United States
Environmental Protection
1=1 m m Agency
EPA/690/R-16/003F
Final
9-08-2016
Provisional Peer-Reviewed Toxicity Values for
^-Heptane
(CASRN 142-82-5)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Lucina E. Lizarraga, PhD
National Center for Environmental Assessment, Cincinnati, OH
CONTRIBUTORS
Q. Jay Zhao, MPH, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Scott C. Wesselkamper, PhD
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
J. Phillip Kaiser, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Ghazi Dannan, PhD
National Center for Environmental Assessment, Washington, DC
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this PPRTV assessment should be directed to the EPA Office
of Research and Development's National Center for Environmental Assessment, Superfund
Health Risk Technical Support Center (513-569-7300).
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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS AND ACRONYMS iv
BACKGROUND 1
DISCLAIMERS 1
QUESTIONS REGARDING PPRTVs 1
INTRODUCTION 2
REVIEW OF POTENTIALLY RELEVANT DATA (NONCANCER AND CANCER) 4
HUMAN STUDIES 9
Oral Exposures 9
Inhalation Exposures 9
ANIMAL STUDIES 10
Oral Exposures 10
Inhalation Exposures 12
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS) 15
Genotoxicity 15
Supporting Human Toxicity Studies 16
Supporting Neurotoxicity Studies in Animals 16
Acute Systemic Toxicity in Animals 16
Absorption, Distribution, Metabolism, and Elimination (ADME) Studies 17
Mode-of-Action/Mechanistic Studies 19
DERIVATION 01 PROVISIONAL VALUES 20
DERIVATION OF ORAL REFERENCE DOSES 20
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS 21
Derivation of a Subchronic Provisional Reference Concentration (p-RfC) 23
Derivation of a Chronic Provisional Reference Concentration (p-RfC) 25
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR 27
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES 28
APPENDIX A. SCREENING PROVISIONAL VALUES 29
APPENDIX B. DATA TABLES 42
APPENDIX C. BENCHMARK DOSE MODELING RESULTS 48
APPENDIX D. REFERENCES 56
iii //-Heptane
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COMMONLY USED ABBREVIATIONS AND ACRONYMS
a2u-g
alpha 2u-globulin
MN
micronuclei
ACGIH
American Conference of Governmental
MNPCE
micronucleated polychromatic
Industrial Hygienists
erythrocyte
AIC
Akaike's information criterion
MOA
mode of action
ALD
approximate lethal dosage
MTD
maximum tolerated dose
ALT
alanine aminotransferase
NAG
N-acetyl-P-D-glucosaminidase
AST
aspartate aminotransferase
NCEA
National Center for Environmental
atm
atmosphere
Assessment
ATSDR
Agency for Toxic Substances and
NCI
National Cancer Institute
Disease Registry
NOAEL
no-observed-adverse-effect level
BMD
benchmark dose
NTP
National Toxicology Program
BMDL
benchmark dose lower confidence limit
NZW
New Zealand White (rabbit breed)
BMDS
Benchmark Dose Software
OCT
ornithine carbamoyl transferase
BMR
benchmark response
ORD
Office of Research and Development
BUN
blood urea nitrogen
PBPK
physiologically based pharmacokinetic
BW
body weight
PCNA
proliferating cell nuclear antigen
CA
chromosomal aberration
PND
postnatal day
CAS
Chemical Abstracts Service
POD
point of departure
CASRN
Chemical Abstracts Service Registry
PODadj
duration-adjusted POD
Number
QSAR
quantitative structure-activity
CBI
covalent binding index
relationship
CHO
Chinese hamster ovary (cell line cells)
RBC
red blood cell
CL
confidence limit
RDS
replicative DNA synthesis
CNS
central nervous system
RfC
inhalation reference concentration
CPN
chronic progressive nephropathy
RfD
oral reference dose
CYP450
cytochrome P450
RGDR
regional gas dose ratio
DAF
dosimetric adjustment factor
RNA
ribonucleic acid
DEN
diethylnitrosamine
SAR
structure activity relationship
DMSO
dimethylsulfoxide
SCE
sister chromatid exchange
DNA
deoxyribonucleic acid
SD
standard deviation
EPA
Environmental Protection Agency
SDH
sorbitol dehydrogenase
FDA
Food and Drug Administration
SE
standard error
FEVi
forced expiratory volume of 1 second
SGOT
glutamic oxaloacetic transaminase, also
GD
gestation day
known as AST
GDH
glutamate dehydrogenase
SGPT
glutamic pyruvic transaminase, also
GGT
'/-glutamyl transferase
known as ALT
GSH
glutathione
SSD
systemic scleroderma
GST
glutathione-S-transferase
TCA
trichloroacetic acid
Hb/g-A
animal blood-gas partition coefficient
TCE
trichloroethylene
Hb/g-H
human blood-gas partition coefficient
TWA
time-weighted average
HEC
human equivalent concentration
UF
uncertainty factor
HED
human equivalent dose
UFa
interspecies uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFS
subchronic-to-chronic uncertainty factor
IVF
in vitro fertilization
UFd
database uncertainty factor
LC50
median lethal concentration
U.S.
United States of America
LD50
median lethal dose
WBC
white blood cell
LOAEL
lowest-observed-adverse-effect level
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
m-HEPTANE (CASRN 142-82-5)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (http://www.epa.gov/iris). the respective PPRTVs are
removed from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
This document has been reviewed in accordance with U.S. EPA policy and approved for
publication. Mention of trade names or commercial products does not constitute endorsement or
recommendation for use.
QUESTIONS REGARDING PPRTVs
Questions regarding the content of this PPRTV assessment should be directed to the EPA
Office of Research and Development's National Center for Environmental Assessment,
Superfund Health Risk Technical Support Center (513-569-7300).
