United States
Environmental Protection
1=1 m m Agency
EPA/690/R-07/031F
Final
5-01-2007
Provisional Peer Reviewed Toxicity Values for
n-Propyl alcohol
(CASRN 71-23-8)
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
NAAQS	National Ambient Air Quality Standards
NOAEL	no-ob served-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-ob served-effect level
OSF	oral slope factor
p-IUR	provisional inhalation unit risk
p-OSF	provisional oral slope factor
p-RfC	provisional inhalation reference concentration
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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
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
n-PROPYL ALCOHOL (CASRN 71-23-8)
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 5 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.
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
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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
No oral reference dose (RfD) for n-propyl alcohol is available on IRIS (U.S. EPA, 2007)
or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2004). The HEAST
(U.S. EPA, 1997) includes a note that data were inadequate for subchronic or chronic RfD
derivation; the source document for this determination was a Health and Environmental Effects
Document (HEED) for n-propyl alcohol (U.S. EPA, 1987). In addition to the HEED, the
Chemical Assessments and Related Activities (CARA) list (U.S. EPA, 1991, 1994) includes a
Health and Environmental Effects Profile (HEEP) for n-propyl alcohol that also declined to
derive toxicity values due to inadequate data (U.S. EPA, 1983). The Agency for Toxic
Substances and Disease Registry (ATSDR, 2006) has not assessed the health effects of n-propyl
alcohol. An Environmental Health Criteria document that did not derive any oral risk
assessment values is available from the World Health Organization (WHO, 1990).
An RfC for n-propyl alcohol is not available on IRIS (U.S. EPA, 2007). The HEAST
(U.S. EPA, 1997) indicates that data are inadequate for subchronic or chronic RfC derivation.
The World Health Organization (WHO, 1990) did not derive any inhalation risk assessment
values for n-propyl alcohol. The American Conference for Governmental Industrial Hygienists
(ACGIH, 2006) recommends a TLV-TWA of 200 ppm and TLV-STEL of 400 ppm for n-propyl
alcohol based on animal models of sensory irritation and its structure-activity relationship to
isopropanol. The National Institute for Occupational Safety and Health (NIOSH, 2006)
recommended exposure limit (REL) and Occupational Safety and Health Administration
(OSHA, 2006) permissible exposure limit (PEL) for n-propyl alcohol are 200 ppm TWA.
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A cancer assessment for n-propyl alcohol is not available on IRIS (U.S. EPA, 2007). The
HEED (U.S. EPA, 1987) assigned n-propyl alcohol to U.S. EPA (1986) Cancer Group C
(possible human carcinogen), based on increased incidences of total malignant tumors in orally
and subcutaneously treated rats and liver sarcomas in subcutaneously treated rats (Gibel et al.,
1974, 1975). These findings were also used as a basis for an ACGIH (2006) cancer notation of
A3 (confirmed animal carcinogen with unknown relevance to humans) for n-propyl alcohol. The
carcinogenicity of n-propyl alcohol has not been assessed by NTP (2006) or IARC (2006).
Literature searches were conducted from the 1960's through August, 2006 for studies
relevant to the derivation of provisional toxicity values for n-propyl alcohol. Data bases
searched included: TOXLINE/TOXCENTER (including BIOSIS, NTIS and Chemical Abstracts
subfiles), MEDLINE (including PubMed cancer subset), TSCATS/TSCATS 2, CCRIS,
DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents.
REVIEW OF PERTINENT DATA
Human Studies
Relevant information regarding the toxicity of n-propyl alcohol in humans was not
located.
Animal Studies
Oral Exposure. Groups of 5-6 male Wistar rats (4 months old) were exposed to n-propyl
alcohol in drinking water at concentrations of 2 M (mol/L) for 2 months or 1 M for 4 months
(Hillbom et al., 1974a,b). Unspecified numbers of control rats received tap water. Both groups
of exposed rats consumed constant amounts of n-propanol in drinking water throughout the test
periods, but consumption data were only reported for the 1 M group (4.8 mmol/100 g-day).
