United States
Environmental Protection
Agency
EPA/690/R-02/01 OF
Final
5-31-2002
Provisional Peer Reviewed Toxicity Values for
Derivation of a Chronic Inhalation RfC
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
Isobutanol
(CASRN 78-83-1)

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
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NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(imol
micromoles
voc
volatile organic compound
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5-31-2002
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
ISOBUTANOL (CASRN 78-83-1)
Derivation of a Chronic Inhalation RfC
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
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5-31-2002
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
An RfC for isobutanol is not available on IRIS (U.S. EPA, 2001) or in the HEAST (U.S.
EPA, 1997). The CARA database (U.S. EPA, 1991, 1994a) lists a Health and Environmental
Effects Profile (U.S. EPA, 1986a) and Reportable Quantity Document (1986b); neither of which
derived an RfC for isobutanol. ATSDR has not published a Toxicological Profile for isobutanol
(ATSDR, 2000).
ACGIH (2000) recommends a ceiling limit (TLV/C) of 50 ppm (152 mg/m3) for
isobutanol. This TLV value is based on the potential for acute toxic effects by analogy to n-
butanol (ACGIH, 1991). In its 1989 ruling, OSHA (1989) established a PEL ceiling limit of 50
ppm (150 mg/m3), based on analogy with n-butanol (irritation and narcosis). However, when this
ruling was vacated in 1993, the PEL reverted to the previously established 8-hour PEL-TWA of
100 ppm (300 mg/m3) (OSHA, 2000). NIOSH established a REL ceiling limit of 50 ppm (150
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5-31-2002
mg/m3) for isobutanol by concurrence with the 1989 OSHA PEL limit and has established an
ILDH value of 8000 ppm (NIOSH, 2000).
IARC (2000), WHO (1987), and NTP (2000) were searched, but contained no relevant
information. Updated literature searches were conducted from 1985 to November 2000 for
studies relevant to the derivation of an RfC. The databases searched were: TOXLINE,
MEDLINE, CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK,
and EMIC/EMICBACK.
REVIEW OF THE PERTINENT LITERATURE
Human Studies
Isobutanol can be absorbed through the lungs in humans (Browning, 1965). No studies
addressing systemic toxicity of isobutanol inhalation in humans were located. In employees
exposed repeatedly to approximately 300 mg/m3, no significant health effects were observed,
although irritation of the eyes and throat were reported in other studies where the vapor
concentrations were higher (NIOSH, 1978). Neither the duration nor range of exposures were
provided in the secondary citation. WHO (1987) reports an odor threshold for isobutanol of
approximately 1.5 ppm (4.5 mg/m3).
Animal Studies
Kushneva et al. (1983) reported inhalation LC50 values for isobutanol of 19,200 mg/m3
in rats, 15,500 mg/m3 in mice, 19,900 mg/m3 in guinea pigs, and 26,250 mg/m3 in rabbits. Smyth
et al. (1954) observed no deaths in rats exposed to a saturated atmosphere of about 49,000 mg/m3
for 2 hours, but found that 2/6 rats died after exposure to about 24,600 mg/m3 for 4 hours.
Mortality was reported among mice exposed to about 48,300 mg/m3 for 250 minutes or about
32,200 mg/m3 for 300 minutes (Weese, 1928).
A report by the International Programme in Chemical Safety (WHO, 1987) includes
comments on a study wherein an unspecified number of rats were exposed continuously to
isobutanol at 0.1, 0.5, or 3 mg/m3 for 4 months (Tsulaya et al., 1978). This secondary citation
reports a depression of leg withdrawal response to electrical stimuli and minor hematological
changes (reduced hemoglobin content, decreased erythrocyte count, and reduced activity of
certain serum enzymes) at 0.5 or 3 mg/m3, but not at 0.1 mg/m3. In addition, WHO (1987) cites a
study (Kushneva et al., 1983) that reported airway irritation in rats and rabbits at 15,700 mg/m3
following a single 4-hour exposure. Three days after the exposure, hematological changes and
dystrophia of hepatocytes and olfactory neurons in the brain were noted. At 8000 mg/m3 the
changes were similar but less severe. An isobutanol concentration of 1300 mg/m3 reduced the
number of lymphocytes in bone marrow. At 100 mg/m3, only respiratory depression was
observed. No other information concerning this study was available from the secondary citation.
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In two separate experiments, Weese (1928) exposed mice to isobutyl alcohol
intermittently. In the first experiment, mice were exposed to 2125 ppm (6440 mg/m3) of isobutyl
alcohol for 223 hours in a series of intermittent experiments (9.25 hours in duration each)
without any significant effects. In the second experiment, Weese reported that the narcotic
inhalation dose in mice over a total of 136 hours is 6400 ppm (19,400 mg/m3). Slight changes in
liver and kidney were observed (reversible fatty degeneration of the liver and kidneys). No
mortality occurred, and the narcotic effects were reported to be transient with no lasting effects