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INTRODUCTION
//-Heptane, CASRN 142-82-5, is a hydrocarbon solvent that is typically isolated via
fractional distillation from light naphtha petroleum streams (OECD. 2010). In addition to being
a solvent, //-heptane is used as a standard in testing knock intensity of gasoline engines (O'Neil et
al.. 2013) and is regulated by the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) as
an inert ingredient in nonfood-use pesticides (HSDB. 2014).
//-Heptane is a liquid at room temperature. In the environment, //-heptane will readily
volatilize from dry soil due to its high vapor pressure. Once in the air, it will stay in the vapor
phase (HSDB. 2014). Based on its estimated Henry's law constant, //-heptane will also exhibit
high volatility from moist soil and water surfaces. In addition, //-heptane deposited on soil may
leach to groundwater or undergo runoff after a rain event based on its moderate water solubility
and moderate soil absorption coefficient. As a result, removal of //-heptane from soil by leaching
with water may compete with volatilization, depending on the local conditions (wet, dry, etc.).
The empirical formula for //-heptane is C7H16 (see Figure 1). A table of physicochemical
properties for //-heptane is provided below (see Table 1).
Figure 1. fl-Heptane Structure
Table 1. Physicochemical Properties of n-Heptane (CASRN 142-82-5)3
Property (unit)
Value
Physical state
Liquidb
Boiling point (°C)
98.5
Melting point (°C)
-90.6
Density (g/cm3)
0.6795b
Vapor pressure (mm Hg at 25°C)
46
pH (unitless)
NA
Solubility in water (g/L at 25°C)
0.0034
Octanol-water partition constant (log Kow)
4.66
Henry's law constant (atm-m3/mol at 25°C) (estimated)
2.27°
Soil adsorption coefficient Koc (mL/g) (estimated)
240
Relative vapor density (air = 1)
3.45b
Molecular weight (g/mol)
100.21
aSRC (2013).
bHSDB (2014).
U.S. EPA (2012b).
NA = not applicable.
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A summary of available toxicity values for //-heptane from U.S. EPA and other
agencies/organizations is provided in Table 2.
Table 2. Summary of Available Toxicity Values for «-Heptane (CASRN 142-82-5)
Source
(parameter)ab
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2016a)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2016)
IPCS
NV
NA
IPCS (2016); WHO (2016)
Cal/EPA
NV
NA
Cal/EPA (2014); Cal/EPA
(2016a): Cal/EPA (2016b)
OSHA (PEL)
500 ppm (2,000 mg/m3)
(TWA)
The PELs are 8-hr TWAs for
general industry, construction,
and shipyard employment.
OSHA (2006a): OSHA
(2006b): OSHA (2011)
NIOSH (REL)
85 ppm (350 mg/m3) (TWA),
440 ppm (1,800 mg/m3)
(15-min ceiling)
For RELs, TWA indicates a
time-weighted average
concentration for up a 10-hr
work day during a 40-hr work
week; the ceiling REL should
not be exceeded at any time.
NIOSH (2015)
NIOSH (IDLH)
750 ppm
Based on acute inhalation
toxicity data in humans
NIOSH (1994): NIOSH
(2015)
ACGIH (TLV-TWA)
400 ppm (1,640 mg/m3)
Based on narcosis and
respiratory irritation
ACGIH (2015)
ACGIH (STEL)
500 ppm (2,050 mg/m3)
Based on narcosis and
respiratory irritation
ACGIH (2015)
Cancer
IRIS (WOE)
Classification D; not
classifiable as to human
carcinogenicity
Basis: no human or animal
data available
U.S. EPA (2012a)
HEAST
NV
NA
U.S. EPA (2011a)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2015)
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Table 2. Summary of Available Toxicity Values for «-Heptane (CASRN 142-82-5)
Source
(parameter)ab
Value (applicability)
Notes
Reference
Cal/EPA
NV
NA
Cal/EPA (2016a): Cal/EPA
(2016b): Cal/EPA (2011)
ACGIH
NV
NA
ACGIH (2015)
aSources: ACGIH = American Conference of Governmental Industrial Hygienists; ATSDR = Agency for Toxic
Substances and Disease Registry; Cal/EPA = California Environmental Protection Agency; DWSHA = Drinking
Water Standards and Health Advisories; HEAST = Health Effects Assessment Summary Tables;
IARC = International Agency for Research on Cancer; IPCS = International Programme on Chemical Safety;
IRIS = Integrated Risk Information System; NIOSH = National Institute for Occupational Safety and Health;
NTP = National Toxicology Program; OSHA = Occupational Safety and Health Administration; WHO = World
Health Organization.
Parameters: IDLH = immediately dangerous to life or health concentrations; PEL = permissible exposure level;
REL = recommended exposure limit; STEL = short-term exposure limit; TLV = threshold limit value;
TWA = time-weighted average; WOE = weight of evidence.
NA = not applicable; NV = not available.
Non-date-limited literature searches were conducted in May 2015 and April 2016 for
studies relevant to the derivation of provisional toxicity values for //-heptane, CASRN 142-82-5.
Searches were conducted using U.S. EPA's Health and Environmental Research Online (HERO)
database of scientific literature. HERO searches the following databases: PubMed, ToxLine
(including TSCATS1), and Web of Science. The following databases were searched outside of
HERO for health-related values: ACGIH, ATSDR, Cal/EPA, U.S. EPA IRIS, U.S. EPA HEAST,
U.S. EPA Office of Water (OW), U.S. EPA TSCATS2/TSCATS8e, NIOSH, NTP, and OSHA.
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
Tables 3A and 3B provide an overview of the relevant noncancer and cancer databases,
respectively, for //-heptane and include all potentially relevant short-term-, subchronic-, and
chronic-duration studies. The phrase "statistical significance" or the term "significant," used
throughout the document, indicates ap-walue of < 0.05 unless otherwise noted.