Multiplying the mean n-propyl alcohol intake of 4.8 mmol/100 g-day (48 mmol/kg-day) by
60.09 g/mol (molecular weight of n-propyl alcohol) yields a dose of 2884 mg/kg-day for the 1 M
group; the dose for the 2 M group can be estimated to be twice as high at 5768 mg/kg-day. Food
consumption, total caloric intake and body weight were evaluated at 2884 mg/kg-day, and liver
weight and liver histology were evaluated at 2884 and 5768 mg/kg-day; additional end points
were not assessed. The rats exposed to 2884 mg/kg-day for 4 months had a reduced ratio of
weight gain to caloric intake (not quantified) which, according to the authors, suggested possible
interference with food utilization. Slight, non-significant increases in relative liver weight were
seen in both treatment groups. Absolute liver weights were not reported. Histological
examination of the livers showed no inflammation, cirrhosis, hepatic steatosis, increase in liver
fat or other changes in the rats exposed to 2884 mg/kg-day for 4 months or 5768 mg/kg-day for 2
months, although it was noted that Mallory alcoholic hyaline bodies were observed in some of
the rats (incidence not reported) at 5768 mg/kg-day. Mallory bodies are characteristic of
alcoholic hepatitis, although also seen in other conditions as well; these are fibrillar proteins of
intracytoplasmic inclusions within swollen hepatocytes that contain little or no fat (Merck,
2006). The toxicological significance of these bodies is uncertain. The researchers conclude
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there was "no clear hepatotoxic effect" in this study. Therefore, the high dose of 5768 mg/kg-
day is identified as a NOAEL.
Groups of 10 Wistar rats (sex not reported) were exposed to drinking water containing 0
or 320,000 mg/L of n-propyl alcohol for 5, 9 or 13 weeks (Wakabayashi et al., 1984). Using a
conversion factor of 0.15 L/kg-day based on the average of male and female subchronic
reference values for water consumption and body weight in Wistar rats (U.S. EPA, 1988), the
estimated dose is 48,000 mg/kg-day. The exposed rats gradually became weak, lost their
appetites and showed decreased body weight gain. Ultrastructural studies of the liver showed
induction of irregularly shaped megamitochondria with few cristae, as well as normally sized but
irregularly shaped mitochrondria with reduced numbers of cristae. Biochemical changes
included a decreased state 3 respiration using glutamate as a substrate, and decreased specific
activities of cytochrome c oxidase and monoamine oxidase. Additional information was not
reported in the available summary of this study (WHO, 1990). The lack of other kinds of liver
evaluations (e.g., histology or serum enzymes) precludes assessing the toxicological significance
of the mitochondrial ultrastructural changes and identification of a NOAEL or LOAEL.
A chronic oral study was conducted in which a group of 18 Wistar rats of both sexes
were administered n-propyl alcohol by gavage at a dose level of 0.3 mL/kg (241 mg/kg using a
specific gravity of 0.804 g/mL) on 2 days/week from 10 weeks of age for life (Gibel et al., 1974,
1975). A control group of 25 rats was similarly exposed to saline. Average survival time was
570 days in the n-propyl alcohol-exposed rats and >643 days in the controls. This study included
parallel experiments in which rats were chronically exposed to n-propyl alcohol by subcutaneous
injection and chronically exposed to two other alcohols by gavage and subcutaneous injection.
