EPA/60O/8-9O/031
September 1989
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 1--BUTANQL
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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4
^
TECHNICAL REPORT DATA
ffleatr read Ins truer ions on tfie reverse be fort completing)
. REP3RTNO.
EPA/600/8-90/031
3. RECIPIENT'S ACCESSION MO.
PB91-2I6465
4. TITLE AND SUBTITLE
Health and Environmental Effects Document for
1-Butanol
6. REPORT DATE
«. PERFORMING ORGANIZATION CODE
?. AUTHOR(S)
0. PERFORMING ORGANIZATION REPORT NO.
9. PER ^ORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
IS. SUPPLEMENTARY NOTES
16. A&JTRACT
Health and Environmental Effects Documents (HEEDS) are prepared for the Office of
Solid Waste and Emergency Response (OSWER). This document series is intended to
support listings under the Resource Conservation and Recovery Act (RCRA) as well as
o provide health-related limits and goals for emergency and remedial actions under
he 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 environmen-
tal effects of hazardous waste constituents.
Several quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these include Reference Doses (RfDs) for chronic
and subchronic exposures for both the inhalation and oral exposures. In the case of
suspected carcinogens, RfDs may not be estimated. Instead, a carcinogenic potency
factor, or q *, is provided. 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 toxicity and carcinogenicity are
derived. The RQ is used to determine the quantity of a hazardous substance for
which notification is required in the event of a release as specified under CERCLA.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
DISTRIBUTION STATEMENT
Public
b.lDENTIFIERS/OPEN ENDED TERMS
19. SECURITY CLASS (This Report)
Unrlassified
3D. SECURITY CLASS (Thispage/
Unclassified
COSATI Field/Group
21. NO. OF PAGES
117
22. PRICE
EPA form 2220-1 (Ha*. 4-77) PREVIOUS KDITION i« OBSOLETE
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DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental Protection Agency's peer and administrative review policies and
approved for publication. 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 (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
1s 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 for 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 (QSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
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 I.e., for an Interval 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 RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-|* (U.S. EPA, 1980), Is provided.
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 toxlclty and carclno-
genldty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification Is required In the event of a release
as specified under the Comprehensive [nvlronmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
genlclty) represent two of six scores developed {the remaining four reflect
IgnltabllHy, reactivity, aquatic toxlclty. and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined In U.S.
EPA, 1984 and 1986c, respectively.
111
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EXECUTIVE SUMMARY
1-Butanol 1s also known by the synonyms n-butanol, n-butyl alcohol,
butan-1-ol, methylolpropane, propylcarblnol and propylmethanol (Chemllne,
1988). It Is a highly refractive colorless liquid with a vinous or wine-
like odor (Wlndholz, 1983; Sherman, 1978; Hawley, 1981). Seven U.S.
manufacturers at eight sites In Texas and Louisiana have a combined
production capacity of 1.3 billion pounds of 1-butanol annually {SRI,
1988). Domestic production of 1-butanol 1n 1987 and 1986 has been reported
to be 1.155 and 0.881 billion pounds, respectively (USITC, 1987, 1988).
1-Butanol Is manufactured primarily by the oxo process. In which propylene
Is reacted with carbon monoxide and hydrogen to form butyraldehyde, which Is
subsequently reduced to butanol (Sherman, 1978). The use pattern for
1-butanol has been reported as follows (CNR, 1984): butyl acrylates and
methacrylate, 30%; glycol ethers, 23%; butyl acetate, 12.5%; solvent, 12.5%;
plastlclzers, 8%; ami no resins, 5%; amines, 1%; miscellaneous, 1%; export,
7%.
When released to the atmosphere, 1-butanol 1s expected to exist In the
vapor phase, where It will degrade relatively rapidly by reaction with
sunlight-formed hydroxyl radicals. Based upon an experimentally measured
rate constant (Atkinson, 1985), the atmospheric half-life for this reaction
In average air Is ~2.2 days. When released to either the aquatic or soil
environments, 1-butanol 1s expected to degrade primarily by mlcroblal
degradation. A number of biological screening studies have demonstrated
that 1-butanol 1s readily biodegradable under aerobic conditions (Hammerton,
1955; Bridle et al., 1979a; Wagner, 1976; Price et al., 1974; Urano and
Kato, 1986; Babeu and Valshnav, 1987; Gellman and Heukeleklan, 1955; Dlas
1v
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and Alexander, 1971; Hatfleld, 1957; PUter, 1976; McKlnney and JeMs, 1955;
Gerhold and Malaney, 1966). A river die-away study that used only natural
rWer water as a mlcroblal Inocula found that 56% of added 1-butanol was
bio-oxidized In a 4-day period (Hammerton, 1955). Chou et al. {1979} found
1-butanol biodegradable under anaerobic conditions. Following a 4-day lag
period, 100% of added 1-butanol was degraded at a rate of ~100 ppm/day. In
a soil degradation study, 51-58% of added butanol was released from the soil
as C0? (presumably from mlcroblal degradation) over a 20-day period
(Fairbanks et al., 1985). Although not as Important as mlcroblal degrada-
tion, volatilization from soil within the first day of addition can be a
significant removal mechanism (Fairbanks et al., 1985). The K of
1-butanol has been estimated to be -10, which Indicates that leaching 1n
soil Is expected {Roy and Griffin, 1985); however, concurrent mlcroblal
degradation may lessen the Importance of leaching.
Human exposure to 1-butanol can occur from both natural and human
sources. Natural sources of air release Include animal wastes, microbes and
Insects; human sources Include volatilization from solvents (such as used In
paints), rendering, sewage treatment, starch manufacture, whiskey manufac-
ture, wood pulping and turbine emissions {Graedel et al., 1986). Concentra-
tions of 34-445 ppb detected In the ambient air at Point Barrows, AL, are
thought to occur as a result of a fermentation process of the tundra cover
{Cavanagh et al., 1969). 1-Butanol appears to occur naturally In volatile
components of apples, pears, grapes, dried legumes and mountain cheese
{Drawert et al., 1962; Stevens et al., 1965; Lovegren et al., 1979; Dumont
and Adda, 1978). Release of 1-butanol to water can occur through wastewater
emissions from chemical and textile plants, sewage treatment plants, oil
refineries, landfill leaching and kraft pulp mills (Shackelford and Keith,
1976; Carlberg et al., 1986). 1-Butanol has been detected tentatively and
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qualitatively In drinking water concentrates collected from Cincinnati, OH,
Miami, FL, New Orleans, LA, Philadelphia, PA, and Seattle, MA (Lucas, 1984).
The 24-hour LC5Q for creek chub exposed to 1-butanol would probably be
between 1000 and 1400 ppm (Gillette et al.f 1952). The threshold narcotic
concentration for 1-butanol In frog tadpoles was 38 mmol/i (Hunch, 1972).
Bridle et al. (1973, 1979b) reported a 24-hour TLffl of 1900 rag/4 for
goldfish exposed to 1-butanol. Bresch and Splelhoff (1974) reported that
the limits of toxlclty to the 8-cell and gastrula stages of the sea urchin
embryo were -8x10"* and ~3xlQ~5 mol/mi, respectively. Price et al.
(1974) reported a 24-hour TL of 2950 mg/l for brine shrimp exposed to
n-butanol, although Hudson et al. (1981) reported the lack of mortality
among brine shrimp exposed to <100 yM n-butanol (<7412 mg/l) for 24
hours. The 96-hour LC5Q for fathead minnows exposed to butanol ranged
from 1510-1940 mg/l (Hattson et al., 1976; Velth et al., 1983; Brooke et
al., 1984). The 24-hour ECCft and LC,n for Daphnla maana exposed to
t>u on
butanol were 1880 and 1855 mg/l, respectively (BMngmann and Kuhn. 1977a,
1982). Juhnke and Luedemann (1978) reported that exposure of the Golden
Orfe to n-butanol for 48 hours produced LC5Q values of 1200 and 1770
mg/l for studies conducted 1n two different laboratories. Linden et al.
(1979) reported 96-hour LC5Qs of 2100 and 2250-2400 mg/a for copepods
and bleaks exposed to 1-butanol, respectively.
Concentrations of butanol In brain tissue of goldfish exposed to 10 and
15 mM solutions of butanol reached equilibrium levels of 0.46 and 0.74 mg/g,
respectively, within ~60 minutes (Hill et al., 1981). Concentrations of
butanol In brain tissue from fish exposed to 20 mM solutions did not plateau
within the first 30 minutes, ultimately reaching an equilibrium concentra-
tion of 0.95 mg/g. The Investigators speculated that goldfish possessed the
ability to metabolize butanol.
v1
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No measured steady-state BCF value for butanol was found In the
literature. An estimated BCF value of 2.75 for this compound suggests that
butanol will not bloaccumulate significantly In aquatic organisms.
Toxiclty threshold levels for exposure of Hlcrocystls aeruglnosa to
n-butanol were 100 and 312 mg/i, while toxldty threshold levels for
exposure of Scenedesmus quadrlcauda to n-butanol were 95 and 875 mg/i
(Brlngmann, 1975; BMngmann and KGhn, 1976, 1977b, 1978, 1979, 1980). Haley
et al. (1987) reported a 96-hour EC™ of 2000 mg/l for the green alga,
Chlorella pyrenoldosa. The toxldty thresholds for an aquatic bacterium,
Pseudomonas put Ida, and a flagellated protozoan, Entoslphon sulcatum,
exposed to butanol were 650 and 55 mg/i, respectively (BMngmann and Kuhn,
1976, 1977b, 1979, 1980, 1981). The toxldty threshold values for a
holozolc bacterlovorous dilated protozoan, Uronema parduczl Chatton-Lwoff,
and a saprozolc ciliated protozoan, Chllomonas paramedum Ehrenberg, exposed
to n-butanol were 8.0 and 27 mg/l, respectively (Brlngmann and KQhn, 1981).
The 15-mlnute log EC,-0 for Photobacterlum phosphoreum exposed to
n-butanol In the Mlcrotox bacterial luminescence assay was 4.58 {-38,000
mg/8.) {Hermens et al., 1985). Tarkpea et al. (1986) reported 5-, 15- and
30-mlnute EC5Q values of 3370, 3690 and 3710 mg/l, respectively, for P.
phosphoreum exposed to 1-butanol In the Hlcrotox assay. Valshnav (1986)
reported an EC5Q of 10,614 mg/8. for a mixed mlcroblal culture from a
wastewater sample exposed to 1-butanol.
Mallard duck eggs Immersed in 100% solutions of butanol for 30 seconds
failed to produce viable chicks by day 18 of Incubation (Hoffman and Eastln,
1981). There were no effects on embryos In duck eggs exposed to distilled
water or 10X butanol. Schafer et al. (1983) estimated an oral ID™ of
<2500 mg/kg for starlings treated with butanol.
vll
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1-Butanol was taken up readily by the respiratory tracts of humans
(Astrand et al., 1976} and dogs (DWIncenzo and Hamilton, 1979). Levels of
1-butanol In the blood of humans following Inhalation exposure were lower
than expected based on a measured blood/air partition coefficient and the
disappearance of the compound from Inhaled air (Astrand et al., 1976). This
observation may reflect sequestration of 1-butanol In mucosal tissue water
In the lung {Astrand et al., 1976) or rapid metabolism of the compound
following absorption (DIVIncenzo and Hamilton, 1979). 1-Butanol appears to
be absorbed rapidly and virtually completely from the gastrointestinal
tracts of rats {DIVIncenzo and Hamilton, 1979).
In addition, 1-butanol Is absorbed through oral mucosa (Siege! et al.,
1976), Intestines {W1nne, 1978, 1979), skin (Scheupleln and Blank, 1973;
Akhter et al.. 1984; DIVIncenzo and Hamilton, 1979; DelTerzo et al., 1986;
Behl et al., 1983, 1984) and the cornea (Grass and Robinson, 1984).
Following oral treatment of rats with l-14C-butanol, the largest amounts
of radioactivity were located In the liver, kidney and blood. Unchanged
1-butanol levels In plasma were below detection limits at 4 hours after
treatment (DIVIncenzo and Hamilton, 1979). 1-Butanol was metabolized
rapidly to carbon dioxide (-80% of the dose) (DIVIncenzo and Hamilton,
1979), primarily by hepatic mlcrosomal alcohol dehydrogenase {Brentzel and
Thurman, 1977; Vldela et al., 1982). Smaller amounts were excreted In the
urine as sulfate and glucuronlde conjugates and as urea.
At 24 hours after rats were treated orally with l-14C-butanol, -14X of
the dose of radioactivity was retained In the carcass, attributed to the
Incorporation of 14C Into the one-carbon pool {DIVIncenzo et al., 1979).
1-Butanol Is mildly toxic to humans and laboratory species. Human
Inhalation exposure to 1-butanol at levels of 25-50 ppm (75-150 mg/m3) 1s
Irritating to the eyes, nose and throat, and can cause headaches, but no
vlll
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systemic effects occur at this exposure level {Nelson et al., 1943; Amoore
and Hautula. 1983; Tabershaw et al., 1944; Seltz, 1972). Sensory Irritation
and neurobehavloral toxlclty have been noted In mice and rats exposed by
Inhalation to high levels of 1-butanol (DeCeaurrlz et al., 1981, 1983;
Alarle, 1981). Acute dermal contact with the liquid In oil Is Irritating to
healthy human skin (Ba'lnova and Hadzhunov, 1984), and eye contact with the
vapor can cause painful keratltls and conjunctivitis (Cogan and Grant, 1945).
Rabbits and male rats appear to be equally sensitive to acute oral doses
of 1-butanol, but female rats are more sensitive; single-dose oral LDr«
values ranged from 0.79-4.36 g/kg (Hunch, 1972; Clugudeanu et al., 1985;
Smyth et al., '1951; Jenner et al., 1964; Purchase, 1969). Acute oral
exposure to 1-butanol at 1200 mg/kg caused decreased ability of rats to
retain balance (Wallgren, 1960). Dose-related hypothermia and Impaired
coordination of muscular activity occurred In mice treated by gavage at 1.0
or 2.0 g/kg (Halckel and Nash, 1985). Single oral 810 mg/kg doses adminis-
tered to rats Induced significant dose-related decreases In liver content of
vitamins (Shehata and Saad, 1978). Sensitivity to Intravenous or Intraperl-
toneal Injection 1s greater than sensitivity by the oral route among rats
and mice, but very little difference In toxic response was found between
these species (Tlchy et al., 1985; Malckel and McFadden, 1979). Abnormal
EEG and loss of righting reflex occur In rats exposed to a single Intra-
venous (500 mg/kg) or Intraperltoneal (600 mg/kg) Injection of 1-butanol
(Marcus et al., 1976).
Subchronlc Inhalation studies have been performed using rats and guinea
pigs, and human epidemiology studies are available. Liver and kidney degen-
eration and hematologic effects were reported In guinea pigs Intermittently
exposed to 100 ppm (300 mg/m3) for 9 weeks (Smyth and Smyth, 1928).
1x
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Foreign studies using rats reported no effects with continuous exposure to
0.09 mg/m3, but effects on the blood and CMS at concentrations of >0.8
mg/ma (SaveTev et a!., 1975; Rumyantsev et al., 1976; Balkov and
Khachaturyan, 1973). In an occupational study, no effects were reported at
100 ppm (300 mg/m3); ocular Irritation was reported at 200 ppm (600
mg/ma) (Sterner et al., 1949).
