United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-G077
September, 1989
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR N-HEPTANE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
U.S EPA Headquarters Librae
,_nno Mail code 3404T
120PA Pennsylvania Avenue NW
Washington, DC 20460
202-566-0556
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
Q construed to represent Agency policy. It Is being circulated for comments
S on Us technical accuracy and policy Implications.
e*
I
HEADQUARTERS WART
ENVIRONMENTAL PROTECTION AGENCY
WASHINGTON, O.C. 20460
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\ UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
| WASHINGTON, D.C. 20460
SEP 2 6 iQftQ - OFFfCE OF
«- " '^OC7 RESEARCH AND DEVELOPMENT
SUBJECT: ^He'alth andEnvironmental Effects Document for N-Heptane
FROM: /William H. FarLend, Ph.D.
(_J>irector
Office of Health and Environmental
Assessment (RD-689)
TO: Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Waste (OS-330)
I am forwarding copies of the Health and Environmental
Effects Document (HEED) for N-Heptane.
The HEEDs support listings under RCRA, as well as provide
health-related limits and goals for emergency and remedial
actions under CERCLA. These documents represent scientific
summaries of the pertinent available data on the environmental
fate and mammalian and aquatic toxicity of each chemical at an
extramural effort of about 510K. The attached document has been
reviewed within OHEA, by staff in OPP and OTS, and by two
external scientists.
Should you wish to see any of the files related to the
development of the HEEDs, please call Chris DeRosa at
FTS: 684-7531.
Attachment
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Haste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as yell 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 1n this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates {front
cover) reflect the date the document 1s sent to the Program Officer (OSHER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include the following:
Reference doses (RfDs) for chronic and subchronlc exposures for both the
Inhalation and oral exposures. The subchronlc or partial lifetime RfO, 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, RfOs are not estimated. Instead,
a carcinogenic potency factor, or qf (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-
genlclty 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. Compen-
sation and Liability Act (CERCLA). These two RQs (chronic toxlclty and
carclnogenlclty) represent two of six scores developed (the remaining four
reflect Ignltablllty, reactivity, aquatic toxlclty, and acute mammalian
toxlclty). Chemical-specific RQs reflect the lowest of these six primary
criteria. The methodology for chronic toxlclty and oancer based RQs are
defined In U.S. EPA, 1984 and 1986a, respectively.
Ill
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EXECUTIVE SUMMARY
Heptane Is a colorless, volatile and flammable organic liquid with a
weak parafflnlc odor. Heptane Is soluble In most polar and nonpolar organic
solvents such as ether, acetone, benzene and chloroform (Sax and Lewis,
1987; Weast et a!., 1988). It 1s only slightly soluble 1n water. Heptane
1s commercially produced by the fractional distillation of suitable petro-
chemical feedstocks. Heptane Is separated from branched heptanes and other
contaminants by rectification. Heptane Is used as a solvent. In organic
synthesis and as an anesthetic. It Is also the low-end standard for
gasoline octane rating (Sax and Lewis, 1987).
In the atmosphere, heptane 1s expected to occur almost entirely In the
vapor phase (E1senre1ch et al., 1981). Apparently, reaction with photochem-
Ically produced HO* Is the primary degradation pathway (half-life = 2.2
days) (Atkinson, 1985). Small amounts of heptane may be removed from the
atmosphere by rain washout; however, It would rapidly revolatnize. Neither
the reaction with ozone nor direct photochemical degradation are expected to
be Important removal processes.
In water, Important fate and transport processes are probably volatili-
zation (estimated half-life <3 hours from a typical river), aerobic degrada-
tion (Oelflno and Miles, 1985; Jamison et al.f 1976), adsorption to sediment
and suspended organic matter and bloconcentratlon In aquatic organisms.
Oxidation, photolysis and hydrolysis are probably not Important fate
9
processes.
In soil, heptane undergoes aerobic degradation (Halnes and Alexander,
1974). Heptane probably volatilizes rapidly to the atmosphere from soil
surfaces; however, heptane's potential to strongly adsorb to sediment and
suspended matter may attenuate the volatilization rate.
1v
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Heptane Is a highly volatile, natural component of crude oil and natural
gas (Dale and Montgomery, 1981). It may be released to the environment from
anthropogenic sources Including losses from wastewater and Fugitive
emissions from the manufacture, formulation, use and transport. Accidental
spills of crude (McDonald et al., 1984) and finished (Jamison et al., 1976)
petrochemdal fuel products and emissions from gasoline (Shamsky and Samlml,
1987), and motor vehicle exhaust (Nelson and Qulgley, 1984) also release
heptane to the atmosphere.
The available monitoring data suggest that the general population may be
exposed to heptane primarily through Inhalation. Exposure may also occur
through direct contact with refined petroleum products. Based on available
monitoring data, the average dally Intakes of heptane through Inhalation In
rural, urban and suburban areas are an estimated 8.95, 78.5 and 48.5 rag,
respectively. Representative heptane concentrations 1n the ambient
atmosphere are summarized In Tables 3-1 and 3-2.
In a genotoxlclty assay conducted In bean plants, mitosis was Inhibited,
and the frequencies of abnormal anaphases and total aberrations were
elevated at all concentrations of heptane tested (1000-30,000 mg/p)
(Gomez-Arroyo et al., 1986). These effects were not concentration-related,
however, which suggests that they may not have been produced by heptane.
The pharmacoklnetlc data for n-heptane are somewhat limited. The
absorption rate In rats exposed to <100 ppm Is 450 ng/kg/mln/ppm (Dahl et
al., 1988), but there 1s no Information regarding the proportion absorbed
O
at the higher levels, for which excretion data (Perbelllnl et al., 1986) are
available. The hydrophoblc parent compound might concentrate In fatty
nervous tissue, but much more appears In perlrenal fat than In the brains of
exposed rats (Savolalnen and PfSffll, 1980).
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The brain/blood partition for Its primary metabolite, 2-heptanol, 1s not
high but Intermediate between muscle or liver and kidney. Moreover, all
tissue and blood measurements Indicate that heptane and Its primary metabo-
lite (2-heptanol) are rapidly removed from the organism when exposure ends.
Considered In combination with metabolic data Indicating low production of
neurotoxlc metabolites, which are entirely conjugated (Bahlma et al., 1984;
PerbelUnl et al., 1986) and thus sequestered from neural targets, heptane
Is expected to be of relatively low neurotoxldty for a C6-C8 alkane. Data
were not located regarding the extent to which a dose of n-heptane Is
eliminated by various routes of excretion.
All available studies of the effects of subchronlc Inhalation of heptane
used rats as the animal model of human toxlclty. Takeuchl et al. (1980,
1981) reported reduced weight gain In one of five monthly weighings and
slight subcellular changes In peripheral neural tissue In seven Ulstar rats
Inhaling 3000 ppm 99*-% pure heptane Intermittently for 16 weeks. The
electrophyslologlcal effects and microscopically observed peripheral neural
degeneration consequent to Intermittent Inhalation of 1500 ppm 52.4%
technical grade heptane by rats of the same strain may have been due to
Impurities In the test chemical .(Truhaut et al., 1973). When Frontal 1 et
al. (1981) Intermittently exposed 7-9 rats of an unspecified strain to 1500
ppm 99% heptane for 30 weeks, the Investigators observed no degeneration In
neural axons, nor were there adverse effects on neurological behavior or
weight gain.
9
In a study by B1o Dynamics (1980), 15 Sprague-Dawley rats/sex were
Intermittently exposed to 400 or 3000 ppm 98.5% heptane over 26 weeks.
Elevated serum alkaline phosphatase levels were reported In high-dose
females at the end of the exposure period; and clinical signs such as
v1
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shallow breathing and prostration In both dose groups were reported during
exposure periods 1n the first week of the experiment.
The only data on chronic exposure to heptane by Inhalation were regard-
Ing workers occupatlonally exposed to 95X heptane vapor for 1-9 years; the
severity of peripheral neuropathy electrophyslologlcally measured closely
correlated with duration of exposure (Crespl et a!., 1979). Information
about the concentration of the Inhaled heptane vapor was lacking, nor was
there any Information on potential contaminants.
There were several studies of acute exposure to n-heptane, mostly by
Inhalation. Savolalnen and PfaffH (1980) reported sporadic alterations 1n
several enzymatic parameters, Including the activity of brain acid proteln-
ase, examined In brain homogenates of rats exposed to 100-500 ppm heptane
Intermittently for 1-2 weeks; however, the biological significance of these
observations 1s unclear. Krlstlansen and Nielsen (1988) exposed mice to
concentrations ranging from 5607-24,801 ppm heptane for 30 minutes to
separately measure bradypnea Induced by Irritation of the upper and lower
respiratory tract. Sufficient data were provided to enable estimation of
threshold levels of 5447-6422 ppm for the upper and 1820 ppm heptane for the
lower respiratory tracts.
In other laboratories, acute exposure of mice to heptane vapor resulted
In more dramatic changes In breathing patterns. Half of the mice exposed by
Furner (1921) to 0.06-0.08 g/l (14,700-19,600 ppm) heptane died of
respiratory arrest within 45 minutes, while others were prostrated and lost
a
reflexes within 90 minutes. However, Lazarew (1929) did not report death of
mice prostrated at 40 mg/l {9800 ppm) for <2 hours, and mice prostrated at
75 mg/ft, (75,000 ppm) died of respiratory arrest within 2 hours without
loss of reflexes. Exposing mice for 5 minutes, Swann et al. (1974) found no
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effects at <4000 ppm, anesthesia at >8000 ppm, respiratory Irregularities at
32,000 ppm and death from respiratory arrest at 48,000 ppm heptane.
Volunteers reported slight vertigo when exposed to 1000 ppm heptane for
6 minutes or to 2000 ppm for 4 minutes; hilarity and Inability to walk when
exposed to 5000 ppm for 4 minutes; Incoordlnatlon after 7 minutes; and
marked vertigo at 10 minutes (Patty and Yant, 1929). Dermal application to
humans produced visual and subjective evidence of severe Irritation that
subsided hours to days after exposure terminated (Oettel, 1936). The
Intravenous L05Q for heptane was 222 mg/kg by bolus Injection Into mice
(Jeppsson, 1975), and the 2-hour Inhalation LC5Q In mice was 75 g/m3
(NIOSH, 1989).
