LO6J
United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-G076
September, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR N-HEXANE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document 1s a preliminary draft. It has not been formally released
__ by the U.S. Environmental Protection Agency and should not at this stage be
*-^ construed to represent Agency policy. It 1s being circulated for comments
on Us technical accuracy and policy Implications.
U.S. Eiivixonusmital Protection Agency
Library, Room 2404 P»-211-A
401 M Street, S.W.
Washington, DO 80460
CM
1..V
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Office files are
aquatic life and
The literature
are Included 1n
Health and Environmental Effects Documents (HEEOs) 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 to provide health-related limits and goals for
emergency and remedial actions under the Comprehensive Environmental
Response, Compensation and Liability Act (CERCLA). Both published
literature and Information obtained for Agency Program
evaluated as they pertain to potential human health,
environmental effects of hazardous waste constituents.
searched for In this document and the dates searched
"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 Is
sent to the Program Officer (OSHER).
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 which would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval which
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
carclnogenlclty 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 the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). These two RQs (chronic toxlclty
and carclnogenlclty) represent two of six scores developed (the remaining
four reflect 1gnHab1l1ty, 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 1986a, respectively.
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EXECUTIVE SUMMARY
n-Hexane Is a colorless, volatile and flammable organic liquid with a
weak paraffin odor. n-Hexane Is soluble 1n most polar and nonpolar organic
solvents such as ether, acetone, benzene and chloroform (Sax and Lewis,
1987; Weast et al., 1988). It Is only slightly soluble In water. n-Hexane
Is commercially produced by the fractional distillation of suitable petro-
chemical feedstocks and subsequent purification with molecular sieves.
n-Hexane Is used as a gasoline additive and as a solvent for numerous
products and processes (Dale and Dreham, 1981).
In the atmosphere, hexane probably occurs almost entirely In the vapor
phase (Elsenrelch et al., 1981). Apparently, reaction with photochemically
produced hydroxyl radicals Is the primary degradation pathway (half-life =
2.9 days) (Atkinson, 1985). Small amounts of n-hexane may be removed from
the atmosphere by rain washout; however, It would be expected to rapidly
revolatlllze. Neither the reaction with ozone nor direct photochemical
degradation are expected to be Important removal processes. In yater,
Important fate and transport processes are expected to be volatilization
(half-life, <3 hours from a typical river), aerobic degradation (Jamison et
al., 1976; Patel et al., 1980a,b) and adsorption to sediment and suspended
organic matter. Estimated BCF values suggest that bloconcentratlon In
aquatic organisms Is not significant. Oxidation, photolysis and hydrolysis
are not expected to be Important fate processes In water. In soil. It
appears that n-hexane undergoes aerobic degradation (Patel et al., 1980a,b).
n-Hexane probably volatilizes rapidly to the atmosphere; however, the
potential for n-hexane to strongly adsorb to sediment and suspended matter
may attenuate the volatilization rate.
1v
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n-Hexane Is a highly volatile, natural component of crude oil and
natural gas. It Is released to the environment from anthropogenic sources
Including wastewater and fugitive emissions from n-hexane's manufacture,
formulation, use and transport. Accidental spills of crude and finished
fuel products and emissions from gasoline, motor vehicle exhaust and
Incinerators also release n-hexane to the atmosphere. n-Hexane was also
detected 1n the air above and In leachate from waste landfills.
The available monitoring data suggest that the general population may be
exposed to n-hexane primarily through Inhalation. Minor exposure may occur
through direct contact with refined petroleum products. Representative
n-hexane concentrations In the ambient and occupational atmospheres are
summarized In Tables 3-1 and 3-2.
Two studies of the effects of n-hexane on aquatic organisms were located
In the literature. The 48-hour LC^ In 4- to 6-day-old Daphnla was 3.88
mg/a (Bobra et al., 1983). n-Hexane was much less toxic to blue-green
algae, with 14-day EC5Q values for reduced growth ranging from 17,000-
80,000 mg/l {Stratton, 1987). In a genotoxlclty assay conducted In bean
plants, 7500 mg/i of n-hexane was found to Inhibit mitosis and appeared to
Increase the frequencies of abnormal anaphases and total aberrations (Gomez-
Arroyo et al., 1986).
n-Hexane Is absorbed readily through the lungs. Respiratory uptake
data In humans (Nomlyama and Nomlyama, 1974) Indicate that =28% of the
Inhaled n-hexane was absorbed by the lungs following exposure to 87-122 ppm
for 4 hours. Respiratory retention of n-hexane was =5.6%. Toxlclty
studies Indicate that n-hexane Is absorbed readily from the gastrointestinal
tract. n-Hexane may be absorbed following dermal exposure, but the rate and
extent of absorption 1s unknown.
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Distribution of n-hexane following Inhalation exposure Is rapid and
widespread. The highest concentration of n-hexane In rats following Inhala-
tion exposure was detected In the sciatic nerves (Bus et al., 1981). The
highest concentrations of radioactivity following Inhalation exposure to
14C-n-hexane In rats were detected In the liver and kidneys (Bus et al.,
1982).
Following absorption, n-hexane undergoes extensive metabolism and
elimination. n-Hexane Is hydroxylated by the mixed function oxldase system
with the formation of hexanols (Kramer et al., 1974). The major metabolite
Is 2-hexanol. n-Hexane shares a common metabolic pathway with methyl-n-
butylketone. 2-Hexanol enters the metabolic pathway for methyl-n-butyl-
ketone, resulting In the formation of 2,5-hexanedlone, the neurotoxlc
metabolite of n-hexane and methyl-n-butylketone. Urinary metabolites of
n-hexane In humans Included 2,5-hexaned1one, 2-hexanol, 2,5-dlmethylfuran
and Y-valerolactone (Perbelllnl et al., 1980).
Nomlyama and Nomlyama (1974) determined that =80% of absorbed n-hexane
was excreted unchanged In the expired air of volunteers. Following exposure
to 14C-n-hexane, rats excreted radioactivity In the urine and expired air
In a blphaslc manner. Of the radioactivity excreted In the expired air,
18-40X was present as 14C02. n-Hexane Is excreted In the urine as
metabolites.
The neurotoxlclty of n-hexane has been demonstrated 1n a number of
subchronlc Inhalation animal studies. Results of these studies Indicate
that n-hexane neurotoxlclty Is characterized by the development of periph-
eral neuropathy (Rebert et al., 1982; Pryor et al., 1982; Frontall et al.,
1981; Takeuchl et al., 1980; Cavender et al., 1984; Ono et al., 1982;
Schaumburg and Spencer, 1976). Peripheral nerve damage Is associated with
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giant axonal swellings, axonal degeneration, hlndllmb drag and weakness of
the forellmbs and hlndHmbs 1n rats. Behavioral alterations 1n rats
following Inhalation exposure to n-hexane have been reported (Rebert et al.,
1982; Pryor et al., 1982). It appears that continuous exposure to lower
concentrations produces more severe effects than Intermittent exposure to
higher concentrations, but axonopathy and nerve conduction alterations of
rats have occurred at Intermittent concentrations as low as 200 ppm (Ono et
al., 1982). Clinical signs of neuropathy have been documented In humans
exposed to an average n-hexane concentration of 650 ppm In the work environ-
ment (Herskowltz et al., 1971). Ruff et al. (1981) reported peripheral
neuropathy 1n a patient exposed to an average n-hexane concentration of 325
ppm.
Two oral studies Indicate that the effects of oral exposure to >570
mg/kg/day n-hexane are similar to those associated with Inhalation exposure
(Krasavage et al., 1980; Ono et al., 1981). Testlcular atrophy was observed
In rats treated by gavage at 4000 mg/kg/day for 120 days (Krasavage et al.,
1980).
Data were not located regarding the carclnogenldty of n-hexane to
animals or humans exposed by any route. However, NTP (1989) has completed
an Inhalation study using mice. The development of a technical report 1s In
progress. No data were located regarding the mutagenkHy of n-hexane.
Harks et al. (1980) found no teratogenlc effects of orally administered
n-hexane (260-2200 mg/kg/day) In rats. A temporary decrease In postnatal
growth occurred In pups born to rat dams exposed by Inhalation to 1000 ppm
on days 8-16 of gestation (Bus et al., 1979).
A subchronlc Inhalation RfD of 0.4 mg/m3 and a chronic Inhalation RfD
of 4x!0~2 mg/ma were derived from the LOAEL of 200 ppm that resulted In
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neurotoxldty In the subchronlc study by Ono et al. (1982). A subchronlc
oral RfD of 0.6 mg/kg/day and a chronic oral RfD of 6xlO~2 mg/kg/day were
derived from the LOAEl of 570 mg/kg/day that resulted In decreased body
weight gain In the subchronlc study by Krasavage et al. (1980). Since no
data regarding the cardnogenldty were available, n-hexane was placed In
Group D, not classifiable as to Us cardnogenlclty to humans. An RQ of
1000 for chronic exposure was derived from the subchronlc Inhalation study
by Ono et al. (1982) that resulted In axonopathy 1n rats.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT 5
2.1. AIR 5
2.1.1. Reaction with Hydroxyl Radicals 5
2.1.2. Reaction with Ozone 5
2.1.3. Photolysis 5
2.1.4. Physical Removal Processes 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. Photolysis 6
2.2.4. Mkroblal Degradation 6
2.2.5. Bloconcentratlon 6
2.2.6. Adsorption 6
2.2.7. Volatilization 7
2.3. SOIL 7
2.3.1. Mlcroblal Degradation 7
2.3.2. Adsorption 7
2.3.3, Volatilization 7
2.4. SUMMARY 7
3. EXPOSURE 9
3.1. WATER 9
3.2. FOOD 10
3.3. INHALATION 10
3.4. DERMAL 13
3.5. OTHER 13
3.6. SUMMARY 13
1x
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TABLE OF CONTENTS (cent.)