Oral exposure data are limited to subchronlc studies. Rats treated by
gavage with 1-butanol at 30 mg/kg/day for 13 weeks showed no toxic effects;
transitory effects on hematology (RBC, PCV) were noted among females but not
males at 125 mg/kg/day, and 500 mg/kg/day caused ataxla and hypoactlvlty 1n
the final 6 weeks of treatment among both sexes (U.S. EPA, 1986a).
1-Butanol administered In drinking water to rats for up to 3 months at a
high dose (9660 mg/kg/day) caused structural alterations of liver
mitochondria, accompanied by moderately decreased MAO and cytochrome oxldase
activity (Hakabayashl et al., 1984).
Data regarding carclnogenlcHy to humans or animals were not located In
the available literature. Results of mutagenlclty and genotoxlclty testing
were mixed. 1-Butanol 1s not scheduled for testing by the NTP (1988).
1-Butanol, when administered by gavage, was not a developmental toxicant
to rats at dosages up to 24% of the oral L05Q (Mankes et al., 1985).
Inhalation exposure to 8000 ppm (24,250 mg/m3) resulted 1n mild maternal
toxlclty and decreased fetal body weight In rats, but teratogenldty was not
evident (Brlghtwell et al., 1987). Reversible effects on testlcular
endocrine function were noted 1n rats Intermittently exposed to 500 ppm
(1516 mg/ma) (Cameron et al., 1985).
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In vitro studies have demonstrated toxic effects of 1-butanol on cardiac
and smooth muscle (Makano and Moore, 1973; Madan et al., 1969) and on
cellular structure and function (Walum and Peterson, 1983; Chen et al.,
1984; Masamoto et al., 1974).
Because of the lack of cancer data for either humans or experimental
animals, 1-butanol was assigned to EPA Group D -- not classifiable as to
carclnogenldty to humans. Therefore, neither cancer potency factors nor a
cancer-based RQ were derived.
Although Inhalation data were available, they were Insufficient for
derivation of RfO values for either subchronlc or chronic Inhalation expo-
sure. The NOAEL of 125 mg/kg/day from the 13-week gavage study sponsored by
U.S. EPA (1986a) served as the basis for the RfD of 1 mg/kg/day for sub-
chronic oral exposure. An RfD of 0.1 mg/kg/day for chronic oral exposure
was derived from the same study.
An RQ for chronic toxUHy of 1000 pounds based on ocular Irritation In
occupatlonally-exposed women (Velasquez, 1964; Velasquez et al., 1969) has
been recommended to supersede that of the earlier analysis (U.S. EPA, 1987b)
In which an RQ of 5000 pounds was derived.
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TABLE OF CONTENTS
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 4
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. Photolysis 6
2.2.4. Mlcroblal Degradation 6
2.2.5. Volatilization 6
2.2.6. Adsorption 7
2.2.7. B1oconcentrat1on 7
2.3. SOIL 7
2.3.1. MUroblal Degradation and Volatilization 7
2.3.2. Adsorption/Leaching 8
2.4. SUMMARY 8
3. EXPOSURE 10
3.1. WATER 10
3.2. FOOD 10
3.3. INHALATION 11
3.4. DERMAL 12
3.5. SUMMARY 12
4. ENVIRONMENTAL TOXICOLOGY 13
4.1. AQUATIC TOXICOLOGY 13
4.1.1. Acute Toxic Effects on Fauna 13
4.1.2. Chronic Effects on fauna 16
4.1.3. Effects on Flora 17
4.1.4. Effects on Bacteria and Other Microorganisms. . . 17
4.2. TERRESTRIAL TOXICOLOGY 19
4.2.1. Effects on Fauna 19
4.2.2. Effects on Flora 19
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TABLE OF CONTENTS (cont.)
Page
4.3. FIELD STUDIES 19
4.4. AQUATIC RISK ASSESSMENT 19
4.5. SUMMARY 21
5. PHARMACOKINETCS 24
5.1. ABSORPTION 24
5.2. DISTRIBUTION 27
5.3. METABOLISM 27
5.4. EXCRETION 30
5.5. SUMMARY 30
6. EFFECTS 32
6.1. SYSTEMIC TOXICITY 32
6.1.1. Inhalation Exposure 32
6.1.2. Oral Exposure 35
6.1.3. Other Relevant Information 36
6.2. CARCINOGENICITY 40
6.2.1. Inhalation 40
6.2.2. Oral 40
6.2.3. Other Relevant Information 40
6.3. MUTAGENICITY 40
6.4. TERATOGENICITY 40
6.5. OTHER REPRODUCTIVE EFFECTS 42
6.6. SUMMARY 43
7. EXISTING GUIDELINES AND STANDARDS 46
7.1. HUMAN 46
7.2. AQUATIC 46
8. RISK ASSESSMENT 47
8.1. CARCINOGENICITY 47
8.1.1. All Routes 47
8.1.2. Weight of Evidence 47
8.1.3. Quantitative Risk Estimates 47
8.2. SYSTEMIC TOXICITY 47
8.2.1. Inhalation Exposure 47
8.2.2. Oral Exposure 49
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TABLE OF CONTENTS (cent.)
Page
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY 51
9.2. BASED ON CARCINOGENICITY 56
10. REFERENCES.
APPENDIX A: LITERATURE SEARCHED
APPENDIX B: SUMMARY TABLE FOR 1-BUTANOL
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
1-BUTANOL
57
82
85
86
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LIST OF TABLES
No. Title Page
1-1 Commercial Manufacturers of 1-Butanol 3
5-1 Tissue Distribution of Radioactivity in Rats Dosed by
Gavage with 450 mg/kg of l-i4C-Butanol 28
6-1 Acute Lethal Toxlcity of 1 -Sutanol 37
6-2 Mutagenldty Testing of 1-Butanol 41
9-1 Toxlcity Summary for 1-Butanol 52
9-2 Composite Scores for 1-Butanol 54
9-3 1-Butanol: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 55
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LIST OF ABBREVIATIONS
BCF
BOD
CAS
CNS
CS
DNA
"50
EEG
GLC
GMAV
GHCV
Koc
Kow
LH
LOAEL
HAD
MED
NADPH
NOAEL
PCV
PEL
Bloconcentratlon factor
Biological oxygen demand
Chemical Abstract Service
Central nervous system
Composite score
Deoxyrlbonuclelc acid
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Electroencephalogram
Gas-liquid chromatography
Genus mean acute value
Genus mean chronic value
Soil sorptlon coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration)
Dose lethal to 50% of recipients
(and all other subscripted dose levels)
Lutelnlzlng hormone
Lowest-observed-adverse-effect level
Monoamlne oxldase
Minimum effective dose
Nlcotlnamlde adenlne dlnucleotlde phosphate
{reduced form)
No-observed-adverse-effect level
Packed cell volume
Permissible expsure level
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LIST OF ABBREVIATIONS (cont.)
ppb Parts per billion
ppm Parts per million
R6C Red blood cell
RD5Q Concentration associated with a 5054 decrease In
respiratory rate
RfO Reference dose
RNA Rlbonuclelc acid
RQ Reportable quantity
RVd Dose-rating value
RVe Effect-rating value
TLm Median tolerance limit
TLV Threshold limit value
TOC Total organic carbon
TWA Time-weighted average
v/v Volume per volume
xv11
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
1-Butanol Is also known by the synonyms n-butanol, n-butyl alcohol,
butan-1-ol, methylolpropane, propylcarblnol and propylmethanol (Chemllne,
1988). The structure, molecular weight, empirical formula and CAS number
for 1-butanol are as follows:
CH3-CH?-CH2-CH2-OH
Molecular weight: 74.12
Empirical formula: c4H-infJ
CAS Registry number: 71-36-3
1.2. PHYSICAL AND CHEMICAL PROPERTIES
1-Butanol Is a highly refractive colorless liquid with a vinous or wine-
like odor (Wlndholz, 1983; Sherman, 1978; Hawley, 1981). It Is mlsclble
with alcohol, ether and many other organic solvents (Wlndholz, 1983).
Selected physical properties are as follows:
Melting point:
Boiling point:
Specific gravity:
Vapor pressure
at 22.6°C:
at 25.0°C:
(using Antolne
equation) at 30.9°C:
-90.2°C
117.7°C
0.810 (20/4°C)
5.5 mm Hg
6.64 mm Hg
10.3 mm Hg
Sherman, 1978
Sherman, 1978
Wlndholz, 1983
Kemme and Kreps, 1969
0169d
-1-
09/18/89
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Water solubility
at 25°C:
Log Kow:
TLV:
Water odor threshold:
Conversion factor:
(air at 20°C)
73,000 ppm
0.88
50 ppm (air)
7.1 ppm
Amoore and Hautala, 1983
Hansch and Leo. 1985
Amoore and Hautala, 1983
Amoore and Hautala, 1983
1 mg/m3 = 0.33 ppm Verschueren, 1983
1 ppm = 3.03 mg/m3
The chemical reactivity of 1-butanol Is based primarily on the hydroxyl
function; therefore, the most Important reactions are dehydration, dehydro-
genatlon, oxidation and esterlflcatlon {Sherman, 1978). 1-Butanol Is
flammable and has a flash point of 36-38°C (Wlndholz, 1983).
1.3. PRODUCTION DATA
Table 1-1 lists commercial manufacturers of 1-butanol and their annual
capacities.
United States production of 1-butanol In 1987 and 1986 has been reported
to be 1.155 and 0.881 billion pounds, respectively (USITC, 1987, 1988).
The primary method of manufacturing 1-butanol In the United States Is
the oxo process, which 1s used by all of the manufacturers cited In Table
1-1 except Ethyl Corp. and Vista Chemical (SRI, 1988). Ethyl Corp. and
Vista Chemical produce 1-butanol by the Zlegler process (SRI, 1988). In the
oxo process, propylene Is reacted with carbon monoxide and hydrogen In the
presence of an appropriate catalyst to yield n- and Iso-butyraldehyde
(Sherman, 1978). Reduction of the n-butyraldehyde yields 1-butanol. The
Zlegler process Involves reaction of ethylene with aluminum alkyls followed
by oxidation and hydrolysis to yield 1-butanol (Gautreaux et al., 1978).
0169d
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TABLE 1-1
Commercial Manufacturers of 1-Butanol*
Company
BASF Corp.
Eastman Kodak
(Texas Eastman)
Ethyl Corp.
Hoechst Celanese
Shell Oil Co.
Union Carbide Corp.
Vista Chemical
Location
Freeport, TX
Longvlew, TX
Pasadena, TX
Bay City, TX
Bishop, TX
Deer Park, TX
Texas City, TX
Lake Charles, LA
Annual Capacity
(millions of pounds)
130
190
5
225
175
180
400
7
*Source: SRI, 1988
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1.4. USE DATA
The following use pattern for 1-butanol has been reported {CMR, 1984)
Butyl acrylates and methacrylate
Glycol ethers
Butyl acetate
Solvent
Plastlclzers
Amlno resins
Amines
Miscellaneous
Exports
30%
23%
12.5%
12.5%
8%
5%
1%
1%
7%
As can be seen from the Information above. 1-butanol Is used mainly as a
chemical Intermediate In the manufacture of other chemicals. About 12.5% of
production Is consumed In solvent applications for fats, waxes, resins,
shellac, varnishes, gums and other materials (Hlndholz, 1983).
1.5. SUMMARY
1-Butanol Is also known by the synonyms n-butanol, n-butyl alcohol,
butan-1-ol, methylolpropane, propylcarblnol and propylmethanol (Chemllne,
1988). It Is a highly refractive colorless liquid with a vinous or wine-
like odor (Hlndholz, 1983; Sherman, 1978; Hawley, 1981). Seven U.S.
manufacturers at eight sites In Texas and Louisiana have a combined
production capacity of 1.3 billion pounds of 1-butanol annually (SRI,
1988). Domestic production of 1-butanol In 1987 and 1986 has been reported
to be 1.155 and 0.881 billion pounds, respectively (USITC, 1987, 1988).
1-Butanol Is manufactured primarily by the oxo process, In which propylene
Is reacted with carbon monoxide and hydrogen to form butyraldehyde, which 1s
subsequently reduced to butanol (Sherman, 1978). The use pattern for
1-butanol has been reported as follows (CMR, 1984): butyl acrylates and
methacrylate, 30%; glycol ethers, 23%; butyl acetate, 12.5%; solvent, 12.5%;
plastlclzers, 8%; amlno resins, 5%; amines, 1%; miscellaneous, 1%; export,
7%.
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based upon Us relatively high vapor pressure of 5.5 ram Hg at 22.6°C
{Kemme and Kreps, 1969), 1-butanol is expected to exist almost entirely In
the vapor phase 1n the ambient atmosphere (Elsenrelch et a!., 1981). The
dominant degradation process In ambient air Is probably reaction with
sunlight-formed hydroxyl radicals. Based upon an experimentally determined
rate constant of 7.32xlO~12 cm3/molecule-sec at 19°C and an average
atmospheric hydroxyl radical concentration of 5xl05 molecules/cm3
(Atkinson, 1985), the half-life for this reaction can be estimated to be 2.2
days.
1-Butanol has a relatively high water solubility of 73,000 ppm (Amoore
and Hautala, 1933), which suggests that physical removal from air by wet
deposition (washout by rainfall, dissolution 1n clouds, etc.) Is possible.
The relatively fast degradation rate by hydroxyl radicals, however, Is
probably more Important than physical removal for the general ambient air
environment.
2.2. WATER
2.2.1. Hydrolysis. Experimental hydrolysis data regarding 1-butanol were
not located. Because alcohols are generally resistant to environmental
hydrolysis (Harris, 1982), hydrolysis of 1-butanol In the aquatic environ-
ment is not expected to be Important.
2.2.2. Oxidation. The rate constant for the reaction between 1-butanol
and hydroxyl radicals In water at room temperature Is ~4xlOVM-sec
(Guesten et al., 1981). Assuming an ambient hydroxyl radical concentration
of lx!0~17 M In brightly sunlit natural water (Mill et al., 1980), the
half-life can be estimated to be -200 days. Therefore, this reaction should
have no environmental significance.
0169d -5- 04/28/89
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2.2.3. Photolysis. Pertinent data regarding the photolysis of 1-butanol
In the aquatic environment were not located; however, 1-butanol does not
contain any significantly active chromophores. Therefore, direct photolysis
In the environment should not be Important.
2.2.4. M1crob1al Degradation. 1-Butanol has been shown to blodegrade
readily In a number of aerobic biological screening studies (Hammerton,
1955; Bridle et al., 1979a; Wagner, 1976; Price et a!., 1974; Urano and
Kato, 1986; Babeu and Valshnav, 1987; Gellman and Heukeleklan, 1955; D1as
and Alexander, 1971; Hatfleld, 1957; PHter, 1976; McKlnney and JerH, 1955;
Gerhold and Malaney, 1966). For example, Hammerton (1955) found that
1-butanol (3 ppm) was degraded readily by biochemical means In a natural
river die-away test using only river water as Inoculum. Graphical Interpre-
tation of results after 4 days of Inoculation Indicated that -56% of Initial
1-butanol had bio-oxidized. The rest of the screening studies cited above
used Inocula such as activated sludge or sewage and test methods such as
standard dilution or resplrometrlc methods. Typical test results for
standard dilution studies are measured 5-day theoretical BODs of 42-86.8%
(Hagner, 1976; Price et al., 1974; Bridle et al., 1979a; Urano and Kato,
1986).
Chou et al. (1979) found 1-butanol biodegradable under anaerobic condi-
tions. Using the Hungate serum bottle technique, 1-butanol at an Initial
concentration of 500 ppm exhibited a 4-day lag period before 10054 of Initial
substrate was degraded at a rate of -100 ppm/day.