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Table 3A. Summary of Potentially Relevant Noncancer Data for «-Heptane (CASRN 142-82-5)
Category3
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference (comments)
Notes0
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)b
Acute
M and F volunteers
(number not reported),
up to 15 min
1,000, 2,000,
3,500,
5,000 ppm
4,000, 8,000,
14,000, 20,000
Vertigo
NDr
NDr
4,000
Path and Yam (1929)
NPR
Long-term
18 M and F (combined),
tire factory workers,
neurophysiological
screen, 1-9 yr
Solvent
containing
>95%
rt-heptane:
concentrations
not reported
Subjective complaints of
numbness and paresthesia of
limbs; altered
neurophysiological parameters
indicative of minimal peripheral
neuropathy
NDr
NDr
NDr
Cresoi et al. (1979)
PR
Animal
1. Oral (mg/kg-d)b
Short-term
3 M/0 F per exposure
(9 M/0 F controls), CD
COBS rat, gavage,
5 d/wk, 3 wk
0, 1,000, 2,000,
4,000
ADD: 0, 714,
1,430, 2,860
Potential treatment-related
effects include elevated serum
LDH, increased kidney and liver
weights, and hyperplasia of the
gastric nonglandular epithelium
NDr
NDr
NDr
Eastman Kodak. (1979)
(Small group sizes and
inadequate reporting
preclude identification of
LOAEL)
NPR
Subchronic
8 M/0 F, CD COBS rat,
gavage, 5 d/wk, 13 wk
0, 4,000
ADD: 0, 2,860
Potential treatment-related
effects include persistent
body-weight depression, gross
liver enlargement, organ-weight
changes, and histopathology of
the forestomach, liver, kidney,
and adrenal glands
NDr
NDr
NDr
Eastman Kodak (1980)
(High gavage-related
mortality [5/8] precludes
determination of LOAEL)
NPR
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Table 3A. Summary of Potentially Relevant Noncancer Data for «-Heptane (CASRN 142-82-5)
Category3
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference (comments)
Notes0
2. Inhalation (mg/m3)b
Short-term
(neurotoxicity)
9-10 M/0 F,
Long-Evans rat,
w-heptane (99.5%
pure), 6 hr/d, 28 d
0,801,
4,006 ppm
HEC: 0,821,
4,105
Abnormal auditory brainstem
responses and increased
auditory threshold, which
indicate a loss of hearing
sensitivity in anaesthetized
rats 2 mo after cessation of
exposure
821
1,170 for
loss of
hearing
sensitivity
4,105
Simonson and Lund
(1995)
(Study examined central
auditory effects)
PR, PS
Subchronic
(neurotoxicity)
7 M/0 F, Wistar rat,
//-heptane (>99% pure),
12 hr/d, 7 d/wk, 16 wk
0, 2,960 ppm
HEC: 0, 6,066
No neurological or body-weight
effects
6,066
NDr
NDr
Takeuchi et al. (1981.
1980)
(Study tested for
peripheral neuropathy,
including
neurobehavioral,
neurophysiological and
neuropathological
measurements;
central-auditory effects
were not examined)
PR
Chronic
15 M/15 F, S-D rat,
n-heptane (98.5% pure),
6 hr/d, 5 d/wk, 26 wk
0, 398,
2,970 ppm
HEC: 0, 291,
2,174
No adverse effects on physical
assessment, body weight,
hematology, serum chemistry, or
urinalysis
NDr
NDr
NDr
Bio Dynamics (1980);
Yeshiva University
(1980) (Inadeauate
reporting of
neurohistological findings
and lack of pathology of
non-nervous system
tissues preclude
determination of
NOAEL/LOAEL)
NPR
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Table 3A. Summary of Potentially Relevant Noncancer Data for «-Heptane (CASRN 142-82-5)
Category3
Number of
Male/Female, Strain,
Species, Study Type,
Study Duration
Dosimetryb
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference (comments)
Notes0
Chronic
(neurotoxicity)
6-9 M/0 F, S-D rat,
//-heptane (99% pure),
9 hr/d, 5 d/wk, up to
30 wk
0, 1,500 ppm
HEC: 0, 1,647
No neurological or body-weight
effects
1,647
NDr
NDr
Frontali et al. (1981)
(Study tested for
peripheral neuropathy,
including hind limb
spread on landing and
tibial nerve histology;
central auditory
measurements were not
conducted)
PR
aDuration categories are defined as follows: Acute = exposure for <24 hours; short-term = repeated exposure for 24 hours to <30 days; subchronic = repeated exposure
for >30 days <10% lifespan for humans or laboratory animal species; and chronic = repeated exposure for >10% lifespan for humans or laboratory animal species (U.S.
EPA. 20021.
bDosimetry: Values are converted to an ADD (mg/kg-day) for oral noncancer effects and a HEC (mg/m3) for inhalation noncancer effects. All repeated exposure values
are converted from a discontinuous to a continuous exposure, with the exception of values from animal developmental studies, which are not adjusted to a continuous
exposure; HECexresp = (ppm x molecular weight ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood-gas partition coefficient. For
//-heptane, the blood-air partition coefficient for rats is greater than that for humans (PECOS. 19931. so a default ratio of 1 is applied (U.S. EPA. 1994a).
°Notes: NPR = not peer reviewed; PR = peer reviewed; PS = principal study.
ADD = adjusted daily dose; BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; COBS = cesarean-obtained
barrier-sustained; F = female(s); HEC = human equivalent concentration; LDH = lactate dehydrogenase; LOAEL = lowest-observed-adverse-effect level; M = male(s);
ND = no data; NDr = not determined; NOAEL = no-observed-adverse-effect level; S-D = Sprague-Dawley.
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Table 3B. Summary of Potentially Relevant Cancer Data for »-Heptane (CASRN 142-82-5)
Category
Number of Male/Female,
Strain, Species, Study
Type, Study Duration
Dosimetry
Critical Effects
NOAEL
BMDL/
BMCL
LOAEL
Reference
(comments)
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
BMCL = benchmark concentration lower confidence limit; BMDL = benchmark dose lower confidence limit; LOAEL = lowest-observed-adverse-effect level; ND = no
data; NOAEL = no-observed-adverse-effect level.
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HUMAN STUDIES
Oral Exposures
No studies have been identified.