Page
4. ENVIRONMENTAL TOXICOLOGY 14
4.1. AQUATIC TOXICOLOGY 14
4,1.1. Acute Toxic Effects on Fauna 14
4.1.2. Chronic Effects on Fauna 14
4.1.3. Effects on Flora 14
4.1.4. Effects of Bacteria 15
4.2. TERRESTRIAL TOXICOLOGY 15
4.2.1. Effects on Fauna 15
4.2.2. Effects on Flora 15
4.3. FIELD STUDIES 15
4.4 AQUATIC RISK ASSESSMENT 15
4.5. SUMMARY 16
5. PHARMACOKINETICS 17
5.1. ABSORPTION 17
5.2. DISTRIBUTION 18
5.3. METABOLISM 19
5.4. EXCRETION 21
5.5. SUMMARY 22
6. EFFECTS 24
6.1. SYSTEMIC TOXICITY 24
6.1.1 Inhalation Exposures 24
6.1.2. Oral Exposures 28
6.1.3. Other Relevant Information 29
6.2. CARCINOGENICITY 29
6.2.1. Inhalation 29
6.2.2 Oral 29
6.2.3. Other Relevant Information 29
6.3. HUTAGENICITY 31
6.4. TERATOGENICITY 31
6.5. OTHER REPRODUCTIVE EFFECTS 31
6.6. SUMMARY 31
7. EXISTING GUIDELINES AND STANDARDS 33
7.1. HUMAN 33
7.2. AQUATIC 33
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TABLE OF CONTENTS (cont.)
Page
8. RISK ASSESSMENT 34
8.1. CARCINOGENICITY 34
8.1.1. Inhalation 34
8.1.2. Oral 34
8.1.3. Other Routes 34
8.1.4. Weight of Evidence 34
8.1.5. Quantitative Risk Evidence 34
8.2. SYSTEMIC TOXICITY 34
8.2.1. Inhalation Exposure 34
8.2.2. Oral Exposure 36
9. REPORTA8LE QUANTITIES 39
9.1. BASED ON SYSTEMIC TOXICITY 39
9.2. BASED ON CARCINOGENICITY 39
10. REFERENCES 44
APPENDIX A A-l
APPENDIX B B-l
APPENDIX C C-l
x1
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LIST OF TABLES
No. Title Page
1-1 Current Domestic Manufacturers of n-Hexane 3
3-1 Representative Concentrations of n-Hexane In A1r 11
3-2 n-Hexane Concentrations In Ambient Air of Representative
Occupations 12
6-1 Acute Lethal Toxldty of n-Hexane 30
9-1 Toxlclty Summary for n-Hexane 40
9-2 Inhalation Composite Scores for n-Hexane 42
9-3 n-Hexane: Minimum Effective Dose (MED) and Reportable
Quant 1 ty {RQ) 43
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LIST OF ABBREVIATIONS
o
AEL
BCF
BAER
CAS
CS
F344
FEL
Koc
Kow
LD50
LOAEL
NOAEL
ppb
ppbv
ppm
ppmv
RfD
RQ
RVd
RV
e
STEL
THOD
TLV
TWA
UV
Adverse effect level
Bloconcentratlon factor
Bralnstem auditory-evoked response
Chemical Abstract Service
Composite score
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Fischer 344
Frank effect level
Soil sorptlon coefficient
Octanol/water partition coefficient
Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
Dose lethal to 5054 of recipients
Lowest-observed-adverse-effect level
No-Observed-adverse-effect level
Parts per billion
Parts per billion volume
Parts per million
Parts per million volume
Reference dose
Reportable quantity
Dose-rating value
Effect-rating value
Short-term exposed level
Theoretical oxygen demand
Threshold limit value
Time weighted average
Ultraviolet
X111
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
n-Hexane is also known as n-hexane, hexyl hydride and Skellysolve 8
(Chemline, 1989; SANSS, 1989). The structure, CAS number, molecular weight
and empirical formula for n-hexane are as follows:
a\ /
CH2
CH
CAS Registry number: 100-54-3
Empirical formula: C0H,«
Molecular weight: 86.18
1.2. PHYSICAL AND CHEMICAL PROPERTIES
n-Hexane is a colorless, flammable liquid with a slightly paraffinic
odor. It is soluble in most organic solvents such as ether, acetone,
benzene and chloroform (Sax and Lewis, 1987; Weast et al., 1988). Selected
physical properties are as follows:
Melting point:
Boi1 ing point:
Density:
Vapor pressure
at 25eC:
Hater solubility
at 25'C:
Log Kow:
Flash point:
-95°C
696C
0.6603 g/ntf
151.5 mm Hg
9.5 mg/^
4.11
-22.7'C
Weast et al., 1988
Neast et al., 1988
Weast et al., 1988
MacKay and Shiu, 1981
MacKay and Shiu, 1981
Hansch and Leo, 1985
Sax and Lewis, 1987
5942H
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06/16/89
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Air odor threshold: 130 ppm Amoore and Hautala, 1983
Nater odor threshold: 0.0064 ppm Amoore and Hautala, 1983
Conversion factor: 1 ppm = 3.52 mg/m3
1.3. PRODUCTION DATA
n-Hexane is produced commercially by the fractional distillation of
suitable hydrocarbon feedstocks, such as crude oil or the liquids stripped
from natural gas. Pure n-hexane is commonly removed from branched hexanes
and other contaminants by molecular sieves or other methodology (Dale and
Dreham, 1981; Sax and Lewis, 1987). Current domestic manufacturers are
given in Table 1-1.
Domestic production volume for recent years is as follows (USITC, 1985,
1986, 1987, 1988):
Year Production Sales
(in thousands of pounds)
1987 852,035 383,310
1986 379,247 209,399
1985 482,457 306,577
1984 469,511 306,924
1.4. USE DATA
Most commercially produced n-hexane is used as a gasoline additive or a
solvent for vegetable oils, paints, inks, etc., and for polymerization and
other chemical reactions. n-Hexane is also used as a denaturant for alcohol
and 1n low-temperature thermometers (Dale and Dreham, 1981; Sax and Lewis,
1987).
5942H -2- 06/16/89
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o
TABLE 1-1
Current Domestic Manufacturers of n-Hexane*
Manufacturer
Ashland Oil Co.
Exxon Corp.
The Humphrey Chemical Corp
Hill Petroleum Co.
Independent Refining Corp.
Pennzoi1 Co.
Phillips Petroleum Co.
Salomon, Inc.
Shell Oil Co.
Texaco, Inc.
Unocal Corp.
Vista Chemical Co.
Location
Ashland, KY
Baytown, TX
North Haven, CT
Houston, TX
Winnie, TX
Shreveport, LA
Borger and Sweeney, TX
Houston, TX
Houston, TX
El Dorado, KA
Beaumont, TX; Lemont, IL
Houston, TX
Source: SRI, 1988; USITC, 1988
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1.5. SUHMARY
n-Hexane 1s a colorless, volatile and flammable organic liquid with a
weak paraffin odor. n-Hexane 1s soluble 1n most polar and nonpolar organic
solvents such as ether, acetone, benzene and chloroform (Sax and Lewis,
1987; Weast et a!., 1988). It Is only slightly soluble In water. n-Hexane
Is commercially produced by the fractional distillation of suitable petro-
chemical feedstocks and subsequent purification with molecular sieves.
n-Hexane Is used as a gasoline additive and a solvent for numerous products
and processes (Dale and Dreham, 1981).
5942H -4- 07/26/89
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on a vapor pressure of 151.5 mm Hg at 25°C (Mackay and Shiu,
1981), n-hexane likely exists almost entirely In the vapor phase In the
ambient atmosphere (Eisenreich et al., 1981)
2.1.1. Reaction with Hydroxyl Radicals. The estimated half-life for the
gas-phase reaction of n-hexane with photochemically produced hydroxyl
radicals in the atmosphere is 2.9 days at 25eC. This value is based on an
experimental rate constant of 5.55x10"'2 cm3/molecule-sec and an average
atmospheric hydroxyl radical concentration of 5.0x10* mol/cm3 (Atkinson,
1985).
2.1.2. Reaction with Ozone. n-Hexane is probably not susceptible to
atmospheric degradation by ozone (Atkinson, 1985; U.S. EPA, 1987).
2.1.3. Photolysis. n-Hexane does not absorb UV light in the environ-
mentally significant range (>290 nm) (Silverstein and Bassler, 1963). Thus,
it probably does not undergo photolytic degradation In the troposphere.
2.1.4. Physical Removal Processes. The limited water solubility of
n-hexane, 9.5 mg/^ (MacKay and Shiu, 1981), suggests that rain washout may
occur. However, it is not expected to be a significant fate process, since
rapid revolatilization to the atmosphere would occur.
2.2. NATER
2.2.1. Hydrolysis. n-Hexane is not expected to hydrolyze under environ-
mental conditions, since it contains no hydrolyzable functional groups
(Lyman et al., 1982)
2.2.2. Oxidation. Pertinent data regarding the oxidation of n-hexane in
water were not located 1n the available literature dted 1n Appendix A.
5942H
-5-
06/16/89
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2.2.3. Photolysis. n-Hexane does not absorb UV light In the environ-
mentally significant range (>290 nm) (Silversteln and Bassler, 1963). Thus,
it probably does not undergo photolytic degradation in water.
2.2.4. Microbial Degradation. Using microbiota from groundwater contami-
nated by a gasoline spill, n-hexane (as a component of high-octane gasoline)
underwent 46% aerobic biodegradation after 192 hours (Jamison et al.,
1976). Bacteria obtained from water and raised using methane as the sole
carbon source rapidly oxidized n-hexane to 2-hexanol and 2-hexanone under
aerobic conditions
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2.2.7. Volatilization. Based on n-hexane's water solubility, 9.5
at 25°C (Mackay and Shiu, 1981), and vapor pressure, 151 mm Hg at 25°C
(Mackay and Shiu, 1981), a Henry's Law constant of 1.81 atm-nr/molecule at
25°C can be calculated (Lyman et al., 1982). Using the group method of Mine
and Mookerjee (1975), a value of 1.69 atm mVmolecule at 25aC is
obtained. The magnitude of these estimates suggests extremely rapid
volatilization of n-hexane from water to the atmosphere. Using the Henry's
Law constants above, the volatilization half-life from a model river 1 m
deep, flowing 1 m/sec, with a wind velocity of 3 m/sec is 2.4-2.7 hours.
2.3. SOIL
2.3.1. Microbial Degradation. Bacteria obtained from soil and enriched
using methane as the sole carbon source rapidly oxidized n-hexane.
2-Hexanol was formed from n-hexane at microorganism-specific rates ranging
from 0.05-0.1 pmo1/hour/5.0 mg enzyme. n-Hexane was converted to 2-hexa-
none at rates between 0.02 and 0.03 nmol/hour (Patel et al., 1980a,b).
