ECAO-CIN-G005
500ECAOCING005
EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR N-PROPYL ALCOHOL
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
U.S. Environmental Protection Agency
, Region V, Library
by 230 South Dearborn Street
Chicago, Illinois 60604
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy and policy implications.
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DISCLAIMER
__ »
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document_ser1es
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfOs 1s the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfOs are not estimated. A
carcinogenic potency factor, or q^* (U.S. EPA, 1980), 1s provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genldty are derived. The RQ 1s used to determine the quantity of a hazar-
dous substance for which notification 1s required In the event of a release
as specified under the CERCLA. These two RQs (chronic toxldty and cardno-
genlcHy) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer-based RQs are defined 1n U.S.
EPA, 1983 and 1986, respectively.
111
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EXECUTIVE SUMMARY
n-Propyl alcohol Is a clear, colorless liquid that 1s produced naturally
by plants, microbes, animal waste, sewage treatment and volcanoes (Unruh and
SplnlcelH, 1982; U.S. EPA, 1983b). It Is mlsdble In water, ethyl ether
and alcohols, and undergoes reactions typical of low molecular weight
primary alcohols (Unruh and SplnlcelH, 1982). n-Propyl alcohol 1s produced
commercially from ethylene using a two-step process known as the oxo process
(Unruh and Sp1n1cell1f 1982). SRI (1986) lists Celanese Corp., Texas
Eastman Co. and Union Carbide Corp. as current domestic manufacturers of
n-propyl alcohol. In 1985, 145.283 million pounds of n-propyl alcohol were
produced In the United States (USITC, 1986). The use pattern for this
compound 1s as follows: end use solvent, 22%; Intermediate for n-propyl-
amlnes, 37%; Intermediate for n-propyl acetate, 19%; Intermediate for other
compounds Including n-propyl halldes and n-propyl esters, 19X; and FDA-
approved feed additive, 3X (U.S. EPA, 1983b).
In water, aerobic blodegradatlon should be the Important mechanism for
removal of n-propyl alcohol. The volatilization half-life for this compound
from water 1 m deep, flowing 1 m/sec with a wind speed of 3 m/sec has been
estimated to be -4 days. n-Propyl alcohol Is not expected to undergo
chemical hydrolysis, oxidation, photolysis or bloaccumulatlon 1n aquatic
organisms or adsorb to suspended solids or sediments. In the atmosphere,
n-propyl alcohol should exist almost entirely 1n the vapor phase (Perry and
Green, 1984; Elsenrelch et al., 1981). This compound will react with photo-
chemlcally generated hydroxyl radicals and has an estimated reaction half-
life of 2-3 days (Campbell et a!., 1976; Atkinson et al., 1979; Overend and
Paraskevopoulos, 1978; U.S. EPA, 1987). Reaction with ozone will not be
1v
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environmentally relevant (U.S. EPA, 1987). Potential, exists for removal of
significant amounts of this compound from the atmosphere by wet deposition.
In soil, leaching 1s expected to be-an Important transport process and
aerobic blodegradatlon 1s probably an Important degradation process. The
persistence of n-propyl alcohol 1n soils cannot be estimated from the data
available.
n-Propyl alcohol may be released to aquatic systems 1n the effluent from
Its manufacturing and use facilities, In leachate from waste disposal sites
and as a result of spoilage and fermentation of natural products (U.S. EPA,
1983b). n-Propyl alcohol has been found In groundwater and leachate under a
municipal solid waste landfill. It has been Identified 1n drinking water
from the District of Columbia (Schelman et a!., 1974) and has been tenta-
tively Identified 1n drinking water from Miami (Lucas, 1984). n-Propyl
alcohol has been detected 1n milk and milk products and forms naturally
during the fermentation of carbohydrates such as grains and fruits during
the production of beer, wine, whiskey and rum (U.S. EPA, 1983b). n-Propyl
alcohol has also been Identified 1n 1/12 samples of mothers' milk
(PelUzzaM et al., 1982). Thus, the general population may be exposed to
n-propyl alcohol by Ingestlon of liquor, fermented foods, milk products
(U.S. EPA, 1983b) and In some Instances drinking water. n-Propyl alcohol
may be released to the atmosphere In emissions from production and use
facilities, solid waste landfills and natural sources such as fermentation
of natural products and volcanic eruptions (U.S. EPA, 1983b). This compound
has been monitored In the air over Tuscon, AZ (Snider and Dawson, 1985) and
has been detected In 196/387 samples of expired air from 54. human subjects
(Krotoszynskl et al., 1979). The general public Is likely to be exposed
dermally to n-propyl alcohol during use of consumer products such as nail
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polishes, metal degreasers, floor waxes, cleaning preparations and anti-
septics, as well as a variety of other consumer products. Adequate monitor-
w . _ *
1ng data were not found 1n the literature for estimating the dally human
exposure to this compound from Inhalation of air and 1ngest1on of foods and
drinking water.
N-propyl alcohol was generally nontoxlc to aquatic organisms at concen-
trations <1000 mg/i. The most sensitive species were the protozoans
ChUomonas paramedum. Entoslphon sulcaturo and Uronema parduczl. and the
blue-green alga H1crocyst1s aeruglnosa. with toxldty thresholds of 38-565
mg/l (Brlngmann and Kuehn, 1978, 1981; Brlngmann et al., 1980).
n-Propyl alcohol 1s absorbed from the gastrointestinal tract, lungs and
skin. Once steady-state Is reached, 1t appears to be uniformly distributed
with no sequestering of the compound or Its metabolites expected (Browning,
1965). n-Propyl alcohol appears to be metabolized 1n the same way as other
primary alcohols. Oxidation to proplonlc add 1s expected to occur using an
aldehyde Intermediate; some lactic add formation 1s also expected; and a
portion of the proplonlc add may undergo further oxidation to CO- and
water (Williams, 1959; Orskov, 1949). Elimination of n-propyl alcohol from
the blood appears to follow zero-order kinetics (Orskov, 1949; Beauge et
al., 1979). Acetic add and acetaldehyde (Salto, 1975) and conjugates of
glucuronlc add (Kami! et al., 1953) have been Identified 1n the urine of
rabbits.
Inhalation exposures of mice to n-propyl alcohol vapors at 165-367
mg/m3 for 7.5-12 hours/day for periods up to 24 days resulted 1n fatty
Infiltration of the liver (Weese, 1928), which was considered reversible.
Pertinent data regarding the effects of chronic Inhalation exposure could
not be located In the available literature as cited 1n Appendix A. When
v1
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n-propyl alcohol was administered to male Wlstar rats as the sole drinking
fluid at 2 M for 2-months or 1 M for 4 months, no hepatotoxlc effects were
observed at 1 M; however, at 2 M, rat's had Increased I1ver-to-body-we1ght
ratios (Hlllbom et al., 1974a,b).
In a chronic study, steatosls, necrosis and cirrhosis of the liver,
necrosis of the myocardium, Interstitial pancreatitis and flbrosls, and
hematotoxlc effects were observed 1n rats treated orally at 0.3 ml/kg or
subcutaneously at 0.06 ml/kg, 2 times/week (G1bel et al., 1974, 1975).
n-Propyl alcohol 1s low 1n acute toxlclty to animals; and acute exposure
may result In mucous membrane Irritation, ataxla, lethargy, prostration and
narcosis (Rowe and McColHster, 1982). LD5Q values for rats have been
reported In the range of 1.87-6.5 g/kg; 4.5 g/kg for mice and 2.82-3.5 g/kg
for the rabbit (U.S. EPA, 1983c).
Pertinent data regarding the cardnogenldty of Inhaled n-propyl alcohol
were not located 1n the available literature. G1bel et al. (1974, 1975)
found Increased total Incidences of malignant tumors In rats treated orally
with n-propyl alcohol at 0.3 ml/kg or subcutaneously at 0.06 mi/kg, 2
times/week for the Hfespan. Malignant tumors Included myelogenlc leukemia,
hepatocellular carcinoma and liver sarcomas. Although It was not clear If
Individual rats had more than one tumor, 1f each malignant tumor occurred 1n
a different rat, the total malignant tumor Incidences In orally and subcuta-
neously treated rats were significantly greater than In the respective
controls. The Incidences of any particular type of tumor 1n orally treated
rats was not significantly different from controls, but the Incidence of
liver sarcomas, a relatively rare tumor type, was significantly higher In
rats treated subcutaneously with n-propyl alcohol than 1n saline-Injected
controls. Information about n-propyl alcohol metabolism shows that U 1s
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metabolized through aldehyde Intermediates. This 1s noteworthy as aldehydes
In general exhibit carcinogenic activity -In animal test systems.
n-Propyl alcohol was Inactive 1n cytogenetlc assays Involving the_Induc-
tion of mlcronuclel or slster-chromatld exchanges 1n Chinese hamster lung
(V79) cells {Lasne et a!., 1984). In a reproduction study, males exposed to
7000 ppm (17,204 mg/m3} n-propyl alcohol for 7 hours/day for 6 weeks
showed reduced fertility when mated with unexposed females (Nelson et al.,
1985). Pregnant rats exposed to 7000 ppm, 7 hours/day from gestation days
1-20 showed reduced weight gain and feed Intake, while female offspring from
this treated group showed reduced weight gain through 3 weeks of age and a
low Incidence of crooked tall.
Grant and Samson (1984) reported reduced brain weight In neonatal rats
receiving n-propyl alcohol through a gastric catheter for 4 consecutive
days. Biochemical Indices of brain growth Indicated that n-propyl alcohol
exposure affected the forebraln, cerebellum and bralnstem.