(Weese, 1928). No further details concerning this study are available.
A more recent study was conducted to determine the relative acute neurotoxicity of
solvents using electrically-invoked seizures (Frantik et al., 1994). Male SFP-Wistar rats and
female mice of the H strain were used. The isoeffective air concentration (i.e., the dose capable
of causing a 30% depression of electrically-induced seizures) for isobutanol was determined to
be 3800 ppm (11,500 mg/m3) in rats and 2500 ppm (7580 mg/m3) in mice after 4 or 2 hours of
exposure, respectively. This acute, subnarcotic effect occurred at nearly the same isobutanol
concentration as respiratory irritation.
A developmental toxicity study by Klimisch and Hellwig (1995) was conducted in rats
(female, SPF-Wistar) and rabbits (female, Himalayan) exposed to isobutanol at 0, 0.5, 2.5, or 10
mg/L (0, 500, 2500, or 10,000 mg/m3) for 6 hours/day for days 6-15 postcoitum (25 rats/group)
and days 7-19 postinsemination (15 rabbits/group). Animals were weighed at 3-day intervals and
observed daily. Rats were sacrificed on day 20 of gestation and rabbits on day 29 of gestation.
All dams underwent gross necropsy and the uterus was weighed. Fetuses were weighed and
examined externally. Soft tissue and skeletal examinations were conducted on all rabbit fetuses.
Visceral examinations were conducted on approximately half the rat fetuses and skeletal
examinations on the remaining rat fetuses in each litter. There was no alteration in intact uterine
weight in either species. When compared at 3-day increments throughout exposure, maternal
weight gain in the exposed rabbits was not statistically significantly different from controls.
However, when evaluated for the entire exposure period (days 7-19), maternal weight gain in
rabbits at the high concentration was decreased to approximately 63% of the control weight gain,
but rebounded following cessation of exposure. Maternal weight gain in the low and mid-
concentration rabbit groups were approximately 99 and 93% of control values. There was no
alteration in maternal weight gain of the rats. There were no alterations in developmental
endpoints in either species. The LOAEL for maternal toxicity in the rabbits is 10,000 mg/m3, and
the NOAEL is 2500 mg/m3. There were no alterations in developmental endpoints in either
species. The developmental NOAEL for the rabbits is 10,000 mg/m3, the highest concentration
tested. For the rats, the maternal and developmental NOAEL in this study is 10,000 mg/m3.
In a study by Monsanto (1996) (the range finding study for Li et al., 1999), 40 male CD
rats (5 rats/group at 8 weeks age and 5 rats/group at 16 weeks age) were exposed for 6 hours/day,
5 days/week for 2 weeks to isobutanol at 0, 750, 1500, or 3000 ppm (0, 2274, 4550, or 9095
mg/m3). This study examined the following parameters: clinical signs, food consumption, body
weight, hematology, ophthalmoscopic examination, a functional observational battery, and
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5-31-2002
complete individual necropsy, with histopathology of major organs at termination. A marginal
decrease in response to external stimuli (i.e., failure to respond to tapping on the exterior walls of
the chamber) was observed in subjective assessments at 2274 mg/m3 (with greater effect at
higher doses). At 4550 mg/m3 or 9095 mg/m3, general CNS depression and labored breathing
occurred, which ceased upon removal from the chamber. There were no differences in observed
response between control and treated rats when they were examined outside the exposure
chamber. No treatment-related changes in any other endpoints were reported.
Li et al. (1999) studied the subchronic neurotoxic effects of isobutanol in adult male and
female Sprague Dawley rats in two experiments. Rats were exposed to 0, 250, 1000, or 2500
ppm (0, 758, 3032, or 7580 mg/m3) of isobutanol for 6 hours/day, 5 days/week for 3 months. In
the first experiment, 20/sex were assigned to control and 758 mg/m3 groups, while 10/sex/group
were assigned to the other two concentration levels. Body weight and food consumption were
measured weekly. Animals were observed during exposure for subjective assessments of reaction
to brushing and tapping the exterior walls of the chamber. Each rat received at least 70
exposures, but was not exposed on the day they underwent neurobehavioral testing. Behavioral
tests (functional observational battery [FOB] and motor activity) were conducted on all but 5
animals/sex in the control and 758 mg/m3 groups. Behavioral tests were conducted prior to
initiation of exposure and during the 4th, 8th and 13th weeks of exposure. Animals were not
exposed to isobutanol on the days of behavioral testing. Neuropathology evaluation was
conducted on 5/sex/group that underwent behavioral testing and full histopathology (adrenals,
brain, eyes, heart, kidneys, liver, lungs, three sections of the nose, ovaries, uterus, vagina/testes
and epididymes, skin and spleen) and clinical pathology (including hematological evaluations)
were conducted on an additional 5/sex/group. The remaining animals underwent gross necropsy.
In the second experiment, 40 male rats (10/concentration level) were tested on a schedule-