Referring to all three alcohols and both routes, the authors reported that a strong hepatotoxic
effect was observed in virtually all treated rats, as shown by histological findings that included
steatosis, necrosis and cirrhosis. Changes in the myocardium, such as the appearance of narrow
scars resulting from necrosis of the heart muscle, were reported in some rats, as were a few
instances of pancreatitis and fibrosis; although the alcohol(s) producing these effects were not
specified, similar actions by the three alcohols are inferred. Hematological effects and
hyperplasia of the hematopoietic parenchyma of the bone marrow were specifically attributed to
n-propyl alcohol. Incidences of non-neoplastic lesions were not reported. Due to the inclusion
of a single dose level, episodic exposure regimen (gavage, 2 days/week) and poor reporting of
results, this study is of limited utility for non-cancer risk assessment.
n-Propyl alcohol-specific tumorigenicity data were reported by Gibel et al. (1974, 1975).
The rats that were orally treated with n-propyl alcohol had a total of 5 malignant and 10 benign
tumors. The malignant tumors were identified as two myeloid leukemias, one hepatocellular
carcinoma, and two liver sarcomas. No malignant tumors occurred in the control group,
although a total of three benign tumors were observed. The benign tumors in the treated and
control rats were mostly papillomas of the anterior stomach and mammary fibroadenomas. It is
not clear if individual rats had more than one tumor. If each malignant tumor occurred in a
different rat, the total incidences of malignant tumors would be 5/18 treated and 0/25 control
rats, a difference that is statistically significant (p=0.009) by the Fisher Exact test. None of the
incidences of individual tumor types are significantly increased.
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Inhalation Exposure. Limited information on the short-term inhalation toxicity of n-
propyl alcohol is available from an early study in which mice were exposed to concentrations in
the range of 0.1-0.2 cm3 liquid/15 L air (Weese, 1928). Using a liquid density of 0.804 g/cm3 for
n-propyl alcohol and assuming that all of the liquid volatilized, the vapor concentrations ranged
from 5330-10,660 mg/m3 (2185-4370 ppm). The following exposures were conducted using one
mouse for each: 2185-4370 ppm for 7.5 hours/day for 8 of 9 days, 3715-4370 ppm for 7.5
hours/day for 14 of 15 days, 2622 ppm for 8.75 hours/day for 14 of 16 days, 2622 ppm for 6.75
hours/day for 24 of 28 days, and 2185-3715 ppm for 8.75 hours/day for 25 of 28 days. Use of
controls was not mentioned. Liver, kidneys, heart and lungs were examined histologically. The
main effect was fatty degeneration of the liver, which occurred in varying degrees in the mice
exposed to 2185-4370 ppm for 14 of 16 days and longer and was considered reversible. The
reliability of these data is questionable due to the small number of animals, apparent lack of
controls, uncertainty regarding the actual exposure concentrations, variable exposure schedules,
reporting insufficiencies and other study limitations.
The developmental toxicity of n-propyl alcohol was evaluated in groups of 15 female
Sprague-Dawley rats that were exposed to 0, 3500, 7000 or 10,000 ppm (0, 8602, 17,204 or
24,578 mg/m3) n-propyl alcohol for 7 hours/day on gestation days 1-19 and sacrificed on
gestation day 20 (Nelson et al., 1988). Maternal body weight, food and water consumption and
clinical signs were assessed throughout the exposure period. Developmental end points included
numbers of pregnancies, corpora lutea, resorptions and live fetuses, and external (all fetuses),
skeletal (half of the fetuses) and visceral (remaining fetuses) abnormalities. No maternal or
developmental effects were observed at 3500 ppm. Maternal food intake (data not shown in
original report) was reduced during the last 2 weeks of gestation at 7000 ppm and throughout
gestation at 10,000 ppm, and maternal body weight gain was reduced during the last 2 weeks of
gestation at 10,000 ppm (-40% less than controls on gestation day 20). Resorptions were
increased at 10,000 ppm; 3/15 litters were totally resorbed, and there were significant (p<0.05)
changes in resorbed implants/litter (increased, 57% compared to 6% in controls) and live
implants/litter (decreased, 43% compared to 94% in controls). Mean fetal body weight was
significantly (p<0.05) reduced at 7000 and 10,000 ppm in both sexes; at 3500, 7000 and 10,000
ppm, fetal weight was 0.6, 17.7 and 46.2% less than controls in males, and 0.9, 16.8 and 46.2%
less than controls in females.