Data were Insufficient to calculate a q * and RfOs for subchronlc and
chronic exposure. Although subchronlc oral data were available, develop-
mental data suggest that the fetus/neonate 1s more sensitive to n-propyl
alcohol exposure than the adult. Data were Inadequate to determine a NOAEL
for central nervous system effects 1n developing mammals. Furthermore,
n-propyl alcohol might be carcinogenic as demonstrated by the evidence In
the Gibe! (1974, 1975) oral and subcutaneous studies. n-Propyl alcohol was
placed In EPA Group C we1ght-of-evidence category. Since data were
Inadequate for quantitative risk assessment, no hazard ranking based on
cancer could be developed. An RQ based on chronic toxlclty of 1000 pounds
resulted when the Increased mortality data from the Glbel et al. (1974,
1975) studies were used. These studies are considered weak because of
reporting deficiencies.
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TABLE OF CONTENTS
Page
1. INTRODUCTION : - 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. WATER 5
2.1.1. Hydrolysis 5
2.1.2. Oxidation 5
2.1.3. Photolysis . 5
2.1.4. B1odegradat1on 5
2.1.5. Adsorption 6
2.1.6. B1oaccumulat1on 6
2.1.7. Volatilization 7
2.2. AIR 7
2.2.1. Reaction with Hydroxyl Radicals 7
2.2.2. Reaction with Ozone 7
2.2.3. Photolysis 7
2.2.4. Physical Removal Processes 8
2.3. SOIL 8
2.3.1. Chemical Degradation 8
2.3.2. H1crob1al Degradation 8
2.3.3. Leaching 8
2.3.4. Volatilization 9
2.4. SUMMARY 9
3. EXPOSURE 10
3.1. WATER 10
3.2. FOOD 10
3.3. INHALATION 11
3.4. DERMAL 11
3.5. OTHER SOURCES 12
3.6. SUMMARY 12
1x
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TABLE OF CONTENTS (cont.)
Page
4. AQUATIC TOXICITY . . . 14
4.1. ACUTE TOXICITY 14
4.2. CHRONIC EFFECTS 14
4.3. PLANT EFFECTS 19
4.4. SUMMARY 19
5. PHARMACOKINETCS 21
5.1. ABSORPTION 21
5.2. DISTRIBUTION 21
5.3. METABOLISM 21
5.4. EXCRETION 22
5.5. SUMMARY 24
6. EFFECTS . . .............. 25
6.1. SYSTEMIC TOXICITY 25
6.1.1. Inhalation Exposures. ....... . . 25
6.1.2. Oral Exposures. ..... 25
6.1.3. Other Relevant Information 27
6.2. CARCINOGENICITY 30
6.2.1. Inhalation 30
6.2.2. Oral'. 30
6.2.3. Other Relevant Information 31
6.3. MUTAGENICITY .' r . 32
6.4. TERATOGENICITY 32
6.5. OTHER REPRODUCTIVE EFFECTS . 33
6.6. SUMMARY. 33
7. EXISTING GUIDELINES AND STANDARDS .... 35
7.1. HUMAN 35
7.2. AQUATIC 35
8. RISK ASSESSMENT 36
8.1. CARCINOGENICITY 36
8.1.1. Inhalation 36
8.1.2. Oral 36
8.1.3. Other Routes. ............. 36
8.1.4. Height of Evidence. ............... 37
8.1.5. Quantitative Risk Assessment. .......... 37
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TABLE OF CONTENTS (cont.)
8.2. SYSTEMIC TOXICITY.
8.2.1. Inhalation Exposure 37
8.2.2. Oral Exposure 38
9. REPORTABLE QUANTITIES 40
9.1. BASED ON SYSTEMIC TOXICITY 40
9.2. BASED ON CARCINOGENICITY 42
10. REFERENCES. . 46
APPENDIX A: LITERATURE SEARCHED 59
APPENDIX B: SUMMARY TABLE 62
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LIST OF TABLES
No.
4-1
4-2
4-3
5-1
9-1
9-2
9-3
Title
Acute ToxIcHy of n-Propyl Alcohol to Freshwater
Vertebrates I
Acute ToxIcHy of n-Propyl Alcohol to Aquatic
Invertebrates .........
Acute ToxIcHy of n-Propyl Alcohol to Aquatic Plants
and Bacteria
n-Propyl Alcohol Concentrations (mg %) 1n Blood After
IntraperHoneal Dosing. ,
ToxIcHy Summary for n-Propyl Alcohol ..........
Oral Composite Score for n-Propyl Alcohol Using
Wlstar Rats ..........
n-Propyl Alcohol: Minimum Effective Dose (MED) and
Reoortable Quantity (RO)
Page
. . .- 15
. . . 17
. . . 20
. . . 23
. . . 41
. . . 43
. . . 44
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LIST OF ABBREVIATIONS
BCF B1ocdncentrat1on factor
bw Body weight
CAS Chemical Abstract Service
COD Carbonaceous oxygen demand
CS Composite score
ONA Oeoxyrlbonuclelc add
ECso Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
FEL Frank effect level
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate (reduced form)
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
NOLC No-observed-lethal concentration
ppb Parts per billion
*
ppm Parts per million
RfO Reference dose
RQ Reportable quantity
RV,j Dose-rating value
RVe Effect-rating value
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LIST OF ABBREVIATIONS (cont.)
STEL Short-term exposure level
ThOO Theoretical oxygen demand
TLV Threshold limit value
TWA Time-weighted average
x1v
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
_ . *
n-Propyl alcohol Is also known as 1-propanol, ethyl carblnol and
1-hydroxypropane. The structure, molecular weight, empirical formula and
CAS Registry number for n-propyl alcohol are as follows:
CH3-CH2-CH2-OH
Molecular weight: 60.09
Empirical formula: C,.HQ0
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1.3. PRODUCTION DATA
n-Propyl alcohol 1s produced by a two-step process, known as the oxo
___ . . *
process, In which ethylene Is hydroformylated to propanal In the presence of
cobalt or rhodium catalysts followed by hydrogenatlon of propanal to
n-propyl alcohol 1n the presence of nickel-based or copper chromium oxide
catalysts:
catalyst
CH2 = CH2 * CO * H2 ^ CH3CH2CHO
A, pressure
catalyst
CH3CH2CHO * H2 ^ CH3CH2CH2OH
A, pressure
Operating conditions vary depending on the type of catalyst used (Unruh and
SplnlcelH, 1982). SRI (1986) currently lists the following companies as
domestic manufacturers of n-propyl alcohol:
Celanese Corp. Bay CHy, TX
Bishop, TX
Texas Eastman Co. Longvlew, TX
Union Carbide Corp. Texas City, TX
The. most recent year for which production data are available Is 1985, during
which 145.283 million pounds of n-propyl alcohol were produced 1n the United
States (USITC, 1986).
1.4. USE DATA
The use pattern for n-propyl alcohol 1s shown 1n Figure 1-1. This com-
pound Is used as a solvent 1n flexographlc printing Inks, particularly for
printing on polyolefln and polyamlde film, water-based printing Inks, nail
polishes, cellulose film, PVC adheslves, metal degreasers, floor wax, clean-
Ing preparations, brake fluids, resins, cellulose esters, waxes, vegetable
oils and antiseptics (Unruh and Sp1n1cell1, 1982; U.S. EPA, 1983b).
OOOSd -2- 04/16/87
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n-Propyl Alcohol
225
End Use Solvent
755
Intermediate and
Other Uses
19% 37%
n-Propyl Acetate n-Propylamines
Solvent in
Paints, Laquers,
and Printing Inks
*
3%
FDA-approved Feed
Additive
Other Including
n-Propyl Hal ides and
n-Propyl Esters
FIGURE 1-1
Use Pattern for n-Propyl Alcohol
Source: U.S. EPA, 1983b
OOOSd
-3-
04/16/87
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n-Propyl alcohol 1s also used 1n the polymerization of acrylonltrUe;
spinning of polyacrylonltrlle and dyeing of wool; In lacquers, dopes,
cosmetics, dental lotions, cleaners, polishes and Pharmaceuticals; and as a
synthetic flavoring (U.S. EPA, 1983b).
1.5. SUMMARY
n-Propyl alcohol Is a clear, colorless liquid that 1s produced naturally
by plants, microbes, animal waste, sewage treatment and volcanoes (Unruh and
Splnlcelll. 1982; U.S. EPA, 1983b). It 1s mlsdble 1n water, ethyl ether
and alcohols, and undergoes reactions typical of low molecular weight
primary alcohols (Unruh and SplnlcelH, 1982). n-Propyl alcohol Is produced
commercially from ethylene using a two-step process known as the oxo process
(Unruh and Splnlcelll, 1982). SRI (1986) lists Celanese Corp., Texas
Eastman Co. and Union Carbide Corp. as current domestic manufacturers of
n-propyl alcohol. In 1985, 145.283 million pounds of n-propyl alcohol were
produced 1n the United States (USITC, 1986). The use pattern for this
compound 1s as follows: end use solvent, 22%; Intermediate for n-propyl-
amlnes, 37%; Intermediate for n-propyl acetate, 19%; Intermediate for other
compounds Including n-propyl halldes and n-propyl esters, 19%; and FDA-
approved feed additive, 3% (U.S. EPA, 1983b).
0005d -4- 04/16/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. WATER
2.1.1. Hydrolysis. Based on the molecular structure of n-propyl alcohol,
this compound 1s likely to be resistant to chemical hydrolysis (Lyman et
al.. 1982).
2.1.2. Oxidation. The half-life for n-propyl alcohol reacting with
photochemically generated hydroxyl radicals In dilute aqueous solution was
estimated to be -1 year, based on a reaction rate constant of 2.7xlO»
M~l sec"1 (Oorfman and Adams, 1973) and an ambient hydroxyl radical
concentration of IxlO'17 mol/l (Mill et al.t 1980). Therefore, this
reaction Is not expected to be environmentally significant.