controlled operant behavior (SCOB) task. Animals performed on the SCOB prior to each
exposure during the exposure period, but only the data collected during the pretest week and the
4th, 8th and 13th weeks of exposure were statistically analyzed, d-Amphetamine and
chlorpromazine were used as positive controls for the SCOB. The study was well-designed,
employing appropriate positive and negative controls, and well-reported (reporting on all
parameters, including clinical observations). Slight increases (9-10%) in hematocrit, erythrocyte
count, and hemoglobin in five female rats achieved statistical significance at the highest
concentration. The authors did not attribute any toxicological significance to these alterations.
The small number of rats examined and the fact that the blood chemistry was only assessed at the
end of the study make it difficult to interpret these results. As noted in the range-finding study
(Monsanto, 1996), a decreased response to external stimuli occurred during exposure early in this
study. This effect occurred at all doses of isobutanol and was slight except for a few rats in the
7580 mg/m3 group early in the study where the effect was more pronounced. At times other than
during the exposures, differences in behavior were not observed between treated and control
animals. Moreover, no differences were noted during the functional observational battery,
including several measurements of responsiveness, conducted within 24 hours of the end of the
preceding exposure. There was stable baseline performance and no significant concentration
time interactions in any SCOB parameters.
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DERIVATION OF A PROVISIONAL RfC
The database is inadequate for deriving an RfC. There are no long-term studies in
humans and limited studies in animals.
The only findings in Li et al. (1999) were subjective observations of alterations in
responsiveness to stimuli and alterations in some hematological parameters. These findings are
difficult to interpret and cannot definitively be considered adverse. Decreased response to
external stimuli (brush and tap on exterior chamber wall) occurred in rats only during exposure to
concentrations of 758 to 7580 mg/m3. Similar decreased responsiveness was also reported in
Monsanto (1996) at 750 ppm (2274 mg/m3) or greater. However, these are subjective measures
made by observers and no incidence or other supporting data are reported. There were negative
findings in the more rigorous FOB, motor activity and SCOB tests and neuropathological
alterations. The highest concentration tested, 2500 ppm (7580 mg/m3) is, therefore, considered a
NOAEL.
IRIS (U.S. EPA, 2001) lists an oral RfD for isobutanol of 3E-01 mg/kg-day based on an
NOEL for hypoactivity and ataxia in rats in a subchronic study (U.S. EPA, 1986c). In this study,
the dose level, duration and incidence supporting the clinical observations were reported.
Li et al. (1999) note that a transient reduction in responsiveness is often associated with
inhalation exposure to high concentrations of solvents which exhibit general and non-specific
narcotic effects. Such nonspecific CNS depression as a result of inhalation exposure to high
concentrations of solvents is also discussed in a textbook chapter by Spencer and Schaumburg
(2000). The observations of altered reactivity in Li et al. (1999), only while the animals were in
the inhalation chamber, reflect an acute, transient effect occurring during exposure to isobutanol
and are not an appropriate basis for the derivation of an RfC.
Klimisch and Hellwig (1995) identify a LOAEL (10,000 mg/m3) and NOAEL (2500
mg/m3) for maternal toxicity in rabbits, based on significantly (approximately 30%) depressed
body weight gain in a developmental study. No developmental toxicity in rabbits nor maternal or
developmental toxicity in rats was found. Similar decreases in maternal weight gain occurred in
rats and rabbits exposed to similar concentrations of isopentanol (Klimisch and Hellwig, 1995).
Developmental effects have been reported for subchronic exposure to n-butanol, but only at
concentrations of 6000 ppm or greater (approximately 18,000 mg/m3) (Nelson et al., 1989). The
decrease in maternal body weight gain occurring during isobutanol exposure in Klimisch and
Hellwig (1995) is a non-specific, overt sign of toxicity occurring after short-term, high
concentration exposure, and is not an appropriate endpoint as the basis for an RfC.
Other inhalation studies in animals are not adequate to serve as the basis for an RfC, as
they are of acute duration, do not identify a NOAEL, or are limited in study design or reporting.
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The RfC guidelines (U.S. EPA, 1994b) state that the minimum laboratory animal
toxicologic database requirement for derivation of a low confidence RfC is a well-conducted
subchronic inhalation bioassay that established an unequivocal NOAEL and LOAEL. As none of
the available inhalation studies meet this criteria, derivation of an RfC is precluded.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Documentation
of the Threshold Limit Values and Biological Exposure Indices, 6th ed. Cincinnati, OH. 1: 815-