The incidence of fetal total external malformations was significantly (p<0.05) increased
at 10,000 ppm (9/12 litters and 34/94 fetuses compared to 0/15 and 0/206 in controls), mostly
due to short or missing tail (p>0.05) or ectrodactyly (missing fingers or toes) (p>0.05) (Nelson et
al., 1988). The incidence of total skeletal malformations was significantly (p<0.05) increased at
7000 ppm (9/15 litters and 19/95 fetuses) and 10,000 ppm (12/12 litters and 22/48 fetuses)
compared to controls (1/15 litters and 1/100 fetuses), mostly due to rudimentary cervical ribs
(p>0.05); incidences of skeletal variants were not increased. The incidence of total visceral
malformations was significantly (p<0.05) increased at 10,000 ppm (10/10 litters and 26/46
fetuses compared to 4/15 and 4/106 in controls), mainly due to various cardiovascular or urinary
system malformations (p>0.05 for specific defects); incidences of visceral variants were not
increased. For maternal toxicity, this study identified a NOAEL of 7000 ppm (17,204 mg/m3)
and LOAEL of 10,000 ppm (24,578 mg/m3) based on reduced body weight gain. For
developmental toxicity, a NOAEL of 3500 ppm (8602 mg/m3) and LOAEL of 7000 ppm (17,204
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mg/m3) were identified, based on decreased fetal weight and increased total skeletal
malformations at >7000 ppm and increased resorptions and external and visceral malformations
at 10,000 ppm. The results of this study suggest that the developing organism may be a sensitive
target for propyl alcohol.
A behavioral teratogenicity study of n-propyl alcohol in Sprague-Dawley rats was
performed by Nelson et al. (1989). Groups of 18 males were exposed to 0, 3500 or 7000 ppm (0,
8602 or 17,204 mg/m3) n-propyl alcohol for 7 hours/day, 7 days/week for 6 weeks and, after 2
nonexposure days, mated with unexposed females. Groups of 15 females were mated with
unexposed males and exposed to the same concentrations of n-propyl alcohol for 7 hours/day on
gestation days 1-19. Litters in both maternally and paternally exposed groups were culled to 4
males and 4 females and fostered by untreated females. Endpoints included mating performance
and fertility, maternal food and water intake, maternal body weight, pup body weight through
postnatal day 35, and pup behavioral performance and brain neurochemistry. Behavioral tests
were conducted on one male and one female pup per litter per dose group during postnatal days
10-60; testing assessed neuromuscular coordination (ascent on wire mesh and rotorod
performance), exploratory activity (open field and optically monitored activity), circadian
activity (running wheel), aversive learning (avoidance conditioning), and appetitive learning
(operant conditioning). Brain neurochemistry (protein, acetylcholine, serotonin, dopamine,
norepinephrine, P-endorphin, substance P, and Met-enkephalin) was evaluated in one male and
one female pup from 5 litters per dose group on PND 21.