No data regarding the carclnogenlclty of n-heptane were found 1n the
available literature, and the compound was reportedly nonmutagenlc to
.bacteria, fungi and cultured mammalian cells (Brooks et al., 1986). There
were no data regarding fetotoxlclty, teratogenUHy or reproductive toxlclty.
vin
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. CHEMICAL AND PHYSICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 2
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 5
2.2.4. Mlcroblal Degradation 6
2.2.5. Bloconcentratlon 6
2.2.6. Adsorption 6
2.2.7. Volatilization 6
2.3. SOIL 7
2.3.1. Mlcroblal Degradation 7
2.3.2. Adsorption/Leaching 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 14
3.5. OTHER 14
3.6. SUMMARY « 14
4. ENVIRONMENTAL TOXICOLOGY 15
4.1. AQUATIC TOXICOLOGY 15
4.1.1. Acute Toxic Effects On Fauna 15
4.1.2. Chronic Effects On Fauna 15
4.1.3. Effects On Flora 15
4.1.4. Effects On Bacteria 15
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TABLE OF CONTENTS (cent.)
Page
4.2. TERRESTRIAL TOXICITY 15
4.2.1. Effects On Fauna 15
4.2.2. Effects On Flora 16
4.3. FIELD STUDIES 16
4.4. AQUATIC RISK ASSESSMENT 16
4.5. SUMMARY 16
5. PHARMACOKINETICS 17
5.1. ABSORPTION 17
5.2. DISTRIBUTION 17
5.3. METABOLISM 18
5.4. EXCRETION 23
5.5. SUMMARY 23
6. EFFECTS 25
6.1. SYSTEMIC TOXICITY 25
6.1.1 Inhalation Exposure 25
6.1.2. Oral Exposure 27
6.1.3. Other Relevant Information 27
6.2. CARCINOGENICITY 30
6.2.1. Inhalation 30
6.2.2. Oral 30
6.2.3. Other Relevant Information 30
6.3. MUTAGENICITY 30
6.4. TERATOGENICITY 31
6.5. OTHER REPRODUCTIVE EFFECTS 31
6.6. SUMMARY 31
7. EXISTING GUIDELINES AND STANDARDS 34
7.1. HUMAN 34
7.2. AQUATIC 34
8. RISK ASSESSMENT 35
8.1. CARCINOGENICITY ! 35
8.1.1. Inhalation 35
8.1.2. Oral 35
8.1.3. Other Routes 35
8.1.4. Weight of Evidence 35
8.1.5. Quantitative Risk Estimates 35
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TABLE OF CONTENTS (cont.)
Page
8.2. SYSTEMIC TOXICITY 35
8.2.1. Inhalation Exposure 35
8.2.2. Oral Exposure 37
9, REPORTABLE QUANTITIES 38
9.1. BASED ON SYSTEMIC TOXICITY 38
9.2. BASED ON CARCINOGENICITY 42
10. REFERENCES 43
APPENDIX A A-l
APPENDIX B 8-1
APPENDIX C C-l
x1
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LIST OF TABLES
No. Title Page
1-1 Current Manufacturers of Heptane In the United States 3
1-2 Heptane Production 1n the United States 4
3-1 Representative Concentrations of Heptane In Air 11
3-2 Heptane Concentrations In the Ambient Air of Representative
Occupational Uses 13
5-1 Metabolites Excreted In Urine of Rats and Humans
Exposed to n-Heptane 19
9-1 Inhalation Toxlclty Summary for n-Heptane 39
9-2 Composite Scores for Inhaled n-Heptane 40
9-3 n-Heptane: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 41
xM
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LIST OF ABBREVIATIONS
AEL Adverse effect level
BCF Bloconcentratlon factor
CS Composite score
PEL Frank effect level
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
LCso Concentration lethal to 50% of recipients
(and all other subscripted dose levels)
LD50 Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
PEL Permissible exposure level
ppb Parts per billion
ppbv Parts per billion volume
ppm Parts per million
RDg Zero effect threshold level for respiratory depression
RDso Median effective dose for respiratory depression
RfD Reference dose
RNA Rlbonuclelc acid
RQ Reportable quantity
RVe Effect-rating value
STEL Short-term exposed level
THOD Theoretical oxygen demand «
TLV Threshold limit value
TWA Time-weighted average
UV Ultraviolet
VOC Volatile organic compound
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Heptane is also known as n-heptane, dipropylmethane, heptyl hydride and
skellysolve C (Chemline. 1989; SANSS, 1989). The structure, CAS number,
molecular weight and empirical formula for heptane are as follows:
CAS Registry number: 142-82-5
Empirical formula: C7H,B
Molecular weight: 100.20
1.2. CHEMICAL AND PHYSICAL PROPERTIES
Heptane is a colorless, flammable liquid with a weak paraffink 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: -90.6°C Weast et al., 1-988
Boiling point: 98.4'C Weast et al., 1988
Density: 0.6837 g/m* Weast et al., 1988
Vapor Pressure 0
at 25'C: 45.8 mm Hg MacKay and Sh1u, 1981
Water Solubility
at 25°C: 2.93 mg/t MacKay and Shlu, 1981
Log Kow: 4.66 Hansch and Leo, 1985
5943H -1- 06/21/89
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Flash point
(closed cup):
A1r odor threshold:
Hater Odor threshold:
Conversion factor:
at 25°C
1 mg/m3 = 0.245 ppm
-3.89°C (25°F)
150 ppm
0.0073 ppm
1 ppm =4.07 rag/m3
Sax and Lewis, 1987
Amoore and Hautala, 1983
Amoore and Hautala, 1983
1.3. PRODUCTION DATA
Heptane Is produced commercially by fractional distillation of suitable
hydrocarbon feedstock, such as crude oil or liquids stripped from natural
gas (Dale and Montgomery, 1981). Pure n-heptane Is removed from branched
heptanes and other contaminants by rectification (Sax and Lewis, 1987).
Current domestic manufacturers are given In Table 1-1. Domestic production
volume for recent years can be found 1n Table 1-2.
1.4. USE DATA
Heptane Is used as the low-end standard for gasoline octane rating, as a
solvent. In organic synthesis, In the preparation of laboratory reagents and
as an anesthetic (Sax and Lewis, 1987).
1.5. SUMMARY
Heptane Is a colorless, volatile and flammable organic liquid with a
weak parafflnlc odor. Heptane Is soluble In most polar and nonpolar organic
solvents such as ether, acetone, benzene and chloroform (Sax and Lewis,
1987; Weast et a!., 1988). It 1s only slightly soluble In water. Heptane
is commercially produced by the fractional distillation of suitable petro-
o
chemical feedstocks. Heptane Is separated from branched heptanes and other
contaminants by rectification. Heptane Is used as a solvent. In organic
synthesis and as an anesthetic. It 1s also the low-end standard for
gasoline octane rating (Sax and Lewis, 1987).
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Company
TABLE 1-1
Current Manufacturers of Heptane In the United States*
Location
Exxon Chemical Americas
The Humphrey Chemical Corp.
Hill Petroleum Co.
Pennzoi1 Co.
Phi 11ips Petroleum Co.
Salomon, Inc.
Texaco Chemical Co.
Union Oil Co.
Baytown, TX
North Haven, CT
Houston, TX
Shreveport, LA
Borger and Sweeny, TX
Houston, TX
El Dorado, KA
Beaumont, TX; Lemont, IL
'Source: SRI, 1988; USITC, 1988
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TABLE 1-2
Heptane Production In the United States*
Year
1987
1986
198S
1984
Production
(In thousands of pounds)
178,497
131,311
123,948
114,677
Sales
127,085
121,890
121,660
119,318
*Source: USITC, 1985, 1986, 1987, 1988
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on a vapor pressure of 45.8 mm Hg at 25°C (Mackay and Shlu, 1981),
heptane Is expected to exist almost entirely 1n the vapor phase In the
ambient atmosphere (Elsenrelch et al.t 1981).
2.1.1. Reaction with Hydroxyl Radicals. The estimated half-life for the
reaction of heptane with photochemical1y produced HO- In the atmosphere Is
2.2 days at 26°C. This value Is based on an experimental rate constant of
7.18xlO~12 cm'/molecules-sec and an average atmospheric HO- concentra-
tion of 5.0x105 molecules/cm3 (Atkinson, 1985).
2.1.2. Reaction with Ozone. Heptane 1s not susceptible to atmospheric
degradation by reaction with ozone (Atkinson, 1985; U.S. EPA, 1987).
2.1.3. Photolysis. Heptane does not absorb UV light In the environ-
mentally significant range >290 nm (Sllversteln and Sassier, 1963) and Is
not expected to undergo photolytlc degradation In the troposphere.
2.1.4. Physical Removal Processes. The limited water solubility of
heptane, 2.93 mg/i at 25'C (MacKay and Shlu, 1981), suggests that rain
washout may occur; however, H Is probably not a significant fate process
since rapid revolatlUzatlon to the atmosphere would be expected to occur.
2.2. WATER
2.2.1. Hydrolysis. Heptane 1s not expected to hydrolyze under environ-
mental conditions, since It contains no hydrolyzable functional groups
(Harris, 1982).
9
2.2.2. Oxidation. Pertinent data regarding the oxidation of heptane In
water were not located In the available literature cited In Appendix A.
2.2.3. Photolysis. Heptane does not absorb UV light 1n the environ-
mentally significant range >290 nm (Sllversteln and Bassler, 1963) and Is
not expected to undergo photolytlc degradation In water.