2.3.2. Adsorption. Using the method of Lyman et al. (1982), a Koc for
n-hexane is calculated to be 1250-4100 (see Section 2.2.6). These values
suggest that n-hexane displays slight to low mobility In soil (Swann et al..
1983).
2.3.3. Volatilization. The vapor pressure of n-hexane, 151 mm Hg at 25*C
(Mackay and Shiu, 1981), suggests that volatilization from soil to the
atmosphere is an important fate process.
2.4. SUMMARY
In the atmosphere, n-hexane probably occurs almost entirely In the vapor
phase (Eisenreich et al., 1981). Apparently, reaction with photochemically
5942H -7- 06/16/89
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produced hydroxyl radicals is the primary degradation pathway (half-life *
2.9 days) (Atkinson, T985). Small amounts of n-hexane may be removed from
the atmosphere by rain washout; however, it would be expected to rapidly
revolatilize. Neither the reaction with ozone nor direct photochemical
degradation are expected to be important removal processes. In water,
important fate and transport processes are expected to be volatilization
(half-life, <3 hours from a typical river), aerobic degradation (Jamison et
al., 1976; Patel et al., 1980a,b) and adsorption to sediment and suspended
organic matter. Estimated BCF values suggest that bloconcentratlon in
aquatic organisms is not significant. Oxidation, photolysis and hydrolysis
are not expected to be important fate processes In water. In soil, it
appears that n-hexane undergoes aerobic degradation (Patel et al.,
1980a,b). n-Hexane probably volatilizes rapidly to the atmosphere; however,
the potential for n-hexane to strongly adsorb to sediment and suspended
matter may attenuate the volatilization rate.
5942H -8- 06/16/89
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3. EXPOSURE
n-Hexane is a highly volatile, natural component of crude oil and
natural gas. It may be released to the environment from anthropogenic
sources Including wastewater and fugitive emissions from n-hexane's manufac-
ture, formulation, use and transport. Accidental spills of crude and
finished fuel products and emissions from gasoline, motor vehicle exhaust
and Incinerators also release n-hexane to the atmosphere.
The National Occupational Exposure Survey estimated that 354,754 workers
are occupationally exposed to n-hexane (NIOSH, 1989). Based on available
monitoring data, the general population ts exposed to n-hexane primarily by
inhalation. Minor exposure may result from direct contact with refined
petroleum products.
3.1. NATER
n-Hexane was found in eight samples from Lake Pontchartrain, LA, at a
mean concentration of 2.4 ^g/^ (McFall et al., 1985). At an offshore
oil production platform in the Gulf of Mexico, the n-hexane concentration
near an underwater gas vent was 7520 ng/^ (Sauer, 1981). n-Hexane was
identified as a component of process water <79 jig/^) from these oil
production platforms. It was detected In wastewater from the processing of
shale oil (Hawthorne and Sievers, 1984). n-Hexane was found in the leachate
of a municipal solid waste landfill in Minnesota at a concentration of 900
yg/^ (Sabel and Clark, 1984). n-Hexane was found in European drinking
water supplies (Kool et al., 1982). n-Hexane entered seawatcr during an
experimental test mimicking an oil spill on the ocean (McDonald et al.,
1984).
5942H -9- 06/16/89
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3.2. FOOD
n-Hexane is a volatile component of roasted filberts (Kinlin et al.,
1972).
3.3. INHALATION
Representative n-hexane concentrations in the ambient atmosphere are
given In Table 3-1. Based on these monitoring data, typical rural
concentrations in the ambient atmosphere range from =0-25 ppb. Similarly,
ambient urban concentrations are ^0-300 ppb. The average ambient
concentration of n-hexane for measured sites in the United States (urban,
rural, suburban and remote) was 3.684 ppmv (Shah and Heyerdahl, 1988).
Based on this average concentration and an average dally air intake by
humans of 20 m3/day, the average daily intake of n-hexane can be estimated
at 259 mg. Using the median n-hexane concentration for rural (0.046 ppbv),
urban (1.690 ppbv), and suburban (1.858 ppbv) areas (Shah and Heyerdahl,
1988), the average daily intakes for each area are calculated to be 3.24,
119 and 131 mg, respectively.
n-Hexane was qualitatively identified in air samples above hazardous
waste sites (LaRegina et al., 1986) and municipal landfills (Young and
Parker, 1984). In a study of emissions from a landfill simulator, n-hexane
was found in 891 of the samples tested (Vogt and Walsh, 1985). Sources for
n-hexane emissions over Tokyo, Japan, were as follows: vehicle exhaust,
26%; gasoline vapor, 19%; petroleum refining, 29.6%; and petrochemical
plants, 15.4% (Madden et al., 1986). n-Hexane was identified 1n emissions
from incinerator stacks and coal combustion (Junk and Ford, 1981).
Representative concentrations of n-hexane 1n ambient air associated with
occupational uses of this compound can be found in Table 3-2.
o
5942H -10- 06/16/89
-------
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TABLE 3-2
n-Hexane Concentrations in Ambient Air
of Representative Occupations
Occupation
Concentration
Reference
Spray painting/spray gluing
Gasoline tank removal
breathing zone
upwind
downwind
in excavation
above excavation
Petroleum industry
outside operators
transport drivers
service attendants
Hood floor finishing
site
0.1-1.3 ppm
0-86.1 ppm
0-0.61 ppm
0-1.96 ppm
0-339 ppm
0-11.1 ppm
0.473 mg/m3
1.019 mg/m3
1.175 mg/m3
NS
Whitehead et al., 1984
Shamsky and Samimi, 1987
Shamsky and Samimi, 1987
Shamsky and Samimi, 1987
Shamsky and Samimi, 1987
Shamsky and Samimi, 1987
Rappaport et al., 1987
Rappaport et al., 1987
Rappaport et al., 1987
Vannetten et al., 1988
NS = Not stated
5956H
-12-
06/02/89
-------
3.4. DERMAL
Pertinent data regarding dermal exposure to n-hexane were not located In
the available literature cited In Appendix A.
3.5. OTHER
n-Hexane was detected In eight of 12 samples of mothers' milk from the
cities of Bayonne, NJ, Jersey City, NJ, Brldgevllle, PA, and Baton Rouge, LA
(Pelllzzarl et al., 1982). It was also found 1n the urine of workers at
chemical, plastic boat, plastic button, paint and shoe factories (GhlttoM
et al., 1987).
3.6. SUMMARY
n-Hexane Is a highly volatile, natural component of crude oil and
natural gas. It 1s released to the environment from anthropogenic sources
Including wastewater and fugitive emissions from n-hexane's manufacture,
formulation, use and transport. Accidental spills of crude and finished
fuel products and emissions from gasoline, motor vehicle exhaust and Incin-
erators also release n-hexane to the atmosphere. n-Hexane was also detected
In the air above and 1n leachate from waste landfills.
The available monitoring data suggest that the general population may be
exposed to n-hexane primarily through Inhalation. Minor exposure may occur
through direct contact with refined petroleum products. Representative
n-hexane concentrations In the ambient and occupational atmospheres are
summarized 1n Tables 3-1 and 3-2.
5942H -13- 07/26/89
-------
4. ENVIRONMENTAL TOXICOLOGY
4.J. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. A single test of the acute toxicity
of n-hexane to aquatic fauna was located In the literature. Groups of 10
water fleas, Daphnia magna. aged 4-6 days, were exposed to five nominal
concentrations of n-hexane (2-4 replicates/concentration) under static
conditions at 21-25°C (Bobra et al., 1983). Untreated controls were
included. The 48-hour LC50 was 45 mmol/m3 (3.88 mq/f).
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY -- Pertinent data regarding the effects of chronic
exposure of aquatic fauna to n-hexane were not located In the available
literature cited in Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION -- Pertinent data regarding
the bioaccumulation/bioconcentration potential of n-hexane in aquatic fauna
were not located in the available literature cited in Appendix A.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY The toxicity of n-hexane to blue-green algae was
investigated by Stratton (1987). Cultures of Anabaena sp., A. variabills.
A. cylindrica. A. inaequalis and Nostoc sp. were each exposed to 10 nominal
concentrations of n-hexane ranging from 1.0-14% (10,000-140,000 mg/^> for
10-14 days under static conditions at 25°C. Five to 10 replicates were used
for each exposure concentration, and the entire experiment was repeated 3-5
times. Untreated controls were included in this study. Optical density was
recorded to monitor the growth of algal cultures. The EC*o values for
reduced growth ranged from 1.71 (17,000 mg/^) In A. Inaequalis to 8.0%
(80,000 mg/^) in Nostoc sp.
5942H -14- 06/16/89
-------
4.1.3.2. 8IOCONCENTRATION -- Pertinent data regarding the bloconcen-
traUon potential of n-hexane In aquatic flora were not located In the
available literature cited In Appendix A.
4.1.4. Effects on Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to n-hexane were not located In the available
literature cited In Appendix A.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Pertinent data regarding the effects of exposure
of terrestrial fauna to n-hexane were not located In the available litera-
ture cited 1n Appendix A.
4.2.2. Effects on Flora. The clastogenlc effects of n-hexane were studied
using the broad bean, Vlcla faba. root tip assay (Gomez-Arroyo et al.,
1986). Root tips were exposed to n-hexane concentrations of 0.1-1.OX (1000-
10,000 mg/i) for 1-4 hours. Untreated controls were also Included. The
Incidences of abnormal anaphases and total aberrations appeared to be
elevated compared with controls at 7500 mg/i, although statistical
analysis was not performed. In addition, n-hexane at this concentration
Inhibited cell division.
4.3. FIELD STUDIES
Pertinent data regarding the effects of n-hexane on flora and fauna In
the field were not located In the available literature cited 1n Appendix A.
4.4. AQUATIC RISK ASSESSHENT
The lack of an adequate quantity of pertinent data regarding the effects
of exposure of aquatic fauna and flora to n-hexane prevented the development
of a freshwater criterion (U.S. EPA/OHRS, 1986). Although studies of acute
toxldty have been conducted In daphnlds and blue-green algae, neither study
5942H -15- 07/26/89
-------
o
met the necessary conditions for inclusion in this calculation. Data
required to derive a freshwater criterion include acute studies with
representatives from eight families of freshwater fauna, chronic studies in
three families of fish and invertebrates, a study in a freshwater plant and
a bioconcentration study.