816.
ACGIH (American Conference of Governmental Industrial Hygienists). 2000. TLVs® and
BEIs®: Threshold Limit Values for Chemical Substances and Physical Agents, Biological
Exposure Indices. Cincinnati, OH.
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Examined November 29, 2000. Online.
http://www.atsdr.cdc.gov/gsql/toxpro2.html
Browning, E. 1965. Toxicology and metabolism of industrial solvents. Amsterdam,
Elsevier, p. 349.
Frantik, E., M. Hornychova and M. Horvath. 1994. Relative acute neurotoxicity of solvents:
Isoeffective air concentrations of 48 compounds evaluated in rats and mice. Environ. Res. 66:
173-185.
IARC (International Agency for Research on Cancer). 2000. Cumulative Cross Index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Online.
http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Klimisch, H.J. and J. Hellwig. 1995. Studies on the prenatal toxicity of 3-methyl-l-butanol and
2-methyl-l-propanol in rats and rabbits following inhalation exposure. Fund. Appl. Toxicol. 27:
77-89.
Korsak, Z. and K. Rydzynski. 1994. Effects of acute combined inhalation exposure to n-butyl
alcohol and n-butyl acetate in experimental animals. Int. J. Occup. Med. Environ. Health. 7(3):
273-280.
Kushneva, V.S., G.A. Koloskova, J.G. Koltunova and V.T. Kirilenko. 1983. Experimental data
to hygienic reglementation of isobutyl alcohol in the working zone. Gid. Tr. Lek. 1: 46-47 (in
Russian), as cited by WHO, 1987.
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Li, A.A., D.C. Thake, T.A. Kaempfe et al. 1999. Neurotoxicity evaluation of rats after
subchronic inhalation exposure to isobutanol. Neurotoxicology. 20(6): 889-900.
Monsanto Company. 1996. Exposure concentration range-finding study for a subchronic
inhalation neurotoxicity study of isobutanol administered by whole-body inhalation to CD rats
(Summary only). Produced for Chemical Manufacturers Association. U.S. EPA/OPTS Public
Files, Fiche #OTS0558856.
Nelson, B.K., W.S. Brightwell, A. Khan, J.R. Burg and P.T. Goad. 1989. Lack of selective
developmental toxicity of three butanol isomers administered by inhalation to rats. Fund. Appl.
Toxicol. 12:469-479.
NIOSH (National Institute for Occupational Safety and Health). 1978. Occupational Health
Guideline for Isobutyl Alcohol, p. 1-5.
NIOSH (National Institute for Occupational Safety and Health). 2000. Documentation for
Immediately Dangerous to Life or Health Concentrations: Isobutanol. Examined online
December 2000. Online, http://www.cdc.gov/niosh/idlh/78831 .html
NTP (National Toxicology Program). 2000. Management Status Report. Examined November
29, 2000. Online.
http://ntp-server.niehs.nih.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
OSHA (Occupational Safety and Health Administration). 1989. 29 CFR Part 1910. Air
Contaminants; Rule. Federal Register. 54(12): 2630-2631.
OSHA (Occupational Safety and Health Administration). 2000. OSHA Standard 1915.1000 for
Air Contaminants. Part Z, Toxic and Hazardous Substances. Examined online December, 2000.
Online.
http://www.osha-slc.gov/OshStd data/1915 1000.html
Smyth, H.F. Jr., C.P. Carpenter, C.S. Weil and U.C. Pisonia. 1954. Range-finding toxicity data:
ListV. Arch. Ind. Hyg. Occup Med. 10:61-68.
Spencer, P.S. and H.H. Schaumburg. 2000. Experimental and Clinical Neurotoxicology, 2nd ed.
Oxford University Press, p. 895.
Tsulaya, V.T., N.V. Morenkova, L.E. Volokhova and V.M. Voronin. 1978. [Description of the
biological properties of small concentrations of isobutyl alcohol.] Gig. I Sanit.
5: 6-9. (Russian) (Cited by WHO, 1987)
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U.S. EPA. 1986a. Health and Environmental Effects Profile for Isobutanol. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1986b. Reportable Quantity Document for Isobutanol. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1986c. Rat oral subchronic toxicity study. Final report. Compound: isobutyl alcohol.
TRL Study # 032-002. Toxicity Research Laboratories, Ltd., Muskegon, MI.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994a. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1994b. Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry. Office of Research and Development, Washington DC.
EPA/600/8-90/066F.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. PB 97-921199.
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC. Examined
December 2000. http://www.epa.gov/iris
Weese, H. 1928. Comparative study of the activity and toxicity of the vapors of the lower
aliphatic alcohols. Arch. Exp. Path. Pharmacol. 135:118-130.
WHO (World Health Organization). 1987. Butanols: Four isomers: 1-butanol,
2-butanol, tert-butanol, and isobutanol. International Programme on Chemical Safety,
Environmental Health Criteria Document No. 65: 93-118. WHO, Geneva.
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Provisional Peer Reviewed Toxicity Values for
Isobutanol
(CASRN 78-83-1)
Derivation of an Oral Slope Factor
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
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NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(imol
micromoles
voc
volatile organic compound
11