Pertinent data regarding the aquatic reaction between n-propyl alcohol
and singlet oxygen or alky! peroxy radicals could not be located 1n the
available literature as cited 1n Appendix A; however, n-propyl alcohol Is
expected to be Inert to these oxldants (Jaber et al., 1984).
2.1.3. Photolysis. Pertinent data regarding the photolysis of n-propyl
alcohol could not be located 1n the available literature as cited 1n
Appendix A. Photolysis of n-propyl alcohol, however, 1s not expected to be
environmentally relevant (Jaber et al., 1984; U.S. EPA, 1983b).
2.1.4. Blodegradatlon. n-Propyl alcohol was readily degradable In
blodegradatlon screening studies using activated sludges, sewage seed and
wastewater Inoculums (Gerhold and Halaney,' 1966; Symons et al., 1961; Price
et al., 1974; Hatfleld, 1957; Pltter, 1976); this compound Is considered to
be easily degradable using activated sludge (Unruh and Sp1n1ce111, 1982).
After 6, 12 and 24 hours of Incubation, 500 mg/i n-propyl alcohol Inocu-
lated with activated sludge consumed 13.9, 26.8 and 36.9% of Its ThOO,
respectively (Gerhold and Malaney, 1966). Incubation of 3, 7 and 10 mg/i
0005d -5- 04/16/87
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n-propyl alcohol 1n freshwater with sewage seed as microblal Inoculum
resulted 1n 64, 76,- 81 and.75% of ThOD after 5, 10, 15 and 20 days, respec-
tively (Price et al., 1974). IncubatTon of 3, 7 and 10 mg/i of n-propyl
alcohol In synthetic seawater seeded with filtered sewage resulted In 43,
64, 67 and 73% ThOO after 5, 10, 15 and 20 days, respectively (Price et al.,
1974). A 98.8% COO removal was observed for n-propyl alcohol 1n 20 days at
an Initial concentration equivalent to 200 mg/i COO with adapted activated
sludge at 20°C (Fitter, 1976). Using sewage as seed and the standard dilu-
tion method, Heukeleklan and Rand (1955) reported blooxldatlon of n-propyl
alcohol that corresponds to 20-63% of ThOO 1n 5 days. These studies suggest
that aerobic blodegradatlon would be an Important removal process for
n-propyl alcohol In water.
n-Propyl alcohol Is reported to be susceptible to anaerobic blodegrada-
tlon (Speece, 1983); however, pertinent data concerning the rate of
anaerobic blodegradatlon under environmental conditions could not be located
1n the available literature as cited In Appendix A.
2.1.5. Adsorption. Experimental data regarding adsorption of n-prapyl
alcohol to suspended solids or sediments 1n water could not be located In
the available literature as cited 1n Appendix A. Given the complete water
solubility of this compound and Us estimated K of 32-33 (Section 2.3.),
physical adsorption to suspended solids and sediments should not be signifi-
cant.
2.1.6. Bloaccumulatlon. Experimental data regarding bloaccumulatlon of
n-propyl alcohol 1n aquatic organisms could not be located In the available
literature as cited In Appendix A. A BCF of 3 was estimated using a log
K value of 0.25 (Hansch and Leo, 1985) and the following equation (Lyman
OQOSd -6- 03/31/87
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et al., 1982): log BCF = 0.76 log KQW - 0.23. This BCF value and the
complete water solubllHy of n-propyl alcohol also Indicate that bloaccumu-
latlon In aquatic organisms should not be significant.
2.1.7. Volatilization. The Henry's Law constant for n-propyl alcohol was
measured to be 6.6xlO~* atm-ma/mol at 25°C (H1ne and Mookerjee, 1975).
Based on this value of Henry's Law constant, the volatilization half-life of
n-propyl alcohol from water 1 m deep, with a current speed of 1 m/sec and a
wind speed of 3 m/sec has been estimated to be -4 days using the method of
Lyman et al. (1982). Therefore, volatilization from water Is not likely to
be significant.
2.2. AIR
2.2.1. Reaction with Hydroxyl Radicals. Based on a vapor pressure of 20
mm Hg at 25.2°C (Perry and Green, 1984), n-propyl alcohol 1s expected to
exist entirely 1n the vapor phase 1n the atmosphere (E1senre1ch et al.,
1981). The rate constant for the reaction of n-propyl alcohol with photo-
chemical ly-generated hydroxyl radicals 1n the atmosphere 1s 4.07xlO~12
cm'/molecule/sec at 19°C (Campbell et al., 1976) and 5.33xlO~12 and
3.21xlO~" cma/molecule/sec at 23°C (Atkinson et al., 1979; Overend and
ParaskevopouTos, 1978). Assuming an ambient hydroxyl radical concentration
of 8xlOs molecules/cm3 (U.S. EPA, 1987), the hydroxyl reaction half-life
has been estimated to be 2-3 days. Therefore, reaction of n-propyl alcohol
with hydroxyl radicals 1n the atmosphere 1s expected to be a significant
removal mechanism.
2.2.2. Reaction with Ozone. n-Propyl alcohol 1s not expected to react
with ozone 1n the atmosphere (U.S. EPA, 1987).
2.2.3. Photolysis. Pertinent data regarding the direct photolysis of
n-propyl alcohol 1n the troposphere could not be located In the available
literature as cited In Appendix A.
OOOSd -7- 04/16/87
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2.2.4. Physical Removal Processes. Significant amounts of this compound
may be removed from the atmosphere by wet deposition because n-propyl
alcohol 1s completely water soluble.
2.3. SOIL
2.3.1. Chemical Degradation. Based on the molecular structure of
n-propyl alcohol, H Is not likely to undergo chemical hydrolysis In soil
(Lyman et al., 1982). Other pertinent data regarding the chemical degrada-
tion of n-propyl alcohol 1n soil could not be located In the available
literature as cited In Appendix A.
2.3.2. M1crob1al Degradation. Limited data pertaining to the blodegrada-
tlon of n-propyl alcohol 1n soil were found In the available literature as
cited 1n Appendix A. Organisms Isolated from soil that are capable of
degrading n-propyl alcohol Include M. trlchospoMum. £. methanlca (Pate! et
al., 1979), Alea11 genes strains MC11, TE8 and PE8 and Corvnebacterlum OEH8
(Harada. and Nagashlma, 1975). Based on results of blodegradatlon studies 1n
aqueous media (see Section 2.1.4.), H may be speculated that aerobic
blodegradatlon of n-propyl alcohol 1n soil would be a significant removal
mechanism.
2.3.3. Leaching. The complete water solubility and the relatively low
K of n-propyl alcohol suggest that 1t may leach readily through soil,
although there are no experimental data available to confirm this predic-
tion. The K of n-propyl alcohol was estimated using the molecular
topology and quantitative structure-activity analysis of Sabljlc (1984) and
the following equation (Lyman et al., 1982): log KQC * 0.544 log KQW +
1.377, where the log K value 1s 0.25 (Hansch and Leo, 1985). Estimated
K values estimated using both methods are 32 and 33, respectively, which
suggest that this compound would be highly mobile In soil (Swann et al.,
1983).
0005d -8- 04/16/87
-------
2.3.4. Volatilization. Pertinent data regarding the volatilization of
n-propyl alcohol from soil could not be Jocated 1n the available literature
as cited 1n Appendix A. The relatively high vapor pressure of nrpropyl
alcohol [20 mm Hg at 25.2°C (Perry and Green, 1984)] suggests that volatili-
zation from dry soil surfaces 1s likely to be significant. Evaporation from
moist soils may not be significant since this compound Is not expected to
volatilize from water significantly (see Section 2.1.7.).
2.4. SUMMARY
In water, aerobic blodegradatlon should be the Important mechanism for
removal of n-propyl alcohol. The volatilization half-life for this compound
from water 1 m deep and flowing 1 m/sec with a wind speed of 3 m/sec has
been estimated to be -4 days. n-Propyl alcohol Is not expected to undergo
chemical hydrolysis, oxidation, photolysis or bloaccumulatlon 1n aquatic
organisms or adsorb to suspended solids or sediments. In the atmosphere,
n-propyl alcohol should exist almost entirely 1n the vapor phase (Perry and
Green, 1984; E1senre1ch et al., 1981). This compound will react with photo-
chemlcally generated hydroxyl radicals and has an estimated reaction half-
life of 2-3 days (Campbell et al., 1976; Atkinson et al., 1979; Overend and
Paraskevopoulos, 1978; U.S. EPA, 1987). Reaction with ozone will not be
environmentally relevant (U.S. EPA, 1987). Potential exists for removal of
significant amounts of this compound from the atmosphere by wet deposition.
In soil, leaching Is expected to be an Important transport process and
aerobic blodegradatlon 1s probably an Important degradation process. The
persistence of n-propyl alcohol 1n soils cannot be estimated from the data
available.
OOOSd -9- 04/16/87
-------
3. EXPOSURE
3.1. WATER
n-Propyl alcohol may be released to aquatic media by the effluent from
Us manufacturing plants, and 1n leachate from waste disposal sites. It may
also enter the environment as a product of spoilage and fermentation of
natural products (U.S. EPA, 1983b). n-Propyl alcohol was Identified 1n 4/6
leachate samples and 2/13 groundwater samples from a municipal solid waste
landfill. Concentrations detected ranged from 76-37,000 vg/i 1n
leachate samples and 55 yg/i In groundwater samples (Sabel and Clark,
1984). n-Propyl alcohol was detected at a concentration of 1000 mg/i In
the leachate from an artificial landfill, which was designed to simulate a
typical solid waste landfill (Burrows and Rowe, 1975). This compound has
been detected 1n drinking water from the District of Columbia at a concen-
tration of 0.001 ppm (Schelman et al., 1974) and 1t has been tentatively
Identified 1n drinking water taken from Miami during 1976 (Lucas, 1984).