2.2.5. Volatilization. The Henry's Law constant for 1-butanol has been
measured experimentally to be 7.89x10"* atm-ma/mole at 25°C (Snider and
Dawson, 1985). A Henry's Law constant of this magnitude Indicates that
volatilization from environmental waters 1s generally slow, although
0169d
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volatilization from shallow rivers may be significant (Thomas, 1982). Using
a model river estimation method {Thomas, 1982), the volatilization half-life
of 1-butanol from a river 1 m deep flowing 1 m/sec with a wind velocity of 3
m/sec can be estimated to be ~4.1 days. The volatilization half-life from a
model environmental pond can be estimated to be -44.5 days (U.S. EPA,
1987a). Based upon these estimates, volatilization from water does not
appear to be as environmentally Important as mlcroblal degradation, with the
possible exception of very shallow rivers.
2.2.6. Adsorption. The relatively high water solubility of 1-butanol
(73,000 ppm at 25°C) suggests that partitioning from the water column to
sediment and suspended material should not be Important.
2.2.7. Bloconcentratlon. Experimental BCFs for 1-butanol In fish were
not located. A BCF of 2.75 can be calculated using a log K value of
a ow
0.88 (Hansch and Leo, 1985) and the following recommended equation (Bysshe,
1982): log BCF = 0.76 log KQW - 0.23. This calculated BCF value
Indicates that b^oconcentratlon 1n aquatic organisms Is not significant.
2.3. SOIL
2.3.1. Mlcroblal Degradation and Volatilization. Fairbanks et al. (1985)
studied the degradation and volatilization of !4-rad1olabeled 1-butanol 1n
two agricultural soils from New Mexico under laboratory conditions. Total
losses In both soils averaged 67% over a 20-day observation period with a
majority of the loss occurring during the Initial 2 days. Degradation
losses of butanol to 14COp (presumably by microblal means) were 2-17
times greater than losses by volatilization. Nearly all of the volatiliza-
tion occurred within the first day as expected, since 1-butanol has a
relatively high vapor pressure. The authors suggested that subsequent
volatilization may be attenuated by sorptlon to clay particles. After 20
0169d -7- 04/28/89
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days, evolution of 14C02 averaged 51-5854 of the total Initial amounts
added. The rates of CCL evolution Indicate that 1-butanol biodegrades
readily In the tested soils. This result 1s consistent with the results of
the biological screening studies noted In Section 2,2.4.
2.3.2. Adsorption/Leaching. Based upon Us water solubility and log
K , the K for 1-butanol has been estimated to be ~10, which Indicates
that It should be very highly mobile In soil (Roy and Griffin, 1985).
Detection of 1-butanol In leachate monitoring wells in the vicinity of a
solid waste landfill and paint factory may demonstrate that 1-butanol 1s
mobile in soil (Dewalle and Chian, 1981; Botta et al., 1984). Alcohols,
such as butanol, can adsorb to clay surfaces (Fairbanks et al., 1985; Stul
et al., 1979), which may retard the rate of leaching In some soils.
2.4. SUMMARY
When released to the atmosphere, 1-butanol Is expected to exist in the
vapor phase, where 1t will degrade relatively rapidly by reaction with
sunlight-formed hydroxyl radicals. Based upon an experimentally measured
rate constant (Atkinson, 1985), the atmospheric half-life for this reaction
in average air 1s ~2.2 days. When released to either the aquatic or soil
environments, 1-butanol Is expected to degrade primarily by microbial
degradation. A number of biological screening studies have demonstrated
that 1-butanol 1s readily biodegradable under aerobic conditions (Hammerton,
1955; Bridie et al., 1979a; Wagner, 1976; Price et al., 1974; Urano and
Kato, 1986; Babeu and Vaishnav, 1987; Gellman and Heukelekian. 1955; Dias
and Alexander, 1971; Hatfield, 1957; Fitter, 1976; HcKlnney and Jeris, 1955;
Gerhold and Halaney, 1966). A river die-away study that used only natural
river water as a microbial Inocula found that 56% of added 1-butanol was
bio-oxidized In a 4-day period (Hammerton, 1955). Chou et al. (1979) found
0169d
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1-butanol biodegradable under anaerobic conditions. Following a 4-day lag
period, 100X of added 1-butanol was degraded at a rate of -100 ppm/day. In
a soil degradation study, 51-58% of added butanol was released from the soil
as CO- {presumably from mlcrobtal degradation) over a 20-day period
(Fairbanks et al., 1985). Although not as Important as mlcroblal degrada-
tion, volatilization from soil within the first day of addition can be a
significant removal mechanism (Fairbanks et al., 1985). The K of
1-butanol has been estimated to be -10, which Indicates that leaching In
soil 1s expected (Roy and Griffin, 1985); however, concurrent mlcroblal
degradation may lessen the Importance of leaching.
0169d
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3. EXPOSURE
3.1. HATER
1-Butanol has been detected tentatively and qualitatively 1n drinking
water concentrates collected from Cincinnati, OH (October 17, 1978), Miami,
FL (February 3, 1976), New Orleans, LA (January 14, 1976}, Philadelphia, PA
(February 10, 1976) and Seattle, WA (November 5, 1976) (Lucas, 1984).
Finished drinking water from Durham, NC, has also been reported to contain
1-butanol (Shackelford and Keith, 1976).
Reported detections of 1-butanol In environmental surface waters are
limited. Qualitative detection of 1-butanol 1n a water sample from the
western basin of Lake Ontario has been reported (Great Lakes Water Quality
Board, 1983). Concentrations of 87-318 ppb were Identified In water samples
from the polluted Hayashlda River 1n Japan In 1980 (Yasuhara et al.f 1981)
while levels <1 ppb were detected 1n water samples collected from the Lee
River 1n England (Haggott, 1981).
1-Butanol can be released to water through various wastewater emissions.
It has been detected In wastewater emissions from chemical manufacturing
plants, textile plants, sewage treatment plants, oil refineries and landfill
leachates (Shackelford and Keith, 1976). It has also been Identified In
wastewater from pulp mills making kraft paper (Carlberg et al., 1986).
3.2. FOOD
1-Butanol appears to occur naturally In various fruits. It has been
detected qualitatively as a volatile component of apple and pear aroma
(Drawert et al., 1962) and grape essence (Stevens et al., 1965). Lovegren
et al. (1979) detected 1-butanol concentrations of 0-7 ppb In dried beans
(lima, common, mung), 150 ppb In split peas and 120 ppb 1n lentils.
0169d -10- 04/12/89
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1-Butanol has also been Identified 1n volatlles from mountain cheese (Dumont
and Adda, 1978), roasted filberts (Klnlln et al., 1972) and fried bacon (Ho
et al., 1983).
PelUzzarl et al. (1982) qualitatively detected 1-butanol 1n 3/12
samples of human milk collected from volunteers In Bayonne, NJ, Jersey CHy,
NJ, BrldgevUle, PA, and Baton Rouge, LA.
3.3. INHALATION
1-Butanol can be released to air by both natural and human sources.
Natural sources of release Include animal wastes, microbes and Insects;
human sources Include volatilization from solvents (such as used 1n paints),
rendering, sewage treatment, starch manufacture, whiskey manufacture, wood
pulping and turbine emissions (Graedel et al., 1986).
Monitoring data for 1-butanol In the ambient atmosphere are limited.
•Juttner (1986) qualitatively detected 1-butanol In forest air of the
Southern Black Forest In Germany in 1983. Smoyer et al. (1971) detected
maximum concentrations of 1-10 ppm (3.03-30.3 mg/ma) In ambient air In the
vicinity of a solvent reclamation plant In Maryland; the solvent plant was
considered the source of exposure. Cavanagh et al. (1969) detected
1-butanol levels of 34-445 ppb (103-1348 pg/m3) In air from Point
Barrows, AL, In 1967, probably resulting from a fermentation process
(various bacteria) of the tundra cover. 1-Butanol was not detected In
marine air samples collected 1n Hawaii (Cavanagh et al., 1969).
An Indoor air sample collected In 1983 from homes In Italy contained a
1-butanol level of 20 yg/m3 (DeBortoll et al., 1986); the source of
exposure was probably solvent evaporation.
The mean concentration of 1-butanol 1n the breathable air of workers
Involved with varnish spraying (varnish containing butanol solvent) In
0169d -11- 04/28/89
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various German plants was found to be 1.2 ppm (3.64 mg/m3) (Angerer and
Hulf, 1985). A similar mean concentration of 1.6 mg/m3 (3.6 mg/m3
maximum) was determined for a group of Belgian workers exposed to solvents
(Veulemans et al., 1987).
3.4. DERMAL
Pertinent monitoring data regarding the dermal exposure of 1-butanol
were not located 1n the available literature cited In Appendix A.
3.5. SUMMARY
Human exposure to 1-butanol can occur from both natural and human
sources. Natural sources of air release Include animal wastes, microbes and
insects; human sources Include volatilization from solvents (such as used 1n
paints), rendering, sewage treatment, starch manufacture, whiskey manufac-
ture, wood pulping and turbine emissions (Graedel et al., 1986). Concentra-
tions of 34-445 ppb detected In the ambient air at Point Barrows, AL, are
thought to occur as a result of a fermentation process of the tundra cover
(Cavanagh et al., 1969). 1-Butanol appears to occur naturally 1n volatile
components of apples, pears, grapes, dried legumes and mountain cheese
(Drawert et al., 1962; Stevens et al., 1965; Lovegren et al., 1979; Dumont
and Adda, 1978). Release of 1-butanol to water can occur through wastewater
emissions from chemical and textile plants, sewage treatment plants, oil
refineries, landfill leaching and kraft pulp mills (Shackelford and Keith,
1976; Carlberg et al., 1966). 1-Butanol has been detected tentatively and
qualitatively In drinking water concentrates collected from Cincinnati, OH,
Miami, FL, New Orleans, LA, Philadelphia, PA, and Seattle, HA (Lucas, 1984).
0169d
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Gillette et al. (1952) exposed
creek chub, Semotltus a. atromaculatus, to 1-butanol In covered "I-gallon
glass jars for 24 hours at temperatures ranging from 15-21°C. Control and
treatment solutions were aerated during the exposure phase. Dilution water
was obtained directly from the East Channel of the Detroit River and was
used untreated. Four fish were used per treatment. The authors gave no
Indication that the treatments were replicated. All fish survived exposure
to 1000 ppm 1-butanol for 24 hours, but all fish died on exposure to 1400
ppm 1-butanol after 24 hours.
Hunch (1972) assessed the narcotizing effects of 1-butanol In frog, Rana
plplens. tadpoles. Tadpoles were exposed to 1-butanol In 500 ml of tap
water at 20°C. The duration of exposure was not specified. The threshold
narcotic concentration was defined as the concentration at which tactile
stimuli failed to cause movement by the tadpole. The threshold narcotic
concentration for 1-butanol 1n frog tadpoles was 38 mmol/i.
Bridle et al. (1973, 1979b) reported a 24-hour TLm of 1900 mg/l for
goldfish, Carasslus auratus, exposed to 1-butanol. Testing was conducted In
all-glass aquaria with 25 I of test solution at ~20°C. Diluent water was
municipal tap water. The concentration of butanol was determined at the
beginning and end of the test by measurement of TOC.
Bresch and Splelhoff (1974) assessed the toxic effects of n-butanol on
early embryonic stages of the sea urchin, Sphaerechinus granular Is. Various
concentrations of the alcohol were added to preparations of embryos 20
minutes after fertilization. Stages of treated embryos were evaluated when
control embryos had reached the 8-cell stage. Investigators also assessed
0169d -13- 04/12/89
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the toxic effects of n-butanol on embryos at the gastrula stage. The limit
of toxlclty was defined as the highest concentration of n-butanol that did
not lead to morphological changes or Inhibition of the swimming movements of
the gastrula. Investigators reported that the limn of toxlclty to the
8-cell stage was ~8xlO~6 mol/mB. and the limit of toxldty to the
gastrula was ~3xlO~5 mol/mi.
Price et al. (1974) exposed brine shrimp, Artemla sallna. to n-butanol
1n artificial seawater at 24.5°C for 24 hours In static tests. The Investi-
gators reported a 24-hour TL of 2950 mg/8,.
Mattson et al. (1976) assessed the static acute toxlclty of 1-butanol to
fathead minnows In Lake Superior water and soft reconstituted water. F1sh
were exposed to 1-butanol In 3-8. cylindrical glass jars with 2 4 of test
solution. Butanol concentrations were not measured. Test temperatures
ranged from 18-22°C. Investigators reported 24-, 48-, 72- and 96-hour
LC5Qs of 1950, 1950, 1950 and 1910 rng/i, respectively, for fish exposed
to 1-butanol In Lake Superior water and ?4- to 96-hour LC5Qs of 1940
mg/i for fish exposed to 1-butanol In soft reconstituted water.
BMngmann and Kuhn (1977a) reported 1C , LC5Q and LC,OQ values for
Daphnla magna exposed to 1-butanol for ?4 hours of 300, 1855 and 5000
mg/l, respectively. Subsequently, BMngmann and Kiihn (1982) reported a
24-hour EC5Q for D_. magna exposed to 1 butanol of 1880 mg/8,, with 95X
confidence limits of 1747-2024 mg/i. The ECQ and EC,QQ values were
1411 and 2500 mg/i, respectively.
Juhnke and Luedemann (1978) reported the results of studies conducted In
two laboratories with the Golden Orfe, Leuc1 scus Idus melanotus. Exposure
of the Golden Orfe to n-butanol for 48 hours produced LCrg values of 1200
and 1770 mg/i. The respective LCQ values were 1170 and 1620 mg/8., and
the respective LC1QO values were 1220 and 1980 mg/i.
0169d
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Linden et a). (1979) assessed the acute toxlclty of 1-butanol to the
harpacticoid copepod, NUocra splnipes. and the bleak, Alburnus alburnus.
Copepods were exposed to 1-butanol in 15-mi test tubes containing 10 mil
of filtered brackish water. Fish were exposed to 1-butanol 1n 70s. glass
aquaria containing 60 s, of brackish water filtered through a 300 jjm
filter. Salinity and temperature of test solutions In both studies were 7
o/oo and 10°C, respectively. The Investigators reported 96-hour LCj-ns of
2100 and 2250-2400 mg/8, for copepods and bleaks, respectively. The 95%
confidence limits for the copepod LC50 were 1900-2300 mg/l.
Hudson et al. (1981) assessed the acute toxlclty of n-butanol to brine
shrimp, Artermla. NaupHus larvae were taken up from culture in a 100 yH
mlcroplpet, counted, and transferred to a glass shell vial containing 0.9
ma seawater. The toxic endpolnt was the lack of movement by larvae.
Tests were conducted at 30°C for 24 hours. No toxic effects were observed
among larvae exposed to <100 jiM concentrations of n-butanol.
Veith et al. (1983) reported the results of flowthrough toxlclty tests
In which fathead minnows, Plmephales promelas. were exposed to 1-butanol at
25il°C. Diluent water was soft (hardness = 56.3 mg/8. as CaCO,) and
0
drawn from Lake Superior. Alcohol concentrations were measured in each tank
throughout the test. The investigators reported a 96-hour LC5Q of 1730
mg/l.
Brooke et al. (1984) assessed the toxlclty of butanol to fathead
minnows, £. promelas. in dynamic acute tests. Fish were exposed to butanol
in soft water (hardness = 47.7 mg/i) at 24.7°C using a cycling propor-
tional diluter with duplicate exposures for each concentration. Butanol
concentrations were measured by GLC. Investigators reported a 24- to
96-hour EC50 of 1510 mg/l. The 48- to 96-hour LC5Q (and 95% confi-
dence limits) was 1730 mg/8. (1630-1840).