-------
5-31-2002
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
ISOBUTANOL (CASRN 78-83-1)
Derivation of an Oral Slope Factor
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
1

-------
5-31-2002
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
A cancer assessment for isobutanol is not available on IRIS (U.S. EPA, 2001), in the
HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list (U.S.
EPA, 2000). The CARA list (U.S. EPA, 1991, 1994) includes a Health and Environmental
Effects Profile for Isobutanol (U.S. EPA, 1986), in which it is indicated that isobutanol should be
assigned to cancer weight-of-evidence Group D, not classifiable as to human carcinogenicity,
based on lack of data concerning carcinogenicity in humans and animals by any route of
exposure. IARC (2000) has not evaluated isobutanol for carcinogenicity. The NTP (2000)
Status Report for isobutanol does not include a chronic toxicity/carcinogenicity bioassay,
although a negative genotoxicity study (Zeiger et al., 1988) is listed. ATSDR has not published a
Toxicological Profile for isobutanol (ATSDR, 2000). Updated literature searches for cancer data
were conducted from 1985 to present. The databases searched were TOXLINE, MEDLINE,
CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and
EMIC/EMICBACK.
2

-------
5-31-2002
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding the carcinogenicity of isobutanol in humans following
oral exposure.
Animal Studies
No studies were located regarding the carcinogenicity of isobutanol in animals following
oral exposure.
Other Studies
Based on genotoxicity studies assessed by U.S. EPA (1986), isobutanol was not
considered to be mutagenic. Update literature searches revealed two subsequent genotoxicity
studies in which isobutanol also failed to demonstrate mutagenic activity (Zeiger et al., 1988;
Mirvish et al., 1993).
FEASIBILITY OF DERIVING A PROVISIONAL ORAL SLOPE FACTOR FOR
ISOBUTANOL
A provisional oral slope factor for isobutanol cannot be derived because human and
animal oral cancer data are lacking.
REFERENCES
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Examined November 29, 2000. Online.
http://www.atsdr.cdc.gov/toxpro2.html
IARC (International Agency for Research on Cancer). 2000. Cumulative Cross Index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Online.
http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Mirvish, S.S., J. Williamson, D. Babcook and S-C Chen. 1993. Mutagenicity of isobutyl nitrite
vapor in the Ames test and some relevant chemical properties, including the reaction of isobutyl
nitrite with phosphate. Environ. Mol. Mutagen. 21(3): 247-252.
3

-------
5-31-2002
NTP (National Toxicology Program). 2000. Management Status Report. Examined November
29, 2000. Online.
http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
U.S. EPA. 1986. Health and Environmental Effects Profile for Isobutanol. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC.
EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Examined November 29,
2000. Online, http://www.epa.gov/ost/drinking/standards/
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
http://www.epa.gov/iris
Zeiger, E., B. Anderson, S. Haworth et al. 1988. Salmonella mutagenicity tests. IV. Results
from the testing of 300 chemicals. Environ. Mol. Mutagen. ll(Suppl 12): 1-158.
4

