1,379
NDr
Lietal. (1999):
PR;
inhalation, 6 h/d, 5 d/wk, 3 mo (13 wk))
relevant effects
Branch et al.
NPR,
(1996)
GLP
Reported analytical concentrations: 0, 258,
1,045, 2,547 ppm
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Table 3A. Summary of Potentially Relevant Noncancer Data for Isobutyl Alcohol (CASRN 78-83-1)
Category3
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
Reproductive/
Developmental
30 M/30 F, Crl:CD (SD) IGS BR rat,
whole-body vapor inhalation, 6 h/d, 7 d/wk,
70 d prior to mating through weaning (Fo)
with the exception of GD 20 to LD 5;
exposure in utero to LD 28, direct exposure
from weaning through mating to LD 21
(Fi); exposure in utero to LD 21 (F2)
Reported analytical concentrations: 0,500,
1,008,2,522 ppm (Fo adults/Fi pups); 0,494,
1,012,2,521 ppm (Fi adults/F2 pups)
0, 369.0, 743.8,
1,861 (F0/F1 pups)
0, 364.5, 746.8,1,861
(Fi adults/F2 pups)
Biologically
significant
decreases (>5%)
in Fi and F2 male
and female pup
body weights at
multiple
postnatal time
points
NDr
369.0
(Fi pups)
364.5
(F2 pups)
Nemec (2003)
NPR,
PS,
GLP
Developmental
25 F SPF-Wistar rat, whole-body vapor
inhalation, 6 h/d, GDs 6-15
Reported analytical concentrations: 0, 0.49,
2.50, 10.10 mg/L
0, 123, 625.0, 2,525
No toxicologically
relevant effects
2,525
NDr
Klimisch and
Hellwig (1995)
PR,
GLP
Developmental
15 F Himalayan rabbits, whole-body vapor
inhalation, 6 h/d, GDs 7-19
Reported analytical concentrations: 0, 0.5,
2.51, 10.00 mg/L
0, 125, 627.5, 2,500
No toxicologically
relevant effects
2,500
NDr
Klimisch and
Hellwig (1995)
PR,
GLP
aDuration categories are defined as follows: Acute = exposure for <24 hours; short term = repeated exposure for 24 hours to <30 days; long term (subchronic) = repeated
exposure for >30 days <10% life span for humans (>30 days up to approximately 90 days in typically used laboratory animal species); and chronic = repeated exposure
for >10% life span for humans (>~90 days to 2 years in typically used laboratory animal species) (U.S. EPA. 2002b).
bDosimetry: Doses are presented as HECs (in mg/m3) for inhalation noncancer effects. The HEC was calculated by treating isobutyl alcohol as a Category 3 gas and
using the following equation from the U.S. EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animal:human), using a default coefficient of 1 because the rat blood-air partition coefficient of 880 is
greater than the range of 541-578 reported for human blood-air partition coefficients and a blood-air partition coefficient for isobutyl alcohol in rabbits has not been
determined.
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study; GLP = reported as adhering to Good Laboratory Practices standards.
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Table 3A. Summary of Potentially Relevant Noncancer Data for Isobutyl Alcohol (CASRN 78-83-1)
Category3
Number of Male/Female, Strain, Species,
Study Type, Reported Doses, Study
Duration
Dosimetryb
Critical Effects
NOAELb
LOAELb
Reference
(comments)
Notes0
ER = extrarespiratory; F = female(s); GD = gestation day; HEC = human equivalent concentration; LD = lactation day; LOAEL = lowest-observed-adverse-effect level;
M = male(s); NDr = not determined; NOAEL = no-observed-adverse-effect level; NV = not evaluated.
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Table 3B. Summary of Potentially Relevant Cancer Data for Isobutyl Alcohol (CASRN 78-83-1)
Category
Number of Male/Female, Strain,
Species, Study Type, Reported
Doses, Study Duration
Dosimetry
Critical Effects
Reference
(comments)
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
ND = no data.
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2.1. HUMAN STUDIES
The three human studies identified in the literature search were considered low
confidence or uninformative during study evaluation (see Figure C-2). The results from these
studies are briefly summarized in Section 2.3.2 but they were not considered adequate for
derivation of a provisional toxicity value.
2.2. ANIMAL STUDIES
2.2.1. Oral Exposures (Cancer Studies Only)
One animal oral cancer study was identified from the literature search (Dow Chemical.
1992); however, it was considered uninformative (see Figure C-2). The results from this study
are briefly summarized in Section 2.3.3 but the study was not considered adequate for derivation
of a provisional toxicity value.
2.2.2. Inhalation Exposures
Five inhalation publications, including two subchronic inhalation studies in rats (Li et al..
1999). one rat and one rabbit developmental study (Klimisch and Hell wig. 1995). and one
two-generation study in rats (Nemcc. 2003). were identified from the literature search and
considered either medium or high confidence.
Subchronic Studies
Li et al. (1999); Li andKaetnnfe (1996): Experiment 1
The subchronic general toxicity and neurotoxicity effects of isobutyl alcohol were
evaluated in adult male and female rats in a peer-reviewed, published study by Li et al. (1999).
Additional methodological details and data were available in an unpublished report by Li and
Kaempfe (1996).
Commercially obtained Sprague Dawley rats (10-20/sex/group), 8 weeks of age at the
start of exposure, were exposed whole body to isobutyl alcohol (99.9% purity) vapors at nominal
concentrations of 0, 250, 1,000, or 2,500 ppm for 6 hours/day for 14 weeks (at least
70 exposures). Exposure occurred 4 days/week during Weeks 4, 8, and 13 (when
neurobehavioral tests were conducted) and 5 days/week for remaining weeks. Measured
analytical concentrations were 0, 258, 1,044, and 2,548 ppm (0, 782, 3,165, and 7,725 mg/m3,
respectively, as calculated by the U.S. EPA using a molecular weight of 74.123 g/mol). Twenty
rats/sex/group were included in the control and high-exposure groups; 10/sex/group were
included in the low- and mid-exposure groups. Experimental groups included Group 1, a
neuropathology group consisting of 5 randomly selected rats/sex/group; Group 2, a general
toxicity group consisting of 5/sex/group; and Group 3, consisting of the remaining 10 animals in
the control and high-exposure groups.
The animals were observed twice daily for mortality and clinical signs of toxicity,
including subjective assessments of reaction to brushing and tapping of the exterior walls of the
chamber during the last hour of exposure. During weekly body-weight measurements, more
detailed observations for signs of toxicity were recorded, including palpation for masses. Food
consumption was recorded weekly. Ophthalmoscopic examinations were performed prior to
study initiation and during Week 14 of exposure in the control and high-exposure animals only.
Behavioral tests (functional observational battery [FOB] and motor activity) were conducted
prior to initiation of exposure and during Weeks 4, 8, and 13 on all but five animals/sex in the
control and high-exposure groups. The animals were not exposed to isobutyl alcohol on the days
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of behavioral testing. At the end of exposure, Group 1 was sacrificed for the collection of a
complete set of neurological tissues, including the brain (olfactory bulbs, forebrain, cerebrum,
cerebellum, midbrain, pons, and medulla oblongata), spinal cord (cervical, thoracic, and lumbar
segments), dorsal and ventral spinal nerve roots with dorsal root ganglia (C3-C6, L1-L4),
Gasserian ganglion, sciatic, tibial, and sural nerves. However, only tissues from the control and
high-exposure groups were examined microscopically. The one female sacrificed moribund from
the high-exposure group was also examined for neuropathological lesions. Testes and
epididymides of males from Group 1 were also removed, weighed, and fixed for
histopathological examination.
In Group 2, blood was drawn at terminal necropsy for hematology (total erythrocyte
count [red blood cells (RBCs)], total leukocyte count [white blood cells (WBCs)], hematocrit
[Hct], hemoglobin [Hb], platelets, mean corpuscular volume [MCV], mean corpuscular
hemoglobin [MCH], mean corpuscular hemoglobin concentration [MCHC], activated partial
thromboplastin time [APTT], and leukocyte differential), and serum clinical chemistry (blood
urea nitrogen [BUN], creatinine, glucose, total protein, albumin, globulin, glutamic pyruvic
transaminase [SGPT]/alanine aminotransferase [ALT], alkaline phosphatase, gamma glutamyl
transpeptidase, glutamic oxaloacetic transaminase [SGOT]/aspartate aminotransferase [AST],
creatine phosphokinase, total and direct bilirubin, cholesterol, sodium, potassium, calcium,
chloride, and phosphorus). Group 2 animals were grossly examined, and organs (brain, lungs,
liver, kidneys, adrenals, testes, and epididymides) were weighed. Select tissues (adrenals, brain,
epididymides, eyes, gross lesions, heart, kidneys, liver, lungs, nose sections, ovaries, skin,
spleen, testes, uterus, and vagina) were fixed for histological analysis.
While Group 3 was intended as a recovery group for neurobehavior, these animals were
sacrificed instead at the end of the exposure along with Groups 1 and 2 because no persistent
neurobehavioral effects were observed during the study. Males from Group 3 underwent gross
necropsy, and testes and epididymides were weighed and fixed for histopathological
examination. Females from Group 3 underwent gross necropsy only. Statistical analysis of FOB,
motor activity, and rearing data consisted of Levene's test for homogeneity, Dunnett's multiple
comparison test, and analyses of variance (ANOVAs) using baseline values as covariates
(analyses of covariance [ANCOVAs]) for parameters with repeated measures. For other
endpoints, Bartlett's test was used for homogeneity of variances, followed by either Dunnett's
test and linear regression, or nonparametric Kruskal-Wallis, Jonckheere's, and/or
Mann-Whitney U test for trend. Incidence data were analyzed using Fisher's exact test
(one-tailed). The Grubb's test was used to detect outliers in organ-weight data.
Quantitative data extraction for Experiment 1 can be found in the Health Assessment
Workspace Collaborative (HAWC) database; links to specific data sets are included below for
ease of review. One moribund female from the high-exposure group was sacrificed at
approximately 2 months due to development of lymphoblastic leukemia of the vertebral column
and surrounding tissues; all other males and females survived. A decrease in response to
chamber brushing was subjectively observed in all examined males and females exposed to
isobutyl alcohol when tested during the last hour of daily exposure (every exposure day
throughout the study); control animals responded normally to chamber brushing. Some rats from
the high-exposure group also showed a decrease in response to chamber tapping during the last
hour of daily exposure (first 3 days of exposure only), with three males and four females affected
during Day 1 of exposure and 0-2 rats/sex affected during Exposure Days 2 and 3. All
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high-exposure animals responded normally to cage tapping after the first 3 exposure days, and all
control animals and animals in the lower exposure groups responded normally throughout the
study. No abnormal clinical signs were observed immediately after cessation of daily exposures
or during weekly detailed clinical assessments. No ophthalmological changes were reported in
the control or high-exposure animals. Body weight and body-weight gain were comparable
across study groups. Statistically significant increases in food consumption in males in the
mid-exposure group were sporadic, and no exposure-response relationship was observed. No
changes in food consumption were observed in females.
There were no statistically significant differences between treated and control groups in
the FOB or motor activity testing at any time point throughout the study. No biologically
relevant changes in hematology or clinical chemistry were observed. The few sporadic findings
that reached statistical significance, including a 9-10% increase in RBC. Hct and Hb in
high-dose females and a <5% increase in serum calcium in mid-dose males, were not considered
biologically relevant given the direction of change (increased) and a lack of exposure-response,
respectively. A statistically significant trend for increased absolute kidnev weight was observed
in exposed males (increases of 4, 17, and 16% in low-, mid-, and high-exposure males,
respectively); however, pairwise statistics did not identify any statistically significant effects
between individual exposure groups and controls. No statistically significant trend or pairwise
effects were observed in relative kidney weights in males (kidnev:body weight [6, 9, 8%] or
kidnev:brain [4, 15, 15%]). Statistically significant positive trends were observed in absolute
liver weight (-5, 9, 17%), liver:body weight (-3, 1, 9%), and liver:brain weight (-4, 9, 18%) in
low-, mid-, and high-exposure males, respectively, but again, pairwise comparisons did not
identify any statistically significant changes between groups. While select kidney and liver
weights in males were elevated by >10%, these findings were not considered indicative of a
biologically relevant effect because (1) there were no exposure-related changes in liver or kidney
serum biochemistry indicative of a functional impairment, (2) there were no associated
histochemical lesions in the liver or kidney, and (3) organ-weight changes were not observed in
females. No exposure-related gross or microscopic lesions were identified in any of the evaluated
organs. All observed gross and microscopic lesions, including those in perfusion-fixed neuronal
tissues, were sporadic, occurred in small numbers, and/or did not exhibit concentration
dependence.
The highest exposure concentration (7,725 mg/m3) is a no-observed-adverse-effect level
(NOAEL) associated with repeated exposure. No biologically relevant effects were noted in
body weight, hematology, clinical chemistry, or histopathology. Biologically significant
increases in liver and kidney weights in male animals were noted but not identified as
lowest-observed-adverse-effect levels (LOAELs) because corroborating evidence was lacking.
The transient central nervous system (CNS) depression observed only during daily exposure
periods was considered an acute response to isobutyl alcohol by the study authors, and not an
indicator of an emerging subchronic neurological effect. The absence of persistent subchronic
neurological effects is supported by the lack of exposure-related findings in the FOB and motor
activity analyses and no evidence of damage to neurological tissues. Analytical concentrations of
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0, 782, 3,165, and 7,725 mg/m3 correspond to extrarespiratory effects human equivalent
concentration (HECer) values of 0, 140, 565.2, and 1,379 mg/m3.1
Lietal. (1999); Branch etal. (1996): Experiment 2
Li et al. (1999) studied the sub chronic neurotoxic effects ofisobutyl alcohol in adult male
Sprague Dawley (CD) rats using schedule-controlled operant behavior (SCOB) training.
Additional methodological details and data are available in an unpublished report by Branch et
al. (1996).
Commercially sourced Sprague Dawley rats were obtained at 5 weeks of age. After a
1-week acclimation period, 40 male rats were placed on a restricted diet (11-14 g/day,
7 days/week); water was available ad libitum. Male rats were trained to perform on the SCOB
test in automated operant chambers. Briefly, SCOB training included 47-minute sessions in
which the animals were trained to press a lever for food reinforcement using both fixed ratio
(FR; rewarded only after a certain number of lever presses), and fixed interval (FI; rewarded for
lever press only after a specified amount of time has elapsed). Rats were fully trained prior to
exposure to isobutyl alcohol, starting with small ratios/intervals and progressing to a final
schedule of four consecutive FR periods of 20 lever presses followed by two consecutive FI
periods of 120 seconds. Most rats reached training criteria within 30 days; however, an
additional 6 weeks of training was required for performance to be stable. The baseline
performance for each animal was established 1 week prior to exposure (during Week 10 of
training).
At 16 weeks of age, groups of trained male rats (10/group) were exposed to isobutyl
alcohol (99.9% purity) vapors at nominal concentrations of 0, 250, 1,000, or 2,500 ppm for
6 hours/day, 5 days/week for 13 weeks (65 exposures), with sacrifice 1 week after the final
exposure. Reported analytical concentrations were 0, 258, 1,045, and 2,547 ppm (782, 3,168, and
7,722 mg/m3, respectively, as calculated by the U.S. EPA using a molecular weight of
74.123 g/mol). Starting 1 week before the first exposure and continuing throughout the study, the
animals were tested 5 days/week (before the daily exposure session) for SCOB performance
(e.g., whether rats pushed the lever the appropriate number of times during the FR period and
waited the appropriate amount of time between lever presses during FI periods). Overall motor
activity and habituation were also recorded during SCOB testing. The animals were observed
twice daily for mortality and clinical signs of toxicity, including subjective assessments of
reactions to brushing and tapping of the exterior walls of the chamber during the last hour of
exposure. Ophthalmoscopic examinations were conducted on all rats prior to study initiation and
3 days after the last exposure. Body weights were recorded weekly and prior to SCOB testing.
During weekly body-weight measurements, more detailed observations for signs of toxicity were
recorded, including palpation for masses. Gross necropsy was performed only in the event of a
finding during detailed clinical observations. Only the SCOB data collected during the pretest
week and during Weeks 4, 8, and 13 of exposure were statistically analyzed, including measures
of SCOB performance, total motor activity, and motor activity habituation. Repeated measures
1HEC calculated by treating isobutyl alcohol as a Category 3 gas (based on the lack of respiratory effects and the
ability of similar alcohols to produce systemic effects when inhaled) using the following equation from the U.S.
EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animakhuman), using a default coefficient of 1 because
the rat blood-air partition coefficient of 880 is greater than the range of 541-578 reported for human blood-air
partition coefficients according to Kaneko et al. (1994) and Fiserova-Bergerova and Diaz (1986).
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analysis of covariance (REPANCOVA) using baseline values as covariates was used to analyze
weekly mean values across time and exposure concentration. Levine's test (p < 0.01) was used to
analyze homogeneity of variance, and Dunnett's multiple comparison test was used to compare
groups. Positive control data for SCOB tests were collected from 40 male rats prior to the study
using d-amphetamine sulfate and chlorpromazine hydrochloride. The same dependent variables
were measured in the experimental and positive control studies.