0169d -15- 04/12/89
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de Zwart and Slooff (1987) assessed the toxIcHy of butanol to larvae of
the clawed toad, Xenopus laevls. Larvae were exposed to butanol In 1 4 of
reconstituted water 1n glass aquaria at 20°C. Toxicant concentrations were
not measured and solutions were not renewed. The 48-hour LCrn for toad
larvae exposed to 1-butanol was 1200 mg/i.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY — Pertinent data regarding the effects of chronic
exposure of aquatic fauna to butanol were not located In the available
literature cited In Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION — Hill et al. (1981)
presented limited data regarding short-term accumulation of butanol In brain
tissues of goldfish exposed to aerated solutions containing 10, 15 or 20 mM
butanol. Pseudo steady-state levels of butanol In brain tissues were
reached within -60 minutes for fish exposed to the two lower concentrations
(-0.5 and 0.7 mg/g for 10 and 20 mM, respectively). Data for time periods
>30 minutes were not presented for fish exposed to the highest concentra-
tion. The authors stated that butanol concentration In brain tissues
declined during exposure periods lasting >4 hours, but data were not
presented 1n the paper. From the unpublished data, the authors speculated
that goldfish can metabolize butanol.
No measured steady-state BCF value for butanol was found In the litera-
ture. Based on the regression equation, log BCF = 0.76 log K - 0.23
(Lyman et al., 1982) and a log KQW value of 0.88 (see Section 1.2.), a BCF
value of 2.75 1s estimated for this compound, suggesting that butanol will
not bloaccumulate significantly In aquatic organisms.
0169d -16- 09/18/89
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4.1.3. Effects on Flora.
4.1.3.1. TOXICITY — Effects of exposure of a green alga, Scenedesmus
quadrlcauda. and a blue-green alga, Hlcrocvstls aeruglnosa. to 1-butanol
were reported by Brlngmann (1975) and Brlngmann and Kuhn {1976, 1977b, 1978,
1979, 1980). Cultures were Incubated with a series of 1-butanol solutions
for 8 days at 27°C to determine the toxlclty threshold. The toxldty
threshold was defined as the concentration of toxicant that Inhibited
multiplication of cells In suspension. The Inhibition was measured turbldl-
metrlcally as a >3% extinction of the primary light of monochromatic
radiation at 436 nm for a layer of cells 10 mm thick. Toxlclty threshold
levels for exposure of M. aeruglnosa to n-butanol were 100 and 312 mg/l.
Toxlclty threshold levels for exposure of S. quadrlcauda to n-butanol were
95 and 875 mg/i.
Haley et al. (1987) reported a 96-hour EC™ of 2000 mg/8, for the
green alga, Chi ore!la pyrenoldosa.
4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bloconcen-
tratlon potential of butanol 1n aquatic flora were not located In the
available literature cited 1n Appendix A.
4.1.4. Effects on Bacteria and Other Microorganisms. Effects of exposure
of an aquatic bacteria, Pseudomonas put Ida, and a flagellated protozoan,
Entoslphon sulcatum. to butanol were reported by Brlngmann and Kuhn (1976,
1977b, 1979, 1980, 1981). Effects on bacterial suspensions were determined
turbldlmetrlcally by the extinction of primary light at 436 nm for a layer
10 mm thick. The toxlclty threshold was defined as the concentration of
toxicant having an extinction value of >354 below the mean value of extinc-
tion for nontoxlc dilutions of the test cultures. Effects on protozoa were
determined by cell counts on a Coulter counter. The toxldty threshold with
0169d -17- 04/12/89
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protozoa was defined as a 5% reduction 1n cell counts obtained mathematic-
ally from regressions between n-butanol concentrations and cell counts.
Bacterial suspensions were exposed to n-butanol for 16 hours at 25°C and
protozoan cultures for 72 hours at 25°C. The Investigators reported
toxlclty thresholds of 650 and 55 mg/i for the bacteria and protozoa,
respectively. Subsequently, Brlngmann and Kuhn (1981) assessed the effects
of exposure of a holozolc bacterlovorous ciliated protozoan Uronema parduez1
Chatton-Lwoff, and a saprozolc ciliated protozoan, Chllomonas paramecturn
Ehrenberg, to n-butanol. They reported toxldty threshold values of 8.0 and
27 mg/8., respectively.
Hermens et al. (1985) assessed the toxldty of n-butanol to Photobac-
terlum phosphorenm by the Mlcrotox bacterial luminescence assay. Tests were
conducted In accordance with procedures recommended by the manufacturer,
Beckman Instruments Inc. Bacteria were Incubated 1n five concentrations of
n-butanol for 15 minutes at 15°C. The EC™ was based on a reduction In
bacterial luminescence. The Investigators reported a 15-mlnute log EC™
for n-butanol of 4.58 (-38000 mg/l). Subsequently, Tarkpea et al. (1986)
reported 5-, 15- and 30-m1nute EC™ values of 3370, 3690 and 3710 mg/l,
respectively, for £. phosphorearn exposed to 1-butanol In the Mlcrotox assay.
Valshnav (1986) assessed the effects of 1-butanol on bacterial respira-
tion rates In a mixed mlcroblal culture from a wastewater sample. Respira-
tion studies were conducted on a Marburg apparatus at 30°C. Oxygen consump-
tion of cultures was monitored at 15-mlnute Intervals for 75 minutes. The
toxic endpolnt represented the concentration of 1-butanol that would reduce
the maximum observed blodegradatlon rate by 50%. The Investigators reported
an EC5Q of 10,614 mg/t.
0169d
-18-
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4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Hoffman and EasUn (1981) assessed the toxlclty
of butanol to mallard duck, Anas platyrhynchos. eggs. On days 3 and 8 of
Incubation, eggs were Immersed for 30 seconds In distilled water or 1n 10
and 100% solutions of butanol. Eggs were examined by the candle method
dally until day 18 of Incubation. There were no effects on embryos exposed
to distilled water or 10% butanol. There were no surviving chicks within
eggs Immersed In 100% butanol for either the 3- or 8-day-old embryos by day
18 of Incubation.
Schafer et al. (1983) determined the acute oral toxlclty of 1-butanol to
starling, Sturnus vulgarls. Birds were trapped In the wild and precondi-
tioned to captivity for a period of 2-6 weeks before the Initiation of
testing. The Investigators estimated an oral LO™ of <2500 mg/kg.
4.2.2. Effects on Flora. Pertinent data regarding the effects of
exposure of terrestrial flora to butanol were not located In the available
literature cited 1n Appendix A.
4.3. FIELD STUDIES
Pertinent data regarding the effects of butanol on flora and fauna 1n
the field were not located 1n the available literature cited In Appendix A.
4.4. AQUATIC RISK ASSESSMENT
Insufficient data prevented the development of a criterion for the
protection of freshwater life exposed to 1-butanol (Figure 4-1} by the
method of U.S. EPA/OWRS (1986). Development of a freshwater criterion
requires the results of acute assays with a salmonld fish species, a benthlc
crustacean, an Insect, a non-Athropod/Chordate, and a new Insect or phylum
representative. Results from chronic assays required for the development of
a freshwater criterion Include assays with two species of fauna and at least
one bloconcentratlon study.
0169d -19- 04/12/89
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i
i Lnordc-t e ( £c*. . mor: i cJ -• f i sr >
^>B_ —»- ...................................... * - ........................ •* " *- -" ~ "*"" ""' "~~ ................ i_ i__ _ „ .mil
r.c-rdDt e '. m- -fvu>ote- ••
| C •
,
i L i
o tfish or
1.757-
Cnror.ic*
NP
Nf.
< p i arikt on i c i
j. '. J. '. .1
1.1 ^ t a c c- f. ;'. '- D o r. t h 1 1: )
Nf!
*•_
T: .-
lv!f:
!
"" f
Ki:
— T -- — —
.!C >i i nsۥ C ' V 5 r. or p KI y i 1.1 n.
re r• s • £• E. e:- r; t r, 11 VE^
N::
J 4
1 I
NI-:
_i s
~ . - -^ .
,;;.,_•..;.•
*• i U
v s c r LI • ? • •• p- i s »•; t
NI-!
N!';
KT:
NA=r:ct fiv£ liable • '='b-n-:.-.ir EC»0''i-C8o ir. mg/L for fstneac minnows
j mgpr.alec pro me -eg * 4B-hour LC» 0 if: rng/L for toad larvae /.enocus
«t.-^--r;:'U.- EL,c/LCBO ir mg/L for Uas^r.ia rn&grir • Si-hour ECS e
g_
FIGURE 4-1
Organization Chart for Listing GMAVs, GHCVs and BCFs Required
to Derive Numerical Water Quality Criteria by the Method
of U.S. EPA/OWRS (1986) for the Protection of Freshwater
Aquatic Life from Exposure to Butanol
0169d
-20-
04/12/89
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Available data regarding the effects of exposure of marine fauna and
flora to butanol were Inappropriate for use In the development of a
saltwater criterion by the method of U.S. EPA/OWRS (1986).
4.5. SUMMARY
The 24-hour LC5_ for creek chub exposed to 1-butanol would probably be
between 1000 and 1400 ppm (Gillette et al., 1952). The threshold narcotic
concentration for 1-butanol 1n frog tadpoles was 38 mmol/8. (Munch, 1972).
Bridle et al. (1973, 1979b) reported a 24-hour TLm of 1900 rag/* for
goldfish exposed to 1-butanol. Bresch and Splelhoff (1974) reported that
the limits of toxldty to the 8-cell and gastrula stages of the sea urchin
embryo were ~8xlO~6 and ~3xlO"5 mol/mi, respectively. Price et al.
(1974) reported a 24-hour TL of 2950 mg/8, for brine shrimp exposed to
n-butanol, although Hudson et al. (1981) reported the lack of mortality
among brine shrimp exposed to <100 pM n-butanol (<7412 mg/ft) for 24
hours. The 96-hour LC5Q for fathead minnows exposed to butanol ranged
from 1510-1940 mg/n (Mattson et al., 1976; Velth et al., 1983; Brooke et
al., 1984). The 24-hour ECrQ and LC,,. for Daphnla maqna exposed to
butanol were 1880 and 1855 mg/8., respectively (BMngmann and Kuhn, 1977a,
1982). Juhnke and Luedemann (1978) reported that exposure of the Golden
Orfe to n-butanol for 48 hours produced LC5Q values of 1200 and 1770
mg/j. for studies conducted 1n two different laboratories. Linden et al.
(1979) reported 96-hour LC5 s of 2100 and 2250-2400 mg/j. for copepods
and bleaks exposed to 1-butanol, respectively.
Concentrations of butanol In brain tissue of goldfish exposed to 10 and
15 mM solutions of butanol reached equilibrium levels of 0.46 and 0.74 mg/g,
respectively, within -60 minutes (Hill et al., 1981). Concentrations of
butanol 1n brain tissue from fish exposed to 20 mM solutions did not plateau
0169d
-21-
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within the first 30 minutes, ultimately reaching an equilibrium concentra-
tion of 0.95 mg/g. The Investigators speculated that goldfish possessed the
ability to metabolize butanol.
No measured steady-state BCF value for butanol was found In the
literature. An estimated BCF value of 2.75 for this compound suggests that
butanol will not bloaccumulate significantly In aquatic organisms.
Toxlclty threshold levels for exposure of Hlcrocystls aeruglnosa to
n-butanol were 100 and 312 mg/l, while toxkUy threshold levels for
exposure of Scenedesmus quadrlcauda to n-butanol were 95 and 875 mg/l
(Brlngmann, 1975; BMngmann and Kuhn, 1976, 1977b, 1978, 1979, 1980). Haley
et al. (1987) reported a 96-hour EC5Q of 2000 mg/l for the green alga,
Chlorella pyrenoldosa. The toxlclty thresholds for an aquatic bacterium,
Pseudomonas putjda, and a flagellated protozoan, Entoslphon sulcatum.
exposed to butanol were 650 and 55 mg/n, respectively (Brlngmann and Kuhn,
1976, 1977b, 1979, 1980, 1981). The toxlclty threshold values for a
holozolc bacterlovorous dilated protozoan, Uronema par duezl Chatton-Lwoff,
and a saprozolc ciliated protozoan, Chllomonas paramecljim Ehrenberg, exposed
to n-butanol were 8.0 and 27 mg/i, respectively (Brlngmann and Kuhn, 1981).
The 15-mlnute log EC50 for PhotobacteMum phosphoreum exposed to
n-butanol 1n the Mlcrotox bacterial luminescence assay was 4.58 (-38,000
mg/i) (Hermens et al., 1985). Tarkpea et al. (1986) reported 5-, 15- and
30-m1nute EC™ values of 3370, 3690 and 3710 mg/l, respectively, for P.
phosphoreum exposed to 1-butanol in the Mlcrotox assay. Valshnav (1986)
reported an EC™ of 10,614 mg/a for
wastewater sample exposed to 1-butanol.
reported an EC™ of 10,614 mg/ft, for a mixed mlcroblal culture from a
0169d -22- 04/12/89
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Mallard duck eggs Immersed in 100% solutions of butanol for 30 seconds
failed to produce viable chicks by day 18 of Incubation (Hoffman and Eastln,
1981), There were no effects on embryos 1n duck eggs exposed to distilled
water or 10% butanol. Schafer et al. (1983) estimated an oral L05_ of
<2500 mg/kg for starlings treated with butanol.
0169d -23- 04/12/89
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5. PHARMACOKINETICS
5.1. ABSORPTION
Uptake by 12 humans exposed to 300 or 600 mg/m3 (100 and 200 ppm,
respectively) of 1-butanol In air for four 30-m1nute periods of rest or
exercise was studied by Astrand et al. (1976). The amount of uptake was
measured as the difference between amounts In Inspired and expired air. The
percentage taken up at rest ranged from -46-48%. During exercise, the
percentage taken up ranged from -37-41%. Therefore, percentage of uptake
decreased with exercise; however, total uptake Increased because ventilation
U/mtnute) Increased during exercise. The percentage of uptake appeared
to be Independent of the concentration of 1-butanol In air and Independent
of the Intensity of exercise (estimated at 50-150 watts). Measured arterial
blood concentrations after 30 minutes of exposure ranged from 0.5-1.3 mg/kg,
proportional to exposure concentration and Intensity of exercise.
The Investigators observed that the arterial concentrations measured
were lower than expected, based on an experimentally determined blood/air
partition coefficient of 1200 and based on the disappearance of the compound
from Inhaled air. They hypothesized that because 1-butanol Is readily
soluble In water, the compound was taken up by the water 1n the mucosa of
the lung during Inspiration, thereby reducing the amount available for
absorption by the blood.
The concentration of 1-butanol In the expired air of four male beagle
dogs exposed to 50 ppm (150 mg/m3) for b hours remained relatively stable,
averaging -22 ppm during the exposure period (D1V1ncenzo and Hamilton,
(1979). From this value, the Investigators estimated that 55% of the
Inhaled vapor was absorbed through the lungs. In addition, they observed
0169d
-24-
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that blood levels of 1-butanol were below detection limits both during and
after exposure, and attributed this to the rapid metabolism of 1-butanol to
carbon dioxide (Section 5.3.).