Male fertility was reduced at 7000 ppm, as shown by litter production in 2/16 mated
males compared to 18/18 in controls (Nelson et al., 1989). Successful mating by the 16 males
was demonstrated by the presence of sperm plugs; of the remaining 2/18 males, one male died as
a result of fighting and another did not mate. Six of the 7000 ppm males were remated at
biweekly intervals to see if the infertility was reversible; litter production in week 1, 3, 5, 7, 9,
11, 13 and 15 was 1/6, 2/6, 4/6, 4/6, 4/6, 3/6, 6/6 and 6/6, respectively, indicating a reversibility
of the effect. Females exposed to 7000 ppm during pregnancy had significantly (p<0.05)
reduced food intake (20, 16 and 13% less than controls in weeks 1, 2 and 3, respectively), but
showed no effect on weight gain. No significant differences were found among any of the
groups for number of live pups per litter, gestation length, birth weight, neonatal survival or pup
weight gain. External examination of the offspring showed that 2/15 litters from the 7000 ppm
maternally exposed group had several pups (2-3/litter) with crooked tails; these defects were
noted soon after birth and persisted. The behavioral and neurochemical tests showed no
exposure-related effects in the offspring of either exposed males or females. This study
identified a NOAEL of 3500 ppm and LOAEL of 7000 ppm for male reproductive toxicity
(infertility). While not statistically increased, the external tail malformations observed in the
7000 ppm maternal exposure group are consistent with the results of the earlier teratogenicity
study (Nelson et al., 1988). The 7000 ppm level was a NOAEL for postnatal neurotoxicity in
offspring of exposed males and females.
Other Studies
Effects of n-propyl alcohol on brain development in neonatal rats were studied by Grant
and Samson (1984). Neonatal Long Evans rats (n=28, sex not specified) were reared using an
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artificial feeding technique (surgically implanted gastric catheter) from postnatal days (PNDs) 5-
18. Half of the pups were gastrically infused with n-propyl alcohol in an artificial milk formula
in mean daily doses of 3800, 7500, 3000 and 7800 mg/kg on PND 5, 6, 7 and 8, respectively;
these pups subsequently received untreated milk formula until PND 18. The doses were
administered in 20-minute feeds every 2 hours with a total of 12 feeds per day. The remaining
pups were controls that received untreated milk formula from PNDs 5-18. A total of 21 pups
completed the experiment; 7 deaths resulted from surgical complications (4) or apparent
overdoses (3). Endpoints assessed during PNDs 5-18 included clinical signs, body weight, and
developmental landmarks (emergence of teeth, eye opening and outer ear development). The
pups were sacrificed on PND 18 for organ weight measurements (brain, liver, kidneys, heart) and
brain biochemical analysis (DNA, cholesterol and protein in forebrain, cerebellum and
brainstem). The pups were observed to be intoxicated during the treatment period on PNDs 5-8,
frequently showing an impaired righting response, and displayed withdrawal symptoms 8-24
hours after the last exposure. Total absolute brain weight was significantly (p<0.001) reduced in
the exposed pups (25.5% less than controls) with no changes in weights of the body or other
organs. The biochemical analysis showed that the exposed pups had significantly decreased
amounts of DNA in the three brain areas, cholesterol in the forebrain and cerebellum, and protein
in the forebrain. The results suggested to the authors that exposure to n-propyl alcohol during
the brain growth spurt in neonatal rats inhibits brain development in a manner similar to ethanol.
A chronic subcutaneous study was conducted in which a group of 31 Wistar rats of both
sexes were injected with n-propyl alcohol at a dose level of 0.06 mL/kg (48.2 mg/kg using a
specific gravity of 0.804 g/mL) on 2 days/week from 10 weeks of age for life (Gibel et al., 1974,
1975). A control group of 25 rats was similarly treated with saline. Average survival time was
643 days in the exposed rats and >643 days in the controls. This study also included parallel
experiments in which rats were chronically exposed to n-propyl alcohol by gavage and
chronically exposed to two other alcohols by gavage and subcutaneous injection. Referring to all
three alcohols and both routes, the authors reported that a strong hepatotoxic effect was observed
in virtually all treated rats, as shown by histological findings that included steatosis, necrosis and
cirrhosis. Although incidences of non-neoplastic liver lesions were not reported, n-propyl
alcohol-specific turnorigenicity data were provided. Histological examinations in the n-propyl
alcohol subcutaneous study showed a total of 15 malignant and 7 benign tumors in the treated
group and 0 malignant and 2 benign tumors in the control group. The malignant tumors in the
treated rats were identified as one local sarcoma, four myeloid leukemias, five liver sarcomas,
one uterine carcinoma, two splenic sarcomas, one renal pelvic carcinoma and one cystic
carcinoma. The benign tumors in treated and control rats were mostly papillomas of the anterior
stomach and mammary fibroadenomas. It is not clear if individual rats had more than one tumor.