Quantitative data extraction for Experiment 2 can be found in the HAWC database; links
to specific data sets are included below for ease of review. No mortalities were observed. A
decrease in response to chamber brushing was subjectively observed in all examined rats
exposed to isobutyl alcohol when tested during the last hour of daily exposure (every exposure
day throughout the study); control animals responded normally to chamber brushing. Control and
exposed animals both responded normally to chamber tapping during the last hour of daily
exposure throughout the study. No other exposure-related clinical signs were observed
immediately before, during, or after daily exposure. No palpable masses were identified during
detailed clinical observations, and no ophthalmological abnormalities were found. There were no
consistent, exposure-related changes in body weight or body-weight gain in exposed animals,
compared with controls. Results from SCOB testing indicated no statistically significant
differences in SCOB performance between controls and treatment groups during any of the
testing weeks. Positive control animals performed as expected in SCOB testing. The only notable
observation at necropsy was swollen testes in one mid-exposure male; this finding was
considered incidental.
The U.S. EPA has identified the highest exposure concentration (7,722 mg/m3) as a
NOAEL based on a lack of toxicologically relevant effects associated with repeated exposure. As
discussed for Experiment 1, the slight, transient CNS depression observed during daily exposure
was considered by the study authors to be an acute response to isobutyl alcohol, and not an
anticipated indicator of an emerging subchronic neurological effect; however, it is unclear if
these transient effects would manifest under longer-duration exposures due to lack of
experimental data. The absence of subchronic neurological effects is supported by the lack of
exposure-related findings in the SCOB testing. The analytical concentrations of 782, 3,168, and
7,722 mg/m3 correspond to HECer values of 0, 140, 565.7, and 1,379 mg/m32
Chronic Studies
No chronic inhalation studies of isobutyl alcohol have been identified.
Reproductive/Development Studies
Nemec (2003)
In an unpublished two-generation study, groups of Crl:CD (SD) IGS BR rats
(30/sex/group) were exposed to clean filtered air or to isobutyl alcohol vapor concentrations of
500, 1,000, or 2,500 ppm (nominal) for 6 hours/day, 7 days/week via whole-body exposure
(Nemec, 2003). Reported analytical mean concentrations were 500, 1,008, and 2,522 ppm
2HEC calculated by treating isobutyl alcohol as a Category 3 gas (based on the lack of respiratory effects and the
ability of similar alcohols to produce systemic effects when inhaled) and using the following equation from the U.S.
EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animakhuman), using a default coefficient of 1 because
the rat blood-air partition coefficient of 880 is greater than the range of 541-578 reported for human blood-air
partition coefficients according to Kaneko et at (1994) and Fiserova-Bergerova and Diaz (1986).
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(1,476, 2,975, and 7,444 mg/m3, respectively, as determined by the study authors) for the
parental (Fo) generation and Fi pups, and 494, 1,012, and 2,521 ppm (1,458, 2,987, and
7,442 mg/m3, respectively, as determined by the study authors) for Fi adults and F2 pups.
Exposure for Fo rats began -70 days prior to mating, and continued in both sexes throughout
mating, gestation, and lactation periods until postnatal day (PND) 28. During this time, exposure
was stopped in Fo females between gestation day (GD) 20 and lactation day (LD) 5 to allow for
parturition. On PND 4, Fi litters were culled to eight rats (preferably to four per sex). Prior to
weaning, 30 Fi pups/sex/group were randomly selected to generate the F2 generation. Additional
weanlings were kept as potential replacement animals. Mated Fo males and females were
necropsied after Fi weaning. The remaining Fo animals were sacrificed on Study Day 133. The
Fi offspring not selected for mating were sacrificed at weaning (PND 28). Fi animals selected for
mating began direct exposure at weaning and were exposed in the same manner as Fo animals
from at least 70 days prior to mating until sacrifice. Second-generation (F2) offspring were
exposed in utero, and during lactation until sacrifice. Mated Fi adults and F2 pups were sacrificed
on PND 21.
All animals were observed twice daily and within 1 hour of exposure for mortality and
clinical signs of toxicity. Subjective assessments of state of arousal and response to a loud-noise
stimulus were included in the evaluations and were difficult to interpret due to reporting
outcomes as results combined from different stimuli. Female estrous cycles were monitored
beginning 21 days prior to pairing until evidence of mating was observed. Fo and Fi male and
female body weights were recorded on Study Days 0, 1,4, and 7, and weekly (males) thereafter.
After mating, female body weights and food consumption were recorded on GDs 0, 4, 7, 11, 14,
and 20 and LDs 1, 4, 7, 14, 21, and 28 (Fo females only). Gross necropsies were performed on all
adult animals. Organ (adrenals, brain, epididymides, kidneys, liver, ovaries, pituitary, prostate,
seminal vesicles with coagulating glands, spleen, testes, thymus gland, and uterus with oviducts
and cervix) weights were recorded. Microscopic examinations were done on all gross lesions and
select tissues (adrenal glands, cortex and medulla, brain, cervix, epididymis, caput, corpus and
cauda, kidneys, liver, ovaries, pituitary, prostate, seminal vesicles, spleen, testis, thymus, uterus,
and vagina) from 10 adults/sex/group from the control and high-exposure groups. Reproductive
performance parameters included mating and fertility indices for Fo and Fi generations.
Spermatogenic endpoints, including mean testicular and epididymal sperm counts, sperm
production rate, motility, progressive motility, and percentage of morphologically normal sperm,
were evaluated in Fo and Fi males. Litter endpoints examined included litter size, postnatal
survival, and pup body weights on PNDs 1, 4, 7, and 21 for Fi and F2 pups and PNDs 28, 32, and
35 for Fi pups. Complete necropsies were performed on Fi and F2 pups that were sacrificed on
PNDs 28 and 21, respectively. Select organ weights (brain, spleen, thymus gland) were recorded
in pups at each sacrifice. Gross lesions were retained for histopathologic examination.
Mating and fertility data were analyzed using the /2 test with Yates' correction factor. For
other endpoints, one-way ANOVA was used to determine intergroup differences followed by the
Dunnett's test if significant. The litter was used as the experimental unit where appropriate.
Nonparametric data were subjected to the Kruskal-Wallis nonparametric ANOVA test followed
by the Mann-Whitney U test, if significant. Using litter size as a covariant, parametric one-way
ANCOVA was used to determine intergroup differences in mean offspring weights, followed by
the Student's Mest, if significant. The two-tailed Fisher's exact test was used on histological
findings to compare test groups to the control.
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Quantitative data extraction for the two-generation study can be found in the HAWC
database; links to specific data sets are included below for ease of review. One Fo female in the
low-exposure group was sacrificed in extremis after 91 days of exposure. No other Fo generation
mortalities were observed, and there were no significant clinical signs of toxicity in any exposure
group. Responses to stimuli (ear flick) were comparable between exposed and control animals.
Overall, there were no exposure-related changes in body weights or body-weight gains for
Fo males or females, and terminal body weights were comparable across all groups. Sporadic, but
statistically significant, body-weight changes that did not exhibit a dose-response relationship
included a 55% reduction in body-weight gain in middle exposure concentration Fo males during
Study Days 84-91, a 7% increase in body weight in low-exposure Fo females on LD 28, and an
18-fold increase in body-weight gain in low-exposure Fo females during LDs 1 —28. These
changes in low-exposure females coincided with an increase in food efficiency in this group
during lactation. Mean body weights and body-weight gains were comparable between all other
exposure groups and controls throughout the study. Statistically significant reductions in food
consumption were observed sporadically during the study in the high-exposure group,
particularly in males, but the reductions were small (generally <5% decrease from controls) and
did not coincide with statistically significant changes in body weight. There were no dose-
response associations observed in Fo adult organ weights; however, sporadic statistically
significant changes were observed. These sporadic changes in males included a 20% increase in
absolute prostate weight in the mid-exposure group and 14-23% increases in relative prostate
weight in the low- and mid-exposure groups, compared with controls. The study authors reported
that because similar effects were not observed in high-exposure group animals, these changes
were not attributable to the test article. In low-exposure females, the sporadic changes were
limited to a 16% decrease in absolute pituitary weight. No statistically significant organ-weight
changes were observed in the high-exposure groups for either sex. The single female euthanized
in extremis had renal and liver necrosis; no exposure-related microscopic changes were observed
in remaining Fo animals that survived until scheduled sacrifice.
The mating and fertility indices in Fo animals were not affected by exposure to isobutyl
alcohol. The fertility index of 97% in low-exposure Fo females was statistically significantly
higher than the fertility index of 73% in controls, but this was not considered biologically
relevant. There were no differences in estrous cyclicity, time to coitus, or gestation length
between exposed animals and controls. Overall, there were no statistically significant effects of
exposure on any sperm parameters, including motility, sperm count, sperm production rates, or
morphology in Fo males. Examination of sperm identified one Fo male in the high-exposure
group with a low percentage of morphologically normal sperm (0.5% vs. a mean of 97.9% in
controls). The study authors concluded that the percentages of morphologically normal sperm
from other males in this exposure group were within the normal biological range for this species
and strain.
No exposure-related effects were observed in Fi litter endpoints. Litter size, sex ratios,
and mean number of pups were comparable across exposure groups. Fi pups in the low-exposure
group showed a 10% decrease in survival between PND 4 and 28. but survival in this group was
comparable to controls on PNDs 0-4. In the higher-exposure groups, survival was comparable to
control on PNDs 0-4 and PNDs 4 28. Reductions in Fi pup body weights and body-weight
gains were observed at various times during the postnatal period in all exposure groups. For the
purposes of this PPRTV assessment, a >5% decrease in pup body weight is considered
biologically significant by the U.S. EPA. In the low-exposure group, statistically and/or
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biologically (i.e., >5%) significant decreases in pup weight (7-18%) were observed in Fi males
on PNDs 4-35 and Fi females on PNDs 1 —35. In the mid-exposure group, statistically and/or
biologically significant decreases in pup weight (7-13%) were observed in Fi males and
Fi females on PNDs 7-35. Biologically relevant reductions in pup weight (5-8%) were also
observed in the high-exposure group in Fi males and Fi females on PNDs 7-28. For
body-weight gain, statistically significant decreases were observed in low-exposure Fi males
(14-34%) on PNDs 4 7. 14 21. and PNDs 1 28 and females (10-40%) on PNDs 4 7. 14 21.
21 28. and 28 35. In the mid-exposure group, statistically significant decreases in body-weight
gains (11 -26%) were observed in Fi males on PNDs 4 7. 14 21. 28 32. and 28 35 and females
on PKDs 4 7. 14 21. 28 35. and 32 35. In the high-exposure group, body-weight gains were
significantly decreased by 12% in Fi males on PNDs 14 21. There were no notable necropsy
findings or exposure-related organ-weight changes in Fi pups on PND 28. Sporadic
organ-weight changes included a statistically significant 19% reduction in absolute thymus
weight in low-exposure males and a 6% decrease in absolute brain weight in low-exposure
females, with no significant effects at higher exposure levels. The mean days to balanopreputial
separation in males and vaginal patency in females were not affected by exposure. Vaginal
patency was slightly, but statistically significantly, delayed by 6% relative to controls in
low-exposure females only; this was likely secondary to the observed decreases in body weight
in this exposure group.
There were no significant exposure-related clinical findings, including response to
stimuli, in either Fi males or females. Like the Fo animals, sporadic and transient changes in
body weights and food consumption occurred in Fi adults, but without indication of
concentration dependence. Reductions in body weights and/or body-weight gains that were
evident in low- and mid-exposure groups during lactation persisted into adulthood, with small
reductions (<10%) occurring primarily in low- and mid-exposure males and only sporadically in
females. At terminal sacrifice, statistically significant 7—8% decreases in Fi adult male body
weight were observed in low- and mid-exposure groups, and a statistically significant 8%
decrease in cumulative body-weight gain was observed in the low-exposure group only. No
statistically significant changes were observed for Fi adult female terminal body weight or
cumulative body-weight gain. Slight (<10%), but statistically significant, reductions in relative
food consumption occurred in high-exposure Fi females during GDs Q-4. 1 1 14. and Q-20.
Sporadic statistically significant changes in organ weights in Fi adults were not considered
related to treatment due to lack of a clear exposure-related response (increased relative brain
weight and relative thymus weight and decreased absolute liver weight in low-exposure males;
reduced absolute pituitary weights in low- and mid-exposure females). At sacrifice, there were
no gross or microscopic findings attributed to exposure. The mating and fertility indices in
exposed adult Fi animals were comparable with controls. No exposure-related changes were
observed in any other reproductive performance measures or in male sperm parameters.
Clinical observations and survival of F2 pups were comparable between exposed and
control animals. Reductions in F2 pup body weight and body-weight gains were observed at
various times during the postnatal period in all exposure groups. In the low- and mid-exposure
groups, statistically and/or biologically (i.e., >5%) significant decreases in body weight (7—17%)
were observed in F2 males and F2 females on PNDs 1-21. In the high-exposure group,
statistically and/or biologically significant decreases in body weight (5—14%) were observed in
F2 males and F2 females on PNDs 14 and 21 only. For body-weight gain, statistically significant
decreases were observed in low-exposure F: males (23-31%) on PNDs 1 4. 4 7. and 14 21 and
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females (21-25%) on PMDs 1 4. 4 7. and 14-21. In the mid-exposure group, statistically
significant decreases in body-weight gain of 25-27% were observed on PNDs 14-21 in males
and females. In the high-exposure group, a statistically significant 21 % decrease in body-weight
gain was observed in F: female pups on PNDs 14 21.
No notable necropsy findings in F2 pups were reported. Sporadic, but statistically
significant, changes in organ weights in F2 pups on PND 21 were not considered related to
treatment due to lack of a clear exposure-response relationship. Sporadic changes in F2 male
pups included a 15—16% increase in relative brain weight, but not absolute brain weight, in the
low- and mid-exposure groups and a 24% decrease in absolute spleen weight, but not relative
spleen weight, in the mid-exposure group only. Similarly, sporadic changes in F: female pups
included a 13% increase in relative brain weight, but not absolute brain weight in the low-, mid-,
and high-exposure groups; a 19-28% decrease in absolute spleen weight across all exposure
groups; and a 24% decrease in relative spleen weight in the mid-exposure group only. At gross
necropsy, there were no exposure-related findings in F2 pups. Dilated renal pelvis was observed
in two pups each in the low- and mid-exposure groups, but the incidences were not significant if
analyzed at either the individual or litter level.
The U.S. EPA considers the lowest concentration (1,476 mg/m3 in Fi pups and
1,458 mg/m3 in F2 pups) a developmental LOAEL based on decreased Fi and F2 male and female
pup body weights at multiple postnatal time points. There were biologically significant (>5%)
decreases in body weights of pups of both sexes at all concentrations in both generations. The
highest concentration (7,444 mg/m3 in Fo adults/Fi pups and 7,442 mg/m3 in Fi adults/F2 pups) is
a systemic and reproductive NOAEL based on a lack of toxicologically relevant effects on
systemic and reproductive endpoints. Analytical concentrations of 0, 1,476, 2,975, and
7,444 mg/m3 for Fo adults and Fi pups correspond to HEC values of 0, 369.0, 743.8, and
1,861 mg/m3, for extrarespiratory effects. Analytical concentrations of 0, 1,458, 2,987, and
7,442 mg/m3 for Fi adults and F2 pups correspond to HEC values of 0, 364.5, 746.8, and
1,861 mg/m3, respectively, for extrarespiratory effects.3
Klimisch and Hellwis (1995): Rats
A published, peer-reviewed developmental toxicity study by Klimisch and Hell wig
(1995) was conducted in female SPF-Wistar rats. Mated females (25/group) were exposed whole
body to nominal concentrations of isobutyl alcohol (99.8% purity) vapors at 0, 0.5, 2.5, or
10 mg/L (0, 500, 2,500, or 10,000 mg/m3, respectively, as converted by the U.S. EPA) for
6 hours/day on GD 6-15. Control groups were exposed to clean air. Measured analytical mean
concentrations were 0, 0.49, 2.50, or 10.10 mg/L (0, 490, 2,500, or 10,100 mg/m3, respectively,
as converted by the U.S. EPA). The animals were weighed at 3-day intervals and observed daily
for clinical signs of toxicity. At sacrifice on GD 20, all dams underwent gross necropsy, and the
uteri were weighed. The numbers of corpora lutea, implants, live fetuses, and early and late
resorptions were recorded. Fetuses were sexed, weighed, and examined externally. Visceral
examinations were conducted on approximately half of the fetuses, and skeletal examinations on
3HEC calculated by treating isobutyl alcohol as a Category 3 gas (based on the lack of respiratory effects and the
ability of similar alcohols to produce systemic effects when inhaled) and using the following equation from the U.S.
EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animakhuman), using a default coefficient of 1 because
the rat blood-air partition coefficient of 880 is greater than the range of 541-578 reported for human blood-air
partition coefficients according to Kaneko et at (1994) and Fiserova-Bergerova and Diaz (1986).
20
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the remaining fetuses from each litter. Statistical analysis of data included the Dunnett's test for
maternal body weights, fetal body weights, and survival data. The Fisher's exact test was used to
evaluate maternal mortality, conception, and fetal examinations.
Quantitative data extraction for this rat developmental toxicity study can be found in the
HAWC database; links to specific data sets are included below for ease of review. No mortalities
were observed, and no clinical signs of toxicity related to exposure were reported. No
exposure-related changes were observed in maternal body-weight gains during exposure or
through GD 20 (with or without correction for gravid uterine weight); absolute body weights
were not reported. Uterine weights were comparable across all groups. Litter parameters,
including corpora lutea, dead implants, live fetuses, implantation, and placental weight, were
comparable across all groups. A statistically significant decrease in postimplantation loss was
observed in the high-exposure group (4.2%) compared with controls (10%); however, this effect
is not considered toxicologically relevant. No statistically significant changes in preimplantation
loss were observed. Fetal body weights were comparable between exposure and control groups.
There were no exposure-dependent increases in visceral or skeletal abnormalities. The only
statistically significant change was a decreased fetal incidence in dilated renal pelvis in the
low-exposure group (31%), compared with controls (47%); however, this effect is not considered
toxicologically relevant, and no changes were observed at higher exposure levels.
The U.S. EPA considers the highest concentration (10,100 mg/m3) a maternal and
developmental NOAEL, based on the lack of toxicologically relevant effects. The reported
concentrations of 0, 490, 2,500, and 10,100 mg/m3 correspond to HEC values of 0, 123, 625.0,
and 2,525 mg/m3 for extrarespiratory effects.4
Klimisch and Hellwis (1995): Rabbits
A published, peer-reviewed developmental toxicity study by Klimisch and Hell wig
(1995) was conducted in female Himalayan rabbits. Inseminated females (15/group) were
exposed whole body to isobutyl alcohol (purity 99.8%) vapors at 0, 0.5, 2.5, or 10 mg/L (0, 500,
2,500, or 10,000 mg/m3, respectively, as converted by the U.S. EPA) for 6 hours/day on
GD 7-19. Reported analytical mean concentrations were 0, 0.5, 2.51, or 10.00 mg/L (0, 500,
2,510, and 10,000 mg/m3, respectively, as converted by the U.S. EPA). Animals in control
groups were exposed to clean air. The animals were observed daily for clinical signs of toxicity,
and body weights were recorded at 3-day intervals. All dams underwent gross necropsy on
GD 29 and the uteri were weighed. The numbers of corpora lutea, implants, live fetuses, and
early and late resorptions were recorded. Fetuses were sexed, weighed, and examined externally.
Soft tissue and skeletal examinations were conducted on all fetuses. Statistical analysis of data
included the Dunnett's test for maternal body weights, fetal body weights, and survival data. The
Fisher's exact test was used to evaluate maternal mortality, conception, and fetal examinations.
Quantitative data extraction for the rabbit developmental toxicity study can be found in
the HAWC database; links to specific data sets are included below for ease of review. One doe in
4HEC calculated by treating isobutyl alcohol as a Category 3 gas (based on the lack of respiratory effects and the
ability of similar alcohols to produce systemic effects when inhaled) and using the following equation from the U.S.
EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animakhuman), using a default coefficient of 1 because
the rat blood-air partition coefficient of 880 is greater than the range of 541-578 reported for human blood-air
partition coefficients according to Kaneko et at (1994) and Fiserova-Bergerova and Diaz (1986).
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the mid-exposure group died on Day 24, and a single doe in the high-exposure group was
sacrificed on Day 21 due to spontaneous abortion. The deaths were not considered exposure-
related. No clinical signs of toxicity were reported. There were no statistically significant
changes in maternal body weight, body-weight gain, or uterine weight between the exposed and
control does. Litter parameters were comparable across all groups, including corpora lutea,
implantations, dead implants, pre- and postimplantation loss, and live fetuses. There was a slight,
but statistically significant, 12% increase in mean placental weight in the mid-exposure group,
compared with control, but statistically significant changes were not observed in the low- or
high-exposure groups. There were no statistically or biologically significant changes in fetal
body weights. No exposure-dependent increases in visceral or skeletal abnormalities were
observed. A statistically significant increase in the overall fetal incidence of a specific heart
variation (traces of interventricular foramen/septum membranaceum) occurred in the
high-exposure group (12/92 = 13%), compared with concurrent controls (2/105 = 2%); however,
the litter incidence for this variation in the high-exposure group (5/13 = 38%) was not
statistically different from concurrent controls (2/15 = 13%).
The highest concentration (10,000 mg/m3) is a maternal and developmental NOAEL
based on the lack of toxicologically relevant effects. Although there was a significant increase in
the fetal incidence of traces of interventricular foramen/septum membranaceum in the heart, the
biological relevance of this effect is unclear. Among an unexposed rat model system examining
this biological phenomenon, alterations of the cardiac membranous ventricular septum were
found to not affect postnatal survival and these alterations resolved spontaneously during
neonatal life, suggesting a lack of toxicity associated with the presence of these membranous
tissues (Solomon et al.. 1997). As there were no other potential toxicologically relevant effects
identified, the U.S. EPA did not identify a LOAEL. The reported concentrations of 0, 500, 2,510,
and 10,000 mg/m3 correspond to HEC values of 0, 125, 627.5, and 2,500 mg/m3 for
extrarespiratory effects.5
Carcinogenicity
No adequate inhalation carcinogenicity studies of isobutyl alcohol in animals have been
identified.
2.3. OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
2.3.1. Genotoxicity
The genotoxicity potential for isobutyl alcohol has been evaluated in a limited number of
in vitro and in vivo studies (see Table 4A for more details). Overall, the available data indicate
that isobutyl alcohol is not a genotoxic agent.
5HEC calculated by treating isobutyl alcohol as a Category 3 gas (based on the lack of respiratory effects and the
ability of similar alcohols to produce systemic effects when inhaled) and using the following equation from the U.S.
EPA (1994) methodology: HECer = exposure level (mg/m3) x (hours/day exposed ^ 24 hours) x (days/week
exposed 7 days) x ratio of blood-gas partition coefficient (animakhuman), using a default coefficient of 1 because
the blood-air partition coefficient for isobutyl alcohol in rabbits has not been determined. The human blood-air
partition coefficient ranges between 541 and 578 according to Kaneko ct al. (1994) and Fiserova-Bergerova and
Diaz (1986).
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Table 4A. Summary of Isobutyl Alcohol Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella typhimurium
TA98, TA100, TA1535,
TA1537
0, 10,33.3, 100,333,
1,000, 3,330,
5,000 ng/plate
Plate incorporation assay. No evidence of
mutagenicity in any of the strains tested, with or
without S9 activation.
American ("vanamid
(1992)
Mutation
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538
0.001-5 |iL/platc
Plate incorporation assay. No evidence of
mutagenicity in any of the strains tested, with or
without S9 activation.
Litton Bionetics
(1978a)
Mutation
S. typhimurium TA1535
0, 1 mg/plate
-
NDr
Ames assay. No evidence of mutagenicity.
Mirvish et al. (1993)
Mutation
S. typhimurium TA98,
TA100, TA1535,
TA1537, TA1538
5, 10, 50, 100, 500,
1,000, 5,000 ng/plate
Preincubation assay. No evidence of
mutagenicity in any of the strains tested, with or
without S9 activation.
Shimizu et al. (1985)
Mutation
S. typhimurium TA97
TA98, TA100, TA1535,
TA1537
0, 100, 333, 1,000,
3,333, 10,000 ng/plate,
or to an upper dose
defined by solubility
Preincubation assay. No evidence of
mutagenicity in any of the strains tested, with or
without rat and hamster S9 activation.
Zeieeretal. (1988)
Mutation
Escherichia coli
WP2uvrA
5, 10, 50, 100, 500,
1,000, 5,000 ng/plate
-
-
Ames assay. No evidence of mutagenicity with
or without S9 activation.
Shimizu et al. (1985)
Mutation
Saccharomyces
cerevisiae D4
0.001,0.01,0.1, 1.0,
5 |iL/platc
-
-
Plate incorporation assay. No evidence of
mutagenicity with or without S9 activation.
Litton Bionetics
f 1978a)
DNA damage
(SOS
induction)
S. typhimurium TL210
NR
(+)
NDr
Luminescent umu microplate assay. TL210 is a
phenotypic transformation of S. typhimurium
TA1535 that contains a plasmid with
luminescent genes LuxA-E extracted from
Vibrio fischeri. Increased luminescence was
observed using DMSO or methanol for dilution.
The data table indicates that the finding was
positive (defined as >twofold increase);
however, the text indicates that the finding was
"pseudopositive" (defined as 1.5-2-fold
increase).
Nakaiima et al. (2006)
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Table 4A. Summary of Isobutyl Alcohol Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
DNA damage
(SOS
induction)
S. typhimurium
TA1535/pSK1002
NR
NDr
Light absorption mmi test. Negative after a 4-h
incubation using DMSO or methanol for
dilution.
Nakaiima et al. (2006)
Genotoxicity studies in mammalian cells—in vitro
Mutation
L5178Y mouse
lymphoma cells
0,0.78, 1.56,3.13,
6.25, 12.5 nL/mL
(without activation)
and 0,0.39, 0.78, 1.56,
3.13, 6.25 |iL/mL (with
activation)
Forward mutation assay. No dose-related
increase in mutation frequencies with or
without S9 metabolic activation. Cytotoxicity
was observed at >12.5 |iL/mL with activation
and at >3.13 and >6.25 |iL/mL without
activation, in two separate trials. Assays were
conducted twice due to contamination issues in
the first trial.
Litton Bionetics
f1978b)
Mutation
V79 Chinese hamster
fibroblasts
0, up to 270 mM
HPRT assay. No genotoxicity was observed
following a 2-h treatment with the test
substance. The highest nontoxic concentration
tested was 107 mM.
Kreia and Seidel
(2002)
DNA damage
V79 Chinese hamster
fibroblasts
0, 53, 270 mM
NDr
Comet assay. No DNA damage was observed
following a 4-h treatment with 53 mM; 270 mM
was cytotoxic.
Kreia and Seidel
(2002)
DNA damage
Human lung carcinoma
epithelial A549 cells
0, 53, 270 mM
NDr
Comet assay. A significant increase in DNA
damage was only seen following a 4-h
treatment with 270 mM. The cytotoxic IC50 was
11 mM; therefore, these results are considered
negative (not tested below cytotoxic
concentrations).
Kreia and Seidel
(2002)
DNA damage
Primary human
peripheral blood cells
0, 53, 270 mM
NDr
Comet assay. No DNA damage was observed
following a 4-h treatment with 53 mM; 270 mM
was cytotoxic.
Kreia and Seidel
(2002)
Clastogenicity
(MN)
V79 Chinese hamster
fibroblasts
0, 11,53 mM
—
NDr
MN were not induced following a 4-h treatment
with the test substance.
Kreia and Seidel
(2002)
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Table 4A. Summary of Isobutyl Alcohol Genotoxicity
Endpoint
Test System
Doses/Concentrations
Tested
Results
without
Activation3
Results
with
Activation3
Comments
References
Genotoxicity studies—mammalian species in vivo
Clastogenicity
(CA)
White rats (8 M) were
administered a single
dose of isobutyl alcohol
via gavage
0, 40% aqueous
solution equivalent to
1/5 LD50.
NA
Without activation, CAs in rat bone marrow
cells 48-h after treatment were described by the
study authors as "less pronounced" than
alcohols with high molecular masses. The
twofold increase in the rate of polyploid cells,
1.3-fold increase in cells with chromosome
gaps, and 1.6% increase in cells with CAs were
interpreted bv OECD (2004) as neeative.
Barilvak and
Kozachuk (1988)
Clastogenicity
(MN)
NMRI mice (M/F) were
administered single oral
doses of isobutyl
alcohol via gavage
0, 500, 1,000,
2,000 mg/kg
NA
No increase in polychromatic erythrocytes
containing small or large MN after treatment.
Positive controls (cyclophosphamide,
vincristine) produced the expected response.
Eneelhardt and
Hoffmann (2000) as
cited in OECD (2004)
a(+) = weak positive, - = negative.
CA = chromosomal aberration; DMSO = dimethylsulfoxide; DNA = deoxyribonucleic acid; F = female(s); IC50 = half maximal inhibitory concentration; LD50 = median
lethal dose; M = male(s); MN = micronuclei; NA = not applicable; NDr = not determined; NR = not reported.
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Available in vitro studies indicate that isobutyl alcohol is not mutagenic to bacteria,
yeast, or mammalian cells. Isobutyl alcohol was not mutagenic with or without metabolic
activation in Salmonella typhimurium (Mirvish et al.. 1993; American Cvanamid. 1992; Zeiger et
at.. 1988; Shimizu et al.. 1985; Litton Bionctics. 1978a). Escherichia coli (Shimizu et al.. 1985).
or Saccharomyces cerevisiae (Litton Bionetics. 1978a). In a German study by Hilscher et al.
(1969). available only from secondary sources (OECD. 2004; U.S. EPA. 1986). a sevenfold
increase in reversions in E. coli CA274 cells was observed following a 72-hour incubation with
2.5% isobutyl alcohol. However, both secondary sources indicated that the methods were
inadequate and considered the study unreliable; therefore, the study was not included in
Table 4A. In mammalian cells, isobutyl alcohol was not mutagenic in mouse lymphoma cells or
Chinese hamster fibroblasts, with or without metabolic activation (Kreia and Seidel. 2002; Litton
Bionetics. 1978b).
Available in vitro studies also indicate that isobutyl alcohol is not clastogenic to
mammalian cells, has a low potential to cause deoxyribonucleic acid (DNA) damage in bacteria,
and does not induce DNA damage in mammalian cells. Isobutyl alcohol did not induce
micronuclei (MN) in Chinese hamster fibroblasts, without metabolic activation (Kreia and
Seidel. 2002). In a study that evaluated DNA damage in bacteria, the SOS response was assessed
using the light absorption umu test and a more sensitive luminescent umu test in a recombinant
S. typhimurium TA1535 strain (Nakaiima et al.. 2006). The SOS response was not increased
using the light absorption test. Data reporting for the more sensitive luminescent test were
inconsistent; isobutyl alcohol was reported as positive (>twofold increase in SOS response) in
the data tables but "pseudopositive" (1.5-2-fold increase in SOS response) in the resulting
discussion. Isobutyl alcohol did not induce DNA damage at noncytotoxic doses in human lung
carcinoma epithelial A549 cells, V79 Chinese hamster fibroblasts, or primary human peripheral
blood cells without metabolic activation (Kreia and Seidel. 2002).
In vivo studies were limited to two cytogenic studies, one with limited details in White
rats and an Organisation for Economic Cooperation and Development (OECD) guideline mouse
MN test in NMRI mice. In rats, there were slight increases (
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EPA/690/R-23/002F
Table 4B. Other Studies
Test3
Materials and Methods
Results
Comments
References
Supporting evidence—noncancer effects in humans following inhalation exposure
Case series
report
Four laboratory workers occupationally exposed to
unspecified levels of isobutyl alcohol for short
periods up to 18 mo.
Vertigo, nausea, and headache were
reported. There was one case of vestibular
irritation and one case of Meniere's disease.
This study is uninformative due to
lack of available details.
Seitz (1972) as
cited in U.S.
EPA (1986)
Occupational
cohort study
Air sampling data from 12 exposed workers and
11 unexposed workers were collected to determine
levels of exposure to multiple compounds.
Exposure was defined by department. Participants
provided self-reported health surveys that included
medical history, as well as sperm samples to
examine for changes in spermatogenesis.
Exposure to isobutyl alcohol was negligible
(below detection level for most
participants). Therefore, no
compound-specific analysis was performed.
Health surveys found no abnormal effects
on spermatogenesis, fertility, or liver or
kidney function between exposed and
control groups.
This study is uninformative
regarding the potential effects of
isobutyl alcohol on male
reproductive toxicity (primary
endpoint) or liver or kidney
function due to negligible
exposure.
Hollett and Aw
(1982)
Skin irritation
In an acute patch test, a 25 |iL volume of a 75%
solution of isobutyl alcohol was applied to the skin
of 12 participants of Asian descent, under occlusive
conditions for 5 min. Prior to patch testing, subjects
were preclassified as "flushers" (n = 8) or
"nonflushers" (n = 4) when drinking alcohol. The
sites were monitored for 60 min for signs of
erythema. The conditions of a positive response
were not defined. Reversibility was not evaluated.
A positive response was reported in
2/12 individuals. Both positive reactions
were in individuals previously determined
to have a predisposition for flushing.
Severity was not described.
This study is of limited usefulness
due to multiple deficiencies,
including short exposure duration
and assessment time, short
follow-up, subjective
determination of results, no
description of participant
selection, and lack of discussion of
confounding factors.