OlVlncenzo and Hamilton (1979) studied the fate of l-14C-butanol
administered 1n corn oil by gavage to groups of 2 or 4 fasted adult male
Charles River CD rats at single doses of 4.5, 45 or 450 mg/kg. At 24 hours
after treatment, 78.3-83.3% of the dose of radioactivity had been recovered
as expired 14CCL, 0.27-0.56% as unchanged compound In the expired air,
2.6-5.0% In the urine and 0.6-1.1% In the feces; 12.1-16.3% remained In the
carcass. These data suggest that absorption of radlolabel from the gastro-
intestinal tract was virtually complete. Within the range tested, absorp-
tion from the gastrointestinal tract appeared to be Independent of the
magnitude of the dose. In rats treated with 450 mg/kg, 44.4 and 69.3% of
the dose was recovered as 14CQ- at 4 and 8 hours, respectively, Indicat-
ing that absorption was rapid. Total recovery In these experiments ranged
from 97.5-102.8% of the dose.
An in vitro study Indicated that 1-butanol Is absorbed through the oral
mucosa of dogs. Slegel et al. (1976) studied the transfer of
l-14C-butanol across a preparation of the lingual frenulum. A mean
permeability constant of 10'* cm/sec was calculated from 12 preparations.
Wlnne (1978, 1979} demonstrated that radioactivity from l-14C-butanol Is
rapidly absorbed Into the blood In perfuslon experiments using in situ rat
jejuna! preparations.
1-Butanol is also absorbed through skin. Scheupleln and Blank (1973)
exposed human adult abdominal skin samples obtained at autopsy to 1-butanol
placed on the donor side of standard pyrex diffusion cells; the receptor
side was filled with distilled water that was stirred continuously. A
0169d -25- 04/12/89
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permeability constant for 1-butanol 1n an aqueous system of 2.5x103
cm/hour was reported for the epidermis, and the stratum corneum was deter-
mined to be the diffusion rate HmHer; 3xl02 cm/hour was the permeability
constant for the dermls. Akhter et al. (1984) reported similar findings for
human skin absorption of 1-butanol (permeability constant = S.QxlQ3
cm/hour). DWIncenzo and Hamilton (1979) measured the dermal uptake of
1-butanol Ui v1vo In young male beagle dogs, then extrapolated their
findings to humans. Their data showed that 29.08 mg was absorbed at 1 hour
at a rate of 8.7 pg mlrT1 cm"2. Assuming that the rate of absorption
through the skin of humans was approximately equal to that of the dog, the
authors calculated that If 4X of the body surface area (approximately equal
to the surface area of the hands) were Immersed In 1-butanol for 1 hour,
-390 mg would be absorbed.
OelTerzo et al. (1986) estimated a permeability constant of 2.4xl03
cm/hour for 1-butanol using a nude rat skin model, and noted that the
results were comparable with those obtained for human skin by Scheupleln and
Blank (1973). Behl et al. (1984) measured permeability constants for
1-butanol In skin preparations of 3.7xl03 cm/hour to 23.7xlOa cm/hour
for nude mice, with variations depending on anatomical site (dorsal vs.
abdominal) and age of the mouse. Dorsal skin appeared to be somewhat more
permeable than abdominal skin, particularly at 4-25 days of age. Behl et
al. (1983) Investigated the effect of aqueous contact on rat skin perme-
ability to 1-butanol and determined that the permeability coefficient
Increased by a small fraction (-15%) through the first 5 hours of hydratlon,
and that H remained at this value (-fi.OxlO3 cm/hour) for the remaining 80
hours of exposure.
0169d
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Grass and Robinson (1984) applied doses of 25 pi of a 92.23 H solution
of 1-butanol to corneas of both eyes of male albino rabbits (number not
reported), the rabbits were sacrificed at various Intervals afterward, and
the aqueous humor of the eyes was analyzed for 1-butanol. At 10 minutes the
aqueous humor concentration of 1-butanol was 56.43x1CT9 H, and at 20
minutes, 35.57xlO~9 M, suggesting that 1-butanol Is absorbed through the
cornea of rabbits' eyes.
5.2. DISTRIBUTION
Distribution of single gavage doses of 450 mg/kg l-14C-butanol 1n male
CO rats was investigated by DIVIncenzo and Hamilton (1979). The results,
presented In terms of the percentage of the dose of radioactivity located 1n
each of several tissues and organs, are presented In Table 5-1. The largest
amounts were located In the liver, blood, kidneys and lungs; peak levels In
these organs occurred 8 hours after treatment. It 1s not possible to
Identify tissue affinities because the results were not presented as concen-
trations 1n the tissues. The plasma concentration of 1-butanol vs. time
plot showed a peak at 1 hour followed by a rapid, blphaslc decline. The
plasma concentration of 1-butanol was below detection limits at 4 hours
after treatment.
5.3. METABOLISM
The most complete l£ vivo Investigation of the metabolism of
l-14C-butanol was the oral rat study by DIVIncenzo and Hamilton (1979)
(see Section 5.1.). The metabolism of 1-butanol was rapid and nearly
complete, with <1% of the dosage eliminated as unchanged compound In expired
air. From 78.3-83.3% of the dose was eliminated as 14COp, and 2.6-5.1%
of the radioactivity was eliminated 1n the urine. Of the radioactivity
eliminated 1n the urine, treatment with hydrochloric acid or B-glucuron1dase
0169d -27- 04/28/89
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TABLE 5-1
Tissue Distribution of Radioactivity in Rats Dosed by
Gavage with 450 mg/kg of l-14C-Butanola
Percentage
Tissue
Liver
Kidney
Lung
Heart
Brain
Adrenal glands
Fatc
Blood
4 Hours
2
0
0
0
0
0
0
0
.64
.24
.11
.05
.03
.006
.05
.51
_f
_+
t i
_+
_*
t
t
+
0.34
0.01
0.008
0.004
0.004
0.002
0.02
0.05
3
0
0
0
0
0
0
0
of Administered
Doseb
8 Hours
.88
.18
.12
.02
.04
.009
.09
.74
+
t
-t-
t
j^
+
^
+
0.40
0.01
0.004
0.002
0.001
0.002
0.01
0.11
2
0
0
0
0
0
0
0
24 Hours
.65
.11
.07
.02
.04
.009
.06
.38
* 0.2
± 0.01
± 0.009
i 0.004
± 0.001
i 0.008
± 0.04
aSource: DlVincenzo and Hamilton, 1979
^Values are expressed as the mean ± SE for four rats.
cPercentage of administered dose per gram of fat.
0169d
-28-
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Indicated that 44.4% was present as the 0-sulfate and 30.7% was present as
the 0-glucuronlde conjugates of 1-butanol. The remainder of the radio-
activity present 1n the urine (24.954) was Identified as urea. The Investi-
gators suggested that radioactivity retained In the carcass (12.1-16.3% of
the dose) represented Incorporation of single 14C-atoms Into normal
metabolic pathways.
OlVlncenzo and Hamilton (1979) administered l-14C-butanol at 1 mg/kg
Intravenously to 3 young male beagle dogs and collected expired air and
urine for 8 hours following treatment. Expired 14CO~ accounted for
12-16% of the dose of radioactivity; 2.2-2.9% was excreted In the urine
(total recovery accounted for 14-19% of the dose). These data suggest that
metabolism of 1-butanol by dogs Is qualitatively similar to rats. Kamll et
al. (1953) administered a single 16 mmol (395 mg/kg) dose of 1-butanol In
water by gavage to large chinchilla rabbits and measured the Increase In
glucuronlc acid excretion In the urine until excretion of glucuronlc acid
above pretreatment levels appeared to be complete. Glucuronlc acid conjuga-
tion accounted for an average of 1.8% of the dose In the three treated
rabbits.
In an Investigation of the elimination of 1-butanol by the Isolated
perfused rat liver, Auty and Branch (1976) found that the concentration 1n
the recycled perfusate decreased as a zero-order process above 0.8 mmol, and
as a first-order process below this level. These data suggest that a
metabolic pathway was saturated at concentrations above 0.8 mmol. Because
1-butanol decreased the rate of metabolism of ethanol when the two alcohols
were combined, the Investigators concluded that alcohol dehydrogenase, the
enzyme primarily responsible for the metabolism of ethanol, was also
responsible for the metabolism of 1-butanol. In a review of the literature,
0169d
-29-
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von Oettlngen (1943) stated that 1-butanol appeared to follow the general
metabolic pathway for primary alcohols: oxidation to the aldehyde, then to
the add, and finally to carbon dioxide and water. Brentzel and Thurman
(1977) presented supporting evidence that oxidation of 1-butanol to aldehyde
occurs In the liver by way of alcohol dehydrogenase, an NADPH-dependent
process carried out 1n the hepatic mkrosomes. Teschke et al. (1974, 1975)
did not find evidence that 1-butanol Is a substrate for catalase, as Is
ethanol. 1-Butanol Is oxidized more rapidly than ethanol; this Is
apparently due to the high substrate affinity of 1-butanol for alcohol
dehydrogenase (Vldela et al., 1982).
5.4. EXCRETION
D1V1ncenzo and Hamilton (1979) administered l-14C-butanol 1n corn oil
by gavage to male Charles River CD rats, and measured excretion rates. At
doses of 4.5-450 mg/kg, 78.3-83.3% of the dose was excreted as labeled CO-
within 24 hours, 2.6-5.IX was eliminated In the urine. 0.69-1.1% was
excreted In feces, and 12.1-16.3% remained In the carcass. Although
kinetic data were not provided, H appears that excretion was rapid.
Rumyantsev et al. (1975) admlnstered 14C-labeled 1-butanol orally to
rats and noted decreased organ levels of radioactivity at 3 hours post-
treatment; 95% of the radioactivity was eliminated from the body after 3
days. Excreta 1n urine and feces accounted for 2.8% of the radioactivity.
No further details were available. Kamll et al. (1953) noted that 1.8% of
the dose administered by stomach tube to chinchilla rabbits was excreted 1n
the urine as glucuronlde.
5.5. SUMMARY
1-Butanol was taken up readily by the respiratory tracts of humans
(Astrand et al., 1976) and dogs (DWIncenzo and Hamilton, 1979). Levels of
0169d -30- 04/28/89
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1-butanol in the blood of humans following Inhalation exposure were lower
than expected based on a measured blood/air partition coefficient and the
disappearance of the compound from Inhaled a\r (Astrand et al., 1976). This
observation may reflect sequestration of 1-butanol In mucosal tissue water
In the lung (Astrand et al., 1976) or rapid metabolism of the compound
following absorption (OWIncenzo and Hamilton, 1979). 1-Butanol appears to
be absorbed rapidly and virtually completely from the gastrointestinal
tracts of rats (DiVlncenzo and Hamilton, 1979).
In addition, 1-butanol Is absorbed through oral mucosa (Slegel et al.,
1976), Intestines {W1nne, 1978, 1979), skin (Scheupleln and Blank, 1973;
Akhter et al., 1984; D1V1ncenzo and Hamilton, 1979; OelTerzo et al., 1986;
Ben! et al., 1983, 1984) and the cornea (Grass and Robinson, 1984).
Following oral treatment of rats with l-14C-butanol, the largest amounts
of radioactivity were located 1n the liver, kidney and blood. Unchanged
1-butanol levels In plasma were below detection limits at 4 hours after
treatment (D1V1ncenzo and Hamilton, 1979). l-8utanol was metabolized
rapidly to carbon dioxide (-80% of the dose) (DiVlncenzo and Hamilton,
1979), primarily by hepatic mlcrosomal alcohol dehydrogenase (Brentzel and
Thurman, 1977; Vldela et al., 1982). Smaller amounts were excreted 1n the
urine as sulfate and glucuronlde conjugates and as urea.
At 24 hours after rats were treated orally with l-14C-butanol, ~14X of
the dose of radioactivity was retained in the carcass, which was attributed
to the incorporation of 14C Into the one-carbon pool (DIVIncenzo et al.,
1979).
0169d -31- 04/28/89
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC — Smyth and Smyth (1928) tested the toxidty of
1-butanol by exposing a group of three guinea pigs to 0 or 100 ppm (300
mg/m3) dally (schedule not stated) for 2 weeks, followed by exposure
periods of 4 hours/day, 6 days/week for another 7 weeks. Effects noted were
decreased red blood cell counts and a relative and absolute lymphocytosls.
Two of the three treated guinea pigs had hemorrhaglc areas In the lungs and
a transient albumlnurla. Follow-up studies at the same concentrations
resulted in reduced red blood cell counts, reduced blood hemaglobin concen-
trations, lymphocytes Is and liver and kidney degeneration.
Savel'ev et al. (1975) exposed rats to Inhalation levels of 212 mg/m3
1-butanol, 5 hours/day for 2 months, and reported decreased oxygen consump-
tion and delayed restoration of normal body temperature after cooling.
Continuing this exposure for another 4 months led to Increased oxygen con-
sumption and accelerated return to normal body temperature after cooling.
The authors concluded that these data Indicate high adaptability of rats to
low doses of 1-butanol. Rumyantsev et al. (1976) exposed male rats and mice
to 1-butanol Inhalation concentrations of 0, 0.8, 6.6 or 40 mg/m3 continu-
ously for 4 months. Rats at 6.6 and 40 mg/m3 had decreases In hexo-
barbltal sleeping time, CNS subliminal impulses, work capacity and oxygen
requirements. Pathologic lesions reported In rats at 6.6 and 40 mg/m3
Included dilation of blood vessels with dlapedesls of erythrocytes, pulmo-
nary edema and atalectasls, and necrotlc changes In the parenchyma of the
Intestines. Some of the vascular changes were also seen at lesser Intensity
In rats at 0.8 mg/m3. Increased reflex activity and thyroid activity, and
0169d
-32-
04/12/89
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a concentration-related Increase In blood chollnesterase levels occurred In
rats In all exposed groups. The only effects reported In mice Included
decreased hexobarbltal sleeping time and CNS subliminal Impulses at 6.6 and
40 mg/m3, and Increased reflex activity at all concentrations. Balkov and
Khachaturyan (1973) administered 0.09 or 21.8 mg/m3 by inhalation to rats
continuously for 92 days and noted no toxic effects at 0.09 mg/m3, but at
21.8 mg/m3, decreased RNA and DNA were noted in blood, along with altera-
tions In enzyme activity. Increased leukocyte luminescence and Increased
penetration of 1-butanol across blood-tissue barriers in testis, spleen and
thyroid. In another part of this study, 18 volunteers were exposed to
1-butanol at concentrations of 0.3-15 mg/m3 by an unspecified schedule for
an unreported duration. Altered sensitivity to light In the dark-adapted
eye and altered electrical activity of the brain were reported at 1.2
mg/m3. No effects were reported at 1 mg/m3.
6.1.1.2. CHRONIC — Sterner et al. (1949) conducted a 10-year study
of occupational exposure to butyl alcohol, examining hematological effects,
liver, lung and kidney function, ophthalmologlcal health and absenteeism
from work among butanol-exposed men vs. all men in the plant. The level of
exposure In air was determined to be 100 ppm (300 mg/ma) during most of
the study period, but was as high as POO ppm (600 mg/m3) In the early
phases of the study. The Initial exposed group consisted of 16 men, but was
gradually Increased to -100. No effects were noted among men exposed to 100
ppm. With concentrations averaging >200 ppm. transient corneal inflamma-
tion, with associated Iacr1mat1on, burning sensation and photophobia, was
encountered occasionally among exposed workmen.
Velasquez (1964) and Velasquez et al. (1969) reported hearing loss In
9/11 workers simultaneously exposed to 1-butanol at 80 ppm (240 mg/m3} and
0169d
-33-
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Industrial noise (unquantlfled) without personal hearing protection. The
affected workers, 20-39 years of age, were exposed for 3-11 years. The
extent of hearing loss correlated positively with duration of exposure. The
control group consisted of 47 workers exposed to Industrial noise at 90-100
dB without exposure to 1-butanol.