Inhalation Exposures
The database for repeated human exposure to //-heptane is limited to a single
occupational study lacking quantitative exposure data (Crespi et aL 1979). The only other
available human study of inhalation exposure to //-heptane is an acute controlled-exposure
inhalation study in volunteers (Patty and Yant 1929).
Acute Exposure
Patty and Yant (1929)
Male and female volunteers (number not reported) between the ages of 20 and 30 years
were observed during exposure to 1,000, 2,000, 3,500, or 5,000 ppm (4,000, 8,000, 14,000, or
20,000 mg/m3) of //-heptane vapor in air for up to 15 minutes. The subjects reported slight
vertigo after 6 minutes at 1,000 ppm or 4 minutes at 2,000 ppm, moderate vertigo after
4 minutes at 3,500 ppm, and marked vertigo after 4 minutes at 5,000 ppm. Additional effects
observed after 4-15 minutes of exposure to 5,000 ppm included hilarity (amusement),
incoordination, and inability to walk straight. The effects lasted for up to 30 minutes following
a 15-minute exposure.
Long-Term Exposure
Crespi et al. (1979)
In an occupational exposure study, neurophysiological examinations were performed in
workers exposed to //-heptane at a small tire factory. A total of 18 workers, who had been
exposed for 1-9 years to unreported concentrations of vapor from a solvent containing >95%
//-heptane (and trace amounts of benzene, toluene, and other hydrocarbons), complained of
numbness and paresthesia of the limbs with a "glove and stocking" distribution. All workers
underwent a neurological examination. However, details of the parameters evaluated were not
provided in the report. Neurophysiological measurements (motor nerve conduction velocity
[MNCV], distal latency [DL], and amplitude desynchronization [AD] of the evoked muscle
action potential [MAP] along the peroneal nerve) were performed on 12 of the workers whose
personal and family history excluded any simultaneous causes of peripheral nerve damage.
Most, but not all, were female, with a mean age of 35.5 years. Measurements were also made
on an age-matched control group; however, control findings were not described in the report.
No signs of peripheral neuropathy were observed during the neurological examinations
(data were not reported). The mean MNCV of the exposed workers was not significantly
different from the controls, and none of the exposed workers had an MNCV below the normal
range. There was, however, a statistically significant correlation between duration of exposure
(years of employment at the factory) and MNCV, such that MNCV decreased as exposure
duration increased (based on 10 of the 12 subjects; 2 were excluded for unreported reasons).
Mean DL in the exposed workers (evaluated in only 10 subjects) did not differ from the
age-matched controls, and DL in individual workers was not correlated with duration of
exposure. Mean AD was significantly increased in the exposed workers compared with
age-matched controls, and 3 of the 12 workers had values at or above the normal limit. AD in
individual workers was not correlated with duration of exposure. The researchers noted that
increased AD of the MAP is a frequent finding in subclinical polyneuropathies. A cumulative
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correlation between pooled electrophysiological data in all subjects and exposure duration was
found at ap-value of 0.05.
On the basis of significantly increased AD of the MAP, and the significant inverse
correlation between MNCV and exposure duration, the researchers concluded that //-heptane
had produced minimal peripheral nerve damage in the exposed workers. The absence of
exposure-level estimates precludes the determination of a no-observed-adverse-effect
level/lowest-observed-adverse-effect level (NOAEL/LOAEL).
ANIMAL STUDIES
Oral Exposures
The oral database for w-heptane is limited to an unpublished sub chronic-duration study
in rats and the short-term-duration, range-finding study that preceded it (Eastman Kodak. 1980.
1979).
Short-Term-Duration Studies
Eastman Kodak (1980, 1979)
In a range-finding study, groups of male Charles River CD cesarean-obtained
barrier-sustained (COBS) rats (three/group) were administered undiluted //-heptane
(95.7% pure) via gavage at dose levels of 1,000, 2,000, or 4,000 mg/kg-day, 5 days/week for
3 weeks. The administered gavage doses were converted to adjusted daily doses (ADDs) of
714, 1,430, and 2,860 mg/kg-day, respectively, by multiplying the administered gavage dose by
(5/7) days per week. A control group of nine male rats was given tap water via gavage using
the same dosing schedule. The animals were observed daily for clinical signs of toxicity, and
food consumption and body weights were recorded on Days 0, 3, 7, 14, and 20 of treatment.
Surviving animals were sacrificed at the end of the exposure period. Blood was collected at
study termination just prior to necropsy for hematology (white blood cell [WBC] count and
differential, hemoglobin [Hb] concentration, and hematocrit [Hct]) and serum chemistry
(alkaline phosphatase [ALP], alanine aminotransferase [ALT], aspartate aminotransferase
[AST], lactate dehydrogenase [LDH], blood urea nitrogen [BUN], and glucose). All animals
sacrificed at termination or that died during the study were necropsied. Liver and kidney
weights were recorded, and an extensive set of tissues from all rats was examined for
histopathology, including five areas of the brain. Statistical analyses were not conducted, and
reporting of continuous data is inadequate for independent statistical analysis (lacks reporting of
standard deviation [SD] values).
No chemical-related mortalities were reported; one animal in the 714-mg/kg-day group
died due to gavage error. No adverse clinical signs were observed. Mean body weights and
food consumption in exposed rats were comparable to controls. Serum LDH was increased
1.5-fold in the 714-mg/kg-day group and 2.4-fold in the 1,430- and 2,860-mg/kg-day groups
(see Table B-l). All other serum chemistry and hematological parameters were comparable
between exposed and control rats. Absolute and relative liver weights in exposed rats were
increased by 14-39% and 19—38%, respectively, compared with controls (see Table B-l); the
larger changes were observed in the low-dose group. Absolute and relative kidney weights in
exposed rats were increased by 6—14% and 8—21%, respectively, compared with controls
(see Table B-l); the larger changes were observed in the high-dose group. Histopathological
examination revealed hyperplasia of the gastric nonglandular (forestomach) epithelium in 1/3,
2/3, and 1/3 rats in the 714-, 1,430-, and 2,860-mg/kg-day groups, respectively (see Table B-l).