No data were located regarding the effects of exposure of marine fauna
and flora to n-hexane. Acute studies with representatives from eight
families of marine fauna and at least three chronic studies and one biocon-
centration study with marine fauna and flora are needed to develop a
saltwater criterion.
4.5. SUMMARY
Two studies of the effects of n-hexane on aquatic organisms were located
in the literature. The 48-hour LCio in 4- to 6-day-old Daphnia was 3.88
mg/^ (Bobra et al., 1983). n-Hexane was much less toxic to blue-green
algae, with 14-day ECso values for reduced growth ranging from 17,000-
80,000 mg/^ (Stratton, 1987). In a genotoxicity assay conducted in bean
plants, 7500 mq/4 of n-hexane was found to inhibit mitosis and appeared to
increase the frequencies of abnormal anaphases and total aberrations
(Gomez-Arroyo et al., 1986).
5942H -16- 06/16/89
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Nomiyama and Nomiyama (1974) studied the respiratory absorption of
n-hexane 1n 10 human subjects exposed for 4 hours at concentrations of
87-122 ppm. A respiratory uptake into the bloodstream of =28X of the
Inhaled n-hexane was determined from the measurement of n-hexane in expired
air. Respiratory retention of n-hexane was *5.6X, and reached constant
levels after 2 hours of exposure.
Baker and Rlckert (1981) studied the absorption of n-hexane (500, 1000,
3000 and 10,000 ppm) in Fischer rats exposed head only by inhalation.
n-Hexane was absorbed rapidly with apparent steady-state levels reached in
blood and tissues within 2 hours. The apparent steady-state n-hexane
concentrations in blood, measured after a 6-hour exposure to n-hexane, were
1.3, 2.2. 8.4 and 21 ng/m^ at 500, 1000, 3000 and 10,000 ppm, respectively.
The gastrointestinal absorption of n-hexane has not been studied.
However, the neurotoxicity study by Krasavage et al. (1980) indicated that
n-hexane is absorbed readily from the gastrointestinal tract of rats.
Krasavage et al. (1980) administered n-hexane (6.6, 13.2 and 46.2 mmol/kg)
to rats by gavage and found that plasma levels of 2,5-hexanedione (the
neurotoxic metabolite of n-hexane) correlated with n-hexane exposure.
The percutaneous absorption of n-hexane has not been investigated,
although severe intoxication has been reported In humans exposed to n-hexane
by this route of exposure (Nomiyama and Nomiyama, 1974). It has been
suggested that cutaneous absorption of n-hexane 1s more hazardous than
inhalation of n-hexane (Nomiyama and Nomiyama, 1974).
5942H -17- 06/16/89
-------
5.2. DISTRIBUTION
Bus et al. (1981) examined the tissue distribution of n-hexane In male
F344 rats exposed by Inhalation to a concentration of 1000 ppm for 6 hours/
day for 1 or 5 days. The highest concentration of n-hexane was found In the
sciatic nerve (46 ^g/g wet weight after 1 day). The concentrations of
n-hexane found In liver, kidney and brain after a 6-hour exposure for 1 day
were 1.23, 5.80 and 3.00 yg/g wet weight, respectively. The concentration
In the blood was 0.50 tig/ml. The concentrations In these tissues were
lower after 5 days of exposure than after 1 day.
The tissue distribution of n-hexane In female albino rats exposed for
2-10 hours to =50,000 ppm vapor has been examined (Bohlen et al., 1973).
Tissue saturation of n-hexane In blood, brain, adrenals, kidneys and spleen
was attained within 4-5 hours. Tissue saturation of n-hexane In the liver
was not reached even after 10 hours of exposure. The lack of saturation of
n-hexane In the liver was attributed to n-hexane-lnduced I1p1d accumulation
within this organ.
The disposition of radioactivity In male F344 rats after single Inhala-
tion exposures for 6 hours to 500, 1000, 3000 or 10,000 ppm (l,2-14C)-n-
hexane was studied by Bus et al. (1982). Seventy-two hours after exposure,
radioactivity was distributed widely, with highest levels In the liver,
kidneys and sciatic nerve.
Bus et al. (1979) Investigated the distribution of n-hexane after
pregnant rats were exposed by Inhalation to 1000 ppm for 6 hours/day during
gestation. The highest concentration of n-hexane was found In the kidney
(6.33 yg/mi), followed by the liver (0.85 vg/mi), blood (0.45
and brain (0.04 iig/mi). The sciatic nerve was not analyzed.
5942H -18- 07/26/89
-------
Levels of n-hexane In the fetuses were comparable with those found In
maternal blood. The plasma half-life for n-hexane was =60 minutes.
5.3. METABOLISH
The metabolism of n-hexane In guinea pigs following a single 1ntraper1-
toneal Injection of 250 mg/kg n-hexane was Investigated by DIVIncenzo et al.
(1976). The two major serum metabolites of n-hexane were 2,5-hexaned1one
and 5-hydroxy-2-hexanone. In humans, 2,5-hexanedlone was the main urinary
metabolite Identified {Perbelllnl et al., 1980); other metabolites Included
2-hexanol, 2,5-d1methylfuran and y-valerolactone. Kramer et al. (1974)
demonstrated that n-hexane was hydroxylated by the mixed function oxldase
system of mice to produce hexanols. The major metabolite was 2-hexanol.
The metabolism of n-hexane In F344 rats following a single 6-hour
inhalation exposure was studied by Baker and Rlckert (1981). The highest
concentrations of 2,5-hexanedlone, the neurotoxlc metabolite of n-hexane,
following exposure to 1000 ppm n-hexane were found In the blood (6.1
, kidneys (55 yg/g), sciatic nerve (25 jig/g) and brain (19
Other metabolites Identified Included methyl-n-butylketone,
2,5-dlmethylfuran, 2-hexanol and 1-hexanol.
DIVIncenzo et al. (1976) and Perbelllnl et al. (1981) suggested a common
metabolic scheme for n-hexane and methyl-n-butylketone. Figure 5-1 depicts
a proposed metabolic scheme for n-hexane based on metabolic studies of these
chemicals. n-Hexane Is hydroxylated primarily to 2-hexanol, which 1n turn
enters the metabolic pathway for methyl-n-butylketone, resulting In the
formation of 2,5-hexanedlone, the neurotoxlc metabolite of n-hexane and
methyl-n-butylketone.
5942H -19- 07/26/89
-------
n-HEXRNE
E-HEXRNOL*
2,5-HEXRNEDIOL S-HEXflNONE
(ethyl-n-butyl let tone)
5-HYDROXY-2-HEXPNONE
a-oxidalion
dec*rboxy 1 at Ion
oxidation
lactonization
y-VRLEROLRCTONE*
oxldktion
tyclization
2,5-DinETHYLFURflN*
2,5-HEXRNEDIONE*
*Found In workers' urine
5942 H
FIGURE 5-1
Metabolism of n-Hexane
Source: Perbellini et al., 1981
-20-
06/16/89
-------
5.4. EXCRETION
Nomlyama and Nomlyama (1974) studied the excretion of n-hexane In
volunteers exposed for 4 hours to 87-122 ppm n-hexane vapor. Approximately
80% of absorbed n-hexane was excreted unchanged In the expired air.
The disposition of (1,2-14C)-n-hexane in F344 rats after a 6-hour
exposure to 500, 1000, 3000 or 10,000 ppm was Investigated by Bus et al.
(1982). The elimination of radioactivity was followed for 72 hours after
exposure. The disposition of radioactivity was dose-dependent, with 12, 24,
38 and 6254 of the acquired body burden excreted as n-hexane by the lung with
Increasing exposure concentration. Of the body burden of radioactivity, 38,
31, 27 and 18% was recovered as expired 14C02 and 35, 40, 31 and 18% was
recovered In the urine with Increasing n-hexane concentration. The
elimination curve for exhaled n-hexane was blphaslc. The Initial rapid
phase, which was observed In the first 4-6 hours after exposure, accounted
for >90% of the total recovered 14C-n-hexane. Excretion of 14C-n-hexane
was essentially complete by 48 hours after exposure. The estimated
half-lives for the alpha (0.8-1.4 hours) and beta (4.4-10.9 hours) excretion
phases were similar at all exposure concentrations. Urinary excretion of
radioactivity was also blphaslc, with >90J4 of the total recovered urinary
radioactivity collected In the first 24 hours after exposure. Estimated
half-lives of the alpha-phase were similar for the 1000, 3000 and 10,000 ppm
groups (6.9-7.6 hours), but the half-life for the 500 ppm group was 12.7
hours. The difference may have been due to altered tissue distribution at
the low exposure level. Half-lives for the beta phase were not calculated.
Excretion of 14CQ? was 85-96% complete 1n the first 24 hours after
exposure. 2,5-Hexanedlone was the main urinary metabolite Identified In
humans (Perbelllnl et al., 1980). Other metabolites Included 2-hexanol,
2,5-dlmethylfuran and y-valerolactone.
5942H -21- 07/26/89
-------
5.5. SUMMARY
n-Hexane Is absorbed readily through the lungs. Respiratory uptake
data In humans (Nomlyama and Nomlyama, 1974) Indicate that =28% of the
Inhaled n-hexane was absorbed by the lungs following exposure to 87-122 ppm
for 4 hours. Respiratory retention of n-hexane was =5.6%. Toxlclty
studies Indicate that n-hexane Is absorbed readily from the gastrointestinal
tract. n-Hexane may be absorbed following dermal exposure, but the rate and
extent of absorption 1s unknown.
Distribution of n-hexane following Inhalation exposure Is rapid and
widespread. The highest concentration of n-hexane In rats following
inhalation exposure was detected In the sciatic nerves (Bus et a!., 1981).
The highest concentrations of radioactivity following Inhalation exposure to
1*C-n-hexane In rats were detected In the liver and kidneys (Bus et al.,
1982).
Following absorption, n-hexane undergoes extensive metabolism and
elimination. n-Hexane 1s hydroxylated by the mixed function oxldase system
with the formation of hoxanols (Kramer et al., 1974). The major metabolite
Is 2-hexanol. n-Hexane shares a common metabolic pathway with methyl-n-
butylketone. 2-Hexanol enters the metabolic pathway for methyl-n-butyl-
ketone, resulting In the formation of 2,5-hexaned1one, the neurotoxlc
metabolite of n-hexane and methyl-n-butylketone. Urinary metabolites of
n-hexane In humans Included 2,5-hexanedlone, 2-hexanol, 2,5-d1methylfuran
and y-valerolactone (Perbelllnl et al., 1980).