5943H -5- 07/26/89
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2.2.4. Mlcroblal Degradation. Heptane was subjected to aerobic degrada-
tion 1n experiments using a shallow well water Inoculum and degraded
completely within 7 days (Delflno and Miles, 1985). Using mlcroblota
obtained from groundwater contaminated by a gasoline spill, heptane (added
as a component of high-octane gasoline) underwent 49% aerobic blodegradatlon
after 192 hours {Jamison et al., 1976). Heptane underwent 23.4% biological
THOD after 72 hours using a benzene-acclimated sludge seed (Malaney and
McKlnney, 1966). However, the heptane concentration In this study, 500
mg/i, was well above heptane's water solubility.
2.2.5. Bloconcentratlon. The 8CF for heptane ranges from 339-2050, based
on Us water solubility, 2.93 mg/i at 25°C (MacKay and Shlu, 1981) and Its
log KQW, 4.66 (Hansch and Leo, 1985). The respective regression
equations, log BCF = 0.76 log KQW - 0.23 and log BCF = 2.791 - 0.564 were
used In this determination (Bysshe, 1982). These values suggest that
bloconcentratlon In fish and aquatic organisms may be significant.
2.2.6. Adsorption. Using the regression equations log K = 0.55 log
KQW * 3.64 and log KQC = 0.544 log KQW + 1.377 (Lyman, 1982), the
KQC for heptane ranges from 2400-8200, based on Us water solubility, 2.93
mg/i at 25°C (MacKay and Shlu, 1981) and Its log kQw, 4.66 {Hansch and
Leo, 1985). These values suggest that adsorption to sediment and suspended
organic matter 1s an Important fate process.
2.2.7. Volatilization Based on heptane's water solubility, 2.93 mg/j. at
25°C (MacKay and Shlu, 1981) and vapor pressure, 45.8 mm Hg at 25'C (MacKay
o
and Shlu, 1981), a Henry's Law constant of 2.06 atm-mVmol at 25°C can be
calculated. Using the group estimation method of Mine and Mookerjee (1975),
a value of 2.39 atm ma/mol 1s obtained. The magnitude of these estimates
suggests extremely rapid volatilization of heptane from water to the
5943H
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07/26/89
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atmosphere. Using the method of Thomas (198?), and the smaller of the two
values given above, the estimated volatilization half-life Is 2.9 hours for
a model river 1 m deep, flowing 1 m/sec with a wind velocity of 3 m/sec.
The actual volatilization half-life of heptane may be somewhat longer than
this model predicts, since the effect of adsorption to suspended solids and
sediments was not considered.
2.3. SOIL
2.3.1. Mlcroblal Degradation. In a survey of the blodegradablllty of high
molecular weight alkanes under aerobic conditions, heptane underwent
degradation using a soil Inoculum (Halnes and Alexander, 1974).
2.3.2. Adsorption. Using the method of Lyman (1982), the KQC for
heptane Is calculated at 2400-8100 {see Section 2.2.6). These values
suggest that heptane adsorbs strongly to soil (Swann et al., 1983).
2.3.3. Volatilization. Heptane's vapor pressure, 45.8 mm Hg at 25°C
(Mackay and Shlu, 1981), suggests that volatilization from soil to the
atmosphere may be an Important fate process, although strong adsorption to
soil, as suggested by Us relatively high K values (see Section 2.2.6),
may attenuate volatilization.
2.4. SUMMARY
In the atmosphere, heptane 1s expected to occur almost entirely 1n the
vapor phase (E1senre1ch et al., 1981). Apparently, reaction with photochem-
Ically produced HO- Is the primary degradation pathway (half-life = 2.2
days) (Atkinson, 1985). Small amounts of heptane may be removed from the
O
atmosphere by rain washout; however, H would rapidly revolatlllze. Neither
the reaction with ozone nor direct photochemical degradation are expected to
be Important removal processes. In water, Important fate and transport
processes are probably volatilization (estimated half-life <3 hours from a
5943H -7- 07/26/89
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typical river), aerobic degradation (Delflno and Miles, 1985; Jamison et
al., 1976), adsorption to sediment and suspended organic matter and blocon-
centratlon 1n aquatic organisms. Oxidation, photolysis and hydrolysis are
probably not Important fate processes In water. In soil, heptane undergoes
aerobic degradation (Halnes and Alaxander, 1974). Heptane probably volati-
lizes rapidly to the atmosphere from soil surfaces; however, heptane's
potential to strongly adsorb to sediment and suspended matter may attenuate
the volatilization rate.
5943H -8- 07/26/89
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3. EXPOSURE
Heptane Is a highly volatile, natural component of crude oil and natural
gas (Dale and Montgomery, 1981). It may be released to the environment from
anthropogenic sources Including losses from wastewater and fugitive
emissions from the manufacture, formulation, use and transport. Accidental
spills of crude (McDonald et al., 1984) and finished fuel products (Jamison
et al., 1976) and emissions from gasoline (Shamsky and Sam1m1, 1987) and
motor vehicle exhaust (Nelson and Qulgley, 1984) also release heptane to the
atmosphere. Heptane has also been found as an Incineration by-product from
the Incomplete combustion of plastics (Junk and Ford, 1981).
Between 1981 and 1983, =235,902 workers were occupationally exposed to
heptane (NIOSH, 1984). Based on available monitoring data, the general
population may be exposed to heptane primarily by Inhalation. Exposure may
also result from direct contact with refined petroleum products.
3.1. WATER
At an offshore oil production platform, the heptane concentration near
an underwater gas vent was 1330 ng/t (Sauer, 1981). In New Mexico,
heptane was detected In the soil and groundwater underneath an earthen
disposal pit used for oil well water (EIceman et al., 1986). Heptane was
found In European drinking water supplies (Kool et al., 1982), In process
water from Gulf of Mexico oil production platforms at <400 wg/l (Sauer,
1981) and In the spent chlorlnatlon liquor used In the bleaching of wood
pulp at *3-7 g/ton of pulp (Carlberg et al., 1986).
3
Heptane was also found 1n 8/9 deep sediment samples from Halvls Bay,
Africa, at <0.63 ng/g (Uhelan et al., 1980). The authors concluded that
this compound probably results from low-temperature (<15°C) biological or
chemical processes. Heptane entered seawater In an experiment that mimicked
an oil spill (McDonald et al., 1984).
5943H
-9-
09/07/89
-------
3.2. FOOD
Heptane has been Identified as a volatile component of fried bacon (Ho
et al., 1983), roasted filberts (Klnlln et al.( 1972) and Intact nectarines
In a head space analysis (Takeoka et al., 1988).
3.3. INHALATION
Representative heptane concentrations In the ambient atmosphere appear
In Table 3-1. Typical values for rural areas are =0-1 ppb, while typical
values for urban settings are =0-140 ppb (see Table 3-1). In a consolida-
tion of the ambient concentrations of VOCs measured In the United States,
the average concentration of heptane for all ambient sites (urban, rural,
suburban and remote) was 1.616 ppbv (6.6 jig/m3) (Shah and Heyerdahl,
1988). Based on this average concentration and an average dally air Intake
by humans of 20 mVday, the average dally heptane Intake Is =132 »ig.
Based on the median heptane concentration for rural, 0.011 ppbv (0.0405
wg/m3), urban, 0.964 ppbv (3.94 pg/ma), and suburban, 0.596 ppbv
(2.43 vig/m3) areas (Shah and Heyerdahl, 1988), the average dally Intakes
for these areas are 8.95, 78.5 and 48.5 vg, respectively.
Heptane was found as a by-product of the Incomplete combustion of
plastics (Junk and Ford, 1980). Heptane was detected In gas samples from a
landfill simulator running on common garbage (Vogt and Malsh, 1985) and as a
gaseous emission of vehicle traffic through the Allegheny Mountain Tunnel of
the Pennsylvania Turnpike (Hampton et al., 1982; Sauer, 1981). The average
exhaust from 67 gasoline-fueled vehicles contained n-heptane at a concentra-
3
tlon 0.9X by weight (Nelson and Qulgley, 1984). Representative ambient air
concentrations associated with occupational usage of this compound appear In
Table 3-2.
5943H -10- 09/07/89
-------
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TABLE 3-2
Heptane Concentrations in the Ambient Air
of Representative Occupational Uses
Occupation
Concentration
Reference
Spray painting/
spray gluing
Screen-printing plant
upstairs apartments
Gasoline tank removal site
breathing zone
upwind
downwind
in excavation
above excavation
Petroleum industry
outside operators
transport drivers
service attendants
Shale oil water facility
Rubber manuf. plant
shoe sole vulcanization
tire retread vulcanization
tire retread extrusion
ND-0.81 mg/m1
ND-7.81 mg/m3
ND-0.51
ND-30.9 mg/m3'
ND-0.24
ND-1.38
ND-387
ND-4.48
0.243 mg/m3
0.275
0.200
24 jag/m3
20-14.000
3-500
ND-70
Hhitehead et al., 1984
Verhoeff et al., 1988
Verhoeff et al., 1988
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
Hawthorne and Sievers,
1984
Cocheo et al., 1983
Cocheo et al., 1983
Cocheo et al., 1983
'Original data reported
factor 1 ppm » 4.07
NO - Not detected
In ppb and converted to mg/m1 by the conversion
5946H
-13-
06/21/89
-------
3.4. DERMAL
Pertinent data regarding dermal exposure to heptane were not located In
the available literature dted In Appendix A.
3.5. OTHER
Heptane was detected 1n 7/12 samples of mothers' breast milk In Bayonne,
NJ, Jersey City, NJ, Brldgevllle, PA, and Baton Rouge, LA (Pelllzzarl et
al., 1982).
3.6. SUMMARY
Heptane Is a highly volatile, natural component of crude oil and natural
gas (Dale and Montgomery, 1981). It may be released to the environment from
anthropogenic sources Including losses from wastewater and fugitive
emissions from the manufacture, formulation, use and transport of this
solvent. Accidental spills of crude (McDonald et al., 1984) and finished
(Jamison et al., 1976) petrochemclal fuel products and emissions from
gasoline (Shamsky and Sam1m1, 1987) and motor vehicle exhaust (Nelson and
Qulgley, 1984) also release heptane to the atmosphere.