Human occupational exposure to 1-butanol at six manufacturing plants was
studied through site visits by "fabershaw et al. (1944), who determined that
eye 1nflammatlon resulted when air concentrations of butanol exceeded 50
ppm. No systemic effects were noted from concentrations <100 ppm. Cogan
and Grant (1945) reported that 19 of -75 female workers exposed to 1-butanol
in a gluing operation complained of ocular irritation. The complaints began
<2 months after various solvents had been replaced with 1-butanol that
4
contained varying amounts of dlacetone alcohol and denatured ethanol.
Ophthalmologlcal examination revealed the presence of characteristic corneal
lesions in 17/19 workers who registered complaints and In 9 others who
worked in the same area. The concentration of 1-butanol 1n the air was
measured at several locations and found to vary from 15-100 ppm (45-300
mg/m3). The largest number of affected employees was found In the area of
greatest contamination. Absence from work for 5-7 days resulted 1n nearly
complete reversal of the ocular effects in the majority of affected workers.
Seltz (1972) reported three cases of severe and persistent vertigo in
laboratory workers after handling 1-butanol and isobutanol for 1 year. Two
of the seven exposed workers showed no HI effects, and another two showed
transitory and brief periods of vertigo. Exposure was In a poorly
ventilated photographic laboratory that was intensely Illuminated, producing
heat that evaporated the substances. Improvement of working conditions
reportedly prevented recurrences of these problems. Concentrations of the
solvents in workroom air were not quantified.
0169d -34- 04/12/89
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6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC — The U.S. EPA (1986a) sponsored a study In
which groups of 30 Charles river CD rats/sex were treated with 1-butanol 1n
water by gavage at dose levels of 0, 30, 125 or 500 mg/kg/day for 13 weeks.
After 6 weeks, an Interim sacrifice of 10 rats/sex was conducted to
determine clInlcopathologlc, biochemical and gross morphological effects.
Survivors were sacrificed on days 92 or 93; endpolnts examined were body and
organ weight changes, food consumption, morlbundlty, mortality, ophthal-
mology, and gross and clinical hlstopathology. In the final 6 weeks of
treatment, males and females 1n the high-dose group showed ataxla and
hypoactlvity within minutes of treatment. Reduced erythrocyte count and
blood hemoglobin concentration were noted In females from the middle- and
high-dose groups at the time of the Interim sacrifice, but these were not
found at the final sacrifice, suggesting that the effects were transitory
rather than adverse. No compound-related differences were noted between
control and treated animals with respect to any of the other endpolnts
evaluated. No effects were noted at 30 mg/kg/day.
Wakabayashl et al. (1984) administered 1-butanol 1n drinking water to
groups of 30 male Wlstar rats at concentrations of 0 or 6.9% for up to 3
months; some of the rats were sacrificed at 5, 9 or 13 weeks. Liver mito-
chondria were examined for effects on ultrastructure and oxldatlve coupling
efficiency. Megamitochondrla, often appearing elongated, constricted or
cup-shaped, were noted 1n treated rats. The number of crlstae membranes per
mitochondrion decreased significantly. Activities of monoamine oxldase and
cytochrome oxldase decreased moderately compared with controls, but there
was no effect on coupling efficiency with either succlnate or glutamate as
the substrate.
0169d
-35-
04/28/89
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, 6.1.2.2. CHRONIC ~ Pertinent data regarding the chronic oral
toxIcHy of 1-butanol were not located in the available literature cited 1n
Appendix A.
6.1.3. Other Relevant Information. Data regarding the acute toxIcHy In
animals of 1-butanol are presented 1n Table 6-1. Oral LD™ values for
rats ranged from 0.7-4.36 g/kg. Female rats appear to be more sensitive
than males (dugudeanu et al., 1985; Smyth et al., 1951; Oenner et al.,
1964; Purchase, 1969), and the sensitivity of rabbits is similar to that of
male rats (Munch, 1972). Little difference 1n response to Intravenous
administration of 1-butanol was noted between mice and rats (Tichy et al.,
1985; Maickel and McFadden, 1979).
Nelson et al. (1943) exposed an average of 10 humans (male and female)
to vapor concentrations of 1-butanol (and other solvents under study) for
3-5 minutes. Subjects were not Informed of the concentrations used, or
whether they were being administered In Increasing or decreasing levels.
After the exposure, subjects classified the effect of the vapor on eyes,
nose and throat, and described the odor as absent, definite, moderate,
strong or overpowering. 1-Butanol at 25 ppm (75 mg/m3) produced mild
irritation to eyes, nose and throat; 50 ppm (150 mg/m3) was Judged objec-
tionable because of pronounced throat Irritation and later onset of mild
headaches. Amoore and Hautala (1983) determined that 50-90% of distracted
persons can perceive the odor of 50 ppm 1-butanol In workplace air.
Ba'lnova and Madzhunov (1984) noted that 24-hour contact with >7.8J4
1-butanol In plant oil Irritated the skin of healthy humans. Details of the
study were not available.
OeCeaurrlz et al. (1981) exposed six Swiss F mice/group to four
concentrations (500-1100 ppm) of 1-butanol for 5 minutes, noting respiratory
0169d -36- 04/12/89
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TABLE 6-1
Acute Lethal Toxklty of 1-Butanol
Species/Strain
Rat/NR
Rat/NR
Rat/Osborne-
Mendel
Rat/NR
Rat/NR
RabbH/NR
Rat/W1star
Mouse/strain H
House/SW
Sex
NR
NR
male
male
female
NR
male
male
male
Route
oral (gavage)
oral (food)
oral (gavage)
oral (gavage}
oral (gavage)
oral (gavage)
Intravenous
Intravenous
Intraperltoneal
LD50
IgAg)
3.83
4.36
2.51
2.02
0.79
3.484
0.310
0.450
0.254
Reference
Clugudeanu
et al.t 1985
Smyth et al.,
1951
Jenner et al.,
1964
Purchase, 1969
Purchase, 1969
Munch, 1972
Tlchey et al.,
1985
Tlchey et al.,
1985
MaUkel and
McFadden, 1979
NR = Not reported
0169d
-37-
04/12/89
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rates as an Indicator of sensory Irritation (assuming that expiratory rate
decreases reflexlvely In the presence of an Irritant). The concentration-
response relationship (percentage decrease In respiratory rate vs. the loga-
rithm of the exposure concentration) was linear, and 1268 ppm (3844 mg/m3)
was determined to be the RD5Q. In a similar study by Alarle (1981), the
R05Q was reported to be 4784 ppm (14,503 mg/m3). Concentrations tested
ranged from 1000 to ~15,000 ppm. Length of exposure was not reported.
Carpenter and Smyth (1946) Investigated the ocular Irritation caused by
applying 0,005 ml 1-butanol to the center of one cornea of each of five
albino rabbits, retracting the eyelids for 1 minute, then scoring the
Injuries on a scale of 1-10. Pure 1-butanol and 40% 1-butanol solution
caused serious Injury (necrosis).
Shehata and Saad (1978) noted significant dose-related decreases In
liver content of thlamlne, rlboflavln, pyrldoxlne, nladn and pantothenU
acid after dally oral administration to rats of 1-butanol In doses of 1 and
2 ma/kg (810 and 1620 mg/kg) for 7 days. Heese (1928) noted liver
toxlclty In three mice after an Inhalation dose of 24,624 mg/m3 was
administered "for several days." Reversible fatty Infiltrations of liver
and kidneys, along with narcosis but no deaths, were noted.
Hallgren (1960) studied the Intoxicating effects on rats of several
alcohols and determined, by a performance test that measured ability to
retain balance on a rising slope, that a dose of 1-butanol of 0.0163 mol/kg
(120B mg/kg) administered orally reduced the performance rate as much as 45X
(approximately), to an average of 73% of the performance measured before
dosing. Marcus et al. (1976) administered 1-butanol to male Sprague-Dawley
rats (number/group unclear) and found that a single Intravenous Injection of
6.7 mmol/kg (497 mg/kg) or an Intraperltoneal Injection of 8.1 mmol/kg (600
mg/kg) Induced abnormal EEG and behavioral effects (loss of righting reflex).
0169d
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04/28/89
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DeCeaurrlz et al. (1983) examined the neurobehavioral toxlclty of
1-butanol 1n male Swiss OF, mice by noting effects on duration of the
period of Immobility In the "behavioral despair" swimming test. 1-Butanol,
delivered as single 4-hour Inhalation exposures ranging from 470-965 ppm
(1425-2925 mg/rn3) to groups of 10 naive mice, significantly decreased
total duration of Immobility during a 3-m1nute postexposure observation
period. The authors suggested that this may be the result of a nonspecific
neurotoxlc action. Malckel and Nash (1985) observed Impairment of coordi-
nated muscular activity among male Swiss-Cox mice, compared with controls
treated by oral Intubation with 1.0 or 2.0 g/kg doses of 1-butanol. This
effect was not observed at 0.5 g/kg. The Investigators reported that
hypothermia occurred In a dose-related fashion, but statistical analysis was
not performed.
Several studies have reported toxic effects of 1-butanol from In vitro
tissue exposures. Nakano and Moore (1973) noted dose-dependent decreases In
the contractile force of Isolated guinea pig myocardlal strips. Madan et
al. (1969) reported relaxation of rat Intestine smooth muscle without
Increased tonldty, and reversible contracture of the frog rectus abdomlnls
muscle with exposure to 1-butanol. Walum and Peterson (1983) tested the
effects of 790 mg/kg 1-butanol on cultured mouse neuroblastoma cells
(C1300), clone 41 A~, and noted 25% cell detachment and morphological
changes (flattened and bearing short processes). Chen et al. (1984)
reported positive results for 1-butanol 1n tests on the effects of a series
of common solvents for their ability to Inhibit metabolic cooperation 1n
Chinese hamster cells. Hasamoto et al. (1974) noted MAO Inhibition In a
concentration-dependent manner by treating rat liver mitochondria with
0169d
-39-
04/28/89
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1-butanol. Swollen mitochondria and lack of matrix and crlstae were noted
following treatment with 0.1-1.0% 1-butanol; at a concentration of 10%,
mHochondrlal structure disappeared.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the Inhalation carcinogen-
Iclty of 1-butanol were not located 1n the available literature cited 1n
Appendix A.
6.2.2. Oral. Pertinent data regarding the oral carclnogenlcHy of
1-butanol were not located 1n the available literature cited In Appendix A.
6.2.3. Other Relevant Information. Pertinent data regarding other
relevant Information on carclnogenlcHy of 1-butanol by other routes of
exposure were not located In the available literature cited 1n Appendix A.
6.3. MUTAGENICITY
1-Butanol has been tested for mutagenlclty In prokaryotes and
eukaryotes, Including several mammalian test systems, with mixed results
(Table 6-2). Tests using Salmonella typhlmurlum have consistently yielded
negative results (Connor et al., 1985; McCann et al., 1975; Nakamura et al.,
1987), while a test using Escher1sch1a coll gave weakly positive results
(Yoshlyama et al., 1973). A chick embryo cytotoxlclty test proved negative
(Bloom, 1982), and mammalian test results were both negative (Lasne et al.,
1984) and positive (Oenfelt, 1987).
6.4. TERATOGENKITY
Without providing additional data or documentation, Rltter et al. (1985)
stated that 1-butanol Is a member of a class of chemical compounds that
exhibit teratogenlc properties. Mankes et al. (1985) treated pregnant
Long-Evans rats with 1-butanol (presumably In water) by gavage at doses of
0.02-24% of the oral LD5Q on days 6-15 of gestation. Controls were
0169d
-40-
04/12/89
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0169d -41- 04/12/89
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treated similarly with distilled water. No effects on the Incidence of
malformations or embryolethalHy were attributed specifically to 1-butanol
In this brief report.
Brlghtwell et al. (1987) administered 1-butanol to groups of 15 pregnant
Sprague-Dawley rats for 7 hours/day throughout gestation at Inhalation
concentrations of 0, 3500, 6000 or 8000 ppm (0, 10,610, 18,190 or 24,250
rag/m3). Previous data showed that a concentration of 8000 ppm produced
maternal toxldty (reduced food consumption and body weight gain) without
mortality. On gestation day 20, dams were sacrificed and fetuses were
divided Into two groups for teratologlcal examination of skeletal and soft-
tissues. Although fetal weights were reduced at 8000 ppm, no teratogenlc
effects were noted.
6.5. OTHER REPRODUCTIVE EFFECTS
The effects of 1-butanol on testlcular function In Sprague-Dawley rats
were studied by Cameron et al. (1985). Groups of five rats were exposed to
0 or 500 ppm (0 or 1516 mg/m3) 1-butanol In Inhalation chambers for 6
hours/day, for up to 1 week. Blood serum samples collected from the heart
were analyzed for effects on testosterone, LH and cortlcosterone levels.
After the first 6-hour exposure, circulating testosterone levels were
significantly depressed and remained so after 18 hours of posttreatment
rest. These changes were not associated with altered levels of circulating
LH. A significant Increase In cortlcosterone levels found after the first
6-hour exposure suggested this to be a result of adrenocortlcal stimulation,
which the authors suggested may explain the decrease In concentration of
circulating testosterone. The rats appeared to adapt after exposure for 1
week, when hormone levels return to near-normal levels. The change may be a
result of Increased breakdown of the alcohol or Its metabolites over time,
or to decreased sensitivity of testlcular or adrenal gland cells.
0169d
-42-
04/28/89
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6.6. SUMMARY
1-Butanol is mildly toxic to humans and laboratory species. Human
Inhalation exposure to 1-butanol at levels of 25-50 ppm (75-150 mg/m3) 1s
Irritating to the eyes, nose and throat, and can cause headaches, but no
systemic effects occur at this exposure level (Nelson et al., 1943; Amoore
and Hautula, 1983; Tabershaw et al., 1944; Seltz, 1972). Sensory Irritation
and neurobehavloral toxldty have been noted In mice and rats exposed by
Inhalation to high levels of 1-butanol (DeCeaurriz et al., 1981, 1983;
Alarie, 1981). Acute dermal contact with the liquid in oil is Irritating to
healthy human skin (Ba'tnova and Madzhunov, 1984), and eye contact with the
vapor can cause painful keratltls and conjunctivitis (Cogan and Grant, 1945).
Rabbits and male rats appear to be equally sensitive to acute oral doses
of l-butanolt but female rats are more sensitive; single-dose oral ID™
values ranged from 0.79-4.36 g/kg (Hunch, 1972; Clugudeanu et al., 1985;
Smyth et al., 1951; Jenner et al., 1964; Purchase, 1969). Acute oral expo-
sure to 1-butanol at 1200 mg/kg caused decreased ability of rats to retain
balance (Wallgren, 1960). Dose-related hypothermia and Impaired coordina-
tion of muscular activity occurred In mice treated by gavage at 1.0 or 2.0
g/kg (Malckel and Nash, 1985). Single oral 810 mg/kg doses administered to
rats Induced significant dose-related decreases in liver content of vitamins
(Shehata and Saad, 1978). Sensitivity lo intravenous or IntraperHoneal
Injection Is greater than sensitivity by the oral route among rats and mice,
but very little difference In toxic response was found between these species
(Tichy et al., 1985; Malckel and HcFadden. 19/9). Abnormal EEG and loss of
righting reflex occur In rats exposed to single Intravenous (500 mg/kg) or
IntraperUoneal (600 mg/kg) Injections of 1-butanol (Marcus et al., 1976).