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The forestomach lesions were reported as moderate in the 714- and 2,860-mg/kg-day groups
and minor in the 1,430-mg/kg-day group. These lesions were not identified in any control rats.
No other treatment-related histopathological findings were noted.
Small group sizes and inadequate reporting of any measure of variability within
treatment groups or statistical analyses preclude the determination of a critical effect or a
LOAEL for this study. Effects possibly related to short-term gavage treatment with //-heptane
include elevated serum LDH, increased liver and kidney weights, and hyperplasia of the gastric
nonglandular epithelium in rats.
Subchronic-Duration Studies
Eastman Kodak (1980)
Eight male Charles River CD COBS rats were administered undiluted //-heptane
(95.7% pure) via gavage at a dose level of 4,000 mg/kg-day, 5 days/week for 13 weeks. The
administered gavage dose of 4,000 mg/kg-day was converted to an ADD of 2,860 mg/kg-day by
multiplying the administered gavage dose by (5/7) days per week. A control group of eight rats
was treated via gavage with tap water using the same dosing schedule. The animals were
observed daily for clinical signs; body weights and food consumption were recorded twice
weekly. Rats surviving treatment were sacrificed at 90 days, and blood was collected for
hematology (WBC count and differential, Hb concentration, Hct) and clinical chemistry (ALP,
ALT, AST, LDH, BUN, glucose). All animals sacrificed at termination or that died during the
study were necropsied. Organ weights were recorded for liver, kidney, brain, adrenal glands,
testes, heart, and spleen. An extensive collection of tissues from all rats was examined for
histopathology, including five areas of the brain, spinal cord, sciatic-tibial nerves, and dorsal
root ganglia. Appropriate statistical tests were conducted.
Five of the eight rats in the treated group died from acute chemically induced
pneumonitis after accidental tracheal intubation or aspiration into the lungs possibly related to
severe gastric irritation observed at autopsy. Timing of the deaths was not reported, but based
on weekly body-weight reporting, it appears that one died during the first week, two died during
Week 7, one died during Week 12, and one died during Week 13. An additional animal that
survived until sacrifice also showed signs of chemical pneumonitis. No clinical signs of
toxicity were seen in treated rats that did not have chemical pneumonitis. Food consumption
was significantly reduced by 23% in exposed rats during the first week but similar to controls
thereafter. Mean body weights were also significantly reduced during the first week of
treatment in exposed rats and remained depressed compared to controls throughout most of the
study (8-15%>) (see Table B-2). A slight, but statistically significant 20% reduction in serum
glucose levels was observed in the three surviving exposed rats, compared with controls
(see Table B-2). The relevance of decreased serum glucose levels is uncertain, given that all
other serum chemistry and hematological parameters were comparable between exposed and
control rats. Statistically significant organ-weight changes in the three exposed rats examined at
study termination, compared with controls, included 28% decrease in absolute heart weight,
17%) increase in relative liver weight, 16%> increase in relative kidney weight, and 36%> increase
in relative adrenal weight (see Table B-2). Numerous gross lesions were observed in the rats
that died by gavage error (e.g., blood in mouth and nares [nostrils], pulmonary edema and
hemorrhage, liver enlargement, hematuria). Excluding changes related to chemically induced
pneumonitis, grossly enlarged livers were found in all treated animals that died, and hematuria
was observed in one rat that died, according to the study authors' descriptions.
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Histopathological examination of exposed rats revealed local irritative effects on the
forestomach mucosa, including moderate to severe suppuration or necrosis of the nonglandular
gastric epithelium in 4/8 rats (3/5 rats that died, 1/3 rats that survived until sacrifice) and mostly
moderate hyperkeratosis with pseudoepitheliomatous hyperplasia in 7/8 rats (4/5 rats that died,
3/3 rats that survived until sacrifice) (see Table B-3). Low incidences of several hepatic
(hepatocyte vacuolation, serosal adhesions, congestion) and renal (hyaline droplets, increased
incidence of tubular dilation with casts, increased incidence of regenerating renal tubular
epithelium, hemorrhage, congestion, focal nephritis) lesions were seen in treated rats; these
lesions were generally characterized as minimal or minor (see Table B-3). The study authors
noted that regenerating renal tubular epithelium and tubular dilation with casts were consistent
with renal effects previously reported for ketones, although these lesions were only slightly
elevated compared to controls. In rats that died by gavage error, the adrenal glands showed
focal cortical hemorrhages in 5/5 rats and congestion in 2/5 rats (minor or moderate for both
lesions). No evidence of neurotoxicity or other prominent treatment-related lesions were found
based on histopathology.
High mortality due to gavage error (5/8 treated rats) precludes the determination of a
critical effect or LOAEL for this study. Potential treatment-related effects include persistent
body-weight depression, gross liver enlargement, organ-weight changes, and histopathology of
the forestomach, liver, kidney, and adrenal glands.
Chronic-Duration/Carcinogenicity Studies
No studies have been identified.
Reproductive/Developmental Studies
No studies have been identified.
Inhalation Exposures
Repeat-exposure inhalation studies of //-heptane toxicity have focused primarily on
potential neurotoxicity (Simonsen and I.und. 1995; Frontali et al, 1981; Takeuchi et al., 1981;
Bio Dynamics. 1980; Takeuchi et aL 1980; Yeshiva University. 1980). Only one
chronic-duration study evaluated a limited set of systemic endpoints; however,
non-nervous-system histopathology was not reported (Bio Dynamics. 1980; Yeshiva University.
1980). Acute inhalation studies of //-heptane toxicity have also been aimed at examining
potential neurotoxicity (see "Supporting Neurotoxicity Studies in Animals" in the "Other Data"
section below).