3.2. FOOD
n-Propyl alcohol 1s a natural product that forms during the fermentation
of carbohydrates (Including grains and fruits) and during the production of
beer, wine, whiskey and rum (U.S. EPA, 1983b). The concentration of
n-propyl alcohol 1n samples of 31 commercial wines ranged between 180 and
380 mg/i of ethyl alcohol content. Cahors wine has been found to contain
33 mg n-propyl alcohol/1 of wine and -Corbler wine has been found to
contain 12 mg n-propyl alcohol/I wine (U.S. EPA, 1983b). This compound
has also been found In beer, cistern room whiskey and Jamaican rum (31,300
mg/l of ethyl alcohol) (U.S. EPA, 1983b).
n-Propyl alcohol was qualitatively Identified 1n 1/12 samples of
mothers' milk obtained from women 1n four urban areas (PelUzzarl et al.,
QOOSd -10- 04/16/87
-------
1982). This compound was detected at concentrations ranging from 1.2-2.5
ppm 1n dairy milk having a strong feed flavor (Gordon and Morgan, 1972) and
was Isolated 1n milk products such as, kefir and yogurt (U.S. EPA, 1983b).
Trace amounts of this compound have also been found 1n fermented eggs (U.S.
EPA, 1983b). n-Propyl alcohol was also Identified as a volatile component
of roasted filbert nuts (Klnlln et al., 1972).
3.3. INHALATION
n-Propyl alcohol may be emitted to air through emissions from production
and use facilities, solid waste landfills and natural sources such as
fermentation of natural products and volcanic eruptions (U.S. EPA, 1983b).
n-Propyl alcohol was detected at a rate ranging between 0.23 and 1400
yg/hour 1n the expired air of 3/8 male subjects; these 3 subjects were the
only smokers In the sample group (Conkle et al., 1975). n-Propyl alcohol
has also been detected 1n the expired air of male and female nonsmokers from
Chicago. (Krotoszynskl and O'Neill, 1982). This compound was detected at a
mean concentration of 21.1 ng/l 1n 196/387 samples of expired air taken
from 54 human subjects living 1n an urban environment {Krotoszynskl et al.,
1979).
n-Propyl alcohol was detected 1n the air of Tuscon, AZ, during 1982 at
an average concentration of 0.02 ppb (Snider and Dawson, 1985), but Us
origin was not clearly Identified. This compound was qualitatively Identi-
fied In the air of the Southern Black Forest 1n Germany during January 1985
(Juettner, 1986).
3.4. DERMAL
The general population Is likely to have dermal contact with n-propyl
alcohol during use of consumer products that contain this compound; some
0005d -11- 04/16/87
-------
examples are nail polishes, metal degreasers, floor waxes, cleaning prepara-
tions, antiseptics as well as a wide variety of other products). As
reviewed by U.S. EPA (1983b), the partition coefficient for the penetration
of human stratum corneum at 25°C by n-propyl alcohol was measured to be 1.1
cma/g. The permeability coefficient for n-propyl alcohol on human
epidermis at 25°C was 0.0012 cm/hour.
3.5. OTHER SOURCES
n-Propyl alcohol has been found In fresh swine feces and urine at levels
of 0.10 and 0.12 vg/g, respectively (Yasuhara et a!., 1984).
3.6. SUMMARY
n-Propyl alcohol may be released to aquatic systems 1n the effluent from
Us manufacturing and use facilities, In leachate from waste disposal sites
and as a result of spoilage and fermentation of natural products (U.S. EPA,
1983b). n-Propyl alcohol has been found In groundwater and leachate under a
municipal solid waste landfill. It has been Identified 1n drinking water
from the District of Columbia (Schelman et al., 1974) and has been tenta-
tively Identified 1n drinking water from Miami (Lucas, 1984). n-Propyl
alcohol has been detected 1n milk and milk products and forms naturally
during the fermentation of carbohydrates such as grains and fruits during
the production of beer, wine, whiskey and rum (U.S. EPA, 1983b). n-Propyl
alcohol has also been Identified In 1/12 samples of mothers' milk
(PelUzzarl et al., 1982). Thus, the general population may be exposed to
n-propyl alcohol by Ingestlon of liquor, fermented foods, milk products
(U.S. EPA, 1983b) and 1n some Instances drinking water. n-Propyl alcohol
may be released to the atmosphere In emissions from production and use
facilities, solid waste landfills and natural sources such as fermentation
of natural products and volcanic eruptions (U.S. EPA, 1983b). This compound
OOOSd -12- 04/16/87
-------
has been monitored 1n the air over Tuscon, AZ (Snider and Oawson, 1985) and
has been detected irv 19.6/387 samples of-explred air from 54 human subjects
(Krotoszynskl et al., 1979). The general public 1s likely to be exposed
dermally to n-propyl alcohol during use of consumer products such as nail
polishes, metal degreasers, floor waxes, cleaning preparations and anti-
septics, as well as a variety of other consumer products. Adequate monitor-
Ing data were not found In the literature for estimating the dally human
exposure to this compound from Inhalation of air and 1ngest1on of foods and
drinking water.
OOOSd -13- 03/31/87
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Data concerning acute toxlclty of.n-propyl alcohol to freshwater fish
and amphibians are shown In Table 4-1. The lowest concentration reported to
ba toxic to fishes was 200-500 mg/i, which was the "critical range" for
creek chub, Semotllus atromaculatus (Gillette et a!., 1952). This critical
range was defined as the concentration below which four test fish survived
24 hours and above which all test fish died. All other acutely toxic
concentrations for fish and amphibians were >2000 mg/i. Additional data
were provided by Llpnlck et al. (1985), who reported that 5 mg/l n-propyl
alcohol was nontoxlc to rainbow trout, Salmo qalrdnerl. brown trout, Sal mo
trutta. bluegllls, Lepomls macrochlrus. and goldfish, Carasslus auratus.
Table 4-2 contains the available Information concerning acute toxlclty
of n-propyl alcohol to freshwater Invertebrates. Of these species, the
protozoans tested by BMngmann and Kuehn (1980) and Brlngmann et al. (1980)
were the most sensitive, having toxlclty thresholds for Inhibition of cell
multiplication <1000 mg/l. The lowest reported toxlclty threshold was 38
mg/l for Entoslphon sulcatum (Brlngmann and Kuehn, 1981). Reported
acutely toxic concentrations for other Invertebrates (crustaceans. Insects,
and mollusks) were all >2000 mg/i.
4.2. CHRONIC EFFECTS
Pertinent data regarding chronic toxlclty of n-propyl alcohol to aquatic
biota could not be located In the available literature as cited 1n
Appendix A.
Q005d -14- 04/16/87
-------
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TABLE 4-2
Acute Toxtc1ty_af n-Propyl Alcohol to Aquatic Invertebrates
Species
Concentration
(mg/i)
Effect
Reference
PROTOZOA
Flagellate protozoan
ChUomonas parameclum
Flagellate protozoan
Entoslphon sulcatum
dilate protozoan
Uronema parduczl
FRESHWATER
175
38
568
SPECIES
Tox1c1ty
threshold3
Tox1c1ty
threshold3
Tox1c1ty
threshold3
Brlngmann
et al., 1980
Brlngmann and
Kuehn, 1981
Brlngmann and
Kuehn, 1981
CRUSTACEANS
Water flea
Daphnla maqna
Water flea
Daphnla pulex
Water flea
Daphnla cucullata
Copepod
NUocra splnlpes
6300
4100
4450
7082
4415
3025
2300
5820
2300
48-hour
48-hour NOLC
48-hour
48-hour LCsob
48-hour ECsoc
48-hour LCso
48-hour NOLC
48-hour
96-hour LC5Q
Slooff-
et al., 1983
Brlngmann and
Kuehn, 1977
Canton and
Adema, 1978
Brlngmann and
Kuehn, 1982
Slooff
et al., 1983
Slooff
et al., 1983
Bengtsson
et al., 1984
OOOSd
-17-
03/31/87
-------
TABLE 4-2 (cont.)
Species
Concentration
(mg/l)
Effect
Reference
INSECTS
Mosquito larvae
Aedes aeqyptl
Mosquito larvae
Culex plplens
FRESHWATER SPECIES (cont.)
4400
3200
4800
3600
48-hour
48-hour NOLC
48-hour
48-hour NOLC
Slooff
et al., 1983
Slooff
et a!., 1983
OTHER
Hydra
Hydra o11gact1s
Snail
Lymnaea staqnalls
6800
5100
6500
4000
48-hour
48-hour NOLC
48-hour
48-hour NOLC
Slooff
et al., 1983
Slooff
et al., 1983
SALTWATER SPECIES
CRUSTACEANS
Brine shrimp
Artemla sallna
Copepod
NUocra splnlpes
4200
2300
24-hour
96-hour
Price et al.,
1974
Linden
et al., 1979
alnh1b1t1on of cell multiplication
bMean of three numbers
cImmobilization
OOOSd
-18-
05/22/87
-------
4.3. PLANT EFFECTS
Data concerning effects of n-propyl alcohol on aquatic plants and
^ **
bacteria are shown 1n Table 4-3. The lowest toxic concentration was 255 43
mg/l, which was the threshold for Inhibition of cell multiplication In the
blue-green alga, H1crocyst1s aeruglnosa (Brlngmann and Kuehn, 1978). The
only other plants tested were species of green algae (Chlorophyta), all of
which had toxlclty thresholds >1000 mg/l. Toxlclty thresholds for
bacteria were also >100Q mg/l (see Table 4-3).