-------
5-31-2002
Provisional Peer Reviewed Toxicity Values for
Isobutanol
(CASRN 78-83-1)
Derivation of an Inhalation Unit Risk
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
1

-------
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor

microgram
(imol
micromoles
voc
volatile organic compound
11

-------
5-31-2002
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
ISOBUTANOL (CASRN 78-83-1)
Derivation of an Inhalation Unit Risk
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
1

-------
5-31-2002
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
A cancer assessment for isobutanol is not available on IRIS (U.S. EPA, 2001), in the
HEAST (U.S. EPA, 1997), or in the Drinking Water Standards and Health Advisories list (U.S.
EPA, 2000). The CARA list (U.S. EPA, 1991, 1994) includes a Health and Environmental
Effects Profile for Isobutanol (U.S. EPA, 1986), in which it is indicated that isobutanol should be
assigned to cancer weight-of-evidence Group D, not classifiable as to human carcinogenicity,
based on lack of data concerning carcinogenicity in humans and animals by any route of
exposure. IARC (2000) has not evaluated isobutanol for carcinogenicity. The NTP (2000)
Status Report for isobutanol does not include a chronic toxicity/carcinogenicity bioassay,
although a negative genotoxicity study (Zeiger et al., 1988) is listed. ATSDR has not published a
Toxicological Profile for isobutanol (ATSDR, 2000). Updated literature searches for cancer data
were conducted from 1985 to present. The databases searched were TOXLINE, MEDLINE,
CANCERLIT, CCRIS, TSCATS, HSDB, RTECS, GENETOX, DART/ETICBACK, and
EMIC/EMICBACK.
2

-------
5-31-2002
REVIEW OF THE PERTINENT LITERATURE
Human Studies
No studies were located regarding carcinogenicity of isobutanol to humans by inhalation
exposure.
Animal Studies
No studies were located regarding the carcinogenicity of isobutanol in animals following
inhalation exposure.
Other Studies
Based on genotoxicity studies assessed by U.S. EPA (1986), isobutanol was not
considered to be mutagenic. Update literature searches revealed two subsequent genotoxicity
studies in which isobutanol also failed to demonstrate mutagenic activity (Zeiger et al., 1988;
Mirvish et al., 1993).
FEASIBILITY OF DERIVING A PROVISIONAL INHALATION UNIT RISK FOR
ISOBUTANOL
A provisional inhalation unit risk for isobutanol cannot be derived because human and
animal inhalation cancer data are lacking.
REFERENCES
ATSDR (Agency for Toxicological Substances Disease Registry). 2000. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Examined November 29, 2000. Online.
http://www.atsdr.cdc.gov/toxpro2.html
IARC (International Agency for Research on Cancer). 2000. Cumulative Cross Index to IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans. IARC Monographs. Online.
http://193.51.164.ll/cgi/iHound/Chem/iH Chem Frames.html
Mirvish, S.S., J. Williamson, D. Babcook and S-C Chen. 1993. Mutagenicity of isobutyl nitrite
vapor in the Ames test and some relevant chemical properties, including the reaction of isobutyl
nitrite with phosphate. Environ. Mol. Mutagen. 21(3): 247-252.
3

-------
5-31-2002
NTP (National Toxicology Program). 2000. Management Status Report. Examined November
29, 2000. Online.
http://ntp-server.niehs.nili.gov/cgi/iH Indexes/Res Stat/iH Res Stat Frames.html
U.S. EPA. 1986. Health and Environmental Effects Profile for Isobutanol. Prepared by the
Office of Research and Development, Environmental Criteria and Assessment Office, Cincinnati,
OH for the Office of Solid Waste and Emergency Response, Washington, DC.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati, OH for the Office of Emergency and Remedial Response, Washington, DC.
EPA/540/R-97/036. NTIS PB 97-921199.
U.S. EPA. 2000. Drinking Water Regulations and Health Advisories. Examined November 29,
2000. Online, http://www.epa.gov/ost/drinking/standards/
U.S. EPA. 2001. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
http://www.epa.gov/iris
Zeiger, E., B. Anderson, S. Haworth et al. 1988. Salmonella mutagenicity tests. IV. Results
from the testing of 300 chemicals. Environ. Mol. Mutagen. 1 l(Suppl 12):
1-158.
4

-------