Short-Term-Duration Studies
Simonsen and Lund (1995)
The study by Simonsen and Lund (1995) is selected as the principal study for the
derivation of the subchronic and chronic provisional inhalation reference concentrations
(p-RfCs). In this neurotoxicity study, groups of male Long-Evans rats (9-10/group) were
placed in whole-body chambers and exposed to //-heptane (99.5% pure) vapors at reported mean
concentrations of 0, 801 ± 79, or 4,006 ± 242 ppm, 6 hours/day for 28 days. The study was
aimed at evaluating potential effects of //-heptane on the central auditory system, given that
exposure to organic solvents has been associated with hearing loss in rats and humans
(Simonsen and Lund. 1995). Feed and water were available ad libitum except during exposure
periods. Six weeks prior to exposure, screw electrodes were mounted in the skull of the rats for
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measurement of auditory brainstem responses. The amplitudes and latencies of Components la
and IV of the auditory brainstem responses elicited at frequencies 4, 8, 16, or 32 kHz and
intensities 25-95 dB were measured in anaesthetized rats 2 months after cessation of exposure
using both implanted electrodes and needle electrodes. Body weight was monitored throughout
the study. No other systemic endpoints were assessed.
Body-weight gain during the first 2 weeks postexposure was significantly decreased by
53% in the 4,006-ppm group. However, body weights were similar in all three exposure groups
during the course of treatment. The peak amplitudes of the la and IV components of the
auditory brainstem responses were reduced in rats exposed to 4,006 ppm at all frequencies and
intensities, compared with control (0-ppm treatment group), but not at 801 ppm. Statistically
significant reductions were reported for Component IV, most prominently at higher frequencies
and intensities (see Table B-4). Decreases in amplitude of Component la displayed a similar
pattern to IV; however statistical analyses for this component were not provided. No
exposure-related changes were observed in the latencies or interpeak latencies of the la and
IV components. The reduction in the peak amplitudes corresponded to an approximate 10-dB
increase in the auditory threshold. The difference in auditory threshold between the control and
the 4,006-ppm group was observed at all frequencies, although statistical significance was only
reached at 8 and 16 kHz (see Table B-5; data have been digitally extracted using Grablt!
Software).
A NOAEL of 801 ppm and a LOAEL of 4,006 ppm is identified for abnormal auditory
brainstem responses and increased auditory threshold that suggest a loss of hearing sensitivity in
rats. Concentrations of 801 and 4,006 ppm are converted to human equivalent concentrations
(HECs) of 821 and 4,105 mg/m3 for extrarespiratory effects by treating //-heptane as a
Category 3 gas (generally water insoluble and unreactive in the extrathoracic or
tracheobronchial regions) and using the following equation (U.S. EPA. 1994a):
HECexresp = (ppm x molecular weight [MW] ^ 24.45) x (hours per day exposed ^ 24) x (days
per week exposed ^ 7) x ratio of blood-gas partition coefficient (animal :human). For //-heptane,
the blood-air partition coefficient for rats is greater than that for humans (Gargas et al„ 1989);
thus, a default ratio of 1 is applied (U.S. EPA. 1994a).
Subchronic-Duration Studies
Takeuchi et al. (1981, 1980)
In a neurotoxicity study, groups of male Wistar rats (seven/group) were exposed to pure
//-heptane (>99%) at measured mean concentrations of 0 or 2,960 ± 200 ppm, 12 hours/day for
16 weeks. Neurological endpoints were assessed prior to exposure and after 4, 8, 12, and
16 weeks of exposure, including neurobehavioral tests (foot drop, altered gait) and
neurophysiological tests (peripheral nerve conduction velocity measured in the tail). After
16 weeks of exposure, rats were euthanized (one rat/group) and selected peripheral nerves,
muscle, and neuromuscular junctions were fixed for histopathological and/or ultrastructural
evaluation. Body weight was recorded prior to exposure and after 4, 8, 12, and 16 weeks of
exposure. No other systemic endpoints were assessed.
No changes were observed in neurological endpoints between the exposed group and
control (0-ppm treatment group). Transient decreases in body weight were observed, with a
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significant 13% decrease in the exposed group at 8 weeks, compared with control, but not at 4,
12, or 16 weeks.
The administered concentration of 2,960 ppm is identified as a NOAEL based on a lack
of neurotoxicity or persistent body-weight changes. The exposure concentration of 2,960 ppm
is converted to an HEC of 6,066 mg/m3 for extrarespiratory effects by treating //-heptane as a
Category 3 gas and using the following equation (U.S. EPA. 1994a):
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week
exposed ^ 7) x ratio of blood-gas partition coefficient (animal: human). For //-heptane, the
blood-air partition coefficient for rats is greater than that for humans (Gargas et aL 1989): thus,
a default ratio of 1 is applied (U.S. EPA. 1994a).
Chronic-Duration Studies
Bio Dynamics (1980); Yeshiva University (1980)
Groups of Sprague-Dawley (S-D) rats (15/sex/group) were exposed to //-heptane
(98.5% reagent grade) vapor at cumulative mean concentrations of 0, 398, or 2,970 ppm for
6 hours/day, 5 days/week for 26 weeks. The animals were observed for mortality twice daily,
and full physical assessments and body weight were recorded weekly. Hematology (Hb, Hct,
red blood cell [RBC] count, WBC count and differential, and clotting time), serum chemistry
(BUN, ALP, ALT, and glucose), and urinalysis determinations (appearance, specific gravity,
occult blood, pH, protein, bilirubin, and ketones and glucose) were performed in
10 rats/sex/group after 13 weeks of exposure and in 5 rats/sex/group after 26 weeks of exposure.
Rats from the exposure groups were sacrificed for neurohistological examination at 9 weeks
(three/sex/group), 18 weeks (five/sex/group), 27 weeks (four/sex/group), and 29 weeks (all
survivors). No control rats (0-ppm treatment group) were sacrificed at 9 weeks; however, the
remaining sacrifice schedule was the same for control and exposed groups (histology of
non-nervous system tissues was not performed). Gross necropsy was conducted on all animals
that died spontaneously or were euthanized in extremis, and selected tissues were prepared for
potential future histological examination, including bone, bone marrow, kidneys, liver, lungs,
pulmonary and mesenteric lymph nodes, sciatic nerves, spinal cord, and gross lesions.