4.4. SUMMARY
N-propyl alcohol was generally nontoxlc to aquatic organisms at
concentrations <1000 mg/l. The most sensitive species were the protozoans
ChUomonas paramedum. Entoslphon sulcatum and Uronema parduczl. and the
blue-green alga Hlcrocystls aeruglnosa. with toxlclty thresholds of 38-565
mg/l (Brlngmann and Kuehn, 1978, 1981; Brlngmann et a!., 1980).
0005d -19- 04/16/87
-------
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OOOSd
-20-
03/31/87
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Portions of this chapter were takenJrorn U.S. EPA (1983c).
n-Propyl alcohol 1s absorbed from the gastrointestinal tract, the lungs
and the skin (Browning, 1965). The only quantitative data by the oral route
were provided 1n a study by Beauge et al. (1979), who administered n-propyl
alcohol by gastric tube to female Wlstar rats at a dose of 50 mmol/kg. A
peak blood level of ~30 mM occurred after -2 hours of postdoslng. As
reviewed by U.S. EPA (1983b), the partition coefficient for the penetration
of human stratum corneum at 25°C by n-propyl alcohol was measured to be 1.1
cmVg. The permeability coefficient for n-propyl alcohol on human
epidermis at 25°C was 0.0012 cm/hour.
5.2. DISTRIBUTION
Once equilibrium 1s reached, n-propyl alcohol appears to be uniformly
distributed with no sequestering of the compound or Its metabolites expected
(Browning, 1965). Quantitative data are not available.
5.3. METABOLISM
n-Propyl alcohol appears to be metabolized 1n the same manner as other
primary alcohols (Williams, 1959). Oxidation to proplonlc add Is expected
to occur through an aldehyde Intermediate. The expected metabolite,
proplonlc acid, has been tentatively Identified In the blood of treated
rabbits; some lactic add may also be formed (Orskov, 1949). By analogy
with other primary alcohols, It 1s expected that a portion of the proplonlc
add will undergo further oxidation to CO- and water (Williams, 1959).
Glucuronlc add conjugates have been Identified In the urine of treated
rabbits and account for <1% of the administered dose (Kamll et al., 1953).
0005d -21- 04/16/87
-------
There are two possible pathways of oxidation: by alcohol dehydrogenase
(lutwak-Hann, 1938; Winer, 1958} or by a mlerosomal alcohol oxidizing system
». *
(Teschke et al., 1974, 1975a,b). The mlerosomal alcohol oxidizing system
requires molecular oxygen and NAOPH and 1s Inhibited by CO-. Catalase
(H-Op) has a very low affinity for n-propyl alcohol and does not appear
to play a role 1n metabolism (Teschke et al., 1975a,b). Beauge et al.
(1979) found that the rate of oxidation of n-propyl alcohol by rats !»> vivo
was 510 mg (8.5 mmol)/kg/hour, with complete elimination from the blood
within 5 hours of oral dosing. Beauge et al. (1979) also found a decrease
1n the C0_ production from palmltate after alcohol administration, as well
as a marked Increase of the lactate/pyruvate and B-hydroxybutyrate/aceto-
acetate ratios, which Increases the Incorporation and accumulation of free
fatty adds (mainly palmltate) Into hepatic trlacylglycerols that are
Initially stored In the liver and contribute to production of fatty liver
associated with alcohol toxIcHy.
n-Propyl alcohol was given by gavage to three rabbits at a dose of 25
nmol/rabbU and 0.9% of the dose was excreted as a conjugate of glucuronlc
add (Kamll et al., 1953). SaHo (1975) found that acetaldehyde and acetic
acid were urinary metabolites of n-propyl alcohol 1n rabbits that were
treated orally.
5.4. EXCRETION
Orskov (1949) studied blood elimination of n-propyl alcohol In rabbits
treated by 1ntraper1toneal Injection. Blood samples were taken 30, 60, 120,
180 and 240 minutes after Injection of doses of 0.8, 1.2 or 1.6 g/kg
(Table 5-1).
OQOSd -22- 04/16/87
-------
TABLE 5-1
n-Propyl Alcohol Concentrations (mg %) 1n Blood
After Intraperltoneal Dosing*
Minutes After Injection
Dose
(g/kg)
0.8
1.2
1.6
30
70
118
162
60
52
89
138
120
29
61
121
180
14
19
93
240
6
9
65
*Source: Orskov, 1949
QOOSd -23- 03/31/87
-------
The elimination of n-propyl alcohol appears to follow zero-order
kinetics, as has been shown for ethanol., If the blood concentration data of
Orskov (1949) are plotted against time, the blood level-time curves are
linear with a slope of 0.0037-0.0058 mg/mi/mlnute depending upon which
dose data are used. Beauge et al. (1979) also found a linear zero-order
blood elimination curve for rats given 50 mmol/kg by mouth. The slope of
this curve 1s 5.55 mM/hour (-0.006 mg/mi/m1nute).
5.5. SUMMARY
n-Propyl alcohol Is absorbed from the gastrointestinal tract, lungs and
skin* Once steady-state Is reached, H appears to be uniformly distributed
with no sequestering of the compound or Its metabolites expected (Browning,
1965). n-Propyl alcohol appears to be metabolized In the same way as other
primary alcohols. Oxidation to proplonlc add 1s expected to occur through
an aldehyde Intermediate; some lactic acid formation Is also expected; and a
portion' of the proplonlc acid may undergo further oxidation to C02 and
water (Williams, 1959; Orskov, 1949). Elimination of n-propyl alcohol from
the blood appears to follow zero-order kinetics (Orskov, 1949; Beauge et
al., 1979). Acetic acid and acetaldehyde (Salto, 1975) and conjugates of
glucuronlc add (Kami! et al., 1953) have been Identified 1n the urine of
rabbits.
0005d -24- 04/16/87
-------
6. EFFECTS
Portions of this chapter were taken from U.S. EPA (1983c).
6.1. SYSTEMIC TOXICITY
&.I.I. Inhalation Exposures.
6.1.1.1. SUBCHRONIC Heese (1928) exposed mice to n-propyl alcohol
vapor at concentrations of 0.1-0.2 ml/15 I (67-133 ppm or 165-367
mg/ma) air. One mouse was exposed for 8 days, two for U days and one for
24 days. Dally exposure periods varied from 7.5-12 hours. Liver, heart,
kidney and lungs were examined h1sto1og1ca!1y. The primary effect noted was
fatty degeneration of the liver, which occurred 1n varying degrees 1n mice
exposed for >14 days and was considered to be reversible.
6.1.1.2. CHRONIC Pertinent data regarding the chronic Inhalation
exposure of n-propyl alcohol could not be located 1n the available litera-
ture as cited 1n Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC HUlbom et al. (1974a,b) gave n-propyl
alcohol, Isopropyl alcohol or ethanol as the sole drinking fluid at concen-
trations of 2 M for 2 months or 1 M for 4 months to groups of five to six
4-month-old male Ulstar rats. Control rats received tap water, and labora-
tory feed was provided ad libitum for all rats throughout the test period.
Food and fluid consumption, as well as weight gain, were recorded for each
rat. All rats were decapitated at the end of the 60- or 120-day test
period, and liver weights were measured. The n-propyl alcohol-treated rats
consumed a relatively constant amount of alcohol throughout the experiment
(an average of 5 mmol/100 g/day), which did not significantly Influence the
food Intake of the rats; however, a lower ratio of weight gain to caloric
0005d -25- 04/16/87
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Intake 1n the groups administered n-propyl alcohol was noted compared with
those receiving ethyl alcohol. The authors suggested that the n-propyl
alcohol-treated groups utilized food- less efficiently than the ethyl
alcohol-treated groups, but the mechanism of Interference with food utiliza-
tion by n-propyl alcohol was not elucidated. Hlstologlcal examination of
the livers showed no Inflammation, cirrhosis or hepatic steatosls In the
n-propyl alcohol-treated rats, but rats treated at 2 H for 2 months had
slightly Increased llver-to-body weight ratios and Nailery's alcoholic
hyaline bodies 1n the liver. No Increase In liver fat content was observed
1n rats receiving n-propyl alcohol. Since no clear hepatotoxlc effects were
Induced by consumption of the three alcohols for periods up to 4 months, the
authors suggested that their findings support the view that dietary factors
(Imbalances) play a significant role 1n the pathogenesls of alcohol-Induced
liver damage. The dally doses of the alcohol In this study greatly exceeded
those generally consumed 1n hard liquors and wine by heavy drinkers, but for
a shorter exposure period.
6.1.2.2. CHRONIC In a long-term study, Gibe! et al. (1974, 1975)
tested three analytical grade alcohols. Including n-propyl alcohol, for
carcinogenic and other toxic effects on Wlstar rats. Oral doses of 0.3 ml
n-propyl alcohol/kg were administered 2 times/week to 18 test rats from 10
weeks of age until spontaneous death, while 30 control rats received 1.0
ml 0.9% Nad/kg at the same treatment rate. Total doses of 50 mi were
administered over the course of the study. In addition to the neoplastlc
activity (Section 6.2.), changes In the myocardium, such as the appearance
of narrow scars resulting from necrosis of the heart muscle, were reported
1n some rats, as were a few Instances of Interstitial pancreatitis and
flbrosls. Although the alcohol(s) producing these effects were not speci-
fied, similar actions by the three alcohols are Inferred. The authors
OOOSd -26- 04/16/87
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reported that a strong hepatotoxlc effect was observed 1n virtually all
rats. Liver steatosls and necrosis In varying degrees and some cirrhosis
_ »
and other undefined hepatic maladies were also associated with alcohol
exposure. Hematotoxlc effects resulting from hyperplasla of the hemato-
poletlc parenchyma of the bone marrow were attributed to n-propyl alcohol.