Nomlyama and Nomlyama (1974) determined that =80% of absorbed n-hexane
was excreted unchanged In the expired air of volunteers. Following exposure
to 14C-n-hexane, rats excreted radioactivity 1n the urine and expired air
o
5942H -22- 07/26/89
-------
In a blphaslc manner. Of the radioactivity excreted In the expired air,
18-40% was present as J4C02. n-Hexane Is excreted In the urine as
metabolites.
5942H -23- 07/26/89
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC Rebert et al. (1982) examined the electro-
physiological correlates of n-hexane neurotoxlclty In groups of 6-15 male
Frats exposed by Inhalation to either 1000 ppm n-hexane, 24 hours/day, 5
days/week for 11 weeks or 10-mlnute exposures to 24,000 or 48,000 ppm
n-hexane 6 or 12 times/day, 5 days/week for 22 weeks. The fifth component
of the BAER, a reflection of activity In the region of the lateral lemnlscus
or Inferior colUculus, Increased In latency and decreased In amplitude In
rats exposed continuously to 1000 ppm n-hexane, compared with controls. The
latency of the compound action potential of the ventral caudal nerve of the
tall was also increased. The amplitude of the fifth BAER component was
decreased In rats exposed Intermittently to 48,000 ppm n-hexane but not to
24,000 ppm. The results of this study Indicate that Intermittent adminis-
tration of n-hexane had little effect on neurophyslologlcal parameters until
exposure frequencies were Increased.
In a similar study, 15 male F344 rats exposed continuously (24 hours/
day) to 1000 ppm n-hexane 5 days/week for 11 weeks exhibited a marked
decrease 1n hlndUmb grip strength and a reduction In multlsensory
conditioned avoidance response compared with controls (Pryor et al., 1982).
Transient decreases In undlfferentlated motor activity and forellmb grip
strength were also seen. Continuous exposure to 1000 ppm n-hexane also
Inhibited weight gain, which became significant after 3 weeks of exposure.
Forellmb grip strength was affected slightly by Intermittent exposure to
24,000 or 48,000 ppm n-hexane, 6, 12 or 24 times/day, 5 days/week for 18
weeks. Degeneration of the sciatic nerves was seen only In rats exposed
5942H -24- 07/26/89
-------
continuously to 1000 ppm n-hexane. The data show that the neurotoxic
effects of Intermittent exposure of rats to high concentrations of n-hexane
are less severe than those after continuous exposure to lower concentrations.
Groups of 6-9 male Sprague-Dawley rats were exposed by Inhalation to
several treatment schedules of n-hexane: 5000 ppm, 9 hours/day, 5 days/week
for 14 weeks; 2500 ppm, 10 hours/day, 6 days/week for 30 weeks; 1500 ppm, 9
hours/day, 5 days/week for 14 weeks and 500 ppm, 9 hours/day, 5 days/week
for 30 weeks (Frontali et al., 1981). Peripheral neuropathy occurred in the
rats following exposure to 5000 ppm and 2500 ppm n-hexane. Alterations
consisted of giant axonal degeneration affecting the lateral, medial and
ventral branches of the tibial nerves supplying calf muscles. Both
paranodal and internodal swellings of the axons were seen. Rats exposed to
1500 or 500 ppm did not show any signs of neuropathy. A significant
decrease in weight gain was seen in rats treated with 5000 and 500 ppm
n-hexane.
The neurotoxicity of n-hexane was studied in groups of seven male Hi star
rats following inhalation exposure to 0 or 3000 ppm, 12 hours/day, for 16
weeks (Takeuchi et al., 1980). Decreased body weight occurred in the
exposed rats after 8 weeks of exposure. Signs of clinical neuropathy
(unsteady and waddling gait) were apparent after 10 weeks of exposure. Two
rats died 1 and 3 days before the end of the 16-week exposure. By the end
of 16 weeks, two of the remaining five rats exhibited foot drop, while all
five rats had muscular atrophy in the legs. Motor and mixed nerve
conduction velocities, as measured In the tall, were significantly less than
those of the controls after exposure for 4 weeks, and gradually decreased
after 8 weeks. A prolongation in the distal latency of peripheral nerves
was seen after 4 weeks of exposure. Histologlcal examination of the
5942H -25- 06/16/89
-------
gastrocnetnlus and soleus muscles, the dorsal trunk of the tall nerve and the
tlblal nerve was performed In two of the n-hexane-treated rats. The tlblal
nerve and the dorsal trunk of the tall nerve showed remarkable paranodal
swellings In the myellnated nerve fibers. Many denervated neuromuscular
junctions were observed \n the muscle of the n-hexane group. Muscle fibers
were severely Impaired.
Cavender et al. (1984) studied the toxlclty of n-hexane In groups of 15
male and 15 female F344 rats. The rats were exposed to 0, 3000, 6500 or
10,000 ppm n-hexane vapors, 6 hours/day, 5 days/week, for 13 weeks. Mean
body weight gain was significantly decreased 1n males In the 10,000 ppm
group. Necropsy analysis of these rats also Indicated a depression In brain
weights. No adverse effect of n-hexane on the brain or body weights of
female rats was found. No hlstopathologlcal lesions were present In the
sciatic and tlblal nerves of treated rats. However, In teased nerve fiber
preparations, axonopathy was observed In the tlblal nerve 1n 4/5 male rats
from the 10,000 ppm group and 1/5 males from the 6500 ppm group. Axonopathy
was not detected 1n female rats. No adverse testlcular effects were noted.
The authors concluded that neurotoxlclty resulting from Intermittent
exposure to n-hexane Is less severe than continuous exposure.
Ono et al. (1982) evaluated the neurotoxlclty of n-hexane In groups of
eight male Wlstar rats exposed by Inhalation to 0, 200 or 500 ppm n-hexane,
12 hours/day, 7 days/week for 24 weeks. Motor nerve conduction velocity and
the distal latency of the peripheral nerve were measured In the ventral
trunk of the tall nerve. n-Hexane treatment did not significantly affect
the body weights of the rats. Nerve conduction velocities were decreased
slightly In rats treated with 200 ppm n-hexane after 20 weeks of exposure.
5942H -26- 07/26/89
-------
A marked decrease In nerve conduction velocities and a prolongation of
distal latencies occurred 1n rats from the 500 ppm group after 8 weeks of
exposure. Degeneration of the myelln sheaths and axons was demonstrated
upon examination of the raveled tall nerves 1n all exposed groups.
Schaumburg and Spencer (1976) examined the neurotoxlc effects of
continuous exposure of rats to n-hexane. Eight Sprague-Dawley rats were
exposed to 400-600 ppm n-hexane for 162 days. Clinical signs of neuropathy
developed In rats after 45 days of exposure. Further exposure resulted In a
progressive, symmetrical, distal hlndUmb weakness with foot-drop.
Axonopathy was also seen.
Herskowltz et al. (1971) reported neuropathy In three cabinet finishers
exposed to an average air concentration of 650 ppm n-hexane. The workers
were also exposed to n-hexane by oral and dermal routes. Symptoms Including
headache, abdominal cramps, burning sensation of the face, bilateral
foot-drop gait, bilateral wrist drop and numbness and weakness of the distal
extremities developed 2-4 months after the beginning of exposure, fibrilla-
tion potentials were observed In the small muscles of the hands and feet.
Scattered groups of small angulated fibers In the anterior tlblal muscle and
sural nerves were noted from biopsy findings. Microscopic examination of
the motor end plates revealed axons with an Increased number of neurofHa-
ments with abnormal membranous structures, and clumping and degeneration of
mitochondria with dense bodies. Swelling of the terminal axons was present
In the motor end plates. The health of the patients Improved after exposure
to n-hexane stopped.
Ruff et al. (1981) reported peripheral neuropathy 1n a patient exposed
occupationally for several years to an average n-hexane concentration of 325
ppm.
5942H -27- 07/26/89
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6.1.1.2. CHRONIC Pertinent data regarding the toxicity of n-hexane
following chronic inhalation exposure in laboratory animals or humans were
not located in the available literature cited in Appendis A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC Krasavage et al. (1980) Investigated the
neurotoxic effects of n-hexane (997. purity) in rats after oral administra-
tion. Groups of five adult male COBS rats were administered 570 mg/kg
n-hexane by gavage, 5 days/week for 90 days or 1140 or 4000 mg/kg doses for
120 days. Controls were treated on the same schedule with distilled water.
Treated rats had reduced food consumption and reduced body weights compared
with controls. Clinical (hindlimb weakness) and histological evidence of
neuropathy was seen in rats treated with a dose level of 4000 mg/kg/day.
Histological changes consisted of multifocal axonal swellings, adaxonal
myelin infolding and paranodal myelin retraction. The lower doses of
n-hexane did not produce evidence of neuropathy. Histological examination
of testicular tissue revealed atrophy of the germinal epithelium following
administration of 4000 mg/kg/day n-hexane.
Ono et al. (1981) described the neurotoxicity of n-hexane after oral
administration. n-Hexane was diluted in olive oil and administered orally
to male Wistar rats <5-7/group) daily for 8 weeks. Mixtures of 0.4 m^
n-hexane plus 0.6 m/ olive oil (=770 mg/kg/day) were administered for
the first 4 weeks. For weeks 5 and 6, the rats were administered 0.6 m^
n-hexane (=1155 mg/kg/day) and for weeks 7 and 8, the rats were
administered 1.2 ml n-hexane (=2310 mg/kg/day). Conduction velocities
of the peripheral nerve were measured in the tail. No changes were seen in
the body weights of n-hexane-treated rats. Motor nerve conduction velocity
was significantly less in treated rats than in controls at 8 weeks of
5942H -28- 06/16/89
-------
administration. Mixed nerve conduction velocity (distal portion) decreased
after 4 weeks, while mixed nerve conduction velocity (proximal portion)
decreased after 6 weeks.
6.1.2.2. CHRONIC Pertinent data regarding the toxlclty of n-hexane
following chronic oral exposure were not located In the available literature
cited 1n Appendix A.
6.1.3. Other Relevant Information. Table 6-1 summarizes the results of
acute lethal exposure to n-hexane derived from a limited number of studies.