Wilkin and
Stewart (1987);
Wilkin and
Fort ner (1985)
Supporting evidence—noncancer effects in animals following inhalation exposure
Acute
(mortality)
Acute toxicity data in rats were reported from
RTECS database.
4-h ALC = 4,000 ppm (12,126 mg/m3)
Kennedy and
(iraenel C199D
Acute
(mortality)
Rats were exposed to isobutyl alcohol via
inhalation. No additional study details were
available.
LC50 = 19,200 mg/m3
Kushneva et al.
(1983) as cited
in OECD
(2004); IPCS
(1987)
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Table 4B. Other Studies
Test3
Materials and Methods
Results
Comments
References
Acute
(mortality)
Rats (6/group) were exposed to saturated isobutyl
alcohol vapors reported to be approximately
16,000 ppm (49,248 mg/m3) for 2 h or to 8,000 ppm
(24,624 mg/m3) for 4 h.
100% survival at 49,248 mg/m3 for 2 h.
Mortality in 2/6 rats at 24,624 mg/m3 for
4 h.
Suivth et al.
(1954) as cited
in IPCS (1987)
Acute
(mortality)
Female rats (6/group) were exposed to saturated
vapors (estimated at 14,000 ppm or 42,441 mg/m3)
of isobutyl alcohol for 2 or 4 h and were observed
for 14 d.
All animals survived following a 2-h
exposure. Mortality was 100% after a 4-h
exposure.
Mellon Institute
(1986)
Acute
(mortality)
Male and female rats (6/group) were exposed to an
isobutyl alcohol concentration of 8,000 ppm
(24,624 mg/m3) for 4 h. Male rats were tested twice
(once with a sample from 1946 and once with a
sample from 1953); females were tested once
(sample NS). Mortality was recorded.
1/6 male rats died following exposure to the
1953 sample; no mortalities following
exposure to the 1946 sample.
No female mortalities.
Mellon Institute
(1986)
Acute
(mortality)
Sprague Dawley rats (10/sex) were exposed to
6.5 mg/L (2,145 ppm) isobutyl alcohol vapors for
4 h. Animals were observed for 14 d following
exposure.
4-I1LC50 >6,500 mg/m3
No deaths or signs or toxicity were
observed.
BASF (undated)
as cited in
OECD (2004)
Acute
(mortality)
Mice were exposed to isobutyl alcohol via
inhalation. No additional study details were
available.
LC50 = 15,500 mg/m3
Kushneva et al.
(1983) as cited
in IPCS (1987)
Acute
(mortality)
Rabbits were exposed to isobutyl alcohol via
inhalation. No additional study details were
available.
LC50 = 26,250 mg/m3
Kushneva et al.
(1983) as cited
in OECD (2004)
Acute
(mortality)
Guinea pigs were exposed to isobutyl alcohol via
inhalation. No additional study details were
available.
LC50 = 19,900 mg/m3
Kushneva et al.
(1983) as cited
in IPCS (1987)
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Table 4B. Other Studies
Test3
Materials and Methods
Results
Comments
References
Acute
(neurotoxicity)
Rats (10/sex/group) were exposed to isobutyl
alcohol vapor concentrations of 1,500, 3,000, or
6,000 ppm (4,547, 9,095, or 18,189 mg/m3) for 6 h.
Animals were observed for mortality and clinical
signs of CNS depression. FOB and motor function
tests were conducted prior to and immediately after
exposure and on Days 1, 7, and 14 after dosing. At
sacrifice (Day 15), animals were grossly examined,
and central and peripheral nervous tissues were
fixed for microscopic examination.
Rapid, but reversible general CNS
depression occurred during exposure in the
3,000- and 6,000-ppm groups. Hypoactivity
was observed at 1,500 ppm. At 6,000 ppm,
females showed a decrease in alertness, and
decreased motor activity was recorded in
both sexes. One male exhibited an
uncoordinated gait. All effects were
transient. There were no treatment-related
findings at gross necropsy.
Monsanto (1994)
Acute
(neurotoxicity)
Male albino SPF rats (4/group) were exposed whole
body to at least three concentrations (NS) of
isobutyl alcohol vapors for 4 h. A neurotropic effect
was determined based on the inhibition of
propagation and maintenance of an electrically
evoked seizure. Baseline durations of hindlimb
tonic extensions in response to 0.2-sec, 50-Hz,
180-V electrical impulses applied through ear
electrodes were established prior to exposure. The
effect of exposure on the duration of maximal tonic
extension was measured. Each animal was tested up
to 4 times with intervals of 3 wk between
exposures. Experiments were performed in
duplicate. Based on a linear regression, the
concentration evoking a 30% depression in the
duration of tonic extension (RC30) was determined.
Rat RC30 (30% depression of seizure
activity) = 3,800 ppm (11,520 mg/m3); this
is considered a sign of CNS depression.
Frantik et al.
(1994)
Acute
(neurotoxicity)
Harlan Sprague Dawley rats (5/sex) were exposed
to saturated isobutyl alcohol vapors for 6 h under
semi-static conditions. Animals were observed for
mortality and clinical signs and were necropsied
14 d following exposure.
No deaths were observed. Animals
exhibited hypoactivity, lacrimation,
narcosis, prostration, and abnormal
breathing during exposure, and prostration,
narcosis, and negative reflexes following
exposure.
Union Carbide
Cora. (1993) as
cited in OECD
(2004)
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Table 4B. Other Studies
Test3
Materials and Methods
Results
Comments
References
Acute
(neurotoxicity)
Female H-strain mice (2/group) were exposed
whole body to isobutyl alcohol vapors for 2 h. A
neurotropic effect was determined based on the
inhibition of propagation and maintenance of an
electrically evoked seizure. Baseline durations of
hindlimb tonic extensions in response to 0.2-sec,
50-Hz, 180-V electrical impulses applied through
ear electrodes were established prior to exposure.
The effect of exposure on the duration of maximal
tonic extension was measured. Each animal was
tested up to 4 times with intervals of 3 wk between
exposures. Experiments were performed in
duplicate. Based on a linear regression, the
concentration evoking a 30% depression in the
duration of tonic extension (RC30) was determined.
Mouse RC30 (30% depression of seizure
activity) = 2,500 ppm (7,579 mg/m3); this is
considered a sign of CNS depression.
Frantik et al.
(1994)
Acute (eye
irritation)
Groups of male and female rats were exposed to
isobutyl alcohol vapor concentrations of 2,000,
6,000, or 8,000 ppm (6,063, 18,189, or
24,252 mg/m3) for 6 h. Animals received
ophthalmoscopic examinations at an unspecified
time following exposure.
Inflammatory changes (iritis, vascular
congestion, anterior synechia) were
observed at >18,189 mg/m3. Inflammatory
changes were accompanied by unilateral or
bilateral corneal opacities, with the greatest
severity at 24,252 mg/m3.
Chemical
Manufacturers
Association
(1994)
Acute
(respiratory
irritation)
Male Swiss OFi mice (6/group) were exposed head
only to four concentrations of isobutyl alcohol
vapors for 5 min (concentrations NR). Respiratory
rates were monitored and the concentration
resulting in a 50% reduction in the breathing rate
(RC50) was determined.
Mouse RD50 (50% decrease in respiratory
rate) = 1,818 ppm (5,511 mg/m3); this is
considered an indication of respiratory
irritation.
de Ceaurriz et al.
(1981)
Acute
(systemic)
Rats and rabbits were exposed to isobutyl alcohol
concentrations of 100, 1,300, 8,000, or
15,700 mg/m3 via inhalation for 4 h. Animals were
sacrificed 3 d later. Results were reported for both
species together (no species-specific data).
Altered breathing frequency at >100 mg/m3;
decreased number of lymphocytes at
>1,300 mg/m3; airway irritation,
hematological changes, and dystrophia of
hepatocytes and olfactory neurons in the
brain at >8,000 mg/m3; and similar but more
severe effects at 15,700 mg/m3.
Kushneva et al.
(1983) as cited
in IPCS (1987)
30
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Table 4B. Other Studies
Test3
Materials and Methods
Results
Comments
References
Short-term
Male CD rats (5/group) were exposed to 0, 2,274,
4,550, or 9,095 mg/m3 for 6 h/d, 5 d/wk for 2 wk.
Animals were examined for changes in mortality,
clinical signs (including subjective evaluations of
response to external stimuli), food consumption,
body weights, and hematological parameters.
Animals were subject to ophthalmoscopic
examinations and FOB testing. Complete
necropsies, organ weights, and histopathological
analyses were done.
A marginal decrease in response to chamber
wall tapping was observed during exposure
starting at 2,274 mg/m3 with more
pronounced effects at higher concentrations.
General CNS depression and labored
breathing occurred at the two higher
exposure levels.
Observed CNS depression was
transient and considered by the
study authors to be due to acute
exposure rather than an indication
of neurotoxicity resulting from
repeated exposures.
Kaemofe and Li
(1996)
Subchronic
Rats (sex, strain, and number NS) were exposed to
isobutyl alcohol vapor concentrations of 0.1, 0.5, or
3.0 mg/m3 continuously for 4 mo.
Reductions in erythrocyte numbers,
hemoglobin content, cholinesterase, and
catalase activity were reported at 0.5 and
3.0 mg/m3. At 3.0 mg/m3, there was an
increased stimulus threshold to trigger
avoidance response, and increased ALT and
AST activities.
Data reporting was inadequate for
independent analysis.
Tsulava (1978)
as cited in
OECD (2004)
Undefined
duration
Mice (sex, strain, and number NS) were
intermittently exposed to 2,125 ppm (6,442 mg/m3)
of isobutyl alcohol for a total of 223 h
(9.25 h/exposure). An additional group was also
given repeated exposures to 6,400 ppm
(19,400 mg/m3); duration of exposure for this group
was NS.
No deaths were reported in the group
exposed to 6,442 mg/m3 (no further details
on this group). Transient narcosis was
observed at 19,400 mg/m3.
Data reporting was inadequate for
independent analysis.
Weese (1928) as
cited in U.S.
EPA (1986)
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Table 4B. Other Studies
Test3
Materials and Methods
Results
Comments
References
Supporting evidence—cancer effects in animals following oral exposure
Carcinogenicity
Male and female Wistar rats (19 in treatment group,
25 in control group; number per sex NS) were
administered isobutyl alcohol via gavage at
0.2 mL/kg or 0.9% NaCl (control) twice/wk for a
lifetime.
The average survival was 643 d for controls
and 495 d for the treatment group. Three
animals in the treatment group had
malignant tumors (an antestomach
carcinoma and a liver cell carcinoma, an
antestomach carcinoma with myeloid
leukemia, and myeloid leukemia). No
tumors were reported in controls. Liver
damage, including steatosis, necrosis,
fibrosis, and cirrhosis, hyperplasia of blood
forming tissues, and damage to heart tissue
were also reported.
This study was uninformative.
Overall, the study has major
design and reporting deficiencies.
Evidence was not presented
clearly or transparently. Dosing
frequency, animal number, and
tumor incidences are too low to
draw meaningful conclusions
regarding the carcinogenic
potential of isobutyl alcohol.
Dow Chemical
(1992): Gibel et
al. (1975)
aAcute = exposure for <24 hours; short term = repeated exposure for >24 hours <30 days; subchronic = repeated exposure for >30 days <10% life span (>30 days up to
approximately 90 days in typically used laboratory animal species); chronic = repeated exposure for >10% life span for humans (more than approximately 90 days to
2 years in typically used laboratory animal species) (U.S. EPA. 2002b).
ALC = approximate lethal concentration; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CNS = central nervous system; FOB = functional
observation battery; LC50 = median lethal concentration; NaCl = sodium chloride; NR = not reported; NS = not specified; RCX = concentration to cause x change in
response (e.g., RC30 = concentration to cause 30% change in response); RTECS = Registry of Toxic Effects of Chemical Substances.
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In a case-series report available only from a secondary source, vertigo, nausea, and
headache were reported by workers occupationally exposed to isobutyl alcohol; no additional
details regarding exposure levels or duration were available (Seitz. 1972 as cited in U.S. EPA.
1986). In an occupational cohort study, sperm analysis, renal and liver function tests, and
medical health survey reports of birth defects in offspring, infertility, miscarriages, and stillbirths
were evaluated in workers exposed to a variety of chemicals; however, air sampling from
potentially exposed factory workers indicated that exposure to isobutyl alcohol was negligible
(Hollett and Aw. 1982). Therefore, no assessments of isobutyl alcohol were made in this study.
The only other available human studies both describe an acute patch test in 12 Asian
volunteers; 8 of these volunteers were classified as "flushers" with a predisposition to skin
redness when drinking alcohol (Wilkin and Stewart. 1987; Wilkin and Former. 1985). Subjects
were dermally exposed to isobutyl alcohol for 5 minutes on presoaked skin. Results were
reported as positive or negative for erythema (as opposed to a graded scoring system), but no
clear definition of erythema was provided. Two of the volunteers, both "flushers," were
classified as positive. Overall, it can be concluded that a 5-minute exposure to isobutyl alcohol
under the test conditions did not cause skin redness in most subjects and that the two subjects
with redness were predisposed as described by the study authors, increasing the uncertainty
surrounding results from these two individuals. However, the usefulness of this study is limited
due to several deficiencies, including short exposure duration and assessment time, short
follow-up, subjective determination of results, no description of participant selection, and lack of
discussion of confounding factors.
2.3.3. Supporting Animal Toxicity Studies
Supporting animal toxicity studies include several acute and short-term inhalation
studies, which indicate CNS depression and eye and respiratory irritation as toxicologically
relevant effects following exposure to high air levels. Other supporting studies include a 4-month
foreign language study in rats available only as a brief description in a secondary source and an
inadequately reported developmental probe study in rats and rabbits. For carcinogenicity, the
database is limited to an oral cancer study with methodological inadequacies and limited data
reporting. See Table 4B for more details.
Supporting Studies for Noncarcinogenic Effects in Animals
Acute lethality studies on isobutyl alcohol indicate that isobutyl alcohol has relatively
low lethality via the inhalation route. Reported median lethal concentration (LCso) values were
19,200 mg/m3 in rats, 15,500 mg/m3 in mice, 26,250 mg/m3 in rabbits, and 19,900 mg/m3 in
guinea pigs (Kushneva et at.. 1983 as cited in OECD. 2004; Kushneva et at.. 1983 as cited in
IPCS. 1987; Melton Institute. 1986). The acute exposure at which mortality first occurred
(approximate lethal concentration [ALC]) for rats was reported as 12,126 mg/m3 (Kennedy and
Graepet. 1991). Other lethality studies in rats reported no mortalities following exposure to
saturated vapors (-42,441-49,248 mg/m3) for 2 hours and 0, 33, and 100% mortality following a
4-hour exposure to 6,500, 24,624, and 42,441 mg/m3, respectively (BASF, undated as cited in
OECD. 2004; Smyth et at.. 1964 as cited in IPCS. 1987; Melton Institute. 1986). In contrast, no
deaths were reported in rats exposed to saturated vapors (estimated exposure not reported) for
6 hours (Union Carbide Corp.. 1993 as cited in OECD. 2004). No mortalities were observed in
mice following repeated exposure to 6,442 mg/m3 for a total of 223 hours (9.25 hours/exposure)
(Wccsc. 1928 as cited in U.S. EPA. 1986).
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Neurotoxicity is the primary effect reported in available acute and short-term inhalation
studies. Transient hypoactivity was reported at acute concentrations >4,547 mg/m3, with more
pronounced CNS depression (e.g., decreased alertness, uncoordinated gait, prostration, narcosis)
occurring at >7,579 mg/m3 (Frantik et al.. 1994; Monsanto. 1994; Union Carbide Corp.. 1993 as
cited in IPCS. 1987). In an unpublished 2-week study in rats, transient decreases in response to
stimuli (cage tapping) were observed during exposure to >2,274 mg/m3, with general CNS
depression at >4,550 mg/m3; the effects ceased after the rats were removed from the chamber
(Kaempfe and Li. 1996). A specialized study by Frantik et al. (1994) evaluated CNS depressant
potential of isobutyl alcohol by evaluating inhibition of the propagation and maintenance of an
electrically evoked seizure in rats and mice. The concentration required for a 30% decrease in
seizure activity (RC30), measured by duration of hindlimb tonic extensions, in rats and mice was
11,520 and 7,579 mg/m3, respectively. One study, available only from a secondary source,
reported dystrophia of olfactory neurons in the brain of rats and rabbits exposed to >8,000 mg/m3
for 4 hours (Kushneva et al.. 1983 as cited in IPCS. 1987).
High air concentrations of isobutyl alcohol vapor are irritating to the eyes and airways.
Exposure to isobutyl alcohol vapors for 6 hours resulted in inflammatory changes in the eye and
corneal opacities in rats at >18,189 mg/m3 (Chemical Manufacturers Association. 1994).