Average survival time of the rats receiving n-propyl alcohol orally was 570
days compared with 643-666 for the control rats.
6.1.3. Other Relevant Information. Grant and Samson (1984) evaluated the
effect of n-propyl alcohol administration upon brain growth 1n neonatal
rats. Seven neonatal rats were reared using an artificial feeding (gastric
catheter) technique from postnatal days 5-13. On days 5, 6, 7 and 8, the
pups received n-propyl alcohol at doses of 0, 3.8, 7.5, 3.0 and 7.8 g
alcohol/kg bw in their milk formula. After the 4-day alcohol exposure, the
pups received a milk formula until day 18 when they were sacrificed for
organ and biochemical analysis. There were no significant differences In
body, heart, kidney or liver weights between the control and n-propyl
alcohol-treated group. Total brain weight and brain-to-body weight ratio
were significantly greater 1n the control group than 1n the treated group.
The biochemical Indices of brain growth examined In the study Indicated that
n-propyl alcohol exposure affected the forebraln, cerebellum and bralnstem.
The n-propyl alcohol-exposed group had a decreased amount of DMA In all of
the three brain areas studied, and cholesterol levels were decreased 1n the
forebraln and cerebellum. There were no differences 1n mg protein or mg
prote1n/mg DNA levels between the control and the treated pups In the brain
areas examined. The results suggest that exposure to n-propyl alcohol during
the brain growth spurt of the neonatal rat Inhibits brain development In a
manner similar to ethanol.
OOOSd -27- 04/16/87
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In studies parallel to those reported In Section 6.1.2.2. (G1bel et al.,
1974, 1975), 31 Hlstar^ rats were given subcutaneous Injections of three
alcohols, Including n-propyl alcohol, jt twice weekly doses of 0.06 mi/kg
from 10 weeks of age until spontaneous death. Control animals received sub-
cutaneous Injections of 1.0 mi 0.9% NaCl/kg on the same schedule. Changes
1n the myocardium, hepatotoxlc and hematologlcal effects were reported.
Although neither the alcohol(s) nor the route of administration producing
these effects were specified, similar action by the alcohols by either route
1s Inferred. No differences were reported 1n survival time between control
rats and rats given n-propyl alcohol by subcutaneous administration.
Gerarde and Ahlstrom (1966) studied the aspiration toxlclty of a
homologous series of n-pr1mary alcohols 1n male Sprague-Dawley rats. After
aspiration with 0.2 ml of n-propyl alcohol, the rats died Instantly of
respiratory or cardiac arrest because of the high concentration of alcohol
In the blood stream. As the chain length of the alcohol Increased, the rats
died of pulmonary edema and hemorrhage.
n-Propyl alcohol Is relatively low 1n acute oral toxlclty to animals
(Rowe and McColHster, 1982). Inhalation 1s the more likely route of
exposure and may cause Irritation of the mucous membranes. n-Propyl alcohol
has been shown to be markedly Irritating and Injurious to the eyes of
rabbits, but was not Irritating to the skin. Acute exposure to this alcohol
may result 1n mucous membrane Irritation,' ataxla, lethargy, prostration and
narcosis.
In acute, lethal exposures to n-propyl alcohol, death Is preceded by
ataxla, hlndUmb paralysis, drop 1n body temperatures, dyspnea and narcosis.
OOOSd -28- 04/16/87
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Oral exposures also result In gastrointestinal Irritation and vomiting
(Browning, 1965). Oral LDgQ values have been reported In the range of
1.87-6.5 g/kg for rats, 4.5 g/kg for mice, and 2.82-3.5 g/kg for rabbits
(U.S. EPA, 1983c).
Starrek (1938) exposed groups of mice to varying concentrations of
n-propyl alcohol In air space. Six groups of two mice were exposed to
n-propyl alcohol levels of 3250, 4100, 8150, 12,250, 16,300 or 24,500 ppm
(8000, 10,000, 20,000, 30,000, 40,000 or 60,000 mg/m3) for 480, 240, 135,
120, 90 or 60 minutes, respectively. The time required for the onset of the
various symptoms was Inversely related to the concentration at which the
mice were exposed. Ataxla was observed within 10-14 minutes of exposure to
24,500 ppm, while 90-120 minutes were required for the onset of ataxla at
the 3250 ppm exposure level. At the 24,500 ppm concentration, prostration
was evident after 19-23 minutes of exposure to n-propyl alcohol vapor, but
165-180 minutes was required for prostration to occur at the 3250 ppm
concentration. Deep narcosis was evident within 60 minutes of exposure to
an atmospheric concentration of 24,500 ppm, while 240 minutes was necessary
for this effect to occur at 4100 ppm. Death occurred 1n 1/12 mice showing
signs of toxlclty. In the same study, another group of mice was exposed to
a concentration of 2050 ppm (5000 mg/m3}, but these mice experienced none
of the adverse effects observed 1n the six groups previously described. A
separate group of mice survived Intermittent exposures to an atmospheric
t
n-propyl alcohol concentration of 7874 ppm (19,300 mg/ma) for a total
exposure time of 95 hours.
Malckel and Nash (1985) reported that the administration of single
gavage doses of 1, 2 or 4 g/kg n-propyl alcohol to male Sw1ss-Cox mice
OOOSd -29- 04/16/87
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resulted 1n hypothermia and Impairment of rotorod performance. No tolerance
was seen In either the Impairment of rotarod performance or hypothermia with
- *
repeated doses at 24- to 72-hour Intervals.
6.2. CARCINOGENICITY
fc.2.1. Inhalation. Pertinent data regarding the carc1nogen1c1ty of
Inhaled n-propyl alcohol could not be located In the available literature as
cited In Appendix A.
6.2.2. Oral. Gibe! et al. (1974, 1975) tested throe analytical grade
alcohols, Including n-propyl alcohol, for carcinogenic and other toxic
effects on Wlstar rats. The alcohols were redistilled twice and adminis-
tered by feed tube to 10-week-old rats of both sexes. The rats were main-
tained on pellets of a standard feed and had access to water ad libitum.
The rats were observed until spontaneous death, at which time they were
necropsled and a hlstologlcal examination of all organs, vertebrae and
femora,, as well as blood smears and differential leukocyte counts, were
conducted. Oral doses of 0.3 ml n-propyl alcohol/kg and 1.0 ml Nad/kg
solutions were administered 2 times/week to 18 test and 25-30 control rats,
respectively, from 10 weeks of age until spontaneous death. Average
survival time of n-propyl alcohol-treated rats was 570 days, while the
control rats survived to day 643, at which time they were killed. Examina-
tion of the test rats revealed the presence of a wide spectrum of tumors.
The n-propyl alcohol-treated rats had a total of 5 malignant and 10 benign
tumors, but 1t was not clear 1f Individual rats had more than one tumor.
The malignant tumors were Identified as two myelogenous leukemlas, one
hepatocellular carcinoma and two liver sarcomas. The. benign tumors were
primarily paplllomas or paplllomatoses of the omasum. In saline-treated
QOOSd -30- 04/16/87
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controls, no malignant tumors but three benign tumors, Identified as papH-
lomas of the omasum.and..flbroadenomas of^the mammae, were observed. If each
malignant tumor occurred In a different rat, the total Incidence of_ma!1g-
nant tumors would be 5/18 treated and 0/25 1n control rats. This difference
1s statistically significant (p=0.009) by the Fisher Exact test. The
Incidences of the Individual tumor types, however, are not statistically
significant.
6.2.3. Other Relevant Information. In a parallel study, Glbel et al.
(1974, 1975) administered three redistilled alcohols, Including n-propyl
alcohol, In subcutaneous dosages of 0.6 mi/kg twice weekly to 31 Wlstar
rats from 10 weeks of age until spontaneous death. Mean survival time was
666 days for treated and >643 days for controls. Control rats (25 or 30)
received subcutaneous Injections of 1.0 ml 0.9% NaCl/kg for the same
schedule. A total of 15 malignant and 7 benign tumors were found 1n subcu-
taneously treated rats, while 2 benign tumors were observed In subcutaneous
controls. The malignant tumors consisted of one local sarcoma, four myelo-
genous leukemlas, five liver sarcomas, one uterine carcinoma, two splenic
sarcomas, one renal pelvic carcinoma and one cystic carcinoma. The benign
tumors were generally paplllomas or paplllomatoses of the omasum. No malig-
nant tumors and two benign tumors were found In saline-treated controls. It
was not clear 1f Individual rats had more than one tumor; however, If each
malignant tumor occurred 1n a different rat, the total Incidence of malig-
nant tumors would be 15/31 treated and 0/25 In controls. This difference 1s
statistically significant (p=1.3xlO~») by the Fisher Exact test. If each
liver sarcoma occurred 1n a different rat', the Incidence would be 5/31
treated and 0/25 controls. This difference Is also statistically signifi-
cant (p=0.04, Fisher Exact test). (Liver sarcomas are a relatively rare
tumor type.)
OOOSd -31- 03/31/87
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6.3. MUTAGENICITY
LHtle Information .regarding the muiagenlclty of n-propyl alcohol was
located In the available literature-. Standard bacterial testing has
apparently not been conducted. In a comparison study of cytogenetlc assays
reported by Lasne et al. (1984), the response of n-propyl alcohol In
addition to three other alcohols was evaluated by the in vitro Induction of
mlcronuclel or of slster-chromatld exchanges 1n Chinese hamster lung (V79)
cells. None of the alcohols were active In these cytogenetlc assays.