The oral LD5Q data Indicate that 14-day-old rats are more sensitive to the
acute toxlclty of n-hexane when compared with young and old adult rats.
Hewitt et al. (1980) examined the acute hepatotoxlclty and nephrotoxl-
clty of n-hexane In male Sprague-Dawley rats following a single gavage dose
of 1292 mg/kg of n-hexane solublllzed In corn oil; controls received corn
oil alone. n-Hexane treatment did not produce liver or kidney Injury.
However, when administered along with chloroform, n-hexane potentiated
chloroform-Induced hepatotoxlclty and nephrotoxlclty In rats.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
n-hexane following Inhalation exposure were not located In the available
literature cited In Appendix A. NTP (1989) has completed an Inhalation
bloassay of n-hexane using mice. The technical report 1s being peer
reviewed for fInallzatlon.
6.2.2. Oral. Pertinent data regarding the carclnogenlclty of n-hexane
following oral exposure were not located In the available literature cited
In Appendix A.
6.2.3. Other Relevant Information. Other relevant Information regarding
the carclnogenlclty of n-hexane were not located 1n the available literature
cited In Appendix A.
5942H -29- 09/26/89
-------
TABLE 6-1
Acute Lethal Toxlcity of n-Hexane
Species
Mouse
Rat
Route
Inhalation
oral
Results
LCLO 120 g/m3
LD,0 15,800 mg/kga
LD50 32,340 mg/kg"
LD50 28,710 mg/kgc
314-day-old rats (16-50 g)
"Young adult rats (80-160 g)
'Older adult rats (300-470 g)
Reference
NIOSH, 1989
Kimura et al., 1971
Kimura et al., 1971
Kimura et al., 1971
5974H
-30-
06/15/89
-------
6.3. MUTAGENICITY
Pertinent data regarding the mutagenldty of n-hexane were not located
In the available literature cited In Appendix A.
6.4. TERATOGENICITY
Bus et al. (1979) examined the perinatal toxldty of n-hexane 1n rats.
Groups of 7-9 pregnant F344 rats were exposed by Inhalation to 0 or 1000 ppm
of 99% n-hexane for 6 hours/day on days 8-12 {7 rats), days 12-16 (9 rats),
or days 8-16 (8 rats) of gestation. No significant changes In fetal resorp-
tlons, body weights or visible anomalies were noted with any of the n-hexane
exposure regimens compared with controls. No significant Increases In the
Incidence of soft tissue or skeletal anomalies were seen. The postnatal
growth of pups born to dams exposed to 1000 ppm n-hexane on days 8-16 of
gestation was depressed up to 3 weeks of birth. However, the litter weights
of the treated pups returned to control values by 7 weeks.
Marks et al. (1980) determined that n-hexane was not teratogenlc 1n
mice. Pregnant CD-I mice were administered n-hexane once dally by gavage
with the following doses: 260 mg/kg/day (13 mice), 660 mg/kg/day (6 mice),
1320 mg/kg/day (6 mice) and 2200 mg/kg/day (14 mice) on days 6-15 of
gestation. One of 14 dams treated with 2200 mg/kg/day n-hexane died. The
Incidence of malformed mouse fetuses was not significantly different between
treated mice and control mice .
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of n-hexane were not
located In the available literature cited In Appendix A.
6.6. SUMMARY
The neurotoxlclty of n-hexane has been demonstrated In a number of
subchronlc Inhalation animal studies. Results of these studies Indicate
5942H -31- 07/26/89
-------
that n-hexane neurotoxicity is characterized by the development of
peripheral neuropathy '(Rebert et al., 1982; Pryor et al., 1982; Frontali et
al., 1981; Takeuchl et al., 1980; Cavender et al., 1984; Ono et al., 1982;
Schaumburg and Spencer, 1976). Peripheral nerve damage is associated with
giant axonal swellings, axonal degeneration, hindlimb drag and weakness of
the forelimbs and hindlimbs in rats. Behavioral alterations in rats
following inhalation exposure to n-hexane have been reported 570 mg/kg/day
n-hexane are similar to those associated with inhalation exposure (Krasavage
et al., 1980; Ono et al., 1981). Testicular atrophy was observed in rats
treated by gavage at 4000 mg/kg/day for 120 days (Krasavage et al., 1980).
Data were not located regarding the cardnogenicity of n-hexane to
animals or humans exposed by any route. No data were located regarding the
mutagenicity of n-hexane. Marks et al. (1980) found no teratogenic effects
of orally administered n-hexane (260-2200 mg/kg/day) in rats. A temporary
decrease in postnatal growth occurred in pups born to rat dams exposed by
inhalation to 1000 ppm on days 8-16 of gestation (Bus et al., 1979).
5942H -32- 06/16/89
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
The ACGIH (1988) recommended TWA-TLV for n-hexane is 50 ppm <180
mg/m3). ACGIH (1988) does not recommend a STEL for n-hexane. These
recommendations are based largely on the inhalation and oral studies in
animals that associate peripheral neuropathy with exposure to the compound
(ACGIH, 1986). OSHA (1989) lists transitional limits for n-hexane of 500
ppm (1800 mg/m3) and final rule limits of 50 ppro (180 mg/m3), identical
to the ACGIH (1988) recommendation. NIOSH (1977) recommended 100 ppm (350
mg/m3) as a workplace environmental TWA limit for n-hexane.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to n-hexane were not located in the available literature cited in
Appendix A.
5942H -33- 06/16/89
-------
8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carcinogenicity of
n-hexane to animals or humans following inhalation exposure were not located
in the available literature cited in Appendix A.
8.1.2. Oral. Pertinent data regarding the carcinogenicity of n-hexane to
animals or humans following oral exposure were not located in the available
literature cited in Appendix A.
8.1.3. Other Routes. Pertinent data regarding the cardnogenicity of
n-hexane following other routes of exposure were not located in the
available literature cited in Appendix A.
8.1.4. Weight of Evidence. The lack of data regarding the carcinogenicity
of n-hexane in humans or animals is the basis for assigning n-hexane to U.S.
EPA Group D not classifiable as to human carcinogenicity, using the U.S.
EPA <1986b> guidelines.
8.1.5. Quantitative Risk Estimates. The lack of positive carcinogenicity
data for n-hexane precludes quantitative estimation of carcinogenic risk.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES
-------
exposed to 2500 ppm for 10 hours/day, 6 days/week for 30 weeks (rec #3).
Takeuchl et al. (1980) reported clinical signs of neuropathy, nerve
conduction changes and decreased body weight In rats exposed to 3000 ppm for
12 hours/day for 16 weeks (rec #5). Cavender et al. (1984) exposed rats 6
hours/day, 5 days/week to 3000, 6500 or 10,000 ppm for 13 weeks (rec #6 and
7). Decreased brain weight and decreased body weight were noted at 10,000
ppm. Axonopathy was observed at both the 6500 and 10,000 ppm concentra-
tions. This treatment regimen had no effect on the hlstopathology of
kidneys, spleen, liver and testes, Indicating that peripheral neuropathy Is
the critical effect of exposure to n-hexane. Schaumburg and Spencer (1976)
reported neuropathy In rats exposed continuously to 400-600 ppm for 162 days
(rec #10). Axonopathy and nerve conduction alterations were observed In
rats (rec #1) exposed to 200 ppm for 12 hours/day, 7 days/week for 24 weeks
(Ono et al., 1982). Because gross Impairment of neurological function was
observed by Rebert et al. (1982) and Pryor et al. (1982) at 1000 ppm, by
Takeuchl et al. (1980) at 3000 ppm and by Schaumburg and Spencer (1976) at
400 ppm, these studies define FELs but do not define LOAELs for peripheral
neuropathy. The results from several studies, such as Frontall et al.
(1981) and Cavender et al. (1984), Indicate that axonopathy resulting from
intermittent exposure to n-hexane Is less severe when compared with contin-
uous Inhalation exposure. Also, axonopathy appears later after Intermittent
exposure. However, Ono et al. (1982) demonstrated that Intermittent
exposure of rats to n-hexane at concentrations as low as 200 ppm can produce
axonopathy and nerve conduction alterations. HerskowHz et al. (1971)
reported neuropathy In humans exposed to n-hexane 1n an occupational
setting. Symptoms developed 2-4 months after exposure began. The average
concentration of n-hexane In the air was 650 ppm. However, the workers were
also exposed orally and dermally to n-hexane.
5942H
-35-
07/26/89
-------
The LOAEL of 200 ppm (expanded to a continuous exposure of 100 ppm or
352 mg/m3) reported by Ono et al. (1982) can be used to calculate a
subchronlc Inhalation RfD for a vapor that causes systemic effects. As
demonstrated by Baker and Rlckert (1981), steady state In rats Is reached
within ? hours during exposure; therefore, equilibrium conditions had
probably been established during the 12-hour exposure periods In the study
by Ono et al. (1982). In the absence of data to the contrary. It Is assumed
that the ratio of the blood/gas partition coefficient 1n animals to humans
Is 1. The human equivalent concentration Is therefore 352 mg/m3.
Applying an uncertainty factor of 1000 (10 to extrapolate from animals to
humans, 10 to estimate a NOAEL from a LOAEL and 10 to protect sensitive
Individuals) results In an RfD for subchronlc Inhalation exposures of 0.352
mg/m3, which rounds to 0.4 mg/m3. Confidence In this RfD Is medium.
Ono et al. (1982) provided hlstologlcal and functional evidence for
neuropathy. The hlstopathology of other organs was not examined. The
chronic neurotoxldty of n-hexane has not been studied.
8.2.1.2. CHRONIC EXPOSURES -- No data regarding the chronic effects of
n-hexane are available. An RfD for chronic Inhalation exposure can be
derived from the subchronlc RfD of 0.352 mg/m3 based on the 24-week study
In rats (Ono et al., 1982). Application of an uncertainty factor of 10 to
extrapolate from subchronlc exposure results In an RfD for chronic Inhala-
tion exposures of 0.0352 mg/m3, which rounds to 4xlO~2 mg/m3.
Confidence In the RfD Is medium (see Section 8.2.1.1).
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES Groups of five rats were
administered 570 mg/kg/day n-hexane by gavage 5 days/week for 90 days or
1140 or 4000 mg/kg/day n-hexane for 120 days (Krasavage et al., 1980).