Respiratory irritation, indicated by altered breathing frequency, was reported in both rats and
rabbits after exposure to >100 mg/m3 for 4 hours (Kushneva et al.. 1983 as cited in IPCS. 1987).
In another study, the 50% reduction in respiratory rates (RC50) in mice after 5 minutes of
exposure to isobutyl alcohol vapors was 5,5 1 1 mg/m3 (de Ceaurriz et al.. 1981). In the 2-week
study by Kaempfe and Li (1996). labored breathing was reported during exposure to
concentrations >4,550 mg/m3; effects ceased upon removal from the chamber.
One acute inhalation study, available only from a secondary source, reported
hematological changes, dystrophia of hepatocytes, and a reduced number of lymphocytes in both
rats and rabbits exposed to >1,300 mg/m3 for 4 hours (Kushneva et al.. 1983 as cited in IPCS.
1987). No further details on these effects are available.
In a foreign-language study available only from a secondary source, transient narcosis
was observed in mice following repeated exposures to 19,400 mg/m3 (number and duration of
exposures not reported) (Weese. 1928 as cited in U.S. EPA. 1986). In a foreign-language
subchronic study also available only from a secondary source, leg withdrawal response to
electrical stimuli was depressed in rats exposed for 4 months to 3.0 mg/m3 (Tsulava. 1978 as
cited in OECD. 2004). Minor hematological changes (reduced hemoglobin content, decreased
erythrocyte count) and increased serum ALT and AST were also reported at >0.5 mg/m3. No
effects were observed at 0.1 mg/m3. Available data from these studies are too limited for
independent analysis.
Supporting Studies for Developmental Effects in Animals
No supporting studies for developmental effects in animals have been identified. The
literature search did identify a technical report (Eastman Kodak. 1992) that, upon analysis, was
found to be the same study as the Klimisch and Hettwig (1995) study.
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Supporting Studies for Carcinogenic Effects in Animals
Data on the carcinogenic potential for isobutyl alcohol are limited to a single foreign
language study by Gibel et al. (1975). with an English translation by Dow Chemical (1992). In
this study, 19 male and female rats (number per sex not specified) were administered isobutyl
alcohol at 0.2 mL/kg via gavage twice weekly until natural death. Twenty-five male and female
controls were similarly treated with 0.9% sodium chloride (NaCl). Three animals in the treated
group had malignant tumors (an antestomach carcinoma and a liver cell carcinoma, an
antestomach carcinoma with myeloid leukemia, and myeloid leukemia). No tumors were
reported in the controls. This study was evaluated as critically deficient (uninformative) during
systematic review because of its limited reporting and several methodological inadequacies
(e.g., inadequate dosing frequency, animal number, and tumor incidences); see Appendix C for
more details.
2.3.4. Metabolism/Toxicokinetic Studies
The toxicokinetic properties of isobutyl alcohol have been evaluated in a limited number
of published studies, and also reviewed by OECD (2004). IPCS (1987). and U.S. EPA (1986);
these secondary sources cite a number of foreign language studies and unpublished data sources
that were not available for independent review. An overview based both on published studies and
these reviews is presented below.
Absorption
Isobutyl alcohol is readily absorbed through the lungs and gastrointestinal tract and is
expected to be readily absorbed through the skin, consistent with general principles associated
with the identified physicochemical properties. Experimental data in rats show rapid absorption
of isobutyl alcohol based on detection of the parent compound and isobutyl alcohol metabolites
in the blood within 5 minutes of inhalation exposure (OECD. 2004; IPCS. 1987; U.S. EPA.
1986). Peak blood concentrations of isobutyl alcohol were observed 15 minutes after inhalation
exposure in rats (OECD. 2004). The blood-air partition coefficient for isobutyl alcohol was
determined to be 541-578 in humans and 880 in rats (Kancko et al.. 1994; Fiserova-Ber gerova
and Diaz. 1986); see Table 5. Experimental data from humans and laboratory animals indicate
that isobutyl alcohol is also rapidly absorbed through the gastrointestinal tract based on detection
of the parent compound and isobutyl alcohol metabolites in the blood and urine <1 hour after
oral administration (OECD. 2004; U.S. EPA. 1986). In humans, blood levels of isobutyl alcohol
peak 45-120 minutes after the start of oral exposure (OECD. 2004). Similarly, peak blood levels
in rabbits were observed 1 hour after oral administration (U.S. EPA. 1986). No in vivo dermal
studies measuring absorption of isobutyl alcohol have been identified; however, dermal
absorption was computationally predicted to be high following direct dermal contact with
isobutyl alcohol liquid or vapors (Fiserova-Bergerova et al.. 1990).
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Table 5. Partition Coefficients for Isobutyl Alcohol
Species
Muscle
Kidney
Lung
Brain
Fat
Liver
Blood
Reference
Tissue-gas partition coefficients for isobutyl alcohol
Human
343 ± 46
371 ±28
400 ± 42
White matter:
337 ±57
Gray matter:
387 ±29
388 ±33
NDr
541±134
Fiserova-
Bergerova and
Diaz (1986)
Human
NDr
NDr
NDr
NDr
NDr
NDr
578 ± 75
Kaneko et al.
(1994)
Rat
850 ± 66
875 ± 42
NDr
868 ± 22
720 ± 52
880 ± 100
880 ± 37
Kaneko et al.
(1994)
Tissue-blood partition coefficients for isobutyl alcohol
Rat
(measured)
0.97
0.99
NDr
0.99
0.82
1.00
NA
Kaneko et al.
(1994)
Human
(predicted)
0.38-0.76
0.41-0.82
0.45-0.88
0.43-0.85
0.43-0.85
NDr
NA
Poulin and
Krishnan (1995)
NA = not applicable; NDr = not determined.
Distribution
Data regarding distribution of isobutyl alcohol or its metabolites to specific tissues
following in vivo exposure were not available. In a developmental toxicity study, Klimisch and
Hettwig (1995) stated that isobutyl alcohol is distributed to both hydrophilic and lipophilic
compartments, but did not cite the source of this information. It is assumed that isobutyl alcohol
in blood can cross the placental barrier, but no specific data to test this hypothesis were available.
Tissue-gas and tissue-blood coefficients have been determined experimentally in rat tissues, and
tissue-blood coefficients have been predicted in human tissues (Poulin and Krishnan. 1995;
Kaneko et al.. 1994) (see Table 5).
Metabolism
The primary metabolites identified in blood and urine in humans and laboratory animals
following exposure include isobutyraldehyde and isobutyric acid (OECD. 2004; U.S. EPA.
1986). Metabolism is rapid, with peak metabolite concentrations in blood observed at 2-4 hours
after the start of oral dosing in humans and 25 minutes after the start of inhalation exposure in
rats (OECD. 2004). Other urinary metabolites identified include acetaldehyde, acetic acid, and
unspecified glucuronic acid conjugates (OECD. 2004; IPCS. 1987; U.S. EPA. 1986).
Metabolism may be dose-dependent because aldehydes were only observed in rabbits following
exposure to drinking water saturated with isobutyl alcohol, but not to single gavage doses of
-618-1,600 mg/kg (U.S. EPA. 1986). Isovaleric acid was also identified in the urine of rabbits
following exposure to drinking water saturated with isobutyl alcohol; however, this
unexplainable metabolite may have been identified in error because of potential co-elution of a
metabolite with isovaleric acid on the chromatogram (OECD. 2004).
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Based on identified metabolites in blood and urine following exposure to isobutyl
alcohol, it is proposed that isobutyl alcohol is oxidized into isobutyraldehyde by alcohol
dehydrogenase (ADH), which is further oxidized into isobutyric acid via aldehyde
dehydrogenases (ALDH) (OHCD. 2005; U.S. EPA. 1986). Subsequently, isobutyric acid reacts
with Coenzyme A (CoA), enters the tricarboxylic acid cycle, and results in liberation of carbon
dioxide (CO:) (U.S. EPA. 1986). ADH inhibition studies confirm the primary role of ADH in
isobutyl alcohol oxidation. Using the ADH inhibitors, 4-methylpyrazole and isobutyramide,
Plapp et al. (2015) estimated that ADH is responsible for approximately 66% of isobutyl alcohol
metabolism in vivo in rats. Pyrazole, another ADH inhibitor, was also effective at reducing
breakdown of isobutyl alcohol by approximately 50% (Lester and Benson. 1970). ADH
metabolism is rapid in both in situ rat liver perfusions and in vitro rat liver homogenates
(2-7 |imol/g liver/minute) (OECD. 2005; U.S. EPA. 1986). Based on in vitro studies with human
liver Class I, II, and III ADHs, Class I ADH isoenzymes are the most active for isobutyl alcohol
(Ehrig et al.. 1988). Human skin ADH enzymes also have demonstrated the ability to oxidize
isobutyl alcohol (Wilkin and Stewart. 1987).
Excretion
Excretion of isobutyl alcohol and its metabolites is primarily via urine, with small
amounts of unchanged isobutyl alcohol and CO: in expired air (OECD. 2005; IPCS. 1987; U.S.
EPA. 1986). Blood and urine samples collected from humans who were administered
approximately 5 mg/kg isobutyl alcohol in an ethanol/water mixture over a 2-hour time period
indicated rapid elimination of unchanged isobutyl alcohol and its primary metabolites in urine
(OECD. 2004). Urinary levels of isobutyl alcohol, isobutyraldehyde, and isobutyric acid peaked
1, 8, and 2 hours after the start of oral exposure in humans, respectively (OECD. 2004). Isobutyl
alcohol was no longer detected in the blood of humans 12 hours after drinking an orange juice,
isobutyl alcohol, and ethanol mixture, although ethanol consumption likely altered toxicokinetics
(U.S. EPA. 1986). Excretion of 14CO: in expired air was used to determine an excretion rate of
6.9 mmol/kg-hour in rats following an intraperitoneal (i.p.) injection of 6.8 mmol/kg of
[14C]-labelled isobutyl alcohol (Lester and Benson. 1970). Another study in rats determined a
first-order elimination rate of 3.8 ± 0.5 mmol/kg-hour following an i.p. injection of 1 M isobutyl
alcohol (Plapp et al .. 2015). Clearance of isobutyl alcohol from blood following intravenous
(i.v.) exposure is 0.13 L/kg-minute in rats (Kielbasa and Fung. 2000).
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3. DERIVATION OF PROVISIONAL VALUES
3.1. DERIVATION OF PROVISIONAL REFERENCE DOSES
Provisional reference dose (p-RfD) values are not derived because an RfD value is
available on the U.S. EPA's IRIS database (U.S. EPA. 1987).
3.2. DERIVATION OF PROVISIONAL REFERENCE CONCENTRATIONS
Available inhalation studies include peer-reviewed subchronic neurotoxicity studies in
rats (Li et al.. 1999). peer-reviewed developmental studies in rats and rabbits (Klimisch and
Hettwig. 1995). and an unpublished, two-generation study in rats (Nemec. 2003).
In peer-reviewed studies, the only treatment-related effect identified was slightly
decreased response to stimuli during daily exposures at >782 mg/m3 (HECer = 140 mg/m3) in
the 13- and 14-week rat studies by Li et al. (1999). However, this transient CNS depression was
considered an acute response by the study authors, and no additional information was identified
to suggest that these effects are an indicator of an emerging subchronic neurological effect.
Rapid, reversible CNS depression has been observed in animals following acute exposure to very
high concentrations of isobutyl alcohol (see Table 4B). None of the available inhalation studies
indicate more serious or permanent alterations in the nervous system following exposure to
isobutyl alcohol. However, due to a lack relevant chronic exposure characterization, it is not
possible to definitively conclude that these transient effects will not manifest at later life stages.
In the Li et al. (1999) study, the absence of subchronic neurological effects is supported by the
lack of exposure assessed outside of the daily exposure period (FOB, motor activity, SCOB) and
no supporting morphological or histological evidence of damage to neurological tissues.
However, a subjectively observed (non-quantitated) decrease in response to chamber brushing
was observed for all exposed rats on days of exposure. Therefore, the highest concentration of
7,725 mg/m3 (HECer = 1,379 mg/m3) in the subchronic studies by Li et al. (1999) is considered
by the U.S. EPA to be a NOAEL for subchronic effects. No toxicologically relevant effects
(including decreased fetal pup body weight) were noted in the developmental studies by
Klimisch and Hettwig (1995) at concentrations up to 10,100 mg/m3 (HECer = 2,525 mg/m3) in
rats or 10,000 mg/m3 (HECer = 2,500 mg/m3) in rabbits.
In the unpublished two-generation study by Nemec (2003). the U.S. EPA identified the
lowest concentration as a LOAEL based on decreased Fi and F2 male and female pup postnatal
body weight at concentrations >1,476 and 1,458 mg/m3 (HECer = 369.0 and 364.5 mg/m3),
respectively. Because the only toxicologically relevant effect following repeated inhalation
exposure to isobutyl alcohol was identified in an unpublished study, the inhalation database is
considered inadequate to support derivation of provisional reference values. However, the
non-peer-reviewed, two-generation study provides sufficient data to develop screening
subchronic and chronic provisional reference concentration (p-RfC) values based on
developmental effects (see Appendix A).
3.3. SUMMARY OF NONCANCER PROVISIONAL REFERENCE VALUES
A summary of the noncancer provisional reference values is shown in Table 6.
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Table 6. Summary of Noncancer Reference Values for Isobutyl Alcohol
(CASRN 78-83-1)
Toxicity Type
(units)
Species/
Sex
Critical Effect
p-Reference
Value
POD
Method
POD
(HED/HEC)
UFc
Principal
Study
Subchronic
p-RfD (mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
Oral RfD value of 0.3 me/ke-d is available on IRIS (U.S. EPA. 1987)
Screening
subchronic
p-RfC (mg/m3)
Rat/both
Developmental
(decreased F2 pup
body weights)
1
LOAEL
364.5
300
Nemec (2003)
Screening
chronic p-RfC
(mg/m3)
Rat/both
Developmental
(decreased F2 pup
body weights)
4 x 101
LOAEL
364.5
1,000
Nemec (2003)
HEC = human equivalent concentration; HED = human equivalent dose; IRIS = Integrated Risk Information
System; NOAEL = no-observed-adverse-effect level; NDr = not determined; POD = point of departure;
p-RfC = provisional reference concentration; p-RfD = provisional reference dose; RfD = oral reference dose;
UFC = composite uncertainty factor.
3.4. CANCER WEIGHT-OF-EVIDENCE (WOE) DESCRIPTOR
Table 7 identifies the cancer WOE descriptor for isobutyl alcohol. No adequate cancer
data are available. In general, available genotoxicity assays of isobutyl alcohol (see Table 4A)
indicate that isobutyl alcohol is not a genotoxic agent. Under the U.S. EPA (2005) cancer
guidelines, the available data are inadequate for an assessment of human carcinogenic potential,
so the cancer WOE descriptor for isobutyl alcohol is "Inadequate Information to Assess the
Carcinogenic Potential' (for both the oral and inhalation routes of exposure).
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Table 7. Cancer WOE Descriptor for Isobutyl Alcohol
Possible WOE
Descriptor
Designation
Route of Entry (oral,
inhalation, or both)
Comments
"Carcinogenic to
Humans "
NS
NA
There are no human carcinogenicity data
identified to support this descriptor.
"Likely to Be
Carcinogenic to Humans "
NS
NA
There are no animal carcinogenicity studies
identified to support this descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no animal carcinogenicity studies
identified to support this descriptor.
"Inadequate
Information to Assess
Carcinogenic Potential"
Selected
Both
This descriptor is selected due to the lack of
any adequate studies evaluating
carcinogenicity of isobutyl alcohol.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
No evidence of noncarcinogenicity is available.
NA = not applicable; NS = not selected; WOE = weight of evidence.
3.5. DERIVATION OF PROVISIONAL CANCER RISK ESTIMATES
Due to lack of adequate carcinogenicity data for isobutyl alcohol, derivation of cancer
risk estimates is precluded (see Table 8).
Table 8. Summary of Cancer Risk Estimates for Isobutyl Alcohol
(CASRN 78-83-1)
Toxicity Type (units)
Species/Sex
Tumor Type
Cancer Risk Estimate
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (lng/in3) 1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
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APPENDIX A. SCREENING PROVISIONAL VALUES
Due to the lack of evidence described in the main provisional peer-reviewed toxicity
value (PPRTV) assessment, it is inappropriate to derive provisional reference concentrations
(p-RfCs) for isobutyl alcohol. However, some information is available for this 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 Center for Public Health
and Environmental Assessment (CPHEA) summarizes available information in an appendix and
develops a "screening value." Appendices receive the same level of internal and external
scientific peer review as the provisional reference values 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 could be more uncertainty associated with
deriving 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 CPHEA.
DERIVATION OF SCREENING PROVISIONAL REFERENCE CONCENTRATIONS
As discussed in the main body of the report, toxicologically relevant effects identified in
inhalation studies are limited to a non-peer-reviewed study. While non-peer-reviewed data are
considered inappropriate to derive p-RfCs, these data are adequate to derive screening p-RfCs.