In-life-phase systemic measurements were reported in Bio Dynamics (1980). while
neurohistological evaluations were summarized in Yeshiva University (1980).
Two deaths occurred in this study: one female in the low-dose group died accidently at
Week 18 during retro-orbital bleeding, and one female in the high-dose group exhibiting
prolapsed urethra and hyperemic vaginal walls was euthanized. These deaths were not
considered exposure related. During the first week of treatment, rats in both the low- and
high-dose groups exhibited prostration and difficulty breathing (more common and more severe
in the high-dose group). Clinical signs observed in Week 1 were apparently transient, as they
were not observed thereafter. No differences in body weights were observed between treated
and control rats. ALP levels showed a slight, dose-related increase in exposed females at
Week 26, reaching statistical significance only in the high-dose group (1.6-fold change from
controls) (see Table B-6). Hematology, urinalysis, and other serum chemistry results were
similar between treated rats and their control counterparts. The neurohistological evaluation of
the central and peripheral nervous systems revealed the presence of pathological changes in
both control and treated animals that were consistent with normal aging, including axonal
swelling in the gracile nucleus and tract, isolated myelin bubbles in dorsal roots, and rare
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segmental remyelination and Wallerian degeneration in the peripheral nerves. Higher incidence
of myelin bubbles was reported at Weeks 27 and 29 in the dorsal roots of exposed rats
compared to controls (incidence data were not provided); however, the study authors questioned
the significance of such findings, indicating the lack of dose-response relationship and
progression of these lesions from Weeks 27-29. Isolated incidences of unilateral and bilateral
optic nerve degeneration with or without changes in lateral geniculate nucleus were found in
both control and exposed animals (incidence data was not provided) and did not appear to be
related to treatment. Due to the lack of reporting on incidence data, the relevance of these
neurohistological lesions could not be independently reviewed and is therefore unclear.
The study inadequately reported neurohistological findings and failed to examine
pathology of non-nervous system tissues, precluding the determination of critical target organs
or a NOAEL/LOAEL. The exposure concentrations of 398 and 2,970 ppm are converted to
HECs of 291 and 2,174 mg/m3 for extrarespiratory effects by treating //-heptane as a Category 3
gas and using the following equation (U.S. EPA, 1994a): HECexresp = (ppm x MW ^ 24.45)
x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x ratio of blood-gas partition
coefficient (animal:human). For //-heptane, the blood-air partition coefficient for rats is greater
than that for humans (Gareas et al.. 1989); thus, a default ratio of 1 is applied (U.S. EPA.
1994a).
Frontali et al. (1981)
In a neurotoxicity study, groups of 6-9 male S-D rats were exposed to pure //-heptane
(99%) at concentrations of 0 or 1,500 ppm, 9 hours/day, 5 days/week for 7, 14, or 30 weeks.
Rats were supplied with food ad libitum except during exposure periods. Body weight was
monitored throughout the study. Neurological endpoints included hind limb spread on landing
after dropping from a 32-cm height and tibial nerve histology after 7, 14, and 30 weeks of
exposure.
Body weights were similar between the exposure group and control (0-ppm treatment
group). No differences in hind limb spread (data were not provided) or tibial neural axon
histology were observed between exposure and control groups.
The exposure concentration of 1,500 ppm is identified as a NOAEL for lack of
neurological or body-weight effects. This concentration was converted to an HEC of
1,647 mg/m3 for extrarespiratory effects by treating //-heptane as a Category 3 gas and using the
following equation (U.S. EPA, 1994a): HECexresp = (ppm x MW ^ 24.45) x (hours per day
exposed ^ 24) x (days per week exposed ^ 7) x ratio of blood-gas partition coefficient
(animal:human). For //-heptane, the blood-air partition coefficient for rats is greater than that
for humans (Gareas et al, 1989): thus, a default ratio of 1 is applied (U.S. EPA, 1994a).
Reproductive/Developmental Studies
No studies have been identified.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Genotoxicity
In the only available genotoxicity study, //-heptane did not induce gene mutation in
Salmonella typhimurium or Escherichia coli, mitotic gene conversion in Saccharomyces
cerevisiae, or chromosome damage in cultured rat liver cells (Brooks et al., 1988).
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Supporting Human Toxicity Studies
Valentini et al. (1994) reported a case of peripheral neuropathy in a 32-year-old female
after about 6 months of working as a shoemaker at home in her garage (Valentini et al.. 1994).
After reproducing her working conditions (8-10 hours/day), the measured air concentration of
//-heptane was 153 mg/m3. Several other solvent exposures occurred, most notably ethyl acetate
(252 mg/m3) and cyclohexane (375 mg/m3). The patient's symptoms included vertigo, leg and
arm paresthesia, leg pain, abnormal electroencephalogram (EEG), and altered peripheral nerve
conduction velocity. A complete recovery was achieved within 7 months after cessation of
exposure. Due to exposure to several solvents, it is unknown if exposure to //-heptane caused or
contributed to the peripheral nervous system deficits.
Supporting Neurotoxicity Studies in Animals
Neurobehavioral changes, including increased motor activity and impaired operant
training, were observed in rats and mice exposed to //-heptane at concentrations >5,600 ppm
(23,000 mg/m3) for 30-240 minutes; no neurobehavioral effects were observed at 3,000 ppm
(12,000 mg/m3) (Gonczi et al.. 2000; Glowa. 1991). Mice were prostrate at 10,000 ppm
(41,000 mg/m3) (Glowa. 1991). In another acute inhalation study, isoeffective concentrations
for 30% inhibition of propagation and maintenance of an electrically evoked seizure were
determined to be 2,740 ppm (11,200 mg/m3) in rats and 4,740 ppm (19,400 mg/m3) in mice
(F'rantik et al.. 1994). These values were used as a criterion of the acute neurotropic effect of
//-heptane.