The available monitoring data suggest that the general population may be
exposed to heptane primarily through Inhalation. Exposure may also occur
through direct contact with refined petroleum products. Based on available
monitoring data, the average dally Intakes of heptane through Inhalation In
rural, urban and suburban areas are an estimated 8.95, 78.5 and 48.5 yg,
respectively. Representative heptane concentrations In the ambient
atmosphere are summarized In Tables 3-1 and 3-2.
5943H
-14-
09/07/89
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects On Fauna. Pertinent data regarding the effects
of acute exposure of aquatic fauna to heptane were not located In the
available literature cited In Appendix A.
4.1.2. Chronic Effects On Fauna.
4.1.2.1. TOXICITY -- Pertinent data regarding the effects of chronic
exposure of aquatic fauna to heptane were not located In the available
literature cited 1n Appendix A.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION -- The BCF for heptane
ranges from 339-2050, based on Us water solubility, 2.93 mg/t at 25°C
(MacKay and Sh1u, 1981) and Us log KQW, 4.66 (Hansch and Leo, 1985). The
respective regression equations, log BCF = 0.76 log K - 0.23 and log
BCF * 2.791 - 0.564 were used 1n this determination {Bysshe, 1982). These
values suggest that bloconcentratlon 1n fish and aquatic organisms may be
significant.
4.1.3. Effects On Flora.
4.1.3.1. TOXICITY Pertinent data regarding the toxic effects of
exposure of aquatic flora to heptane were not located In the available
literature cited 1n Appendix A.
4.1.3.2. 8IOCONCENTRATION The BCF for heptane ranges from 339-2050,
based on Its water solubility, 2.93 mg/i at 25°C {MacKay and Shlu, 1981)
and Its log K , 4.66 (Hansch and Leo, 1985). The respective regression
ow o
equations, log BCF = 0.76 log KQW - 0.23 and log BCF = 2.791 - 0.564 were
used In this determination (Bysshe, 1982). These values suggest that
bloconcentratlon In fish and aquatic organisms may be significant.
5943H -15- 09/07/89
-------
4.1.4. Effects On Bacteria. Pertinent data regarding the effects of
exposure of aquatic bacteria to heptane were not located 1n 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 heptane were not located In the available literature
dted In Appendix A.
4.2.2. Effects On Flora. The clastogenlc effects of heptane were studied
using the broad bean, Vlcla faba. root tip assay (Gomez-Arroyo et al.,
1986). Root tips were exposed to heptane concentrations of 0,1-3.0%
(1000-30,000 mg/l) for 4 hours. Untreated controls were also Included.
Cell division was Inhibited by all heptane concentrations tested, but the
effect was not concentration-related. The percentages of total anaphases
and total aberrations were elevated at all exposure concentrations compared
with controls; however, these effects were not concentration-related.
4.3. FIELD STUDIES
Pertinent data regarding the effects of heptane on flora and fauna In
the field were not located In the available literature cited In Appendix A.
4.4. AQUATIC RISK ASSESSMENT
No data were available regarding the effects of exposure of aquatic
flora and fauna to heptane, precluding the development of freshwater and
saltwater criteria by the method of U.S. EPA/OWRS (1986).
4.5. SUMMARY
3
In a genotoxldty assay conducted 1n bean plants, mitosis was Inhibited,
and the frequencies of abnormal anaphases and total aberrations were
elevated at all concentrations of heptane tested (1000-30,000 mg/l)
(Gomez-Arroyo et al., 1986). These effects were not concentration-related,
however, which suggests that they may not have been produced by heptane.
41
^^ 5943H -16- 09/07/89
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Dahl et al.. (1988) exposed one male Fischer 344/N rat (nose only) to
100 ppm 99+X n-heptane for 80 minutes, sampling the Intake and exhaust
streams by gas chromatography at I0-m1nute Intervals. Actual Intake and
exhaust stream concentrations were not reported; therefore, percent
retention could not be estimated. They estimated, however, a 4.5 ± 0.3
nmol/kg/mln/ppm (450 ng/kg/mln/ppm) uptake of n-heptane and Justified the
o
normalization to body weight and Inhaled concentration on the grounds that
It facilitated comparisons among the alkanes under different exposure
conditions.
5.2. DISTRIBUTION
Savolalnen and Pfaffll (1980) exposed groups of 15 adult male Ulstar
rats to 4.2 (100 ppm), 21 (500 ppm) or 62 ymol/l (1500 ppm) 6 hours
dally, 5 days/week for 1-2 weeks and a control group to 0 ppm n-heptane and
determined n-heptane levels 1n the brain and perlrenal fat taken from groups
t
of animals sacrificed after 1- or 2-week exposure or after a 2-week recovery
period. Heptane concentration (In both brain and fat) Increased linearly
with atmospheric concentration during the first week of exposure; the rate
of uptake In these tissues Increased from 1 to 2 weeks because of retention,
but none of the solvent remained 2 weeks posttreatment. The level of
n-heptane was higher 1n perlrenal fat than In the brain, and the ratio of
perlrenal fat to brain levels Increased with length of exposure and with
<3
atmospheric concentration.
Perbelllnl et al. (1986) exposed 10 young adult male Sprague-Dawley rats
for 6 hours to 7680 mg/m3 (1860 ppm) >90% pure n-heptane. Half the
5943H -17- 09/07/89
-------
animals were sacrificed Immediately after exposure for analysis of acid
hydrolysates of blood and tissue samples for heptane metabolites by gas
chromatography and mass spectroscopy. The authors reported only small
amounts of heptane and Its metabolite, 2-heptanol. Of 2-heptanol, 5.7,
25.6, 22.9, 10.1 and 18.4 mg/i were found In blood, liver, muscle, kidney
and nervous tissue, respectively. Tissue/blood partition coefficients were
thus 4, 1.8, 4.5 and 3.2 for muscle, kidney, liver and brain, respectively.
Neither heptane nor this metabolite was found In blood or tissues In animals
sacrificed 24 hours after exposure. This, however, conflicts with the
findings of Savolalnen and Pfa'ffll (1980) who found retention of the
chemical during a 1- to 2-week exposure.
5.3. METABOLISM
Perbelllnl et al. (1986) exposed rats to n-heptane (see Section 5.2).
Urine was collected from five animals over the 24 hours following the
exposure, while urine from before the exposure served as control.
Additionally, five shoe factory and three rubber workers (gender not
reported) who were exposed to 5-196 mg/m3 n-heptane In a mixture of C-6 to
C-8 normal, branched-chaln and cyclic alkanes submitted urine samples at the
end of their work shifts; urine from an unexposed worker served as control.
Acid hydrolysates of the urine were analyzed for heptane metabolites by gas
chromatography and mass spectroscopy using literature data for comparison,
rather than Internal standards. Results are presented 1n Table 5-1.
Bahlma et al. (1984) exposed groups of six female Ulstar rats to 0 or
a
2000 ppm n-hepatane 6 hours/day, 5 days/week for 12 weeks, collecting urine
for the remaining 18 hours of each exposure day. Samples were analyzed by
gas chromatography/mass spectroscopy for free, 0-g1ucuron1dase-1ab1le,
5943H -18- 09/07/89
-------
TABLE 5-1
Metabolites Excreted 1n Urine of Rats and Humans Exposed to n-Heptanea
Metabolite
1-Heptanol
2-Heptanol
3-Heptanol
4-Heptanol
2-Heptanone
3-Heptanone
4-Heptanone
2,5-Heptanedlol
2,6-Heptanedlol
5-Hydroxy-2-heptanone
6-Hydroxy-2-heptanone
6-Hydroxy-3-heptanone
2,5-Heptanedlone
2,6-Heptaned1one
Rat
(vg/day)
ND
29.0
264
561.0
201
381.9
ND
17,2
20.0
10.6
8.4
NQ
7.3
ND
ND
14.1
ND
141.9
ND
74. 3b
ND
433. 6C
ND
13. 6d o
4.4
14.1
ND
7.46
Human
ND
NA
0.65
NA
0.39
NA
ND
NA
0.17
NA
ND
NA
0.28
NA
ND
NA
ND
NA
ND
NA
ND
ND
ND
0.25
NA
ND
NA
5943H
-19-
07/26/89
-------
TABLE 5-1 (cont.)
Metabolite Rat Human
Ug/day) (mg/t)
gamma-Valerolactone 65.4 3.49
190.9 NA
2-Ethyl-5-methyl-2,3-d1hydrofuran NQ NO
74.3f NA
2,6-D1methyl-2,3-d1hydropyran NQ NO
NO NA
aSource: Perbelllnl et al., 1986; Bahlma et al.t 1984
bDetected as 2-ethyl-5-methyl-2,3-d1hydrofuran
cDetected as 2,5-dtmethyl-2,3-d1hydropyran
dfletected as 5-ethyl-2-methyl-2,3-d1hydrofuran
eDetected as 1-methyl cyclohex-l-en-3-one
^Reported as 5-hydroxy-2-heptanone
ND = Not detected; NQ = not quantified; NA = not applicable
5943H -20- 07/26/89
-------
acid-labile, acid-labile volatlles, and B-glucuronldase- plus add-lablle
metabolites at various times during the exposure period, alone or In combi-
nation, and always with Internal standards. None of the metabolites were
excreted In urine as the free compounds; they were blotransformed to
sulfates and, to a lesser extent, to beta-glucuronldes. Results of the
urlnalyses are shown In Table 5-1.
The data of these two laboratories support the pathways for oxldatlve
degradation of n-heptane shown 1n Figure 5-1 (Bahlma et al., 1984). Conver-
sion of n-heptane to the four alcohols (1-, 2-, 3- and 4-hepatanol) Is by
hydroxylatlon, primarily at the omega minus one and two positions to 2- and
3-heptanol. The other metabolites then arise from further omega minus one
or two hydroxylatlons and/or oxidation of the secondary alcohols to the
corresponding ketones and dlketones. The relative amounts of the excreted
metabolites (Table 5-1) Indicated the primary target of hydroxylatlon was
the omega minus one carbon, rather than the omega minus two pathway, which
would lead to production of neurotoxlc Intermediates with gamma-hydroxy-
ketone or y-d1ketone structures. Additionally, a-ox1dat1on of
6-hydroxy-3-heptanone to gama-valerolactone and conjugation of the mono-
alcohols further protect against build-up of such neurotoxlc substances.