Derivation of Screening Subchronic Provisional Reference Concentration
Decreased body weight in Fi and F2 male and female pups in the unpublished
two-generation rat study (Nemec, 2003) is the most sensitive target of inhalation toxicity
identified for isobutyl alcohol. There were biologically significant (>5%) decreases in body
weights of pups of both sexes at all concentrations in both generations. Similar alterations to pup
body weight were not observed in a developmental study in rats by Klimisch and Hell wig
(19951 although the exposure regimens and experimental design were significantly different
among the two studies (two-generations vs. 10 days). For the purposes of this PPRTV
assessment, a >5% decrease in pup body weight is considered biologically significant by the
U.S. Environmental Protection Agency (U.S. EPA). Due to lack of clear dose-response, these
data were not amenable to benchmark dose (BMD) modeling. Therefore, the U.S. EPA selected
the LOAEL of 1,458 mg/m3 (HECer = 364.5 mg/m3), based on F2 pup exposure, as the point of
departure (POD) for derivation of the screening subchronic p-RfC.
The screening subchronic p-RfC of 1 mg/m3 for isobutyl alcohol is derived by applying a
composite uncertainty factor (UFc) of 300 (reflecting an interspecies uncertainty factor [UFa] of
3, an intraspecies uncertainty factor [UFh] of 10, a database uncertainty factor [UFd] of 1, and a
LOAEL-to-no-observed-adverse-effect level (NOAEL) uncertainty factor [UFl] of 10) to the
selected POD of 364.5 mg/m3, as follows:
Screening Subchronic p-RfC = POD (HEC) ^ UFc
= 364.5 mg/m3 300
= 1 mg/m3
Table A-l summarizes the uncertainty factors for the screening subchronic p-RfC for
isobutyl alcohol.
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Table A-l. Uncertainty Factors for the Screening Subchronic p-RfC for
Isobutyl Alcohol
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans, using toxicokinetic cross-species dosimetric adjustment for extrarespiratory effects from a
Category 3 gas, as specified in the U.S. EPA (1994) guidelines for deriving p-RfCs.
UFd
1
A UFd of 1 is applied to account for deficiencies and uncertainties in the database. The database
includes a comprehensive two-generation toxicity study in rats, that has not been published or
peer-reviewed. Other available studies include a subchronic study in rats and developmental studies in
rats and rabbits. The database lacks documentation that portal-of-entry effects were evaluated. Based
011 the available subchronic information (Li et al. (1999). it appears that developmental toxicity is
more sensitive than systemic toxicity at least in a subchronic setting, and it is unlikely that additional
subchronic studies would provide a lower POD. Therefore, a UFD of 1 was selected.
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of isobutyl alcohol in humans.
UFl
10
A UFl of 10 is applied because the POD is a LOAEL.
UFS
1
A UFS of 1 is applied because the POD is a developmental effect observed in a two-generation study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; UF = uncertainty factor; 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 Screening Chronic Provisional Reference Concentration
The screening chronic p-RfC is derived using the same POD for decreased body weight
(LOAEL of 1,458 mg/m3 [HECer = 364.5 mg/m3]), based on F2 pup exposure in the unpublished
two-generation study by Nemec (2003) that serves as the basis for the screening sub chronic
p-RfC. Therefore, the lowest LOAEL of 1,458 mg/m3 (HECer = 364.5 mg/m3), based on F2 pup
exposure, was selected as the POD for derivation of the screening chronic p-RfC.
The screening chronic p-RfC of 4 x 10"1 mg/m3 for isobutyl alcohol is derived by
applying a UFc of 1,000 (reflecting a UFa of 3, a UFh of 10, a UFd of 3, and a UFl of 10) to the
selected POD of 364.5 mg/m3, as follows:
Screening Chronic p-RfC = POD (HEC) UFc
364.5 mg/m3 - 1,000
= 4 x 10"1 mg/m3
Table A-2 summarizes the uncertainty factors for the screening chronic p-RfC for
isobutyl alcohol.
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Table A-2. Uncertainty Factors for the Screening Chronic p-RfC for
Isobutyl Alcohol
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for uncertainty associated with extrapolating from animals to
humans, using toxicokinetic cross-species dosimetric adjustment for extrarespiratory effects from a
Category 3 gas, as specified in the U.S. EPA (1994) guidelines for deriving p-RfCs.
UFd
3
A UFd of 3 (10°5) is applied to account for deficiencies and uncertainties in the database. The
database includes a comprehensive two-generation toxicity study in rats, that has not, however, been
published or peer-reviewed. Other available studies include a subchronic study in rats and
developmental studies in rats and rabbits. The database lacks documentation that portal-of-entry
effects were evaluated and is considered to be overall limited in scope. No chronic inhalation
exposure studies were identified to inform the sensitivity of potential systemic effects compared to the
identified reproductive/developmental toxicities characterized in Ncmcc (2003).
UFh
10
A UFh of 10 is applied to account for human variability in susceptibility, in the absence of
information to assess toxicokinetic and toxicodynamic variability of isobutyl alcohol in humans.
UFl
10
A UFl of 10 is applied because the POD is a LOAEL.
UFS
1
A UFS of 1 is applied because the POD is based on a developmental effect observed in a
two-generation study. While the exposure period was less-than-chronic, 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 lifetime exposure (U.S. EPA. 1991).
UFC
1,000
Composite UF = UFA x UFD x UFH x UFL x UFS.
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; UF = uncertainty factor; 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.
43
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APPENDIX B. SYSTEMATIC LITERATURE SEARCH METHODS AND RESULTS
As discussed in the main body of the Provisional Peer-Reviewed Toxicity Value
(PPRTV) assessment, a systematic review was conducted to identify studies relevant to the
derivation of inhalation provisional toxicity values and oral and inhalation cancer weight of
evidence (WOE) for isobutyl alcohol. Because an oral reference dose (RfD) value is available on
the U.S. Environmental Protection Agency (U.S. EPA) Integrated Risk Information System
(IRIS) database (U.S. EPA. 1987). oral noncancer data for isobutyl alcohol were not reviewed.
LITERATURE SEARCH
Literature searches were conducted in April 2019 and updated in August 2022 for studies
relevant to the derivation of provisional toxicity values for isobutyl alcohol. Searches were
conducted using the U.S. EPA's Health and Environmental Research Online (HERO) database of
scientific literature. HERO searches the following databases: PubMed, TOXLINE6 (including
TSCATS1), and Web of Science (see Table B-l). The following resources were searched outside
of HERO for health-related values: American Conference of Governmental Industrial Hygienists
(ACGIH), Agency for Toxic Substances and Disease Registry (ATSDR), California
Environmental Protection Agency (CalEPA), Defense Technical Information Center (DTIC),
European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC), European
Chemicals Agency (ECHA), the U.S. EPA Chemical Data Access Tool (CDAT), the U.S. EPA
ChemView, the U.S. EPA Integrated Risk Information System (IRIS), the U.S. EPA Health
Effects Assessment Summary Tables (HEAST), the U.S. EPA Office of Water (OW),
International Agency for Research on Cancer (IARC), the U.S. EPA TSCATS2/TSCATS8e,
U.S. EPA High Production Volume (HPV), Chemicals via IPCS INCHEM, Japan Existing
Chemical Data Base (JECDB), Organisation for Economic Cooperation and Development
(OECD) Screening Information Data Sets (SIDS), OECD International Uniform Chemical
Information Database (IUCLID), OECD HPV, National Institute for Occupational Safety and
Health (NIOSH), National Toxicology Program (NTP), Occupational Safety and Health
Administration (OSHA), and World Health Organization (WHO) (see Table B-2).
6Note that this version of TOXLINE is no longer updated
(https://www.nlm.nih.gov/databases/download/toxlinesubset.html'): therefore, it was not included in the literature
search updates performed after April 2019.
Isobutyl Alcohol
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Table B-l. Database Query Strings for Isobutyl Alcohol (CASRN 78-83-1)
(PubMed, TOXLINE, WOS, TSCATS)
Database
(search date)
Query String
PubMed
8/1/2022
(78-83-l[rn] OR "isobutyl alcohol"[nm]) OR (("l-Hydroxymethylpropane"[tw] OR "1-Propanol,
2-methyl-"[tw] OR "2-METHYL PROPANOL"[tw] OR "2-Methyl-l-propanol"[tw] OR
"2-Methylpropan-l-ol"[tw] OR"2-methylpropane-l-ol"[tw] OR "2-Methylpropanol"[tw] OR
"2-Methylpropyl alcohol" [tw] OR "Butanol (iso)"[tw] OR "BUTYL ISO ALCOHOL" [tw] OR
"Fermentation butyl alcohol" [tw] OR "iso-butanol"[tw] OR "iso-Butyl alcohol" [tw] OR
"Isobutanol"[tw] OR "Isobutyl alcohol" [tw] OR "Isopropyl carbinol"[tw] OR
"Isopropylcarbinol"[tw]) NOT medline[sb])
WOS
8/1/2022
TS=("l-Propanol, 2-methyl-" OR "2-METHYL PROPANOL" OR "2-Methyl-1-propanol" OR
"2-Methylpropan-l-ol" OR "2-Methylpropanol" OR "iso-butanol" OR "iso-Butyl alcohol" OR
"Isobutanol" OR "Isobutyl alcohol" OR "1-Hydroxymethylpropane" OR "2-methylpropane-l-ol"
OR "2-Methylpropyl alcohol" OR "Butanol (iso)" OR "BUTYL ISO ALCOHOL" OR
"Fermentation butyl alcohol" OR "Isopropyl carbinol" OR "Isopropylcarbinol") AND
((WC=("Toxicology" OR "Endocrinology & Metabolism" OR "Gastroenterology & Hepatology"
OR "Gastroenterology & Hepatology" OR "Hematology" OR "Neurosciences" OR "Obstetrics &
Gynecology" OR "Pharmacology & Pharmacy" OR "Physiology" OR "Respiratory System" OR
"Urology & Nephrology" OR "Anatomy & Morphology" OR "Andrology" OR "Pathology" OR
"Otorhinolaryngology" OR "Ophthalmology" OR "Pediatrics" OR "Oncology" OR "Reproductive
Biology" OR "Developmental Biology" OR "Biology" OR "Dermatology" OR "Allergy" OR
"Public, Environmental & Occupational Health") OR SU=("Anatomy & Morphology" OR
"Cardiovascular System & Cardiology" OR "Developmental Biology" OR "Endocrinology &
Metabolism" OR "Gastroenterology & Hepatology" OR "Hematology" OR "Immunology" OR
"Neurosciences & Neurology" OR "Obstetrics & Gynecology" OR "Oncology" OR
"Ophthalmology" OR "Pathology" OR "Pediatrics" OR "Pharmacology & Pharmacy" OR
"Physiology" OR "Public, Environmental & Occupational Health" OR "Respiratory System" OR
"Toxicology" OR "Urology & Nephrology" OR "Reproductive Biology" OR "Dermatology" OR
"Allergy")) OR (WC="veterinary sciences" AND (TS="rat" OR TS="rats" OR TS="mouse" OR
TS="murine" OR TS="mice" OR TS="guinea" OR TS="muridae" OR TS=rabbit* OR
TS=lagomorph* OR TS=hamster* OR TS=ferret* OR TS=gerbil* OR TS=rodent* OR TS="dog"
OR TS="dogs" OR TS=beagle* OR TS="canine" OR TS="cats" OR TS="feline" OR TS="pig"
OR TS="pigs" OR TS="swine" OR TS="porcine" OR TS=monkey* OR TS=macaque* OR
TS=baboon* OR TS=marmoset*)) OR (TS=toxic* AND (TS="rat" OR TS="rats" OR
TS="mouse" OR TS="murine" OR TS="mice" OR TS="guinea" OR TS="muridae" OR
TS=rabbit* OR TS=lagomorph* OR TS=hamster* OR TS=ferret* OR TS=gerbil* OR
TS=rodent* OR TS="dog" OR TS="dogs" OR TS=beagle* OR TS="canine" OR TS="cats" OR
TS="feline" OR TS="pig" OR TS="pigs" OR TS="swine" OR TS="porcine" OR TS=monkey*
OR TS=macaque* OR TS=baboon* OR TS=marmoset* OR TS="child" OR TS="children" OR
TS=adolescen* OR TS=infant* OR TS="WORKER" OR TS="WORKERS" OR TS="HUMAN"
OR TS=patient* OR TS=mother OR TS=fetal OR TS=fetus OR TS=citizens OR TS=milk OR
TS=formula OR TS=epidemio* OR TS=population* OR TS=exposure* OR TS=questionnaire OR
SO=epidemio*)) OR TI=toxic*) Indexes=SCI-EXPANDED, CPCI-S, CPCI-SSH, BKCI-S,
BKCI-SSH, CCR-EXPANDED, IC Timespan=All years
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Table B-l. Database Query Strings for Isobutyl Alcohol (CASRN 78-83-1)
(PubMed, TOXLINE, WOS, TSCATS)
Database
(search date)
Query String
TOXLINE
4/9/2019
(78-83-1 [rn] OR "1-propanol 2-methyl-" OR "2-methyl propanol" OR "2-methyl-l-propanol" OR
"2-methylpropan-l-ol" OR "2-methylpropanol" OR "iso-butanol" OR "iso-butyl alcohol" OR
"isobutanol" OR "isobutyl alcohol" ) AND (ANEUPL [org] OR BIOSIS [org] OR CIS [org] OR
DART [org] OR EMIC [org] OR EPIDEM [org] OR HAPAB [org] OR HEEP [org] OR HMTC
[org] OR IP A [org] OR RISKLINE [org] OR MTGABS [org] OR NIOSH [org] OR NTIS [org]
OR PESTAB [org] OR PPBIB [org]) AND NOT PubMed [org] AND NOT pubdart [org]
"1-Hydroxymethylpropane" OR "2-methylpropane-l-ol" OR "2-Methylpropyl alcohol" OR
"Butanol (iso)" OR "BUTYL ISO ALCOHOL" OR "Fermentation butyl alcohol" OR "Isopropyl
carbinol" OR "Isopropylcarbinol"
TSCATS1
4/9/2019
78-83-1 [rn] AND tscats[org]
TSCATS = Toxic Substances Control Act Test Submission; WOS = Web of Science.
Table B-2. Resources Searched to Augment the Database Search Strings for
Isobutyl Alcohol (CASRN 78-83-1)
Additional
Strategies
Query and/or Link
ChemView
httDs://chemview.eDa.gov/chemview/?tf=2&ch=78-83-l&su=2-5-6-7&as=3-10-9-8&ac=l-15-16-
6378999&ma=4-l 1-
1981377&tds=0&tdl=10&tasl=l&tas2=asc&tas3=undefined&tss=&modal=detail&modalld=9983
9&modalSrc=2-5-10-4
NTP
• httDs://ntD.niehs.nih.gov/testing/status/agents/ts-78831.html
• 78-83-1
• "isobutanol" "isobutyl alcohol" "2-methyl propanol" "2-methyl-l-propanol"
• "1-propanol, 2-methyl-" "2-methylpropan-l-ol" "2-methylpropanol" "iso-butanol"
• "iso-butyl alcohol"
• "1-hydroxymethylpropane" "2-methylpropane-l-ol" "2-methylpropyl alcohol" "butanol (iso)"
• "butyl iso alcohol" "fermentation butyl alcohol" "isopropyl carbinol" "isopropylcarbinol"
httns ://nto.niehs.nih. gov/Dubhealth/roc/index-1 .html
ACGIH
ACGIH. 2018. 2018 TLVs and BEIs: Based on documentation of the threshold limit values for
chemical substances and physical agents and biological exposure indices. Cincinnati, OH:
American Conference of Governmental Industrial Hygienists
ATSDR
httD://www.atsdr.cdc.gov/toxorofiles/index.asD
CalEPA
htto://www.oehha. ca.gov/tcdb/index.asD
DWSHA
httDs://www.eDa.gov/svstem/files/documents/2022-01/dwtable2018.Ddf
ECETOC
htto://www.ecetoc.org/Dublications
ECHA
httDs://echa.euroDa.eu/substance-information/-/substanceinfo/100.001.044
httD://echa.euroDa.eu/infomiation-on-chemicals/information-from-existing-substances-regulation
HEAST
httD://era-heast.ornl.gov/heast.DhD
HP VIS
httos://iasoub.era.gov/oDDthnv/Dublic search.html oage
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Table B-2. Resources Searched to Augment the Database Search Strings for
Isobutyl Alcohol (CASRN 78-83-1)
Additional
Strategies
Query and/or Link
IARC
http://monographs.iarc.fr/ENG/Classification/List of Classifications.pdf
InChem—
OECD SIDS
http://www.inchem.ore/paees/sids.html
IRIS
http://www.epa. eov/iris/
JECDB
http://dra4.nihs.eo.ip/mhlw data/isp/SearchPaeeENG.isp
NIOSH
http://www.cdc.eov/niosh/npe/npedcas.html
OECD (HPV,
SIDS,
IUCLID)
http://webnet.oecd.ore/hpv/ui/Search.aspx
OSHA
http://www.osha.eov/pls/oshaweb/owadisp.show document?p table STANDARDS&n id=9992
http://www.osha.eov/pls/oshaweb/owadisp.show document?p table STANDARDS&n id=10629
https://www.osha.eov/pls/oshaweb/owadisp.show document?p table STANDARDS&n id= 10286
WHO
https ://www. who. int/publications/
ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic Substances
and Disease Registry; BEI = biological exposure index; CalEPA = California Environmental Protection Agency;
DWSHA = Drinking Water Standards and Health Advisories; ECETOC = European Centre for Ecotoxicology and
Toxicology of Chemicals; ECHA = European Chemicals Agency; HEAST = Health Effects Assessment Summary
Tables; HPV = High Production Volume; HPVIS = High Production Volume Information System;
IARC = International Agency for Research on Cancer; IRIS = Integrated Risk Information System;
IUCLID = International Uniform Chemical Information Database; JECDB = Japan Existing Chemical Data Base;
NIOSH = National Institute for Occupational Safety and Health; NTP = National Toxicology Program;
OECD = Organisation for Economic Cooperation and Development; OSHA = Occupational Safety and Health
Administration; SIDS = Screening Information Data Sets; TLV = threshold limit value; WHO = World Health
Organization.