6.4. TERATOGENICITY
Nelson et al. (1985) studied the teratogenlc and reproductive effects of
Inhalation exposures to ethanol and n-propyl alcohol 1n male and female
Sprague-Oawley rats. Eighteen males were exposed for 7 hours/day for 6
weeks and 15 females for 7 hours/day on gestation days 1-20 at concentra-
tions of 0, 3500 or 7000 ppm {0, 8602 or 17,204 mg/m3} n-propyl alcohol.
Exposed males were mated with unexposed females, and 1n both maternally and
paternally exposed groups. Utters were culled to four pups of each sex and
fostered by untreated females. Hales exposed to 7000 ppm showed reduced
fertility; only 2/18 males produced Utters, 1n spite of the presence of
sperm plugs, and, furthermore, examination of the uteri of the mated females
without Utters Indicated that pregnancy had not occurred. Pregnant females
exposed to 7000 ppm showed reduced weight gain and feed Intake; the female
offspring also showed reduced weight gain through 3 weeks of age. In addi-
tion, at the higher concentration, a low Incidence of a minimal teratogenlc
response, crooked tails, was observed 1n the offspring. No significant
differences were found between controls and treated offspring when tested
for neuromotor coordination, activity levels or learning ability.
OOOSd -32- 03/31/87
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6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of n-propyl alcohol
could not be located 1n the available literature as cited 1n Appendix A.
6.6. SUMMARY
Inhalation exposures of mice to n-propyl alcohol vapors at 165-367
rng/m3 for 7.5-12 hours/day for periods up to 24 days resulted In fatty
Infiltration of the liver (Heese, 1928), which was considered reversible.
Pertinent data regarding the effects of chronic Inhalation exposure could
not be located 1n the available literature as cited 1n Appendix A. When
n-propyl alcohol was administered to male Hlstar rats as the sole drinking
fluid at 2 M for 2 months or 1 M for 4 months, no hepatotoxlc effects were
observed at 1 M; however, at 2 M, rats had Increased I1ver-to-body weight
ratios (Hlllbom et al., 1974a,b).
In a chronic study, steatosls, necrosis and cirrhosis of the liver,
necrosis of the myocardium. Interstitial pancreatitis and flbrosls and
hematotoxlc effects were observed 1n rats treated orally at 0.3 mi/kg or
subcutaneously at 0.06 ml/kg, 2 times/week (Gibe! et al., 1974, 1975).
n-Propyl alcohol 1s low In acute tox1c1ty to animals, and acute exposure
may result 1n mucous membrane Irritation, ataxla, lethargy, prostration and
narcosis (Rowe and McColllster, 1982). LD5Q values have been reported 1n
the range of 1.87-6.5 g/kg for rats, 4.5 g/kg for mice, and 2.82-3.5 g/kg
for rabbits (U.S. EPA. 1983c).
Pertinent data regarding the carc1nogen1c1ty of Inhaled n-propyl alcohol
could not be located In the available literature as cited 1n Appendix A.
G1bel et al. (1974,. 1975) found Increased total Incidences of malignant
tumors 1n rats treated orally with n-propyl alcohol at 0.3 ml/kg or subcu-
taneously at 0.06 ml/kg, 2 times/week for the Hfespan. Malignant tumors
Included myelogenlc leukemia, hepatocellular carcinoma and liver sarcomas.
OOOSd -33- 04/16/87
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Although It was not clear 1f Individual rats had more than one tumor, 1f
each malignant tumor occurred In a different rat, the total malignant tumor
Incidences 1n orally and subcutaneously treated rats were significantly
greater than In the respective controls. The Incidences of any particular
type of tumor In orally treated rats was not significantly different from
controls, but the Incidence of liver sarcomas, a relatively rare tumor type,
was significantly higher In rats treated subcutaneously with n-propyl
alcohol than 1n saline-Injected controls.
n-Propyl alcohol was Inactive 1n cytogenetlc assays Involving the Induc-
tion of mlcronuclel or sister-chromatld exchanges 1n Chinese hamster lung
(V79) cells (Lasne et a!., 1984). In a reproduction study, males exposed to
7000 ppm (17,204 mg/ma) n-propyl alcohol for 7 hours/day for 6 weeks
showed reduced fertility when mated with unexposed females (Nelson et a!.,
1985). Pregnant rats exposed to 7000 ppm, 7 hours/day from gestation days
1-20 showed reduced weight gain and feed Intake, while female offspring from
this treated group showed reduced weight gain through 3 weeks of age and a
low Incidence of crooked tall.
Grant and Samson (1984) reported reduced brain weight 1n neonatal rats
receiving n-propyl alcohol through a gastric catheter for 4 consecutive
days. Biochemical Indices of brain growth Indicated that n-propyl alcohol
exposure affected the forebraln, cerebellum and bralnstem.
OOOSd -34- 03/31/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
_-__- * * -
A TLV-TWA of 200 ppm (500 mg/m3) has been adopted by the ACGIH
(1986-1987) with a skin notation Indicating that exposure also occurs by the
dermal route. A TLV-STEL of 250 ppm (625 mg/m3) has also been adopted.
The principal action of n-propyl alcohol 1s reported to be that of a mild
narcotic and 1s considered to be more toxic than Isopropyl alcohol (ACGIH,
1986). Since no data are available on the response 1n humans to n-propyl
alcohol vapors, the recommended TLV of 200 ppm 1s Intermediate between the
limits for Isopropyl alcohol and the various butyl alcohols. The OSHA
(1985) standard for n-propyl alcohol 1s also 200 ppm (500 mg/m3).
According to U.S. EPA (1983c), OSHA believes that all employees who have
the potential of exposure to hazardous levels of n-propyl alcohol 1n their
occupations should be screened medically for history of certain conditions
that might place the employee at Increased risk (Impaired renal, liver or
pulmonary function). In addition, since n-propyl alcohol 1s a defattlng
agent and can cause dermatitis on prolonged exposure, persons with pre-
existing skin disorders may be more susceptible to the effects of this
compound. Persons with obstructive airways diseases should not be exposed
to n-propyl alcohol since H has Irritant properties that might cause
exacerbation of symptoms.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects on n-propyl alcohol could not be located In the available
literature as cited 1n Appendix A.
OOOSd -35- 04/16/87
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8. RISK ASSESSMENT
8.1. CARCIN06ENICITY
* ----- *
8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled n-propyl alcohol could not be located 1n the available literature as
cited In Appendix A.
8.1.2. Oral. In rats treated orally with n-propyl alcohol at 0.3
mi/kg, '2 times/week for life, Increased total Incidences of malignant
tumors (two myelogenous leukemlas, one hepatocellular carcinoma, two liver
sarcomas) were observed compared with saline-treated controls (G1bel et al.,
1974, 1975). Although H was not clear If Individual rats had more than one
tumor, 1f each malignant tumor occurred 1n a different rat, the total Inci-
dence would be 5/18 treated and 0/25 controls (p=0,009, Fisher Exact test).
The Incidences of the Individual tumor types, however, were not signifi-
cantly different from those found In controls.
8.1.3.. Other Routes. In parallel studies (G1bel et a!., 1974, 1975), 31
Hlstar rats were given subcutaneous Injections of n-propyl alcohol, twice
weekly until spontaneous death. A group of 25-30 rats received subcutaneous
Injections of saline. Although 1t was not clear 1f Individual rats had more
than one tumor, If each malignant tumor occurred In a different rat, the
Incidence would be 15/31 treated and 0/25 controls, a highly significant
difference (p=1.8x!0"s. Fisher Exact test). The 15 malignant tumors 1n
treated rats consisted of one local sarcoma, four leukemlas, five liver
sarcomas, one uterine carcinoma, two splenic sarcomas, one renal pelvic
carcinoma and one cystic carcinoma. If each liver sarcoma occurred 1n a
different rat, the Incidence would be 5/31 treated and 0/25 controls. This
difference Is also statistically significant (p=0.04, Fisher Exact test).
OOOSd -36- 04/16/87
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8.1.4. Weight of Evidence. No data are available from the literature
regarding the cardnogealclty of n-propyl alcohol In humans either by
Inhalation or oral exposure routes. Also, pertinent data regarding cardno-
genlclty of Inhaled n-propyl alcohol In animals could not be located 1n the
available literature as cited 1n Appendix A. The studies by G1bel et al.
(1974, 1975) provided limited evidence that n-propyl alcohol Is carcinogenic
1n rats. Limitations of the study Include poor dosing regimen, one dose
level and one species. There were also reporting Inadequacies regarding
tumor Incidences; however, the relatively high numbers of malignant tumors
1n treated rats, compared with no malignant tumors 1n controls, raises
concern. Furthermore, 1f 1t 1s assumed that each tumor occurred 1n a
different rat, the Increased Incidences of total malignant tumors 1n orally
and subcutaneously treated rats compared with controls, and of liver
sarcomas, a relatively rare tumor type, In subcutaneously treated rats
compared with controls are statistically significant. Thus, according to
U.S. EPA (1986b) n-propyl alcohol 1s an EPA Group C chemical, I.e., a
possible human carcinogen. Information about n-propyl alcohol metabolism
shows that 1t Is metabolized through aldehyde Intermediates. This Is
noteworthy as aldehydes 1n general exhibit carcinogenic activity In animal
test systems.
8.1.5. Quantitative Risk Estimates. Because no Individual tumor types
were significantly greater 1n orally treated rats compared with controls, a
q * for oral or Inhalation exposure cannot be calculated. Furthermore, a
q * cannot be calculated from the subcutaneous data.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) One subchronlc
Inhalation study (Meese, 1928} was available for consideration for an RfO.