Bahlma et al. (1984) speculated that Initial Increases 1n. urinary
content of the metabolites following the first two or three exposures
(Section 5.4) could be attributed to Induction of hepatic mlcrosomal
enzymes. At least three monooxygenase activities with different susceptl-
O
bllltles to phenobarbltal or benzpyrene pretreatment are Involved In the
mlcrosomal hydroxyalatlon of n-heptane (Frommer et al., 1972). However,
Jaervlsalo et al. (1982) showed that male Wlstar rat liver cytochrome P-450
Is only moderately Increased by Inhalation of 100 ppm (p<0.05) or 500 ppm
5943H 21- 07/26/89
-------
CHjCMjCMjCHjCHjCMjCMjOM
CHjCMjCH^HiCHjCHjO*,
OM
CHjCHiCMiCH CHjCWjCM,
OH
OH
2-HtpUnol
»-loiid«iai
CM,CM,CH,CM,CM CMjCM,
CMjCH 04,04,04,01 CH, CH,C CH,CM,CM,CH,CMj
OHf"""*"""
eiidiiian
C
CM,
«-Hy*wy.
CM,
oiidilian
CHjC CHjCHjCHjC CM,
NOW
XHUMion y^ii
0 /OH
CM,C CMjCMjCM CMjCH,
OH
CM£M CHjCHjCM CM,CM,
2,S-HtpdMdiOl
0
CM,C CM,CM,C CM,CH,
w-1 oiiditien
?*l
CHjCM CM,CHjC CMjCH,
Hydrocy-i HtpUnorw
ON 00
I I «
CM, CM eM,CM,C CMjCOM
OOOM
tetian
OM 0
CM,CM CH,CH,COH
4-Mydroiy pcntmoic *e«l
FIGURE 5-1
Metabolic Scheme for n-Heptane
Source: Bahlma et al., 1984
S943H
-22-
07/26/89
-------
(0<0.01} and unaffected by Inhalation of 1500 ppm n-heptane 6 hours/day, 5
days/week for 1-2 weeks. Jji yUro exposure of guinea pig liver mlcrosomes
to n-heptane also Increased NADPH-cytochrome P-450 reductase activity at low
(0.07X), but not at high, concentrations (l.OX) (Notten and Henderson,
1975); Incubation of the mlcrosomes wHh concentrations >0.5X (5 mM) heptane
depressed the activity. Rabovsky et al. (1986) found that the cytochrome
P450- mediated activities of benzp[a]pyrene hydroxylase and 7-ethoxycoumarln
deethylase were reduced to =25-65% of control In male Sprague-Dawley rat
lung and liver mlcrosomes by 2 mM n-heptane.
5.4. EXCRETION
The major metabolites from add hydrolysates of urine from rats exposed
to 2000 ppm n-heptane were quantified dally over 1 week from urine samples
collected by Bahlma et al. (1984) during the 18 hours following each of five
dally 6-hour exposures and on 2 subsequent nonexposure days. Following
sharp Increases over 2 or 3 days, steady-state concentrations of 2- and
3-heptanol, y-valerolactone and 2,6-heptanedlol were achieved after 2
days, and of 5- and 6-hydroxy-2-heptanone. after 3 days of exposure. On the
first day postexposure, 2-heptanol, 2-hydroxy-2-heptanone, and 3-heptanol,
the only metabolites above the detection limit, were 2% of their steady-
state values. By the second day postexposure, 2-hepatanol, 2-hydroxy-2-
heptanone and 3-heptanol were =0.3% of their steady-state values. Data
were not located regarding the proportion of a dose of n-heptane excreted In
the urine or by other routes of elimination.
a
5.5. SUMMARY
The pharmacoklnetlc data for n-heptane are somewhat limited. The
absorption rate In rats exposed to <100 ppm Is 450 ng/kg/m1n/ppm (Dahl et
al., 1988), but there Is no Information regarding the proportion absorbed
5943H -23- 07/26/89
-------
at the higher levels, for which excretion data {Perbelllnl et al., 1986) are
available. The hydrophoblc parent compound might concentrate 1n fatty
nervous tissue, but much more appears In perlrenal fat than In the brains of
exposed rats (Savolalnen and Pfaffll, 1980). The brain/blood partition for
Its primary metabolite, 2-heptanol, 1s not high but Intermediate between
muscle or liver and kidney. Moreover, all tissue and blood measurements
Indicate that heptane and Its primary metabolite (2-heptanol) are rapidly
removed from the organism when exposure ends.
Considered 1n combination with metabolic data Indicating low production
of neurotoxlc metabolites, which are entirely conjugated (Bahlma et al.,
1984; Perbelllnl et al., 1986) and thus sequestered from neural targets,
heptane Is expected to be of relatively low neurotoxlclty for a C6-C8
alkane. Data were not located regarding the extent to which a dose of
n-heptane Is eliminated by various routes of excretion.
5943H -24- 07/26/89
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.'1.1. SU8CHRONIC -- Takeuchl et al. (1980, 1981) exposed groups of
seven adult male Wlstar rats to 0 or 3000 ppm 99OS heptane 12 hours/day for
16 weeks to evaluate neurotoxlctty. There was a significant decrease In
weight gain at 8, but not at 4, 12 or 16 weeks of exposure and slight
subcellular changes In peripheral nerves, muscles, and neuromuscular
synapses at the end of the exposure period. There were no hlstopathologlcal
changes (examination was limited to selected peripheral nerves and
gastronemus muscle), no effects on nerve conduction or walking gait and no
evidence of foot drop.
Truhaut et al. (1973) exposed Wlstar rats (sex and number not reported)
to 1500 ppm technical grade (52.4%) heptane In air 5 hours/day, 5 days/week
for 1-6 months. The Investigators removed the sciatic and saphenous nerves
after varying lengths of exposure and stimulated them with square pulses at
various voltages. They found decreased threshold conduction rates and
excitability, and Increased refractory periods. Microscopic examination
after 5-6 months of exposure revealed retraction of myelln sheaths and
rupture of Schwann cell membranes. However, the authors noted that such
Impurities as 3-methylhexane, benzene, toluene and cyclohexanes In the
heptane may have contributed to their results.
In an unpublished study at Bio Dynamics (1980), groups of 15 male and 15
o
female Sprague-Oawley rats were exposed to 0, 400 or 3000 ppm 98.5% n-
heptane, respectively, 6 hours/day, 5 days/week, for 26 weeks. Clinical
signs observed In a dose-related fashion with regard to Incidence and
severity during exposure In both treatment groups at 1 week, but not at 2
5943H -25- 07/26/89
-------
weeks, Included rapid shallow breathing, prostration and. 1n the high-dose
group, Insensltlvlty to sound. More persistent observations Included dry
rales, exopthalmla and yellow staining of ano-genltal fur In the high-dose
group, but not at significant frequency In the low-dose group. Serum
alkaline phosphatase levels Increased In a dose-related fashion In female
rats, reaching statistical significance (p<0.05) In high-dose females only
at 26, but not 13 weeks. There were no treatment-related effects noted In
weekly observations of body weight gain, hematology or urlnalyses. Results
of gross or microscopic pathological examinations were not reported.
Frontall et al. (1981) exposed groups of 6-9 rats (strain and gender not
reported) to 1500 ppm 99X n-heptane 9 hours/day, 5 days/week for 30 weeks
and saw no change In hind limb spread or weight gain and no degeneration In
tlblal neural axons such as that observed with n-hexane treatment. Control
rats were mentioned In the presentation of results, but It was unclear
whether controls were concurrent, historical or pretreatment data on the
experimental rats.
6.1.1.2. CHRONIC -- Of 18 employees 1n a Milanese tire factory, 12
whose personal and family history excluded nonoccupatlonal causes of
peripheral neuropathy underwent electrophyslologlcal study (Crespl et al.,
1979). They had been occupaUonally exposed for 1-9 years to un.reported
concentrations of vapor from a solvent containing >95X n-heptane with traces
of other linear and allcycllc hydrocarbons, benzene and toluene In
concentrations under their statutory limits. The subjects complained of
a
numbness and paresthesla of the limbs with a glove and stocking distribu-
tion. Most, but not all, were female. Motor conduction velocity of 10
workers, while not under the "normal range," decreased with exposure time
with a statistically significant (p>99%) age-Independent correlation.
5943H -26- 07/26/89
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Distal latency was not different from age-matched controls or related to
exposure time, but amplitude desynchronlzatlon of the evoked muscle action
potential along the peroneal nerve of 12 subjects did differ significantly
(p>95%) from controls (not duration-related). Pooled electrophyslologlcal
data In all subjects correlated with exposure time (p>95X) and was
Independent of age.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC -- Pertinent data regarding the systemic toxlclty
of subchronlc oral exposure to n-heptane were not located In the available
literature cited 1n Appendix A.
6.1.2.2. CHRONIC Pertinent data regarding the systemic toxlclty of
chronic oral exposure to n-heptane were not located In the available
literature cited 1n Appendix A.
6.1.3. Other Relevant Information. Savolalnen and Pfaffll (1980) exposed
groups of 15 adult male Wlstar rats to 4.2 (100 ppm), 21 (500 ppm) or 62
ttmol/R, (1500 ppm) n-heptane and a control group of rats (number not
reported) to 0 ppm n-heptane 6 hours dally, 5 days/week for 1-2 weeks.