If each malignant tumor occurred in a different rat, the incidences of liver sarcomas (5/31 treated
and 0/25 controls) and total malignant tumors (15/31 treated and 0/25 controls) were
significantly increased (p=0.044 and p<0.001, respectively, by Fisher Exact test).
A limited amount of information is available on the genotoxicity of n-propyl alcohol.
Negative results were obtained in in vitro assays for reverse mutations in Salmonella
typhimurium TA98 and TA100 (Khudoley et al., 1987; Stolzenberg and Hine, 1979), DNA
damage in Escherichia coli PQ37 (Mersch-Sundermann et al., 1994), sister-chromatid exchanges
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in Chinese hamster ovary and V79 cells (Obe and Ristow, 1977; von der Hude et al., 1987), and
micronuclei in Chinese hamster V79 cells (Lasne et al., 1984).
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR n-PROPYL ALCOHOL
Subchronic RfD
Information on the subchronic oral toxicity of n-propyl alcohol is available from two
drinking water studies in rats. In one of the studies (Hillbom et al., 1974a,b), rats were exposed
to 2884 mg/kg-day for 4 months or 5768 mg/kg-day for 2 months. This study found no
significant effects on food consumption, body weight, or liver weight or histology, making the
dose of 5768 mg/kg-day a NOAEL. However, it cannot be determined whether the NOAEL is
protective of other potential effects of n-propyl alcohol, such as neurotoxicity, because end
points other than food consumption, body weight gain and liver histology were not evaluated.
The other study (Wakabayashi et al., 1984) was even more limited, with rats evaluated only by
an ultrastructural evaluation of the liver that found minor mitochondrial changes (e.g., irregular
shape and reduced numbers of cristae) of uncertain toxicological significance. Therefore, the
available data are inadequate to support derivation of a subchronic RfD.
Chronic RfD
The data base for chronic oral toxicity of n-propyl alcohol consists of one lifetime study
in which 18 rats were exposed to 241 mg/kg by gavage 2 times a week (Gibel et al., 1974, 1975).
Due to poor reporting of results, it is unclear what observations pertain specifically to oral
exposure to propyl alcohol, as other routes and substances were tested and the results presented
only as generalities. However, it does appear that degenerative liver lesions (e.g., steatosis,
necrosis and cirrhosis) were observed in exposed animals, and average survival time was
reduced. Due to the inclusion of a single dose level, episodic exposure regimen (gavage, 2
days/week) and poor reporting of results, this study is inadequate to support derivation of an
RfD.
FEASIBILITY OF DERIVING PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR n-PROPYL ALCOHOL
Subchronic RfC
Information on the subchronic inhalation toxicity of n-propyl alcohol is available from
one systemic toxicity study in mice and two developmental toxicity studies in rats. In the
systemic toxicity study (Weese, 1928), a total of 5 mice were exposed to concentrations ranging
from 2185-4370 ppm for 6.75-8.75 hours/day for 8-25 days. Liver degeneration was observed in
4 of the 5 mice (i.e., those exposed for >14 days), but the reliability of the effect level is
questionable due to the small number of animals, apparent lack of controls, uncertainty regarding
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the actual exposure concentrations, variable exposure schedules, reporting insufficiencies and
other study limitations.