0005d -37- 05/22/87
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In this study, exposure of mice to n-propyl alcohol vapors at 165-367
mg/m3 for 7.5-12 hours/day for up to 2,4 days resulted In fatty Infiltra-
tion of the liver. Since exposure concentrations and durations varied, 1t
1s not possible to quantify a dose. Furthermore, the use of controls was
not mentioned. Therefore, derivation of a subchronlc Inhalation RfD 1s
precluded.
8.2.1.2. CHRONIC EXPOSURES Pertinent data regarding chronic
Inhalation exposures to n-propyl alcohol could not be located 1n the
literature as cited In Appendix A. Therefore, no RfD for chronic Inhalation
exposure can be derived.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) A NOAEL can be
Identified from the study of Hlllboro et al. (1974a,b). Wlstar rats were
given n-propyl alcohol 1n 2 and 1 M solutions as the sole drinking fluid for
60 and' 120 days, respectively. A reduced ratio of weight gain to caloric
Intake was noted In the rats drinking n-propyl alcohol, but no hepatotoxlc
effects were observed at 1 M. At 2 M, the rats had Increased I1ver-to-body
weight ratios. Therefore, the 1 M concentration 1s the NOAEL and 2 M
concentration Is the LOAEL. The rats treated with 1 M n-propyl alcohol for
120 days consumed a constant amount of alcohol throughout the test period (5
mmol/100 g/day) No alcohol consumption data were provided for the rats at
2 M. The dose of 5 mmol/100 g or 50 mmol/kg multiplied by 60.09 (molecular
weight of n-propyl alcohol) yields a dose of 3005 mg/kg/day.
The potential developmental effects of n-propyl alcohol have been Inade-
quately tested by the oral route. This 1s cause for concern, first because
of the known effects of ethanol on the developing fetus and second because
of the data of Grant and Samson (1984) that show substantial effects on
OOOSd -38- 05/22/87
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brain development 1n neonatally-exposed rat pups at an exposure level simi-
lar to that yielding no adverse effects. In treated adult rats. Therefore,
until the threshold for developmental- effects following oral exposure to
n-propyl alcohol 1s adequately characterized, a subchronlc oral reference
dose will not be derived.
8.2.2.2. CHRONIC EXPOSURES One study was available for considera-
tion for a chronic oral RfO. Gibe! et al. (1974, 1975) administered
n-propyl alcohol, among other alcohols, to Hlstar rats twice weekly from 10
weeks of age until spontaneous death. Controls received saline and were
killed after 643 days. The total dose administered over the course of the
study was 50 mi. The authors reported myocardlal necrosis, hepatotoxlc
effects, Including steatosls, necrosis and some cirrhosis, and hematotoxlc
effects resulting from hyperplasla of the parenchyma of the bone marrow.
Although the alcohol(s) producing these effects were not specified, a
similar action by each of the alcohols was Inferred. Survival time for the
treated rats was 570 days compared with >643 for the controls. Since the
total dose of 50 mi of n-propyl alcohol was administered from 10 weeks of
age (70 days) and lasted until death (-570 days), the test period was 500
days and the average dally dose would be 0.1 mi. Multiplying 0.1 mi/day
by 0.804 g/ml (specific gravity of n-propyl alcohol) resulted 1n 0.0804
g/day or 80.4 mg/day. Assuming the average body weight of the rat to be
0.35 kg, the dosage would be 80.4 mg/day or 230 mg/kg/day. The dosing
*
schedule, however, actually represented repeated acute exposures. Further-
more, since the effects associated with this dose are clearly adverse, this
dose represents a PEL; therefore, an RfO cannot be derived.
OOOSd -39- 05/22/87
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
*
The toxldty of n-propyl alcohol was discussed 1n Chapter 6 and the data
are summarized In Table 9-1. Two oral exposure studies, one.subchronlc and
one chronic, could be considered for determination of the RQ. The sub-
chronic oral study (HUlbom et al., 1974a,b) reported a lower ratio of
weight gain to caloric Intake at a human equivalent dose of 514 mg/kg/day.
This dose was administered for 120 days. More severe effects were reported
1n the S1bel et al. (1974, 1975) studies at a lower human equivalent dose.
A total of 50 ml/kg bw n-propyl alcohol was administered to rats over a
570-day test period, thus constituting a chronic exposure period. The
effects reported were liver steatosls, necrosis and some cirrhosis, hyper-
plasla of the hematopoletlc parenchyma of the bone marrow and decreased
survival (average of 73 days). The major weakness of this study was the
Inadequate reporting of experimental detail. Two other alcohols were admin-
istered 1n addition to n-propyl alcohol by the same schedule. -The authors
did not Indicate which effects were associated with the specific alcohol;
therefore, 1t 1s assumed that n-propyl alcohol administration produced these
effects.
Reduced fertility was reported In male rats receiving Inhalation
exposures of 7000 ppm (17,204 mg/m3), 7 hours/day for 6 weeks (Nelson et
al., 1985) The human equivalent dose was 547 mg/kg/day (see Table 9-1).
Reduced weight gain -and feed Intake were reported In pregnant rats also
receiving 7000 ppm (17,204 mg/ma) n-propyl alcohol vapor, 7 hours/day for
gestation days 1-20 (Nelson et al., 1985). Reduced weight gain was also
reported 1n the female offspring of these rats. The human equivalent dose
was 546 mg/kg/day (see Table 9-1).
0005d -40- 04/16/87
-------
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-------
Data used to calculate the RQ are shown 1n Table 9-2. The most severe
effect was the decreased survival (RV =10} In the chronic studies by G1bel
et al. (1974, 1975). The MED of 843.9 mg/day, which corresponds to an RVd
of 1.11. Multiplying by RVg by the RVd yields the CS of 11.1, which
corresponds to an RQ of 1000.
The effects seen 1n the subchronlc and reproduction studies were less
severe and occurred at higher doses (even 1f the doses are divided by an
uncertainty factor of 10 to approximate chronic exposure). Therefore, there
1s no need to calculate CSs from these data, and the RQ of 1000 derived from
the data of G1bel et al. (1974, 1975) 1s recommended for n-propyl alcohol
(Table 9-3).
9.2. BASED ON CARCINOGENICITY
In rats treated orally with n-propyl alcohol at 0.3 ml/kg, 2 times/
week for life, Increased total Incidences of malignant tumors (two myelo-
genous . leukemlas, one hepatocellular carcinoma, two liver sarcomas) were
observed compared with saline-treated controls (Gibe! et al., 1974, 1975).
Although 1t was not clear 1f Individual rats had more than one tumor, If
each malignant tumor occurred 1n a different rat, the total Incidence would
be 5/18 treated and 0/25 controls (p=0.009. Fisher Exact test). The
Incidences of the Individual tumor types, however, were not significantly
different from control; therefore, an F Factor cannot be derived.
Gibe! et al. (1974, 1975) also treated 31 Wlstar rats with n-propyl
alcohol subcutaneously at 0.06 ml/kg, twice weekly until spontaneous
death. A group of 25-30 rats received subcutaneous Injections of saline.
QOOSd -42- 04/16/87
-------
TABLE 9-2
Oral Composite Score for n-Propyl Alcohol Using Wlstar Rats*
Animal Dose
(mg/kg/day)
230
Chronic
Human MED RVd
(mg/day)
2730 1
Effect
Decreased survival;
liver steatosls,
necrosis and cirrho-
sis; hyperplasla of
the hematopoletic
parenchyma of the
bone marrow
RVe CS RQ
10 10 1000
*Source: 61bel et al., 1974, 1975
OOOSd
-43-
04/16/87
-------
TABLE 9-3
n-Propyl Alcohol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
oral
2730 mg/day
decreased survival; liver steatosls, necrosis and
cirrhosis; hyperplasla of hematopoletic parenchyma
of the bone marrow
Gibe! et al., 1974, 1975
1
10
10
1000
^Equivalent human dose
00050
-44-
04/16/87
-------
Although H was not clear 1f Individual rats had more than one tumor, 1f
each malignant tumor occurred In a different rat, the Incidence would be
15/31 treated and 0/25 controls (p=l.Bx!0~5, Fisher Exact test). The 15
malignant tumors In treated rats consisted of one local sarcoma, four
laukemlas, five liver sarcomas, one uterine carcinoma, two splenic sarcomas,
one renal pelvic carcinoma and one cystic carcinoma. If each liver sarcoma
occurred In a different rat, the Incidence would be 5/31 treated and 0/25
controls (p=0.04. Fisher Exact test). Because the route of exposure was
*
subcutaneous, an F Factor cannot be derived from these data.
As discussed In Section 8.1.4., n-propyl alcohol was placed In EPA Group
C, and, since an F factor cannot be derived, 1t 1s not possible to develop a
hazard ranking.
0005d -45- 04/16/87
-------
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______ *
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OOOSd -58- 04/16/87
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APPENDIX A
LITERATURE-SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n December, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986-1987. TLVs: Threshold limit Values for Chemical Substances 1n
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton. G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John WHey and
Sons, NY. 2878 p.
Claytoitr S.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
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Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M.. W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., MY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Henlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983.. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz. H., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
u <; Fm/ironmenta! Protection Agency.
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Region V, Library
230 South Dearborn Street
Chicago, Illinois 60604
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In addition, approximately 30 compendia of aquatic tox1c1ty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. " 1971. Water Quality Cr1ter4a
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, OC.
Johnson, W.H. and H.T. Flnley. 1980. Handbook of Acute ToxIcHy
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, OC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A<
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. P8-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0005d -61- 04/16/87
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