Brain RNA, glutathlone, add protelnase, NADPH-dlaphorase and superoxlde
dlsmutase were quant Ha ted. Sporadic Increases and decreases at the
different treatment levels at 1 and 2 weeks were reported. The acid
protelnase level, which decreased (p<0.05) 1n the 500 ppm group at 1 week
and Increased (p<0.01 or 0.001) In all treated groups at 2 weeks appeared
the most likely of these variations to be treatment-related, but the
o
biological significance of this finding Is unclear.
KMstlansen and Nielsen (1988) exposed groups of four male Intact CF-1
mice with a mean weight of 27 g to 8157, 9609, 15,513, 18,600, or 24,801 ppm
99.5% n-heptane for 30 minutes to study heptane-Induced sensory Irritation
5943H -27- 07/26/89
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of the upper respiratory tract; groups of four male tracheally-cannulated
mice of the same weight were exposed to 5607, 9507, 15,668 and 21,746 ppm n-
heptane for 30 minutes to study pulmonary Irritation. Irritants of the upper
respiratory tract stimulate trlgemlnal nerve endings, and Irritants of the
lungs In rats In which the trlgemlnal system 1s bypassed stimulate pulmonary
receptors. The bradypnea from the two reflexive responses were studied
separately as percent decreases In respiratory rate, which showed signifi-
cantly linear responses to the logarithm of atmospheric heptane concentra-
tion In the first (p<0.005) and last 10 minutes (p<0.01) of exposure of
Intact mice, and for the first 10 minutes (p<0.025) exposure of tracheally-
cannulated mice.
The RDc0 (0-10 minutes) was 17,400 ppm because of the sensory
Irritation of the upper respiratory tract and the RD5Qx0.03, the maximum
acceptable In Industrial situations (Alarle, 1981) was 520 ppm. The authors
argued that
"for substances with a low slope of the concentration-response
curves, a better approach may be to use the threshold response for
sensory Irritation (ROp, 5447) and multiply by 0.2 . . . giving
the value 1090 ppm for heptane."
The value after adjusting for bias Is 1205 ppm. From the authors' regres-
sion equations, ROQs of 5447, 6422 and 1820 ppm can be estimated for the
0-10 minute Intact animal, 21-30 minute Intact animal and 0-10 minute
cannulated animal data sets, respectively.
Furner (1921) exposed white mice (strain, sex amd total numbers not
reported) one at a time to 0.06-0.08 g/l heptane and recorded times that
the animal became prostrate, lost reflexes, was removed from exposure or
died. For 4/8 mice, the exposure resulted 1n narcosis followed by respira-
tory arrest In 15-41 minutes. Other mice became prostrate In 22-99 minutes,
5943H
-28-
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lost reflexes In 37-85 minutes and were removed from exposure to recover
after 39-340 minutes.
In a similar protocol In which concentrations but not durations
resulting In these effects were recorded, Lazarew (1929) reported that mice
(sex, strain and number not reported) exposed <2 hours became prostrate at
40 mg/s. but maintained their reflexes until death at 75 mg/i n-heptane.
Swarm et al. (1974) exposed groups of four Swiss mice [25 g (sex not
reported)] head only to 1000, 2000, 4000, 8000, 16,000, 32,000 and 48,000
ppm 99% n-heptane for 5 minutes. Anesthesia was reported at 8000 and very
deep anesthesia at 32,000 ppm. Respiratory Irregularities were observed at
32,000 and 48,000 ppm, and 3/4 died of respiratory arrest In 3-3.75 minutes
at 48,000 ppm.
Patty and Yant (1929) exposed groups of volunteers (sex and number not
reported) for 4-10 minutes to 1000, 2000 or 5000 ppm. Slight vertigo was
reported at 1000 ppm (6 minutes) and 2000 ppm (4 minutes). Within 4 minutes
at 5000 ppm, the subjects were hilarious and unable to walk; by 7 minutes
they exhibited Incoordlnatlon. At 10 minutes, they complained of marked
vertigo.
Oettel (1936) applied undiluted heptane to a 1 cm diameter circle of the
forearm skin of five volunteers for <5 hours. The exposures resulted In
Immediate development of Irritation with erythema, hyperemla, swelling and
pigmentation. Blisters formed after 5 hours of exposure. The subjects
reported a constant burning and Itching sensation that took 2 hours after
o
termination of exposure to subside. Exposures of 1 hour caused erythema and
pigmentation that peaked 96 hours after termination of exposure, then
gradually returned to normal with no scarring.
5943H
-29-
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The 2-hour LC5Q for Inhaled heptane Is 75 g/m3 In the mouse (NIOSH,
1989). Jeppsson (1975) determined the Intravenous LD In 60 male NMRI
fasted mice was 2.22 mol x 10~3/kg (222 mg/kg) heptane by bolus Injection.
When given by continuous Intravenous Infusion, 2.87 mol x 10~Vkg (287
mg/kg) heptane caused a loss \n righting reflex.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled n-heptane were not located 1n the available literature dted In
Appendix A.
6.2.2. Oral. Pertinent data regarding the carclnogenlclty of orally
administered n-heptane were not located In the available literature cited In
Appendix A.
6.2.3. Other Relevant Information. Other pertinent data regarding the
carclnogenlclty of n-heptane were not located 1n the available literature
cited In Appendix A.
6.3. MUTAGENICITY
n-Heptane was negative 1n reverse mutation prelncubatlon assays In
Salmonella typhlmurlum strains TA1535, TA1537, TA1537, TA1538, TA98 and
TA100 with or without S9 from livers of Aroclor-lnduced rats using <250
vg/mi heptane. Negative results were also obtained In differential
killing assays with Escherlchla coll WP. and WP_ uvr A. Assays for
^ ^
mltotlc gene conversion using log-phase cultures of Saccharomyces cerevlslae
JD1 with an 18-hour Incubation with 5 mg/mi heptane with or without S9
a
were also negative. Also, <10 vg/mi heptane failed to Induce chromosome
damage In cultured rat liver cells using a 22-hour Incubation (Brooks et
al., 1988). Gomez-Arroyo et al. (1986) found the compound to have an
Inhibitory effect upon cell division.
5943H
-30-
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6.4. TERATOGENICITY
Pertinent data regarding the teratogenkity of n-heptane were not
located In the available literature dted 1n Appendix A.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding the reproductive toxlclty of n-heptane were not
located In the available literature cited In Appendix A.
6.6. SUMMARY
All available studies of the effects of subchronlc inhalation of heptane
used rats as the animal model of human toxlclty. Takeuchl et al. (1980,
1981} reported reduced weight gain In one of five monthly weighings and
slight subcellular changes In peripheral neural tissue In seven Wlstar rats
inhaling 3000 ppm 99*% pure heptane Intermittently for 16 weeks. The
electrophyslologlcal effects and microscopically observed peripheral neural
degeneration consequent to Intermittent Inhalation of 1500 ppm 52.4%
technical grade heptane by rats of the same strain may have been due to
impurities In the test chemical (Truhaut et al., 1973). When Frontall et
al. (1981) Intermittently exposed 7-9 rats of an unspecified strain to 1500
ppm 99X heptane for 30 weeks, the Investigators observed no degeneration in
neural axons, nor were there adverse effects on neurological behavior or
weight gain.
In a study by B1o Dynamics (1980), 15 Sprague-Dawley rats/sex were
intermittently exposed to 400 or 3000 ppm 98.5% heptane over 26 weeks.
Elevated serum alkaline phosphatase levels were reported In high-dose
a
females at the end of the exposure period; and clinical signs such as
shallow breathing and prostration In both dose groups were reported during
exposure periods 1n the first week of the experiment.
5943H
-31-
07/26/89
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The only data on chronic exposure to heptane by Inhalation were regard-
Ing workers occupatlonally exposed to 95X heptane vapor for 1-9 years; the
severity of peripheral neuropathy electrophyslologlcally measured closely
correlated with duration of exposure {Crespl et al., 1979). Information
about the concentration of the Inhaled heptane vapor was lacking, nor was
any Information available on potential contaminants.
There were several studies of acute exposure to n-heptane, mostly by
Inhalation. Savolalnen and Pfaffll (1980) reported sporadic alterations In
several enzymatic parameters, Including the activity of brain acid protein-
ase, examined In brain homogenates of rats exposed to 100-500 ppm heptane
Intermittently for 1-2 weeks; however, the biological significance of these
observations Is unclear. Krlstlansen and Nielsen (1988) exposed mice to
concentrations ranging from 5607-24,801 ppm heptane for 30 minutes to
separately measure bradypnea Induced by Irritation of the upper and lower
respiratory tract. Sufficient data were provided to enable estimation of
threshold levels of 5447-6422 ppm for the upper and 1820 ppm heptane for the
lower respiratory tracts.
In other laboratories, acute exposure of mice to heptane vapor resulted
In more dramatic changes In breathing patterns. Half of the mice exposed by
Furner (1921) to 0.06-0.08 g/l (60000-80000 ppm) heptane died of
respiratory arrest within 45 minutes, while others were prostrated and lost
reflexes within 90 minutes. However, Lazarew (1929) did not report death of
mice prostrated at 40 mg/t (40,000 ppm) for <2 hours, and mice prostrated
a
at 75 mg/l (75,000 ppm) died of respiratory arrest within 2 hours without
loss of reflexes. Exposing mice for 5 minutes, Swann et al. (1974) found no
effects at <4000 ppm, anesthesia at >8000 ppm, respiratory Irregularities at
32,000 ppm and death from respiratory arrest at 48,000 ppm heptane.
5943H
-32-
07/26/89
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Volunteers reported slight vertigo when exposed to 1000 ppra heptane For
6 minutes or to 2000 ppm for 4 minutes; hilarity and Inability to walk when
exposed to 5000 ppm for 4 minutes; Incoordlnatlon after 7 minutes; and
marked vertigo at 10 minutes (Patty and Yant. 1929). Dermal application to
humans produced visual and subjective evidence of severe Irritation that
subsided hours to days after exposure terminated (Oettel, 1936). The
Intravenous LDrQ for heptane was 222 mg/kg by bolus Injection Into mice
(Jeppsson, 1975), and the 2-hour Inhalation LC In mice was 75 g/m3
(NIOSH, 1989).