5942H -36- 07/26/89
-------
Peripheral neuropathy, paralysis and testlcular atrophy were observed 1n
rats (rec #2) treated with 4000 mg/kg/day n-hexane. Signs of neuropathy or
testlcular atrophy were not seen In rats exposed to 570 or 1140 mg/kg/day.
Significant decreases In body weight gain were seen at these two dose
levels. Because paralysis represents a gross Impairment of neurological
function, the 4000 mg/kg/day dosage 1s considered a PEL rather than a LOAEL.
Decreased nerve conduction velocities were observed In rats (rec #3)
following oral administration of 770-2310 mg/kg/day n-hexane dally for 8
weeks (Ono et al., 1981). n-Hexane (770 mg/kg/day) was administered for the
first 4 weeks. The rats were administered 1155 mg/kg/day for weeks 5 and 6,
and 2310 mg/kg/day for weeks 7 and 8.
The lowest dose administered 1n the oral studies, 570 mg/kg/day (rec #1)
reported by Krasavage et al. (1980), Is a LOAEL because the body weight gain
of the rats treated with this dose was significantly depressed. The
decreased body weight gain appeared to be associated with clinical signs of
neuropathy at higher doses. The LOAEL can be used to derive a subchronlc
oral RfO of 0.57 mg/kg/day (rounded to 0.6 mg/kg/tJay) by dividing by an
uncertainty factor of 1000 (10 to extrapolate from animals to humans, 10 for
the use of a LOAEL and 10 to protect sensitive Individuals). Confidence 1n
this RfD Is low. For risk assessment 1t would be desirable to have a strong
data base that defines both a LOAEL and a NOAEL and contains corroborative
studies. The data reported by Krasavage et al. (1980) were part of a broad
study that evaluated the relative neurotoxlclty of n-hexane, methyl-n-
butylketone, and their metabolites. In addition, the chronic neurotoxlclty
of n-hexane following oral exposure has not been studied.
5942H -37- 07/26/89
-------
8.2.2.2. CHRONIC EXPOSURES Studies of chronic oral exposure to
n-hexane were not available. A chronic oral RfD of 0.057 mg/kg/day (rounded
to 6xlO~2 mg/kg/day) for n-hexane can be derived by dividing the subchro-
n1c oral RfD by an additional uncertainty factor of 10 to extrapolate from
subchronlc exposure. Confidence In this RfD 1s low (see Section 8.2.2.1).
5942H
-38-
07/26/89
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEHIC TOXICITY
The toxldty of n-hexane was discussed In Chapter 6 and dose-response
data considered for CS derivation are summarized In Table 9-1. Since no
chronic toxlclty data are available, subchronlc data were considered. Both
Inhalation and oral studies Indicate that neuropathy 1s the critical effect
of n-hexane toxlclty. In addition, decreased body weight gain Is often
associated with the neurotoxldty. Takeuchl et al. (1980) also found that
2/7 rats died after 15 weeks of treatment with 3000 ppm for 12 hours/day.
The occupational study by Herskowltz et al. (1971), In which neuropathy was
reported In workers who experienced Inhalation, oral and dermal exposure, 1s
not Included In Table 9-1.
Besides typical signs of n-hexane neuropathy, Krasavage et al. (1980)
found testlcular atrophy In rats administered 4000 mg/kg/day n-hexane by
gavage, 5 days/week for 120 days.
Table 9-2 presents CSs and RQs derived for the lowest human equivalent
dosages associated with each of the effects summarized In Table 9-1. The
highest CS calculated, 13, associated with neuropathy In rats exposed by
Inhalation (Ono et al., 1982), was selected as most representative of the
chronic toxlclty of n-hexane. The CS of 13 and Us corresponding RQ of 1000
are presented In Table 9-3.
9.2. BASED ON CARCINOGENICITY
No data were located regarding the carclnogenlclty of n-hexane In humans
or animals, and the compound was placed 1n EPA Group D. Hazard ranking
based on carclnogenlclty Is not possible for EPA Group D substances; there-
fore, an RQ based on carclnogenlclty cannot be assigned. NTP (1989) has
recently completed an Inhalation bloassay of n-hexane using mice. The final
technical report 1s 1n preparation.
5942H -39- 09/26/89
-------
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5942H
-42-
07/26/89
-------
TABLE 9-3
n-Hexane
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: inhalation
Species: rat
Dose3: 270 mg/day
Duration: 24 weeks
Effect: axonopathy, nerve conduction alterations
RVd: 1.85
RVe: 7
CS: 13
RQ: 1000
Reference: Ono et al., 1982
'Equivalent Human Dose
5974H -43- 06/15/89
-------
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5942H -58- 09/26/89
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APPENDIX A
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
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)
HSDB
These searches were conducted In May 1989, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices. 5th ed. Cincinnati, OH.
ACGIH (American Conference cf Governmental Industrial Hyglenlsts).
1987. TLVs: Threshold Limit Values for Chemical Substances In the
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. 3ohn 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. 28. John Wiley and Sons,
NY. 2879-3816 p.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2C. John Wiley and Sons,
NY. 3817-5112 p.
5942H A-l 07/26/89
-------
Grayson, M. and D. Eckroth, Ed. 1978-84. K1rk-0thmer Encyclopedia
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., MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Monographs
on the Evaluation of Carcinogenic Risk of Chemicals to Humans. IARC,
Lyons, France: WHO.
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 P884-243906) Menlo Park, CA: SRI Inter-
national.
NIP (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
edition. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Stanford, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
USITC (United States International Trade Commission). 1986.
Synthetic Organic Chemicals. U.S. Production and Sales, 1985, USITC
Publication 1892. Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd edition. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M. Ed. 1983. The Merck Index. 10th ed. Merck and Co.,
Inc., Rahway, NJ.
5942H A-2 07/26/89
-------
In addition, approximately 30 compendia of aquatic toxicity 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, h.W. and M.T. Fin ley. 1980. Handbook of Acute Toxicity of
Chemicals to Fish and Aquatic Invertebrates. Summaries of Toxicity
Tests Conducted at Columbia National Fisheries Research Laboratory.
1965-1978. United States 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.
Pimental, D. 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.
5942H A-3 5/3/89
-------
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO n-HEXANE
C.I. DISCUSSION
Dose/duration-response graphs for inhalation and oral exposure to
n-hexane generated by the method of Crockett et al. (1985) using the
computer software by Durkin and Meylan <1988) developed under contract to
ECAO-Cincinnati are presented in Figures C-l, C-2, C-3, C-4 and 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 (FEL,
AEL or LOAEL) or non-adverse (NOEL or NOAEL) for plotting. For inhalation
exposure the ordinate expresses concentration in either of two ways. In
Figures C-l 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 Figure C-2, the expanded experimental 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
Schneiderman, 1975) to estimate an equivalent human or scaled concentration
[scaled cone (mg/m3)]. For oral exposure, the ordinate expresses dosage
as human equivalent dose. The animal dosage in mg/kg/day is multiplied by
the cube root of the ratio of the animal :human body weight to adjust for
species differences 1n basal metabolic rate (Mantel and Schneiderman,
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.
The Boundary for Adverse Effects (solid line) is drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
6107H
C-l
06/16/89
-------
n
\
9>
X
u
a
u
e
u
laeaa
i0ee - -
100
A6
ft?
rs
A3
'NTT
,_. uf>
* "" ^^^BD
Fie
e.ei
(Inhalation Exposure)
0.1
HUMAN EQUIU DURATION (fraction lifcspan)
' ENVELOP METHOD
FIGURE C-1
Dose/Duration-Response Graph for Inhalation Exposure to n-Hexane,
Expanded Experimental Concentration (Envelop Method)
Key: F » FEL
A - AEL
I = LOAEL
n - NOAEL
N - NOEL
Solid Line « Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
6107H
C-2
06/19/89
-------
I
9
v
U
I
V
8
ieeee
i0ee -r
IBB -7
I I T
A6
A7
F5
A3
-H8
F18
I l j
e.ei
n Exposure)
0.1
HUNAN EQUIU DURATION (fraction lifospan)
' ENVELOP NCTHOD
FIGURE C-2
Dose/Duration-Response Graph for Inhalation Exposure to n-Hexane,
Scaled Concentration (Envelop Method)
Key:
F
A
L
n
N
FEL
AEL
LOAEL
NOAEL
NOEL
Solid Line « Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
6107H
C-3
06/19/89
-------
o
u
i
u
u
0
u
e
I
6.
X
U
IBB
I 1 1
A6
A7
F5
A3
"HIT
B.B1
< I nh«» I * t i on Exposure )
4-
Fie
B.l
HUMAN EQUIU DURATION (fraction lifcspan)
CEMSORED DATA HETHOD
FIGURE C-3
Dose/Duration-Response Graph for Inhalation Exposure to n-Hexane,
Expanded Experimental Concentration (Censored Method)
Key:
F
A
L
n
N
FEL
AEL
LOAEL
NOAEL
NOEL
Solid Line * Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
6107H
C-4
06/19/89
-------
r
leeee
n
c
c
u
idea -r
188 -r
18
-mi-
A6
ft?
MB
rs
A3
Fie
8.81
C InhAl at i 011 Exposure >
8.1
HUMAN EQUIU DURATION (fraction I if(span)
CENSORED DATA METHOD
Key:
FIGURE C-4
Dose/Duration-Response Graph for Inhalation Exposure to n-Hexane,
Scaled Concentration (Censored Method)
F
A
L
n
N
FEL
AEL
LOAEL
NOAEL
NOEL
Solid Line = Adverse Effects Boundary
Dotted Line = No Adverse Effects Boundary
6107H
C-5
06/19/89
-------
1088800 r
15
r
5
M
a
e
u
186000 r
10000~ r
1800 -t-
0.801
(Oral Exposure)
0.01 8.1
HUNAN EQUIU DURATION (fraction
' ENVELOP HETHOD
Key:
FIGURE C-5
Dose/Duration-Response Graph for Oral Exposure to n-Hexane,
Envelop Method
F * FEL
A * AEL
L » LOAEL
Solid Line = Adverse Effects Boundary
6107H
C-6
06/19/89
-------
exposure at which an adverse effect occurred. From this point an infinite
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
concentration 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
concentration. 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 lower 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 No Adverse Effects Region lies below the No Adverse
Effects Boundary. At either end 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 1s redrawn so that 1t 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.