Both of the developmental toxicity studies are comprehensive in design and well
reported. In one of the studies (Nelson et al., 1988), female rats were exposed to 3500, 7000 or
10,000 ppm for 7 hours/day on gestation days 1-19. This is a conventional teratogenicity study
that identified a NOAEL of 7000 ppm and LOAEL of 10,000 ppm for maternal toxicity (reduced
body weight gain) and a NOAEL of 3500 ppm and LOAEL of 7000 ppm for prenatal
developmental toxicity (decreased fetal weight and increased total skeletal malformations, with
additional effects at 10,000 ppm). The other study (Nelson et al., 1989) is a behavioral
teratogenicity study that included postnatal evaluations of behavioral performance and brain
chemistry in offspring of females that were exposed to 3500 or 7000 ppm for 7 hours/day on
gestation days 1-19, and in offspring of untreated females that were mated to males that were
exposed to 3500 or 7000 ppm for 7 hours/day, 7 days/week for 6 weeks prior to mating. This
study identified a NOAEL of 3500 ppm and LOAEL of 7000 ppm for male reproductive toxicity
(infertility), as well as a NOAEL of 7000 ppm for postnatal neurotoxicity in offspring of exposed
males and females.
Although 3500 ppm is an apparent NOAEL for male reproductive, maternal and
developmental toxicity, including postnatal neurotoxicity (a potential effect of concern for n-
propyl alcohol), it is not known if 3500 ppm is a NOAEL for systemic toxicity, because maternal
endpoints were limited to clinical signs, body weight, and food and water consumption (Nelson
et al., 1988, 1989). Other studies indicate that the liver is a target for n-propyl alcohol. Fatty
liver degeneration occurred in the short-term inhalation study of mice exposed to 2185-4370
ppm (Weese, 1928), but study limitations preclude identification of a reliable effect level.
Chronic oral exposure induced steatosis, necrosis and cirrhosis in the liver of rats (Gibel et al.,
1974). The available information, therefore, suggests that exposures below the 3500 ppm
NOAEL for developmental toxicity may be hepatotoxic, but derivation of a subchronic RfC is
precluded by the unreliability of the mouse study (Weese, 1928) and the lack of information on
liver toxicity and other systemic effects in the developmental toxicity studies in rats (Nelson et
al., 1988, 1989).
Chronic RfC
There are no chronic inhalation toxicity studies of n-propyl alcohol available. Derivation
of a chronic RfC is precluded by the lack of suitable data.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR n-PROPYL ALCOHOL
Weight-of-evidence Classification
Information on the carcinogenicity of n-propyl alcohol is limited to the results of one
gavage and one subcutaneous study in which a single dose level (241 and 48 mg/kg,
respectively) was administered to rats on 2 days/week for life (Gibel et al., 1974, 1975).
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Findings included low, but statistically significant, increases in incidences of total malignant
tumors in the gavage study and total malignant tumors and liver sarcomas in the subcutaneous
study, as well as hepatotoxicity (lesions that included steatosis, necrosis and cirrhosis) in most
treated rats in both studies and decreased survival time in the gavage study. Although there were
apparent increases in total malignant tumors by both routes and liver sarcomas by subcutaneous
injection, the studies are inadequate for carcinogenicity assessment due to limitations that
include the use of single dose levels, doses that exceeded the maximum tolerated dose (as shown
by the liver damage and decreased survival time), low dosing frequency (twice weekly), small
numbers of animals (18/route) for a cancer bioassay, and lack of information on the histological
type of liver sarcoma.
A limited amount of information is available on the genotoxicity of n-propyl alcohol,
which did not induce reverse mutations in S. typhimurium (Khudoley et al., 1987; Stolzenberg
and Hine, 1979), DNA damage in E. coli (Mersch-Sundermann et al., 1994), or sister-chromatid
exchanges or micronuclei in Chinese hamster cells (von der Hude et al., 1987; Obe and Ristow,
1977) in in vitro assays.
In accordance with current EPA cancer guidelines (U.S. EPA, 2005), the available data
are inadequate for an assessment of human carcinogenic potential.
Quantitative Estimates of Carcinogenic Risk
Derivation of quantitative estimates of cancer risk for propyl alcohol is precluded by the
lack of suitable data.
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