No data regarding the cardnogenlclty of n-heptane were found In the
available literature, and although the compound was reportedly nonmutagenlc
to bacteria, fungi and cultured mammalian cells (Brooks et al., 1986),
Gomez-Arroyo et al. (1986) found It to have an Inhibitory effect upon cell
division. There were no data regarding fetotoxldty, teratogenldty or
reproductive toxldty.
5943H
-33-
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1988) recommended a TLV-TWA and STEL of 400 ppm (1600 mg/m3)
and 500 ppm (2,000 mg/m3), respectively, for heptane, based on its
narcotic and Irritative effects (ACGIH, 1986). NIOSH (1985) recommended
that OSHA adopt a 10-hour TWA of 85 ppm (350 mg/m3) with an action level
of 200 mg/m1 based on skin and nervous system effects, presumably by
analogy to the neurotoxic effects of hexane (ACGIH, 1986; OSHA, 1989). OSHA
(1989) disagreed with this reasoning, arguing that the neurotoxicity of
hexane derived from a class of metabolites (gamma diketones) that make
hexane uniquely toxic. OSHA (1989) lowered Us earlier 500 ppm TWA-PEL of
500 ppm to 400 ppm and adopted a 500 ppm STEL to protect workers against the
risk of narcosis from acute exposures.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic life from
exposure to heptane were not located in the available literature cited In
Appendix A.
5943H
-34-
06/21/89
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenldty of
Inhaled n-heptane were not located In the available literature cited 1n
Appendix A.
8.1.2. Oral. Pertinent data regarding the cardnogenldty of orally
administered n-heptane were not located In the available literature cited In
Appendix A.
8.1.3. Other Routes. Pertinent data regarding the cardnogenldty of n-
heptane administered by other routes were not located 1n the available
literature cited 1n Appendix A.
8.1.4. Weight of Evidence. Because data were not located regarding the
cardnogenldty of n-heptane In humans or 1n animals, the compound 1s
classified In U.S. EPA Group D -- not classifiable as to human cardno-
genldty under the guidelines of the U.S. EPA (1986b).
8.1.5. Quantitative Risk Estimates. The absence of cancer data by either
the inhalation or oral routes precludes derivation of potency factors for
either route of exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) All available
studies of the effects of subchronlc Inhalation of heptane used rats as the
animal model of human toxldty. Takeuchl et al. (1980, 1981), listed In rec
o
#4, reported reduced weight gain In one of five monthly weighings and
slight, but not demonstrably adverse, subcellular changes In peripheral
neural and muscle tissue In seven Ml star rats Inhaling 3000 ppm 99*X pure
heptane Intermittently for 16 weeks.
5943H
-35-
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The transient weight effect reported by Takeuchl et al. (1980, 1981) was
not reported 1n the larger dose groups studied (weekly weighings) by B1o
Dynamics (1980). In this study, 15 Sprague-Oawley rats/sex Intermittently
Inhaled 400 (rec #3) or 3000 (rec #2) ppm 98.5X heptane over 26 weeks.
Clinical signs such as shallow breathing and prostration In both dose groups
and evidence of hearing loss In the high-dose group suggested neurotoxlclty.
These clinical signs apparently did not persist beyond 2 weeks, although dry
rales, exophthalmla and urine stains persisted throughout the experiment.
Elevated serum alkaline phosphatase levels were observed In high-dose
females at the end of the experimental period. Lack of hlstopathologlcal
examination precluded use of this study In risk assessment.
The electrophyslologlcal effects and microscopically observed peripheral
neural degeneration consequent to Intermittent Inhalation of 1500 ppm 52.4X
technical grade heptane by Hlstar rats may have been due to Impurities In
the test chemical (Truhaut et al., 1973); therefore, the study 1s not
suitable for the assessment of the risk from n-heptane. When Frontall et
al. (1981) Intermittently exposed 7-9 rats of an unspecified strain to 1500
ppm 9954 heptane (rec #1) for 30 weeks, they observed no degeneration In
neural axons or adverse effects on neurological behavior or weight gain such
as that seen 1n response to Inhalation of hexane. However, because controls
were not clearly reported, a more comprehensive toxlcologlcal evaluation of
a wider spectrum of organ systems was lacking, and there was an absence of
higher dose groups producing adverse effects, this study Is also unsuitable
9
for risk assessment.
Given the lack of firm evidence for adversity or nonadverslty of effects
from n-heptane over durations In the subchronlc range, derivation of a
subchronlc Inhalation RfD from these rat studies Is Inappropriate.
5943H
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8.2.1.2. CHRONIC EXPOSURES -- The only data on chronic exposure to
heptane by Inhalation were of workers occupatlonally exposed to 95% heptane
vapor for 1-9 years; the severity of peripheral neuropathy electrophyslo-
loglcally measured positively correlated with duration of exposure (Crespl
et al., 1979). However, Information about the concentration of the Inhaled
heptane vapor was lacking, making the study unsuitable for risk assessment.
The study suggests the existence of a neurotoxldty to humans arising from
long-term repeated exposure, a toxlclty not demonstrated by the animal
data. Future epIdemlologUal studies and chronic bloassays addressing this
gap In the heptane data base would be helpful.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) Pertinent data
regarding the systemic toxlclty of subchronlc oral exposure to n-heptane
were not located 1n the available literature dted 1n Appendix A; hence, an
RfD for subchronlc oral exposure cannot be estimated.
8.2.2.2. CHRONIC EXPOSURES - Pertinent data regarding the systemic
toxlclty of chronic oral exposure to n-heptane were not located In the
available literature dted In Appendix A; hence, an RfD for chronic oral
exposure cannot be estimated.
5943H
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The chronic and subchronlc toxUUy of n-heptane, limited to Inhalation
exposure, were discussed In Chapter 6. Dose-response data useful for
derivation of candidate CSs are summarized In Table 9-1. The study of tire
Factory workers by Crespl et al. (1979) supplied the only chronic data.
Since exposure concentrations were not given, these data cannot generate an
RQ value. Of subchronlc studies, the effects reported by Truhaut et al.
(1973) are not listed In Table 9-1 because they may have stemmed from
Impurities In the hexane. Frontall et al. (1981) reported no effects at
all, leaving for Inclusion In Table 9-1 only the observations of Takeuchl et
al. (1980, 1981) and Bio Dynamics (1980). The biological significance of
the decreased weight gain reported by Takeuchl et al. (1980, 1981) Is
suspect because the effect was seen 1n only one of four Intervals. However,
the absence of weight effects In the Bio Dynamics (1980) study may have been
a consequence of the different strains of rats used.
The responses listed In Table 9-1 can be sorted Into categories listed
In descending order of severity as follows: body weight effects (RV = 4);
dry rales, exophthalmla and elevated alkaline phosphatase (RV = 6); and
C
subcellular changes 1n peripheral nerves, muscles and neuromuscular synapses
(RVe = 2). The lowest human equivalent dose causing each effect Is listed
In Table 9-2, 1n which CSs and RQs are computed. RQ values of 5000 were
derived from the weight effect and subcellular changes (Takeuchl et al.,
a
1980, 1981), and an RQ of 1000 was derived from dry rales, exophthalmla and
elevated serum alkaline phosphatase (B1o Dynamics, 1980) (Table 9-3). While
neither work may be considered a strong key study, the composite score of
6.0 and the RQ of 1000, derived from subchronlc effects reported by B1o
5943H
-38-
07/26/89
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06235H
-40-
09/07/89
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TABLE 9-3
n-HEPTANE
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Species/sex:
Dose*:
Duration:
Effect:
RVd:
RVe:
CS:
RQ:
Reference:
Inhalation
rat/female
1673 mg/day
26 weeks
dry rales, exophthalmla, yellow staining of
ano-genltal fur, elevated serum alkaline phosphatase
1.0
6
6.0
1000
Bio Dynamics, 1980
*Equ1valent human dose
5943H
41
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Dynamics (1980) based on observations of 15 animals, are chosen to represent
the chronic (noncancer) toxlclty of n-heptane.
9.2. BASED ON CARCINOGENICITY
Because no Information could be found about the carclnogenlcHy of n-
heptane In humans or 1n animals, In Chapter 8 the compound was classified In
U.S. EPA Group 0 -- not classifiable as to human cardnogenlclty, under the
guidelines of the U.S. EPA (1986b). Substances so classified are not
assigned a hazard ranking; therefore, an RQ based on cardnogenlclty cannot
be derived.
5943H
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5943H -57- 09/07/89
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APPENDIX A
This HEEO Is based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
70XLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORE 1
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCH
Federal Research In Progress
These searches were conducted 1n April. 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, OK.
ACGIH (American Conference of 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. John Wiley and Sons,
NY. 2878 p.
3
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology. 3rd rev. ed. Vol. 2B. 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.
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Grayson, H. and 0. Eckroth, Ed. 1978-84. Klrk-Othmer 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. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA-600/6-84-010. (NTIS PB84-2439Q6) Menlo Park, CA: SRI Inter-
national.
NTP (National Toxicology Program). 1988. 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.,
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5943H A-2 07/26/89
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In addition, approximately 30 compendia of aquatic toxlcity 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. Finley. 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.
5943H
A-3
05/10/89
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO n-HEPTANE
C.I. DISCUSSION
Dose/duration-response graphs for Inhalation exposure to n-heptane
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 to C-4. 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 nonadverse
(NOEL or NOAEL) for plotting. For Inhalation exposure, the ordlnate
expresses concentration In either of two ways. In Figures C-l and C-2, the
experimental concentration expressed as mg/m3 was multiplied by the time
parameters of the exposure protocol (hours/day and days/week) and 1s
presented as expanded experimental concentration [expanded exp cone
(mg/m3)]. In Figures C-3 and C-4, 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
Schnelderman, 1975) to estimate an equivalent human or scaled concentration
[scaled cone (mg/m3)].
The Boundary for Adverse Effects (solid line) 1s 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
line Is extended upward, parallel to the dose axis. The starting point Is
3
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
6222H C-l 07/26/89
-------
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 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.