0169d -43- 04/12/89
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Subchronlc Inhalation studies have been performed using rats and guinea
pigs, and human epidemiology studies are available. Liver and kidney degen-
eration and hematologlc effects were reported 1n guinea pigs Intermittently
exposed to 100 ppm (300 mg/m3) for 9 weeks (Smyth and Smyth, 1928).
Foreign studies using rats reported no effects with continuous exposure to
0.09 mg/m3, but effects on the blood and CMS at concentrations of >0.8
mg/m3 (Savel'ev et al., 1975; Rumyantsev et a!., 1976; Balkov and
Khachaturyan, 1973}. In an occupational study, no effects were reported at
100 ppm (300 mg/m3); ocular UrHaUon was reported at 200 ppm {600
mg/m3) (Sterner et al., 1949).
Oral exposure data are limited to subchronlc studies. Rats treated by
gavage with 1-butanol at 30 mg/kg/day for 13 weeks showed no toxic effects;
transitory effects on hematology (RBC, PCV) were noted among females but not
males at 125 mg/kg/day, and 500 mg/kg/day caused ataxla and hypoactlvlty In
the final 6 weeks of treatment among both sexes (U.S. EPA, 1986a).
1-Butanol administered In drinking water to rats for up to 3 months at a
high dose (9660 mg/kg/day) caused structural alterations of liver
mitochondria, accompanied by moderately decreased MAO and cytochrome oxldase
activity (Uakabayashl et al., 1984).
Data regarding cardnogen1c1ty to humans or animals were not located In
the available literature. Results of mutagenlclty and genotoxUHy testing
were mixed. 1-Butanol Is not scheduled for testing by the NTP (1988).
1-Butanol, when administered by gavage, was not a developmental toxicant
to rats at dosages up to 24% of the oral IDS_ (Mankes et al., 1985).
Inhalation exposure to 8000 ppm (24,250 mg/m3) resulted In mild maternal
toxlclty and decreased fetal body weight In rats, but no evidence of
0169d -44- 09/18/89
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teratogenklty (Srlghtwell et al., 1987). Reversible effects on testlcular
endocrine function were noted 1n rats Intermittently exposed to 500 ppm
(1516 mg/m3) (Cameron et al., 1985).
In vitro studies have demonstrated toxic effects of 1-butanol on cardiac
and smooth muscle (Nakano and Moore, 1973; Madan et al., 1969) and on
cellular structure and function (Walum and Peterson, 1983; Chen et al.,
1984; Masamoto et al., 1974).
0169d
-45-
09/18/89
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUNAN
ACGIH (1988) recommended a celling limit THA-TLV for 1-butanol of 50 ppm
(150 mg/m3), and warned that dermal absorption may contribute signifi-
cantly to the body burden. These recommendations are based on data showing
hearing Impairment in workers between the ages of 20 and 39 years
(Velasquez, 1964; Velasquez et al., 1969), and Impairment of vestlbular
function (vertigo) (Seltz, 1972). OSHA (1985) has established a PEL 1n air
of 100 ppm (300 mg/m3).
The U.S. EPA (1988a) has established a verified RfD of 0.1 mg/kg/day for
chronic oral exposure to 1-butanol, based on an oral subchronlc study
sponsored by U.S. EPA (1986a).
1-Butanol Is approved for human use both as a direct and an Indirect
food additive (CFR, 1984).
The RQ for 1-butanol 1s 5000 based on application of the secondary
criterion of blodegradatlon to the primary criterion RQ of 1000, which 1s
determined by Its Ignltablllty (U.S. EPA, 1988b).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to butanol were not located In the available literature cited In
Appendix A.
0169d -46- 09/18/89
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8. RISK ASSESSMENT
Statements concerning available literature 1n this document refer to
published, quotable sources and are In no way meant to Imply that confiden-
tial business Information (CBI), which this document could not address, are
not In existence. From examination of the bibliographies of the CBI data,
however. It was determined that CBI data that would alter the approach to
risk assessment or the risk assessment values presented herein do not exist.
6.1. CARCINOGENICITY
8.1.1. All Routes. Pertinent data regarding the carclnogenlclty of
1-butanol by Inhalation, oral or other routes of exposure were not located
In the available literature cited 1n Appendix A.
8.1.2. Weight of Evidence. No data are available concerning the carclno-
genlclty of 1-butanol to animals or humans. The most appropriate classifi-
cation according to the U.S. EPA (1986c) classification scheme for this
substance 1s Group D, not classifiable as to human carclnogenlclty.
8.1.3. Quantitative Risk Estimates. Lack of data precludes derivation of
estimates of carcinogenic potency by any route of exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) -- Smyth and Smyth
(1928) reported hematologlc effects, pulmonary hemorrhage and liver and
kidney degeneration In guinea pigs Intermittently exposed to 100 ppm (300
mg/m3), the only concentration tested, for 9 weeks. Rumyantsev et al.
(1976) reported hlstopathologlc lesions In the blood vessels, lungs and
Intestines of rats exposed continuously to 6.6 or 40 mg/m3 for 4 months.
0169d -47- 07/11/91
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Subtle nervous system effects were reported In rats and mice at 0.8 mg/m3,
the lowest concentration tested. Balkov and Khachaturyan (1973) reported
biochemical changes 1n the blood and Increased passage of 1-butanol Into the
testls, spleen and thyroid of rats exposed continuously to 21.8 mg/m3 for
92 days. No effects were reported at 0.09 mg/ma. The lexicological
significance of the effects 1n rats reported by Balkov and Khachaturyan
(1973) Is unclear. Balkov and Khachaturyan (1973) also reported changes 1n
vision and 1n the electrical activity of the brain 1n humans exposed to 1,2
mg/m3 by an unspecified schedule. No effects were reported at 1.0 mg/m3.
The subchronlc Inhalation studies In animals and humans discussed above
were all Insufficiently reported for critical evaluation and, therefore, the
data are judged Insufficient for derivation of an RfD for subchronlc Inhala-
tion exposure to 1-butanol. Furthermore, the data do not clearly Identify a
target organ or suggest a specific syndrome for the toxlclty of 1-butanol.
These data are Included, however, 1n the generation of dose/duration-effect
graphs presented 1n Appendix C.
8.2.1.2. CHRONIC EXPOSURE — Data regarding chronic Inhalation
exposure of animals to 1-butanol were not located. Human occupational data
suggest that the central and peripheral nervous system and the eyes may be
targets for the toxlclty of 1-butanol. Sterner, et al. (1949) reported no
effects on hematology, liver, lung or kidney function, ophthalmologlcal
health or absenteeism 1n workers exposed to 100 ppm (300 mg/m3). Ocular
Irritation was reported at 200 ppm (600 mg/m3). Ocular Irritation was
also reported by Tabershaw et al. (1944) at concentrations >50 ppm (150
mg/m3) and by Cogan and Grant (1945) at concentrations ranging from 15-100
ppm (45-300 mg/m3). Velasquez (1964) and Velasquez et al. (1969) reported
0169d -48- 04/28/89
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hearing loss In workers exposed to 1-butanol at 80 ppm (240 mg/ma). Seltz
(1972) reported vertigo In workers exposed to (presumably) high but unquan-
Ufled levels of 1-butanol In workroom air.
These data suggest that ocular Irritation may be the critical effect 1n
humans exposed to 1-butanol In air. The lowest level associated with ocular
Involvement was IS ppm (45 mg/m3) In the Cogan and Grant (1945) study with
female workers exposed to 1-butanol and other chemicals. This study Is not
a suitable basis for an RfD for Inhalation exposure, however, because
symptoms were reported after less than 2 months of exposure and because
exposure Involved a mixture of chemicals. Furthermore, the ocular effects
reported were probably the result of local contact with the vapor, and
therefore were dependent upon concentration rather than duration of exposure
or absorbed dose.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) -- Two studies are
available for consideration In the derivation of an RfD for subchronlc oral
exposure to 1-butanol. Wakabayashl et al. (1984) reported adverse effects
on liver mltochondrlal structure and function In male Hlstar rats treated
with 6.9X 1-butanol In the drinking water for up to 13 weeks. Assuming rats
drink 0.049 l of water/day and weigh 0.35 kg {U.S. EPA, 1986b), this
concentration 1s equivalent to a dosage of 9660 mg/kg/day. No other dose
was tested.
A verified RfD for chronic oral exposure of 0.1 mg/kg/day has been
derived by the U.S. EPA (1988a) using data from a 13-week study sponsored by
U.S. EPA (1986a). Gavage doses of 1-butanol In delonlzed water at levels of
0, 30, 125 and 500 mg/kg/day were given to groups of 30 CDR(SO)B rats/sex.
0169d
-49-
09/18/89
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Females showed slightly reduced red blood cell, hematocrU and blood
hemoglobin concentration at 125 and 500 mg/kg/day at the end of 6 weeks, but
this was not found at 13 weeks and was not noted 1n males at any time. The
researchers did not consider this an adverse effect. At 500 mg/kg/day,
ataxla and hypoactlvlty were noted 1n both sexes within minutes of treat-
ment, which was probably due to the bolus nature of gavage administration
during the final 6 weeks of the experiment. The NOAEL Is therefore 125
mg/kg/day for CNS effects In rats, and the LOAEL 1s 500 mg/kg/day.
The NOAEL of 125 mg/kg/day Is the most appropriate basis for deriving an
RfD for subchronlc oral exposure to 1-butanol. Applying an uncertainty
factor of 100, 10 to extrapolate from rats to humans and 10 to provide for
Individual variations In sensitivity among humans, results In an RfD of 1.25
mg/kg/day, which Is rounded to 1 mg/kg/day. The key study was a well
designed and performed comprehensive toxlcologlcal experiment; therefore,
confidence 1n the study Is high. Confidence In the data base Is low,
because adequate developmental and reproductive toxldty studies are
lacking. Confidence In the RfD, therefore. Is low.
8.2.2.2. CHRONIC EXPOSURE — No reports of chronic experiments with
orally administered 1-butanol were located In the available literature.
U.S. EPA (1988a) derived an RfO for chronic oral exposure from the 13-week
gavage experiment 1n rats sponsored by U.S. EPA (1986a). Applying an uncer-
tainty factor of 1000 (10 for Interspecles extrapolation, 10 for Individual
human variation and 10 to expand from subchronlc to chronic exposure) to the
NOAEL of 125 mg/kg/day resulted In an RfD of 0.125 mg/kg/day, which was
rounded to 0.1 mg/kg/day. This value is adopted as the RfD for chronic oral
exposure to 1-butanol for the purposes of this document. U.S. EPA (1988a)
considered confidence In the study to be high, and confidence In the data
base and RfD to be low.
0169d -50- 09/18/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxlclty of 1-butanol was discussed 1n Chapter 6. Animal Inhalation
data for 1-butanol consist of a number of subchronlc studies that are
considered Inadequate for risk assessment because of technical limitations
(Smyth and Smyth, 1928) or because they were available only as abstracts of
the foreign literature (Savel'ev et al., 1975; Rumyantsev et al., 1976;
Balkov and Khachaturyan, 1973). Most human occupational studies Identify
levels associated with local Irritation (Tabershaw et al,, 1944; Cogan and
Grant, 1945; Sterner et al., 1949). These endpolnts are Inappropriate for
consideration 1n deriving an RQ based on chronic toxlclty. Seltz (1972)
associated vertigo with exposure to high but unquantlfled levels of
1-butanol. Velasquez (1964) and Velasquez et al. (1969) associated hearing
loss with occupational exposure to 1-butanol at 80 ppm (243 mg/m3). The
hearing loss reported by Velasquez (1964) and Velasquez et al. (1969) Is
presented in Table 9-1 and considered for calculation of a candidate CS for
1-butanol.
Table 9-1 also presents data from oral exposure studies considered for
derivation of CSs. Pertinent chronic oral exposure data are lacking for
1-butanol. Two subchronlc oral exposure studies provide data suitable for
deriving candidate CSs. U.S. EPA (198ba} reported a study In which rats
were administered gavage doses of 0, 30. l?b or 500 mg/kg/day 1-butanol In
delonlzed water for 13 weeks. Ataxla and hypoactlvlty were noted In both
sexes at 500 mg/kg/day. Transitory decreases in RBC, hematocrU and blood
hemoglobin concentration at 125 and 500 mg/kg/day (noted at 6 weeks, but not
at 13 weeks) were not considered adverse effects. Wakabayashl et al. (1984)
0169d
-51-
04/12/89
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fed male WUtar rats 0 or 6.9 ppm (9660 mg/kg/day) 1-butanol 1n drinking
water for 3 months and noted morphological and functional changes 1n liver
mitochondria.
Composite scores and RQ values for the effects listed In Table 9-1 are
computed In Table 9-2. Reportable quantities of 5000 are derived for
transient hematologk effects In rats treated by gavage at 125 mg/kg/day for
13 weeks (U.S. EPA, 1986a) and for ultrastructural and biochemical changes
In the livers of rats that consumed 9660 mg/kg/day In drinking water
(Wakabayashl et al., 1984). Reportable quantities of 1000 were derived for
CNS signs In rats treated by gavage at 500 mg/kg/day for 13 weeks (U.S. EPA,
1986a) and for hearing loss In humans occupatlonally exposed to 80 ppm (243
mg/m3) (Velasquez, 1964; Velasquez et al., 1969). The RQ of 1000
associated with hearing loss In humans 1s chosen to represent the chronic
toxlcity of 1-butanol. The Velasquez (1964) and Velasquez et al. (1969)
data In humans are selected over the U.S. EPA (1986a) data In rats to avoid
the uncertainties associated with Interspecies extrapolation. The well-
designed and conducted experiment In rats Is considered to support the human
data. The RQ of 1000 based on the Velasquez (1964) and Velasquez et al.
(1969) data 1s presented in Table 9-3.
The RQ for chronic toxldty derived In this document differs from that
of U.S. EPA (1987b), In which an RQ of 5000 was derived based on unspecified
effects In mice, reported In an abstract of a Russian study by Rumyantsev et
al. (1975). This appears to be the same study cited herein as Rumyantsev et
al. (1976). It Is unclear what. If any, other data were considered by U.S.
EPA (1987b) In deriving the RQ. The U.S. EPA (1986a) gavage study using
rats probably was not available at the time the U.S. EPA (1987b) analysis
was made. Because more complete supporting documentation Is provided for
0169d
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0169d
-54-
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-------
TABLE 9-3
1-Butanol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
RVd:
RVe:
Composite Score:
RQ:
Reference:
Inhalation
1155 mg/day
hearing loss
1
7
7
1000
Velasquez, 1964; Velasquez et al., 1969
0169d
-55-
04/28/89
-------
the RQ for chronic toxlclty derived herein, U Is recommended that the RQ of
1000 based on the Velasquez (1964) and Velasquez et al. (1969) data
supersede that of the earlier (U.S. EPA, 1987b) analysis.
9.2. BASED ON CARCINOGENICITY
Data regarding the cardnogenlcUy of 1-butanol to humans or laboratory
animals by any route of exposure were not located. The compound was
assigned to EPA Group D: unable to be classified as to carclnogenldty to
humans. Hazard ranking 1s not possible for chemicals assigned to EPA Group
0; therefore, an RQ based on carclnogenlcHy cannot be derived for 1-butanol.
0169d -56- 04/28/89
-------
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0169d -64- 04/28/89
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0169d
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APPENDIX A
LITERATURE SEARCHED
This HEED U based on data Identified by computerized literature
searches of the following:
CHEHLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSOB
SCISEARCH
Federal Research in Progress
These searches were conducted In Hay, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hygienists).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
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Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John Wiley and
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Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
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Grayson, M. and 0. 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, HA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, 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.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Nenlo
Park, CA.