SCREENING PROCESS
Two screeners independently conducted a title and abstract screening of the search results
using DistillerSR7 to identify study records that met the Population, Exposure, Comparator, and
Outcome (PECO) eligibility criteria (see Table B-3).
'DistillerSR is a web-based systematic review software used to screen studies available at
https://www.evidencepartners.com/products/distillersr-svstematic-review-software.
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Table B-3. PECO Criteria for Isobutyl Alcohol (CASRN 78-83-1)
PECO Element
Evidence
Population
Humans, laboratory mammals, and other animal models of established relevance to human
health (e.g., Xenopus embryos); mammalian organs, tissues, and cell lines; and bacterial and
eukaryote models of genetic toxicity.
Exposure
In vivo (all routes), ex vivo, and in vitro exposure to isobutyl alcohol, including mixtures to
which isobutyl alcohol may contribute significantly to exposure or observed effects.
Comparator
Any comparison (across dose, duration, or route) or no comparison (e.g., case reports without
controls).
Outcome
Any endpoint suggestive of a toxic effect on any bodily system, or mechanistic change
associated with such effects. Any endpoint relating to disposition of the chemical within the
body.
PECO = Population, Exposure, Comparator, and Outcome.
Records that were included based on title and abstract screening advanced to full-text
review using the same PECO eligibility criteria. Full-text copies of potentially relevant records
identified from title and abstract screening were retrieved, stored in the HERO database, and
independently assessed by two screeners using DistillerSR to confirm eligibility. If studies were
considered PECO-relevant based on full-text review, screeners tagged the studies as one of the
following study types: human (all studies); animal (oral route); animal (inhalation chronic/
carcinogenicity); animal (inhalation subchronic); animal (inhalation reproductive/
developmental); animal (inhalation acute); animal (other routes besides oral or inhalation);
absorption, distribution, metabolism, and excretion/physiologically based pharmacokinetic
(ADME/PBPK); genotoxicity; mechanistic; or reviews/secondary sources. If "animal (oral
route)" was selected, reviewers were asked to indicate whether the study was a chronic/
carcinogenicity study (yes/no). Because the focus of the PPRTV assessment was to assess data
relevant to derivation of provisional reference concentrations (p-RfCs) and inhalation and oral
cancer assessment (but not provisional reference doses [p-RfDs]), only studies tagged as animal
(inhalation subchronic), animal (inhalation reproductive/developmental), and animal (oral
chronic/carcinogenicity study) moved onto the study evaluation stage. All other PECO-relevant
studies were retained as supplemental information.
At both title/abstract and full-text review levels, screening conflicts were resolved by
discussion between the primary screeners in consultation with a third reviewer to resolve any
remaining disagreements.
RESULTS
Literature searches yielded 1,298 unique records (see Figure B-l). Of the 1,298 studies
identified, 1,099 were excluded during title and abstract screening, while 199 were reviewed at
the full-text level. After full-text review, 114 studies were excluded, and 74 studies were tagged
as supplemental including acute inhalation studies, studies evaluating routes other than inhalation
or oral, mechanistic studies, toxicokinetic studies, genotoxicity studies, and reviews and
secondary sources of information. Eleven studies were considered further as relevant to
inhalation provisional toxicity values and oral and inhalation cancer assessment for isobutyl
alcohol, including three human health studies (described in three publications), three subchronic
48
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animal inhalation studies (described in one peer-reviewed and two non-peer-reviewed
publications), three reproductive/developmental animal inhalation studies (described in one
peer-reviewed publication and one non-peer-reviewed publication), and two oral cancer study in
animals (described in one foreign language publication and one English translation report).
Database and Supplemental Searches
PubMed
n=569
WOS
n=252
Toxtine
n=414
TSCATS
n=50
Additional
Strategies
n=73
Other(n=17)
Resources listed in
Table 2
\
Title and Abstract
Figure B-L Literature Search and Screening Flow Diagram for
Isobutvl Alcohol (CASRN 78-83-1)
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APPENDIX C. DATA EVALUATION METHODS AND RESULTS
METHODOLOGY
Based on the literature screen, there were 11 separate studies considered relevant to
inhalation provisional toxicity values and oral and inhalation cancer weight of evidence (WOE)
for isobutyl alcohol. Study evaluation proceeded for eight studies, including a cross-sectional
occupational exposure study (Hollett and Aw. 1982). a human patch-test study (Wilkin and
Stewart. 1987; Wilkin and Former. 1985). two subchronic inhalation studies in rats (Li et at..
1999; Branch et at.. 1996; Kaempfe and Li. 1996). a two-generation inhalation study in rats
(Nemec. 2003). a developmental inhalation study in rats and rabbits (Ktimisch and Hell wig.
1995). and an oral cancer study in rats (Dow Chemical. 1992).
Study evaluations were conducted by two independent reviewers using the
U.S. Environmental Protection Agency (U.S. EPA) version of the Health Assessment Workspace
Collaborative (HAWC) database, a free and open-source, web-based software application
designed to manage and facilitate the process of conducting literature assessments.8 Study
evaluation conflicts were resolved by discussion between the primary reviewers in consultation
with a third reviewer to resolve any remaining disagreements.
The general approach for evaluating human health and animal toxicology studies is
presented in Figure C-l. For each of the outcomes in a study, reviewers evaluated each of the
domains shown in Figure C-l. Reviewers reached a consensus judgment of good, adequate,
deficient, not reported, or critically deficient in each domain, as defined in Figure C-l. Questions
used to guide the development of criteria for each domain in human health and animal
toxicology studies are presented in Tables C-l and C-2, respectively. Evaluations were focused
on the methodological approaches and adequacy of reporting in the individual studies and did not
consider either the direction or the magnitude of the study results. Key concerns for the review of
epidemiology and animal toxicology studies are potential sources of bias (factors that could
systematically affect the magnitude or direction of an effect) and insensitivity (factors that limit
the ability of a study to detect a true effect). Once the evaluation domains were rated, a study
confidence rating of high, medium, low, or uninformative for a specific health outcome was
determined by considering the strengths and limitations, as defined in Figure C-l. Study
confidence ratings were based on reviewer judgments across the evaluation domains, including
the likely impact that the noted deficiencies in bias and sensitivity, or inadequate reporting, may
have on the results.
8HAWC: A modular web-based interface to facilitate development of human health assessments of chemicals
(https ://hawcprd. epa. gov).
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Individual Study Level Domains
Domain Judgments
Epidemiological
Animal
Exposure Measurement
Reporting Quality
Outcome Ascertainment
Selection or Performance Bias
Population Selection
Confounding/Variable Control
Confounding
Reporting or Attrition Bias
Analysis
Exposure Methods Sensitivity
Sensitivity
Outcome Measures and Results Display
Selective Reporting
Judgement
Interpretation
++
Good
The study was conducted appropriately in relation to the evaluation domain and any deficiencies, if present,
are minor and would not be expected to influence the study results.
+
Adequate
There are methodological limitations relatingto the evaluation domain, butthat those limitations are not
likely to be severe or to have a notable impact on the results.
-
Deficient
Identified biases or deficiencies that are interpreted as likely to have had a notable impact on the results or
that prevent interpretation of the study findings.
NR
Not
reported
The information necessary to evaluate the domain was not available in the study. Generally, this term carries
the same functional interpretation as deficientforthe purposes of the study confidence classification.
Critically
Deficient
The study conduct introduced a serious flaw that makes the observed effect(s) uninterpretable. Studies with
a determination of critically deficient in an evaluation domain will almost always cause the study to be
considered overall "uninformative".
Overall Study Rating
Domain Judgments
Interpretation
High
Good across all or most evaluation domains
A well-conducted study with no notable deficiencies or concerns
were identified; the potential for bias is unlikely or minimal, and
the study used sensitive methodology.
Medium
Good or Adequate across most domains; may have a
Deficient evaluation in domain(s) considered to minimal
influence on the magnitude or direction of effect
A satisfactory (acceptable) study in which deficiencies or
concerns were noted, but the limitations are unlikely to be of a
notable degree.
Low
Deficient in one or more domains
A substandard study in which deficiencies or concerns were
noted, and the potentialfor bias or inadequate sensitivity could
have a significant impact on the study results or their
interpretation.
Uninformative
Critically Deficient in one or more domains
An unacceptable study in which serious flaw(s) make the study
results unusable for informing hazard identification.
Figure C-l. Approach for Evaluating Epidemiological and Animal Toxicology Studies
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Table C-l. Questions Used to Guide the Development of Criteria for Each
Domain in Epidemiology Studies
Core Question
Prompting Questions
Follow-Up Questions
ExDOSure
• For all:
o Does the exposure measure capture the variability in
exposure among the participants, considering intensity,
frequency, and duration of exposure?
o Does the exposure measure reflect a relevant time
window? If not, can the relationship between measures
in this time and the relevant time window be estimated
reliably?
o Was the exposure measurement likely to be affected by a
knowledge of the outcome?
o Was the exposure measurement likely to be affected by
the presence of the outcome (i.e., reverse causality)?
• For case-control studies of occupational exposures:
o Is exposure based on a comprehensive job history
describing tasks, setting, time period, and use of specific
materials?
• For biomarkers of exposure, general population:
o Is a standard assay used? What are the intra- and
interassay coefficients of variation? Is the assay likely to
be affected by contamination? Are values less than the
limit of detection dealt with adequately?
• What exposure time period is reflected by the biomarker? If
the half-life is short, what is the correlation between serial
measurements of exposure?
• Is the degree of
exposure
misclassification
likely to vary by
exposure level?
• If the correlation
between exposure
measurements is
moderate, is there an
adequate statistical
approach to
ameliorate variability
in measurements?
• If there is a concern
about the potential
for bias, what is the
predicted direction
or distortion of the
bias on the effect
estimate (if there is
enough
information)?
Measurement
Does the exposure
measure reliably
distinguish between
levels of exposure in
a time window
considered most
relevant for a causal
effect with respect to
the development of
the outcome?
Outcome
• For all:
o Is outcome ascertainment likely to be affected by
knowledge of, or presence of, exposure (e.g., consider
access to health care, if based on self-reported history of
diagnosis)?
• For case-control studies:
o Is the comparison group without the outcome
(e.g., controls in a case-control study) based on objective
criteria with little or no likelihood of inclusion of people
with the disease?
• For mortality measures:
o How well does cause of death data reflect occurrence of
the disease in an individual? How well do mortality data
reflect incidence of the disease?
• For diagnosis of disease measures:
o Is diagnosis based on standard clinical criteria? If based
on self-report of diagnosis, what is the validity of this
measure?
• For laboratory-based measures (e.g., hormone levels):
o Is a standard assay used? Does the assay have an
acceptable level of interassay variability? Is the
sensitivity of the assay appropriate for the outcome
measure in this study population?
• Is there a concern
that any outcome
misclassification is
nondifferential,
differential, or both?
• What is the predicted
direction or
distortion of the bias
on the effect estimate
(if there is enough
information)?
Ascertainment
Does the outcome
measure reliably
distinguish the
presence or absence
(or degree of
severity) of the
outcome?
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Table C-l. Questions Used to Guide the Development of Criteria for Each
Domain in Epidemiology Studies
Core Question
Prompting Questions
Follow-Up Questions
ParticiDant
• For longitudinal cohort:
o Did participants volunteer for the cohort based on
knowledge of exposure and/or preclinical disease
symptoms? Was entry into the cohort or continuation in
the cohort related to exposure and outcome?
• For occupational cohort:
o Did entry into the cohort begin with the start of the
exposure?
o Was follow-up or outcome assessment incomplete, and if
so, was follow-up related to both exposure and outcome
status?
o Could exposure produce symptoms that would result in a
change in work assignment/work status ("healthy worker
survivor effect")?
• For case-control study:
o Were controls representative of population and time
periods from which cases were drawn?
o Are hospital controls selected from a group whose
reason for admission is independent of exposure?
o Could recruitment strategies, eligibility criteria, or
participation rates result in differential participation
relating to both disease and exposure?
• For population-based survey:
o Was recruitment based on advertisement to people with
knowledge of exposure, outcome, and hypothesis?
• Were differences in
participant
enrollment and
follow-up evaluated
to assess bias?
• If there is a concern
about the potential
for bias, what is the
predicted direction
or distortion of the
bias on the effect
estimate (if there is
enough
information)?
• Were appropriate
analyses performed
to address changing
exposures over time
in relation to
symptoms?
• Is there a comparison
of participants and
nonparticipants to
address whether
differential selection
is likely?
Selection
Is there evidence that
selection into or out
of the study (or
analysis sample) was
jointly related to
exposure and to
outcome?
Confounding
• Is confounding adequately addressed by considerations in...
o participant selection (matching or restriction)?
o accurate information on potential confounders, and
statistical adjustment procedures?
o lack of association between confounder and outcome, or
confounder and exposure in the study?
o information from other sources?
• Is the assessment of confounders based on a thoughtful
review of published literature, potential relationships (e.g., as
can be gained through directed acyclic graphing), minimizing
potential overcontrol (e.g., inclusion of a variable on the
pathway between exposure and outcome)?
• If there is a concern
about the potential
for bias, what is the
predicted direction
or distortion of the
bias on the effect
estimate (if there is
enough
information)?
Is confounding of
the effect of the
exposure likely?
Analysis
• Are missing outcome, exposure, and covariate data
recognized, and if necessary, accounted for in the analysis?
• Does the analysis appropriately consider variable
distributions and modeling assumptions?
• Does the analysis appropriately consider subgroups of
interest (e.g., based on variability in exposure level or
duration, or susceptibility)?
• Is an appropriate analysis used for the study design?
• Is effect modification considered, based on considerations
developed a priori?
• Does the study include additional analyses addressing
potential biases or limitations (i.e., sensitivity analyses)?
• If there is a concern
about the potential
for bias, what is the
predicted direction
or distortion of the
bias on the effect
estimate (if there is
enough
information)?
Does the analysis
strategy and
presentation convey
the necessary
familiarity with the
data and
assumptions?
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Table C-l. Questions Used to Guide the Development of Criteria for Each
Domain in Epidemiology Studies
Core Question
Prompting Questions
Follow-Up Questions
Sensitivitv
• Is the exposure range adequate?
• Was the appropriate population included?
• Was the length of follow-up adequate? Is the time/age of
outcome ascertainment optimal given the interval of exposure
and the health outcome?
• Are there other aspects related to risk of bias or otherwise
that raise concerns about sensitivity?
Is there a concern
that sensitivity of the
study is not adequate
to detect an effect?
Selective Renortina
• Are the results needed for the IRIS analysis (based on a priori
specification) presented? If not, can these results be
obtained?
• Are only statistically significant results presented?
Is there reason to be
concerned about
selective reporting?
IRIS = Integrated Risk Information System.
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
ex
s
"H
o
s.
(2
Reporting Quality—
Does the study report
information for evaluating
the design and conduct of
the study for the
endpoint(s)/outcome(s) of
interest?
Notes: Reviewers should
reach out to study authors
to obtain missing
information when studies
are considered key for
hazard evaluation and/or
dose-response. This
domain is limited to
reporting. Other aspects of
the exposure methods,
experimental design, and
endpoint evaluation
methods are evaluated
using the domains related
to risk of bias and study
sensitivity.
Does the study report the following?
• Critical information necessary to
perform study evaluation:
o Species, test article name, levels and
duration of exposure; route
(e.g., oral; inhalation), qualitative or
quantitative results for at least one
endpoint of interest.
• Important information for evaluating
the study methods:
o Test animal: strain, sex, source, and
general husbandry procedures,
o Exposure methods: source, purity,
method of administration,
o Experimental design: frequency of
exposure, animal age and life stage
during exposure and at
endpoint/outcome evaluation,
o Endpoint evaluation methods: assays
or procedures used to measure the
endpoint(s)/outcome(s) of interest.