Figure C-l represents the dose/duration response graph of Inhalation
data expressed as expanded concentrations and generated by the envelope
method. The Adverse Effects Boundary is defined by an LDSO value for mice
(NIOSH, 1989), listed in rec #9; a LOAEL for reflex bradypnea in
uncannulated mice (Kristiansen and Nielsen, 1988), listed in rec #5; and a
LOAEL for reflex bradypnea in cannulated mice responding to pulmonary
6222H C-2 06/21/89
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irritation (Krlstlansen and Nielsen, 1988), listed In rec #7, after which
the Boundary continues horizontally Mghtward to Infinity as described
above, since no clearly adverse effects were demonstrated In this data base
outside of the acute range.
The No Adverse Effects Boundary Is defined by a NOAEL (the RDQ In
uncannulated mice Is a NOAEL, rather than a NOEL, since this concentration
Is above the ROQ for cannulated mke responding to pulmonary Irritation)
for reflex bradypnea In uncannulated mice (Krlstlansen and Nielsen, 1988),
listed In rec #6; a NOAEL In rats undergoing a transient decrease In weight
gain and minor subcellular changes In peripheral nervous tissue, both
effects deemed nonadverse (Takeuchl et al., 1980, 1981), listed In rec #4; a
NOAEL In rats undergoing dry rales, exophthalmla, yellow staining of
ano-genltal fur and Increased levels 1n female serum alkaline phosphatase,
both effects deemed nonadverse (Blodynarolcs, 1980), listed 1n rec #2; and a
NOEL for rats falling to exhibit the neurotoxlc effects and weight losses
Induced by hexane (Fontall et al., 1981), listed In rec #1.
A Region of Contradiction Is enclosed. The Region Is eliminated using
the censored method In Figure C-2. The Initial datum defining the No
Adverse Effects Boundary has been changed from the NOAEL of rec #6 to the
NOEL (the RDfl for mice cannulated to bypass trlgemlnal nerve ends) for
pulmonary Irritation (Krlstlansen and Nielsen, 1988), listed In rec #8. The
price of elimination of the Region of Contradiction by the censored method
Is that the Regions of Ambiguity are joined by an additional such Region,
considerably enlarging the ambiguity of the data.
6222H C-3 07/26/89
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These inhalation data are replotted In Figure C-3 after scaling as
previously explained to adjust for the difference between the metabolic
rates of rats and mice. Note that Regions of Contradiction and Ambiguity
are now smaller because of the change 1n scale on the ordlnate axis.
However, the data defining the Adverse and No Adverse Effects Boundaries are
the same as In Figure C-l. As before, the Region of Contradiction Is
eliminated by using the censored method, this time In Figure C-4. Again,
the datum of rec #6 ceases to be the Initial deflner of the No Adverse
Effects Boundary, but now, because scaling has resulted 1n an apparent
Increased sensitivity for mice (recs #5-9) relative to rats (recs #1-4), the
first datum defining this Boundary 1s the NOAEL of rec #4 (see above); the
Boundary line Is extended horizontally leftward to Infinity from this datum,
as described above. This time, the Increase In the area of the Region of
Ambiguity Is less than In Figure C-2 because of the differences In mouse and
rat metabolic rates.
In these graphs, concentrations at which nonadverse effects of sub-
chronic repeated exposure were observed In rats were expanded to continuous
24 hour/day, 7 days/week exposure, while the concentrations at which adverse
effects of acute exposure for part of a day were observed were not expanded
to 24 hours exposure. This was because the acute effects appeared to be the
consequence of reflexive response to upper (or lower) respiratory response,
which Is particularly dramatic In mice. Reviewing the data presented by
Swann et al. (1974) [also see the observations of Fuhner (1921) and Lazarew
o
(1929) In Section 6.1.3] suggests the possibility that the death of heptane-
exposed mice from respiratory arrest may be extreme cases of reflexive
bradypnea, which 1s an acute response to an Irritant. It Is not appropriate
6222H C-4 07/26/89
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to assume that concentrations below a short-term Irritation threshold, when
used for more prolonged dosing, will exert the same Irritant effect as the
acute exposures at higher concentration.
Some Inhalation data reviewed In Chapter 6 were not appropriate for
Inclusion In the dose/duration graphs {Truhaut et al., 1973; Crespl et al.,
1979; Savolalnen and Pfaffll, 1980; FQhner, 1921; Lazarew, 1929; Patty and
Yant, 1929).
C.2. DATA USED TO GENERATE OOSE/DURATION-RESPONSE GRAPHS
C.2.1. Inhalation Exposure
C.2.2. Oral Exposure. Data regarding the systemic toxlclty of oral
exposure to n-heptane were not located In the available literature cited In
Appendix A.
Chemical Name:
CAS Number:
Document Title:
Document Number
Document Date:
Document Type:
RECORD #1:
n-Heptane
142-82-5
Health and Environmental Effects
Document on n-Heptane
Pending
Pending
HEED
Species: Rats Dose: 1643.000
Sex: N.S. Duration Exposure:
Effect: NOEL Duration Observation:
Route: Inhalation
30.0 Weeks
30.0 Weeks
7
0
DEGEN
PNS
8
7
0
NEURB
LIMBS
7
7
0
WGTDC
BODY
4
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Comment: 1500 ppm, 9 h/d, 5 d/w to group of 6-9; 1
concentration used. No degen." tlblalneural axons.
No change hind 11mb spread. No deer. wt. gain,
any effect seen with hexane.
Citation: Fontal! et al., 1981
6222H
C-5
07/26/89
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RECORD #2: Species: Rats Dose: 2195.000
Sex: Female Duration Exposure:
Effect: NOAEL Duration Observation:
Route: Inhalation
Number Exposed: 15 30
Number Responses: NR NR
Type of Effect: ENZYM IRRIT
Site of Effect: LIVER BODY
Severity Effect: 6 6
Comment: 3000 ppm, 6 h/d, 5 d/w. Range
rales, exophthalmla, yellow
genital fur both doses, both
alk. phos. In fern, high dose,
effects body weight.
Citation: B1o Dynamics, 1980
26.0
28.0
Weeks
Weeks
400, 3000 ppm; dry
staining of ano-
sexes. Incr. ser.
26 weeks only. No
RECORD
Species: Rats Dose: 293.000
Sex: Female Duration Exposure: 26.0 Weeks
Effect: NOEL Duration Observation: 28.0 Weeks
Route: Inhalation
Number Exposed: 15 30
Number Responses: NR NR
Type of Effect: ENZYM IRRIT
SHe of Effect: LIVER BODY
Severity Effect: 6 6
Comment: 400 ppm. See prev. record
Alk. Phos. Clln. signs too
Citation: B1o Dynamics, 1980
for details. No effect
rare to be significant.
6222H
C-6
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RECORD #4: Species: Rats Dose: 6147.000
Sex: Male Duration Exposure: 16.0 Weeks
Effect: NOAEl Duration Observation: 16.0 Weeks
Route: Inhalation
Number Exposed: 7 7
Number Responses: NR NR
Type of Effect: WGTDC SUBCC
Site of Effect: BODY PNS
Severity Effect: 4 2
Comment: 3000 ppm, 12 hours/day. Decrease weight gain 8
weeks only. Slight subcellular changes dorsal
trunk tail nerve. No effects nerve conduction,
walking gait, foot drop.
Citation: Takeuchi et al., 1980, 1981
RECORD #5: Species: Mice Dose: 33429.000
Sex: Male Duration Exposure: 1.0 Days
Effect: LOAEL Duration Observation: 1.0 Days
Route: Inhalation
Number Exposed: 4
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: PNS
Severity Effect: 7
Comment: 8157 ppm 30 minutes; studied 8157, 9609, 15,513,
18,600, 24,801 ppm for reflex bradypnea
(trigeminal nerve ends) uncannulat. animals. Dose
not expanded to full day's exposure.
Citation: Kristiansen and Nielsen, 1988
6222H C-7 06/21/89
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RECORD #6: Species: Mice Dose: 26318.000
Sex: , Male Duration Exposure: 1.0 Days
Effect: NOAEL Duration Observation: 1.0 Days
Route: Inhalation
Number Exposed: 4
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: PNS
Severity Effect: 7
Comment: 6422 ppm cak. by extrap. to no effect level from
authors' data. Uncannulated animals. Dose not
expanded to full day's exposure.
Citation: Kristiansen and Nielsen, 1988
RECORD #7:
Species:
Sex:
Effect:
Route:
Mice Dose: 22978.000
Male Duration Exposure:
LOAEL Duration Observation:
Inhalation
1.0 Days
1.0 Days
Number Exposed: 4
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: PNS
Severity Effect: 7
Comment: 5607 ppm 10 minutes; studied 5607, 9507, 15,668,
21,746 ppm for reflex bradypnea (pulmonary
receptors), cannulated Animals. Dose not expanded
to full day's exposure.
Citation: Kristiansen and Nielsen, 1988
6222H
C-8
06/21/89
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RECORD #8: Species: Mice Dose: 7459.000
Sex: . Male Duration Exposure: 1.0 Days
Effect: NOEL Duration Observation: 1.0 Days
Route: Inhalation
Number Exposed: 4
Number Responses: NR
Type of Effect: IRRIT
Site of Effect: PNS
Severity Effect: 7
Comment: 1820 ppm calc. by extrap. to no effect level from
Authors' data, cannulated animals. Dose Not
expanded to 24 hours.
Citation: Kristiansen and Nielsen, 1988
RECORD #9:
Species:
Sex:
Effect:
Route:
Mice Dose: 75000.000
N.S. Duration Exposure:
PEL Duration Observation:
Inhalation
1 .0 Days
1.0 Days
Number Exposed: NR
Number Responses: NR
Type of Effect: DEATH
Site of Effect: N.S.
Severity Effect: 10
Comment: Two-hour LC50 value, not expanded to 24 hours,
Citation: NIOSH, 1989
6222H
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