NTP (National Toxicology Program). 1987. 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., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report 1n the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call in Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Ranway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0169d
-83-
04/12/89
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In addition, approximately 30 compendia of aquatic toxIcHy data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
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, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute ToxIcHy
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
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, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-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.
0169d -84- 04/12/89
-------
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 1-BUTANOl
C.I. DISCUSSION
Dose/duration-response graphs for oral and Inhalation exposure to
1-butanol generated by the method of Crockett et al. (1985) using the
computer software by Durkln and Meylan (1988) are presented In Figures C-l
through C-5. Data used to generate these graphs are presented In Section
C.2. In the generation of these figures, all responses are classified as
adverse (PEL, AEL or LOAEL) or nonadverse {NOEL or NOAEl) for plotting. For
oral exposure, the ordlnate expresses dosage expressed as human equivalent
dose. The animal dosage expressed as mg/kg/day Is multiplied by the cube
root of the ratio of the animal:human body weight to adjust for species
differences In basal metabolic rate (Mantel and Schnelderman, 1975). The.
result Is then multiplied by 70 kg, the reference human body weight, to
express the human equivalent dose as mg/day for a 70 kg human. For Inhala-
tion exposure, the ordlnate expresses concentration In either of two ways.
In Figures C-2 and C-3, the experimental concentration expressed as mg/m3
was multiplied by the time parameters of the exposure protocol (e.g., hours/
day and days/week) and Is presented as expanded experimental concentration
[expanded exp cone (mg/m3)]. In Figures C-4 and C-5, the expanded experi-
mental concentration was multiplied by the cube root of the ratio of the
animal:human body weight to adjust for species differences In basal
metabolic rate (Mantel and Schnelderman, 1975) to estimate an equivalent
human or scaled concentration [scaled cone (mg/m3)].
The boundary for adverse effects (solid line) Is drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an Infinite
0169d -86- 04/12/89
-------
ieceeee
A
9
«
\
R
iu
!
3
9
Z
ll
L5
R
LI 5
L13
L4
iee
-H2
Q.oeai
(Oral Exposure>
e.eei a.ai e.i
HUMAN EQUIU DURATION (fraction lif«$P»n)
ENVELOP METHOD
Key: F . PEL
L - IOAEL
n . NOAEL
N . NOEL
Solid line « Adverse effects boundary
Dashed line « No adverse effects boundary
Dose/Duration -
FIGURE C-l
Response Graph for Oral Exposure to 1-Butanol:
Envelope Method
0169d
-87-
04/12/89
-------
\
X
fr
I
1808
tee --
18--
i •-
e.i •-
8.01
L9
a.eei
J.J1
LI 4
All
'*-., L2
X»i.
L7
A8
8.81 8.1
HUNAN EQUIV MIRATION (fraction lif«sp»n)
1
Key: F . PEL
L « LOAEL
n . NOAEL
N . NOEL
Solid line « Adverse effects boundary
Dashed line - No adverse effects boundary
FIGURE C-2
Oose/Ouratton - Response Graph for Oral Exposure to 1-Butanol,
Expanded Experimental Concentration: Envelope Method
01694
04/12/89
-------
leeee
r
\
r
f
V
V
fc.
c
z
ft
k
iee --
18--
B.i -F-
8.81
L14
All
L2
nl
n3
L7
--M6
8.801
e.ei 8.1
HUMAN EQUIV DURATION (fraction 1 iffspan)
KFTHCr
Key:
F
L
n
N
FEL
LQAEL
NOAEL
NOEL
Solid line - Adverse effects boundary
Dashed Hne - No adverse effects boundary
FIGURE C-3
Dose/Duration - Response Graph for Inhalation Exposure to 1-Butanol,
Expanded Experimental Concentration: Censored Data Method
0169d
-89-
04/12/89
-------
n
f
e-
6
18980
1080 • r-
180 -r
10 -r
i -r
8.1 •-
e.ei
I I I
8.881
4-
N6
o.ei 0.1
HUNAN EQUIU MIRATION (fraction 1 if•span)
FWFIOF
Key: F « FEL
L » LOAEL
n - NOAEL
M « NOEL
Solid line . Adverse effects boundary
Dashed line » No adverse effects boundary
FIGURE C-4
Dose/Duration - Response Graph for Inhalation Exposure to 1-Butanol,
Scaled Concentration: Envelope Method
OU9d
-90-
04/12/89
-------
n
:c
st
if!
it
ii
V
ki
41
V
10080
1890
180 "
e.ei
e.i-r
e.eei
<" ) nha* ^"» on
e.Qi e.i
HUMAN EQUIU DURATION (fraction lifcspan)
CFNSOPFt 1>«TP KFTHOF
Key: F = FEL
L = LOAEL
n = NOAEL
N = NOEL
Solid line « Adverse effects boundary
Dashed line » No adverse effects boundary
FIGURE C-5
Dose/Duration - Response Graph for Inhalation Exposure to 1-Butanol,
Scaled Concentration: Censored Data Method
0169d
-91-
04/12/89
-------
line is extended upward parallel to the dose axis. The starting point Is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process Is continued
to the lowest adverse effect dose or concentration. From this point, a line
is extended to the right parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
Using the envelope method, the boundary for no adverse effects (dashed
line) is drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point, a line parallel to the duration axis Is extended
to the dose or concentration axis. The starting point is then connected to
the next highest or equal no adverse effect dose or concentration at a
longer duration of exposure. When this process can no longer be continued,
a line Is dropped parallel to the dose or concentration axis to the duration
axis. The region of no adverse effects Hes below the no adverse effects
boundary. At either ends of the graph between the adverse effects and no
adverse effects boundaries are regions of ambiguity. The area (If any)
resulting from Intersection of the adverse effects and no adverse effects
boundaries Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located In the
region of contradiction are dropped from consideration, and the no adverse
effect boundary Is redrawn so that It does not Intersect the adverse effects
boundary and no region of contradiction Is generated. This method results
in the most conservative definition of the no adverse effects region.
The dose/duration-response graph for oral exposure to 1-butanol
generated by the envelope method Is presented In Figure C-l. The adverse
effects boundary 1s defined by an LD5Q value In rabbits (Hunch, 1972, Rec.
0169d
-92-
04/12/89
-------
#11) and a LOAEL for CNS effects In mice given a single gavage treatment
(Malckel and Nash, 1985, Rec. #3). The no adverse effect boundary Is
defined by a NOAEL for CNS effects In mice In the study cited above (Rec.
#12) and a NOAEL associated with mild and transient effects on hematology In
rats treated by gavage for 13 weeks (U.S. EPA, 1986a, Rec. #2). The latter
data point served as the basis for the RfD values for subchronlc and chronic
oral exposure to 1-butanol. Because of the absence of a region of contra-
diction, a graph generated by the censored data method would be Identical to
Figure C-l.
Figures C-2 and C-3 present dose/duration-response graphs for Inhalation
exposure to 1-butanol using the envelope method and censored data method,
respectively, with the ordlnate expressed \n terms of expanded experimental
concentration. The adverse effects boundary 1s defined by a LOAEL for CNS
effects in mice following one exposure (De CeaurMz et al., 1983, Rec. #9),
a LOAEL for ocular irritation in occupatlonally exposed women (Cogan and
Grant, 1945, Rec. #15) and a LOAEL for CNS effects in mice exposed continu-
ously for 4 months (Rumyantsev et al., 1976, Rec #10). The boundary for no
adverse effects is defined by a NOEL for developmental toxlclty In rats
(BMghtwell et al., 1987, Rec. #12), a NOAEL in occupatlonally exposed men
(Sterner et al., 1949, Rec. #1) and a NOAEL for systemic effects 1n rats
exposed for 6 months (Savel'ev et al., 1975, Rec. #3). The large region of
contradiction in Figure C-2 probably reflects the unreliability of the data
base, as discussed in Section 8.2.1. When graphed by the censored data
method, the only point defining the no adverse effects boundary is a NOEL
for hematologlcal effects In rats exposed for 92 days (Balkov and
Khachaturyan, 1973, Rec. #6).
0169d -93- 04/12/89
-------
Figures C-4 and C-5 present the Inhalation data using the scaled concen-
tration. The large region of contradiction observed In Figure C-2 also
appears In Figure C-4, which Is generated by the envelope method. The
region of contradiction disappears In Figure C-5, generated by the censored
data method.
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
Oral Exposure
Chemical Name: 1-Butanol
CAS Number; 71-36-3
Document Title: Health and Environmental Effects Document for 1-Butanol
Document Number: SRC-TR-88-189
Document Date: 03/09/89
Document Type: HEED
RECORD #1:
Comment:
Citation:
Species: Rats
Sex: Both
Effect: NOEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
No effects on RBC,
U.S. EPA, 1986a
30
0
HE HAT
BLOOD
6
Dose: 30
Duration Exposure: 13
Duration Observation: 13
30
0
BEHAV
CNS
8
PCV averages; no ataxla or hypoactl
.000
.0 weeks
.0 weeks
vlty.
0169d
-94-
09/18/89
-------
RECORD #2:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
F ema1e
NOAEL
Gavage
Dose: 125.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks
Number Exposed: 30
Number Responses: NR
Type of Effect: HEMAT
Site of Effect: BLOOD
Severity Effect: 6
Reversible effect: RBC and PCV slightly reduced at 6 weeks.
but effect not noted at 13 weeks.
U.S. EPA, 1986a
RECORD #3:
Species:
Sex:
Effect:
Route:
Mice
Male
LOAEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
1000.000
1.0 days
1 .0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: FUNS
SHe of Effect: CNS
Severity Effect: 6
Comment:
Citation:
RECORD #4:
MaUkel and Nash,
Species: Rats
Sex: Both
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect;
1985
60
16
MOTOR
CNS
7
Dose:
Duration Exposure:
Duration Observation:
60
16
MOTOR
PNS
7
500.000
13.0 weeks
13.0 weeks
Comment: Ataxla and hypoactlvHy noted 1n both sexes during final
6 weeks of test.
Citation: U.S. EPA, 1986a
0169d
-95-
04/12/89
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RECORD #5:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Mater
Dose:
Duration Exposure:
Duration Observation:
9660.000
3.0 months
3.0 months
Number Exposed: 30
Number Responses: NR
Type of Effect: SUBCC
SHe of Effect: LIVER
Severity Effect: 1
Megamltochondrlal formation In liver cells; significantly
Increased crlstae membranes per mitochondrion; reduced HAD
and cytochrome oxldase activity.
Uakabayashl et al., 1984
RECORD #6:
Comment:
Citation:
RECORD #7:
Species: Rats
Sex: NR
Effect: FEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
NR
NR
MORTL
HEART
9
1050 value. Rumanian study.
dugudeanu et al. ,
Species: Rats
Sex: NR
Effect: FEL
Route: Food
1985
Dose:
Duration Exposure:
Duration Observation:
Abstract available.
Dose:
Duration Exposure:
Duration Observation:
3830.000
1 .0 days
7.0 days
4360.000
1.0 days
14.0 days
Comment:
Citation;
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 9
Range-finding 1059 value.
Smyth et al., 1951
0169d
-96-
05/04/89
-------
RECORD #8:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Gavage
Dose: 2510.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: 10
Number Responses: 5
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 9
1050 value; death occurred within 4-18 hours,
Jenner et al., 1964
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Hale
PEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
2020.000
1.0 days
7.0 days
Comment:
Citation:
Comment:
Citation:
Number Exposed: 4
Number Responses: 2
Type of Effect: DEGEN
Site of Effect: LIVER
Severity Effect: 9
1050 value; kidney lesions as well as liver lesions.
Earliest deaths were from congestion, with degenerative
changes noted In later deaths.
Purchase, 1969
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
Female
PEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
790.000
1 .0 days
7.0 days
Number Exposed: 4
Number Responses: 2
Type of Effect: OEGEN
Site of Effect: LIVER
Severity Effect: 9
1050 value; degenerative changes In liver and kidney.
Purchase, 1969
0169d
-97-
04/28/89
-------
RECORD #11
Species:
Sex:
Effect:
Route:
Rabbits
Both
PEL
Gavage
Dose: 3484.000
Duration Exposure: 1.0 days
Duration Observation: 1.0 days
Number Exposed: 100
Number Responses: 50
Type of Effect: DEATH
Site of Effect: NR
Severity Effect: 9
Comment:
Citation:
RECORD #12:
Comment:
Citation:
RECORD #13:
LD5Q value.
Munch, 1972
Species: Mice
Sex: Male
Effect: NOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
MaUkel and Nash,
Species: Rats
Sex: NR
Effect: LOAEL
Route: Oral (I
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
NR
NR
FUNS
CNS
6
1985
JOS)
NR
NR
ENZYM
LIVER
1
Dose:
Duration Exposure:
Duration Observation:
0
0
NOS
NR
1
Dose:
Duration Exposure:
Duration Observation:
500.000
1.0 days
1.0 days
810.000
7.0 days
7.0 days
Comment: Significant decrease 1n vitamin content of liver, proportional
to dose administered.
Citation: Shehata and Saad, 1978
0169d
-98-
04/12/89
-------
RECORD #14;
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
NR
AEL
Oral
(NOS)
Dose: 1620.000
Duration Exposure: 7.0 days
Duration Observation: 7.0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: ENZYM
Site of Effect: LIVER
Severity Effect: 1
Significant dose-related decrease In liver content of
vitamins.
Shehata and Saad, 1978
RECORD #15: Species: Rats
Sex: Both
Effect: LOAEL
Route: Oral
Number Exposed:
Number Responses
Type of Effect:
Site of Effect:
Severity Effect:
(NOS)
10
: NR
MOTOR
CNS
6
Dose:
Duration Exposure:
Duration Observation:
10
NR
MOTOR
PNS
6
1208.000
1.0 days
1.0 days
Comment: Decrease 1n ability to maintain balance on a rising slope;
average decrease of 73% that measured prior to dosing.
Citation: Wallgren, 1960
Inhalation Exposure
RECORD #1
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Gavage
Number Exposed: 30
Number Responses: 0
Type of Effect: HEMAT
Site of Effect: 8LOOO
Severity Effect: 6
Dose:
Duration Exposure:
Duration Observation:
30
0
BEHAV
CNS
8
30.000
13.0 weeks
13.0 weeks
No effects on RBC, PCV averages; no ataxla or hypoactlvlty.
U.S. EPA, 1986a
0169d
-99-
04/12/89
-------
RECORD #2:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
F erna 1 e
NOAEL
Gavage
Dose:
Duration Exposure:
Duration Observation:
125.000
13.0 weeks
13.0 weeks
Number Exposed: 30
Number Responses: NR
Type of Effect: HEMAT
Site of Effect: BLOOD
Severity Effect: 6
Reversible effect: RBC and PCV slightly reduced at 6 weeks,
but effect not noted at 13 weeks.
U.S. EPA, 1986a
RECORD #3:
Species:
Sex:
Effect:
Route:
Mice
Male
LOAEL
Gavage
Dose:
Duration
Duration
Exposure:
Observation:
1000.000
1.0 days
1 .0 days
Number Exposed: NR
Number Responses: NR
Type of Effect: FUNS
Site of Effect: CNS
Severity Effect: 6
Comment:
CHatlon:
RECORD #4:
Malckel and Nash,
Species: Rats
Sex: Both
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
1985
60
16
MOTOR
CNS
7
Dose:
Duration Exposure:
Duration Observation:
60
16
MOTOR
PNS
7
500.000
13.0 weeks
13.0 weeks
Comment: Ataxla and hypoacUvlty noted in both sexes during final
6 weeks of test.
CHatlon: U.S. EPA, 1986a
0169d
-100-
04/12/89
------- |