These considerations typically do not need to be refined by assessment
teams, although in some instances the important information may be
refined depending on the endpoint(s)/outcome(s) of interest or the chemical
under investigation.
A judgment and rationale for this domain should be given for the study.
Typically, these will not change regardless of the endpoint(s)/outcome(s)
investigated by the study. In the rationale, reviewers should indicate
whether the study adhered to GLP, OECD, or other testing guidelines.
• Good: All critical and important information is reported or inferable
for the endpoint(s)/outcome(s) of interest.
• Adequate: All critical information is reported, but some important
information is missing. However, the missing information is not
expected to significantly impact the study evaluation.
• Deficient. All critical information is reported but important
information is missing that is expected to significantly reduce the
ability to evaluate the study.
• Critically deficient. Study report is missing any pieces of critical
information. Studies that are critically deficient for reporting are
uninformative for the overall rating and not considered further for
evidence synthesis and integration.
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
as
tu
u
s
cS
e
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a.
s
cS
S
o
a>
cn
a
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S
Allocation—
Were animals assigned to
experimental groups using
a method that minimizes
selection bias?
For each study:
• Did each animal or litter have an equal
chance of being assigned to any
experimental group (i.e., random
allocation)?
• Is the allocation method described?
• Aside from randomization, were any
steps taken to balance variables across
experimental groups during allocation?
These considerations typically do not need to be refined by assessment
teams.
A judgment and rationale for this domain should be given for each cohort or
experiment in the study.
Good: Experimental groups were randomized, and any specific
randomization procedure was described or inferable
(e.g., computer-generated scheme). (Note that normalization is not the
same as randomization [see response for adequate].)
Adequate: Study authors reported that groups were randomized but did
not describe the specific procedure used (e.g., "animals were
randomized"). Alternatively, study authors used a nonrandom method
to control for important modifying factors across experimental groups
(e.g., body-weight normalization).
Not reported (interpreted as deficient): No indication of randomization
of groups or other methods (e.g., normalization) to control for
important modifying factors across experimental groups.
Critically deficient. Bias in the animal allocations was reported or
inferable.
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
es
S
tu
Observational
Bias/Blinding—
Did the study implement
measures to reduce
observational bias?
For each endpoint/outcome or grouping of
endpoints/outcomes in a study:
• Does the study report blinding or other
methods/procedures for reducing
observational bias?
• If not, did the study use a design or
approach for which such procedures can
be inferred?
• What is the expected impact of failure to
implement (or report implementation) of
these methods/procedures on the results?
These considerations typically do not need to be refined by the assessment
teams. (Note that it can be useful for teams to identify highly subjective
measures of endpoint[s]/outcome[s] where observational bias may strongly
influence results prior to performing evaluations.)
A iudement and rationale for this domain should be siven for each
u
s
cndDoint/outcomc or aroiiD of endooints/outcomes investigated in the studv.
0>
a.
¦a
s
CS
S
_o
ts
—
"3
in
CS
s
«4-
o
a
%
3
• Good\ Measures to reduce observational bias were described
(e.g., blinding to conceal treatment groups during endpoint evaluation;
consensus-based evaluations of histopathology lesions).3
• Adequate: Methods for reducing observational bias (e.g., blinding) can
be inferred or were reported but described incompletely.
• Not reported: Measures to reduce observational bias were not
described.
o Interpreted as adequate—The potential concern for bias was
mitigated based on use of automated/computer-driven systems,
standard laboratory kits, relatively simple, objective measures
(e.g., body or tissue weight), or screening-level evaluations of
histopathology.
o Interpreted as deficient—The potential impact on the results is
major (e.g., outcome measures are highly subjective).
• Critically deficient Strong evidence for observational bias that could
have impacted results.
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
Risk of Bias: Confounding/Variable Control
Confounding—
Are variables with the
potential to confound or
modify results controlled
for and consistent across
all experimental groups?
For each study:
• Are there differences across the treatment
groups (e.g., co-exposures, vehicle, diet,
palatability, husbandry, health status, and
so forth) that could bias the results?
• If differences are identified, to what
extent are they expected to impact the
results?
These considerations may need to be refined by assessment teams, as the
specific variables of concern can vary by experiment or chemical.
A iudement and rationale for this domain should be siven for each cohort or
experiment in the studv. notins when the potential for confoundine is
restricted to specific cndDoint(s)/outcomc(s).
• Good: Outside of the exposure of interest, variables that are likely to
confound or modify results appear to be controlled for and consistent
across experimental groups.
• Adequate: Some concern that variables that were likely to confound or
modify results were uncontrolled or inconsistent across groups but are
expected to have a minimal impact on the results.
• Deficient. Notable concern that potentially confounding variables were
uncontrolled or inconsistent across groups and are expected to
substantially impact the results.
• Critically deficient. Confounding variables were presumed to be
uncontrolled or inconsistent across groups and are expected to be a
primary driver of the results.
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
Selective Reporting and
For each study:
These considerations typically do not need to be refined by assessment
Attrition—
teams.
Did the study report results
• Selective reporting bias:
for all prespecified
o Are all results presented for
A iudement and rationale for this domain should be siven for each cohort or
outcomes and tested
endpoint(s)/outcome(s) described in
experiment in the studv.
es
S
s
animals?
the methods (see note)?
• Good: Quantitative or qualitative results were reported for all
_o
Note: This domain does
• Attrition bias:
prespecified outcomes (explicitly stated or inferred), exposure groups,
X
not consider the
o Are all animals accounted for in the
and evaluation time points. Data not reported in the primary article is
appropriateness of the
results?
available from supplemental material. If results, omissions, or animal
¦a
s
analysis/results
o If there are discrepancies, do study
attrition is identified, the study authors provide an explanation, and
a
#J3
presentation. This aspect of
authors provide an explanation
these are not expected to impact the interpretation of the results.
.c
study quality is evaluated
(e.g., death or unscheduled sacrifice
• Adequate: Quantitative or qualitative results are reported for most
&
o
in another domain.
during the study)?
prespecified outcomes (explicitly stated or inferred), exposure groups
&
(2
o If unexplained results, omissions,
and evaluation time points. Omissions and/or attrition are not explained
and/or attrition are identified, what is
but are not expected to significantly impact the interpretation of the
ffl
«4-
the expected impact on the
results.
interpretation of the results?
• Deficient. Quantitative or qualitative results are missing for many
o
prespecified outcomes (explicitly stated or inferred), exposure groups
S
and evaluation time points and/or high animal attrition; omissions
and/or attrition are not explained and may significantly impact the
interpretation of the results.
• Critically deficient. Extensive results omission and/or animal attrition
is identified and prevents comparisons of results across treatment
groups.
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
s
a>
in
o
JS
a
¦-
s
%
o
s.
H
W
S
0>
IS1
Characterization—
Did the study adequately
characterize exposure to
the chemical of interest and
the exposure
administration methods?
Note: Consideration of the
appropriateness of the
route of exposure is not
evaluated at the individual
study level. Relevance and
utility of the routes of
exposure are considered in
the PECO criteria for
study inclusion and during
evidence synthesis.
For each study:
• Does the study report the source and
purity and/or composition (e.g., identity
and percent distribution of different
isomers) of the chemical? If not, can the
purity and/or composition be obtained
from the supplier (e.g., as reported on the
website)?
• Was independent analytical verification
of the test article purity and composition
performed?
• Did the study authors take steps to ensure
the reported exposure levels were
accurate?
o For inhalation studies: Were target
concentrations confirmed using
reliable analytical measurements in
chamber air?
o For oral studies: If necessary, based
on consideration of chemical-specific
knowledge (e.g., instability in
solution; volatility) and/or exposure
design (e.g., the frequency and
duration of exposure), were chemical
concentrations in the dosing
solutions or diet analytically
confirmed?
• Are there concerns about the methods
used to administer the chemical
(e.g., inhalation chamber type, gavage
volume, etc.)?
It is essential that these criteria are considered and potentially refined by
assessment teams, as the specific variables of concern can vary by
chemical.
A judgment and rationale for this domain should be given for each cohort or
experiment in the study.
Good: Chemical administration and characterization is complete
(i.e., source, purity, and analytical verification of the test article are
provided). There are no concerns about the composition, stability, or
purity of the administered chemical or the specific methods of
administration. For inhalation studies, chemical concentrations in the
exposure chambers are verified using reliable analytical methods.
Adequate: Some uncertainties in the chemical administration and
characterization are identified, but these are expected to have minimal
impact on interpretation of the results (e.g., source and vendor-reported
purity are presented, but not independently verified; purity of the test
article is suboptimal but not concerning). For inhalation studies, actual
exposure concentrations are missing or verified with less reliable
methods.
Deficient. Uncertainties in the exposure characterization are identified
and expected to substantially impact the results (e.g., source of the test
article is not reported; levels of impurities are substantial or
concerning; deficient administration methods such as use of static
inhalation chambers or a gavage volume considered too large for the
species and/or life stage at exposure).
Critically deficient. Uncertainties in the exposure characterization are
identified, and there is reasonable certainty that the results are largely
attributable to factors other than exposure to the chemical of interest
(e.g., identified impurities are expected to be a primary driver of the
results).
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
Sensitivity: Outcome Measures and Results
Display
Endpoint Sensitivity and
Specificity—
Are the procedures
sensitive and specific for
evaluating the
endpoint(s)/outcome(s) of
interest?
Note: Sample size alone is
not a reason to conclude
an individual study is
critically deficient.
For each endpoint/outcome or grouping of
endpoints/outcomes in a study:
• Are there concerns regarding the
specificity and validity of the protocols?
• Are there serious concerns regarding the
sample size (see note)?
• Are there concerns regarding the timing
of the endpoint assessment?
Considerations for this domain are highly variable depending on the
endpoint(s)/outcome(s) of interest and must be refined by assessment
teams.
A iudement and rationale for this domain should be siven for each
cndDoint/outcomc or aroiiD of endooints/outcomes investigated in the studv.
Examples of potential concerns include:
• Selection of protocols that are insensitive or nonspecific for the
endpoint of interest.
• Use of unreliable methods to assess the outcome.
• Assessment of endpoints at inappropriate or insensitive ages, or
without addressing known endpoint variation (e.g., due to circadian
rhythms, estrous cyclicity, etc.).
• Decreased specificity or sensitivity of the response due to the timing of
endpoint evaluation, as compared to exposure (e.g., short-acting
depressant or irritant effects of chemicals; insensitivity due to
prolonged period of nonexposure prior to testing).
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
Sensitivity: Outcome Measures and Results
Display
Results Presentation—
Are the results presented in
a way that makes the data
usable and transparent?
For each endpoint/outcome or grouping of
endpoints/outcomes in a study:
• Does the level of detail allow for an
informed interpretation of the results?
• Are the data analyzed, compared, or
presented in a way that is inappropriate or
misleading?
Considerations for this domain are highly variable depending on the
outcomes of interest and must be refined by assessment teams.
A iudement and rationale for this domain should be siven for each
cndDoint/outcomc or aroiiD of endooints/outcomes investigated in the studv.
Examples of potential concerns include:
• Nonpreferred presentation such as developmental toxicity data
averaged across pups in a treatment group when litter responses are
more appropriate.
• Failing to present quantitative results.
• Pooling data when responses are known or expected to differ
substantially (e.g., across sexes or ages).
• Failing to report on or address overt toxicity when exposure levels are
known or expected to be highly toxic.
• Lack of full presentation of the data (e.g., presentation of mean without
variance data; concurrent control data are not presented).
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Table C-2. Questions Used to Guide the Development of Criteria for Each Domain in Experimental Animal Toxicology
Studies
Evaluation
Type
Domain-Core Question
Prompting Questions
Basic Considerations
0>
u
s
0>
¦a
SB
s
o
U
13
•-
a>
>
O
Overall Confidence—
Considering the identified
strengths and limitations,
what is the overall
confidence rating for the
endpoint(s)/outcome(s) of
interest?
Note: Reviewers should
mark studies that are rated
lower than high confidence
only due to low sensitivity
(i.e., bias towards the null)
for additional
consideration during
evidence synthesis. If the
study is otherwise well
conducted and an effect is
observed, the confidence
may be increased.
For each endpoint/outcome or grouping of
endpoints/outcomes in a study:
• Were concerns (i.e., limitations or
uncertainties) related to the reporting
quality, risk of bias, or sensitivity
identified?
• If yes, what is their expected impact on
the overall interpretation of the reliability
and validity of the study results, including
(when possible) interpretations of impacts
on the magnitude or direction of the
reported effects?
The overall confidence rating considers the likely impact of the noted
concerns (i.e., limitations or uncertainties) in reporting, bias, and sensitivity
on the results.
A confidence rating and rationale should be given for each
endpoint/outcome or group of endpoints/outcomes investigated in the study.
High: No notable concerns are identified (e.g., most or all domains
rated good).
Medium: Some concerns are identified but expected to have minimal
impact on the interpretation of the results (e.g., most domains rated
adequate ox good, may include studies with deficient ratings if
concerns are not expected to strongly impact the magnitude or direction
of the results). Any important concerns should be carried forward to
evidence synthesis.
Low: Identified concerns are expected to have significant impact on the
study results or their interpretation (e.g., generally, deficient ratings for
one or more domains). The concerns leading to this confidence
judgment must be carried forward to evidence synthesis (see note).
Uninformative: Serious flaw(s) that make the study results unusable for
informing hazard identification (e.g., generally, critically deficient
rating in any domain; many deficient ratings). Uninformative studies
are considered no further in the synthesis and integration of evidence.
Tor nontargeted or screening-level histopathology outcomes often used in guideline studies, blinding during the initial evaluation of tissues is generally not
recommended as masked evaluation can make "the task of separating treatment-related changes from normal variation more difficult" and "there is concern that masked
review during the initial evaluation may result in missing subtle lesions." Generally, blinded evaluations are recommended for targeted secondary review of specific
tissues or in instances when there is a predefined set of outcomes that is known or predicted to occur (Crissman et al.. 2004).
GLP = Good Laboratory Practice; OECD = Organisation for Economic Co-operation and Development; PECO = Population, Exposure, Comparator, Outcome.
63
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RESULTS
Based on the study evaluations, all human studies and the animal oral cancer study (Dow
Chemical 1992) were considered low confidence or aninformative (see Figure C-2); therefore,
these studies were only briefly discussed in Section 2.3 of this document (see Table 4B).
AX& -10V1-
^ ^
Participant
Measures
Outcome -
Confounding
Analysis
Selective
Study sensitivity
Overall confidence
NR
+
+
+
B
N/A
+
++ ++
H
H
.f0>
dSSl *** , ¦£&
Reporting ¦
Study Design Applicability
Outcome Assessment
Results Presentation
Overall confidence
¦ -
-
NR
-
NR
NR
• H
++
B
B
¦
,,
1
¦
«¦ «¦
1
Good
Adequate
Deficient
Not
Not assessed 1
Critically
(metric)
(metric) or
(metric)
NR
reported
N/A
due to critical 1
deficient (metric)
or High
Medium
or Low
(metric)
deficiency in 1
or Uninformative
(overall)
(overall)
(overall)
other domain 1
(overall)
Click to see human interactive data graphic and animal interactive data graphic for rating rationales.
Figure C-2. Evaluation Results for Human (A) and Animal (B) Studies Assessing Effects of
Isobutyl Alcohol
The remaining five in vivo animal studies are represented in three publications, including
one rat and one rabbit developmental study (Klimisch and Hell wig. 1995). two subchronic
inhalation studies in rats [Branch et al. (1996); Li and Kaempfe (1996); both studies also
presented in Li et al. (1999)1. and one two-generation study in rats (Nemec. 2003). which were
included in Section 2 of this document (see Table 4A). As shown in Figure C-2, these studies
were rated as high or medium confidence.
DATA EXTRACTION
Information on study design, methods, results, and data from animal toxicology studies
were extracted into HAWC and are available at https://hawcprd.epa.gov/assessment/100500Q33/.
Visual graphics prepared from HAWC are embedded as hyperlinks and are fully
interactive when viewed online by way of a "click to see more" capability. Clicking on content
allows access to study evaluation ratings, methodological details, and underlying study data. The
action of clicking on content contained in those visual graphics (e.g., data points, endpoint, and
study design) will yield the underlying data supporting the visual content. Note: The following
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browsers are fully supportedfor accessing HAWC: Google Chrome (preferred), Mozilla Firefox,
and Apple Safari. There are errors in functionality when viewed with Internet Explorer. Any
discrepancies in data extraction were resolved by discussion or consultation with a third member
of the evaluation team. Analytical concentrations were extracted as reported in the study and
converted to mg/m3 human equivalent concentrations (HECs).
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APPENDIX D. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2001). Isobutanol. In
Documentation of the threshold limit values and biological exposure indices. Cincinnati,
OH.
ACGIH (American Conference of Governmental Industrial Hygienists). (2018). Isobutanol. In
2018 TLVs and BEIs: Based on the documentation of the threshold limit values for
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