6107H
C-7
06/19/89
-------
Figures C-l and C-2 present dose/duration-response graphs for Inhalation
exposure drawn by the envelope method. Figure C-1 presents results using an
expanded experimental concentration. The Adverse Effects Boundary is
defined by several experimental points (rec #1, 2 and 9) associated with
peripheral neuropathy (Ono et al., 1982; Rebert et al., 1982; Pryor et al.
1982) in rats. Record #1 <0no et al., 1982) served as the basis for the
determination of the RfD for subchronic and chronic inhalation exposure.
The No Adverse Effects Boundary is defined by two points (rec #4 and 8) also
associated with peripheral neuropathy (Frontal 1 et al., 1981; Cavender et
al., 1984). The rather small Region of Contradiction reflects the
possibility that Wistar rats are more sensitive than Sprague-Dawley rats to
n-hexane. When the graphs are redrawn to eliminate the Region of
Contradiction (Figures C- 3 and C-4), the No Adverse Effects Boundary Is now
defined by only one NOAEL for peripheral neuropathy in rats (Cavender et
al.. 1984; rec #8).
Figures C-2 and C-4 present the graph redrawn so that the data are
expressed as scaled concentration. Scaling produced the same Adverse and No
Adverse Effects Boundary as drawn by using an expanded experimental
concentration.
Figure C-5 presents the dose/duration-response graph generated by the
envelope method for oral exposure. The Adverse Effects Boundary 1s defined
by lethality data in mice (rec #4) and rats (rec #5), and AEL (rec #3) for
peripheral neuropathy in rats and a LOAEL (rec #1) for decreased body weight
gain in rats (Krasavage et al.. 1980). Since no oral study defined a NOAEL
or NOEL, the No Adverse Effects Boundary could not be drawn. The LOAEL (rec
#1) served as the basis for determining the RfD for subchronic and chronic
oral exposure.
6107H C-8 06/19/89
-------
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
C.2.1. INHALATION EXPOSURE
Chemical Name:
CAS Number:
Document Title:
Document Number:
Document Date :
Document Type :
n-Hexane
110-54-3
Health and Environmental
pending
pending
HEED
Effects Document on n-Hexane
RECORD
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 352.000
Duration Exposure: 20.0 weeks
Duration Observation: 24.0 weeks
8
NR
NEURP
PNS
6
Comment: Doses: 200 or 500 ppm. Motor nerve conduct.
veloc. (MCV) was slightly dec. at 200 ppm.
MCV was markedly dec. at the highest dose
after 8 wk. Axonal degeneration was also
noted.
Citation: Ono et al., 1982
RECORD #2:
Species:
Sex:
Effect:
Route :
Rats
Male
AEL
Inhalation
Dose: 2517.000
Duration Exposure: 18.0 weeks
Duration Observation: 18.0 weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
15
NR
NEURP
PNS
6
Comment: Doses: 24,000 and 48,000 ppm,10 min expos. 6
or 12 times/d,5 h/d. Forelimb grip strength
decreased. Brainstem auditory-evoked resp.
was decreased at the highest dose.
Citation: Rebert et al., 1982; Pryor et al., 1982
6107H
C-9
06/19/89
-------
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Male
AEL
Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 3147.000
Duration Exposure: 30.0 weeks
Duration Observation: 30.0 weeks
6
NR
NEURP
PNS
6
Comment: Doses and duration: 500 ppm,9 h/d, 5 d/wk, 30
wk; 1500 ppm 9 hr/d, 5 d/wk, 14 wk; 2500 ppm,
10 hr/d, 5 d/wk, 30 wk; EDOO ppm, 9 hr/d, 5
d/wk, 14 wk. Peripheral neuropathy was ob-
served at 2500 and 5000 ppm concentrations.
Citation: Frontali et al., 1981
RECORD #4:
Species: Rats
Sex: Male
Effect: NOAEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 629.000
Duration Exposure: 30
Duration Observation:
6
NR
NEURP
PNS
6
.0 weeks
30.0 weeks
Comment: See previous record for doses and durations.
Rats sxpcsed to 500 and 1500 ppm doses did
not show signs of neuropathy. Decreases In
weight gain were seen in rats at 500 and 5000
ppm, but not at other cone.
Citation: Frontali et al., 1981
RECORD #5:
Species: Rats
Sex: Male
Effect: FEL
Route: Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 5287.000
Duration Exposure: 16
Duration Observation:
7
NR NR
NEURP WGTDC
PNS BODY
7 4
.0 weeks
16.0 weeks
7
NR
DEATH
NS
10
Comment: Dose: 3000 ppm, 12 hr/d for 16 wks. Dec. body
wt., muscular atrophy, foot drop, nerve con-
duct veloc. changes and axonal degen. were ob-
served. Two rats died by end of 16 wk. expo.
Citation: Takeuchi et al., 1980
6107H
C-10
06/19/89
-------
RECORD #6:
RECORD #7:
Species:
Sex:
Effect:
Route:
Rats
Both
AEL
Inhalation
Dose: 6294.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks
15
NR
WGTDC
BRAIN
6
15
NR
NGTDC
BODY
4
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Comment: Doses: 3000, 6500 or 10,000 ppm 6 hr/d, 5 d/
wk. Decreases In brain weight and body weight
observed only in male rats at 10,000 ppm.
Citation: Cavender et al., 1984
Species:
Sex:
Effect:
Route:
Rats
Both
AEL
Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 4091.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks
15
NR
NEURP
PNS
6
Comment: Doses same as previous record. Axonopathy was
observed In male rats rats exposed to 6500 ppm
(1/5 rats) and 10,000 ppm (4/5 rats). Female
rats did not show any signs of axonopathy
after expos.
Citation: Cavender et al., 1984
RECORD #8:
Species:
Sex:
Effect:
Route:
Rats
Both
NOEL
Inhalation
Dose: 1888.000
Duration Exposure: 13.0 weeks
Duration Observation: 13.0 weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
15
NR
NEURP
PNS
6
Comment: See previous records. No effects at 3000 ppm.
Citation: Cavender et al., 1984
6107H
C-11
06/16/89
-------
RECORD #9:
RECORD #11
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Inhalation
Number Exposed:
Number Responses:
Type of Effect:
SUe of Effect:
Severity Effect:
Dose: 2518.000
Duration Exposure: 11.0 Weeks
Duration Observation: 11.0 Weeks
15
NR
NEURP
PNS
7
Comment: Dose: 1000 ppm, 24 hr/d, 5 d/wk. Alterations
1n bralnstem auditory-evoked resp. and de-
creases In hlndllmb strength, avoidance resp.,
body weight gain and motor activity observed.
Citation: Rebert et al., 1982; Pryor et al.. 1982
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
N.S.
PEL
Inhalation
Dose: 1410.000
Duration Exposure: 162.0 days
Duration Observation: 162.0 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
8
NR
NEURP
PNS
8
Comment: Range: 400-600 ppm continuously. Unsteady,
waddling gait devel. In rats after 45 days
Further expos, resulted 1n a progressive,
distal hlndllmb weakness with foctdrop.
Axonopathy also seen.
Citation: Schaumburg and Spencer, 1976.
Species:
Sex:
Effect:
Route:
Rats
Female
NOEL
Inhalation
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 1762.000
Duration Exposure: 9.0 days
Duration Observation: 9.0 days
9
NR
TERAS
FETUS
8
Comment: Rats were exposed to 1000 ppm for 6 hr/d on
days 8-12(7rats), days 12-16(9 rats), or days
8-16 (8rats) of gestation.
Citation: Bus et al., 1979
6107H
C-12
07/26/89
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C.2.2. ORAL EXPSOSURE
RECORD #1
RECORD #3:
Species:
Sex:
Effect:
Route:
Rats
Male
LOAEL
Gavage
Dose: 407.000
Duration Exposure: 90.0 days
Duration Observation: 90.0 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
5
NR
NEURP
PNS
7
5
NR
ATROP
TESTE
6
Comment: Doses: 570 mg/kg/d 5 d/wk for 90 d, 1140 mg/
kg/d 5 d/w 4000 mg/kg/d 5 d/wk 120 days.
Decreased body weight gain at all doses.
Citation: Krasavage et al., 1980
RECORD #2:
Species:
Sex:
Effect:
Route:
Rats
Male
PEL
Gavage
Dose: 2857.000
Duration Exposure: 120.0 days
Duration Observation: 120 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
5
NR
NEURP
PNS
7
5
NR
ATROP
TESTE
6
Comment: See previous record. Hindiimb weakness, axonal
swelling, myelin retraction; testicular
atrophy at 4000 rng/kg/day, 5 days/week for 120
days.
Citation: Krasavage et al., 1980
Species:
Sex:
Effect:
Route:
Rats
Male
AEL
Oral.(NOS)
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 770.000
Duration Exposure: 8.0 weeks
Duration Observation: 8.0 weeks
7
NR
NEURP
PNS
6
Comment: Doses: 770 mg/kg/d for 1st 4 wks, 1155 mg/kg/d
for wks 5 and 6, and 2310 mg/kg/d for wks 7 and
8. Motor and mixed nerve conduction velocities
were decreased. No hlstopathology was
performed.
Citation: Ono et al., 1981
6107H
C-13
06/16/89
-------
RECORD #4:
Species:
Sex:
Effect:
Route:
Mice
Female
PEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Dose: 2200.000
Duration Exposure: 10.0 days
Duration Observation: 10.0 days
14
NR
DEATH
NS
10
Comment: Doses: 260 mg/kg/d (13 mice), 660 mg/kg/d <6
mice), 1320 mg/kg/d (6 mice) and 2200 mg/kg/d
(14 mice) on days 6-15 of gestation. One of 14
dams died. No teratogenic effects were found.
Citation: Marks et al., 1980
RECORD #5:
Species:
Sex:
Effect:
Route:
Rats
NS
FEL
Oral.(NOS)
Dose: 15800.000
Duration Exposure: 1
Duration Observation
.0 days
: 1.0 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
NR
NR
DEATH
NS
10
Comment: LD5Q of 15800 mg/kg/d for 14-day-old rats.
LDso of 32340 mg/kg/d for young adult rats.
LD50 of 28710 mg/kg/d for older adult rats.
Symptoms of acute toxlclty was not reported.
Citation: Kimura et al.. 1971
6107H
C-14
06/16/89
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