Altered electrophysiology and histopathological lesions in peripheral nerves were
observed in rats exposed to 1,500 ppm of technical-grade //-heptane (52.4% pure) 5 hours/day,
5 days/week for 1-6 months (Truhaut et al.. 1973). Impurities in the test material included
benzene, toluene, 3-methylhexane, cyclohexanes, and other compounds. The extent to which
the observed effects were due to //-heptane is unclear because high levels of potentially
neurotoxic impurities were found in the test material and may have contributed to the effects.
Acute Systemic Toxicity in Animals
Acute lethality tests have reported rat 4-hour inhalation median lethal concentration
(LCso) values of >17,937 ppm (73,5 18 mg/m3) (Hazleton Laboratories. 1982) and 1 mmol/L
(100,210 mg/m3) (Hau et al.. 1999). Saturated air levels of //-heptane caused convulsions and
death in rats within 20-26 minutes due to asphyxiation (displacement of oxygen due to high
vapor pressure); if animals were removed within 12 minutes, they survived but showed slight
liver and kidney damage at autopsy (Dow Chemical Co. 1962). Respiratory arrest was observed
in Swiss mice exposed to w-heptane at concentrations >48,000 ppm (200,000 mg/m3) for up to
5 minutes (Swann et al.. 1974). Central nervous system (CNS) depression and cyanosis was
observed in mice following brief exposures (2-3 minutes of spraying time) to aerosols
containing //-heptane at concentrations of 800-2,500 ppm (3,300-10,200 mg/m3); the animals
recovered once removed from the exposure chamber, and no lung damage was observed at
autopsy (Yamashita and Tanaka. 1995).
A concentration inducing 50% respiratory depression (RD50) of 17,400 ppm
(71,300 mg/m3) was identified in CF-1 male mice exposed to w-heptane for 10 minutes via
inhalation; the RD50 represents the concentration required to reduce the respiration rate by 50%
(Kristiansen and Nielsen. 1988). Respiratory irritation was not observed in outbred specific
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pathogen-free male mice (CD-I, COBS) exposed to //-heptane for 1-minute intervals at a
concentration of 20,000 ppm (80,000 mg/m3) via inhalation (U.S. EPA. 1994b).
Rats treated with 1 mL/kg (0.684 mg/kg) of //-heptane via daily intraperitoneal (i.p.)
injection for 1-45 days did not exhibit any overt toxic symptoms, but did show hepatic effects
that included significant decreases in serum cholinesterase activity, albumin content, cholesterol
content, hepatic protein, total sulfhydryl content, and glucose-6-phosphatase, and a significant
increase in fructose-1,6-diphosphate (FDP) and lipid peroxidation (Goel et al.. 1988. 1982).
Absorption, Distribution, Metabolism, and Elimination (ADME) Studies
The absorption, distribution, metabolism, and elimination of //-heptane are summarized
below based on reviews by PECOS (1993), MAK Commission (2012), and EC (1996).
The primary route of exposure to //-heptane in humans is via inhalation. Pulmonary
retention following inhalation exposure is 25-29% in humans and rats. The blood-air partition
coefficients for //-heptane are 1.9-2.85 in humans and 4.75-5.4 in rats. A minor amount of
dermal absorption is possible. In vitro studies using abdominal rat skin indicate a dermal
penetration rate of 0.14-0.15 |ig/cm2-hour.
Organ/air distribution coefficients determined in vitro for humans and rats indicate that
//-heptane is distributed in the whole body, with the highest accumulation in the adipose tissue
(Gargas et al. 1989; Perbellini et al.. 1985). At steady-state exposure levels <35 ppm
(146 mg/m3), the body clearance half-lives for w-heptane are 0.17 ± 0.02 hours in rats and
1.88 ± 0.20 hours in humans. With repeated exposure at higher concentrations (>100 ppm),
accumulation of //-heptane was observed in the brain and perirenal fat of rats exposed for
1-2 weeks via inhalation. //-Heptane was no longer detectable following a 2-week recovery
period (Savolainen and Pfaffli. 1980).
//-Heptane is metabolized via a number of oxidative steps, which are typical of //-alkane
metabolism. At least three cytochrome P450 (CYP450) enzymes are responsible for the liver
metabolism of heptane, as determined by in vitro studies. //-Heptane is initially metabolized to
its parent alcohols, mainly 2- and 3-heptanol, and to a minor extent, 1- and 4-heptanol.
//-Heptane can be further metabolized at relatively high rates via hydroxylation and
dehydrogenation, leading to monohydroxy, dihydroxy, hydroxyketo, and diketo derivatives.
Metabolic disposition studies in rats revealed that the most abundant metabolites recovered in
urine following acute and prolonged inhalation exposures to //-heptane include 2- and
3-heptanol, y-valerolactone, and 6-hydroxy-2-heptanone [see Tables 4—6;(Perbellini et al. 1986;
Bahima et al. 1984)1. Biotransformation of 2-heptanol to 2,5-heptanedione, a metabolic
product with apparent neurotoxic properties (Misumi and Nagano, 1984; Katz et al, 1980), has
also been demonstrated; however, this metabolite is measured in small quantities in rats (<1%
of the total concentration or mass of metabolites excreted; see Tables 4-6). 2,5-Heptanedione
has been similarly detected in urine samples of factory workers exposed to technical heptane
(//-heptane concentrations ranging from 5-196 mg/m3) at lower concentrations (0.1-0.4 mg/L)
relative to the primary metabolite, 2-heptanol (0.1-1.9 mg/L) (Perbellini et al. 1986).
Correspondingly, Filser et al. (1996) reported that 2,5-heptanedione accounted for 0.01% of the
total //-heptane metabolized in healthy volunteers exposed to //-heptane concentrations of up to
500 ppm. Heptanol metabolites are conjugated by glucuronates or sulfates prior to excretion in
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the urine; thus, their detection in urine depends upon pretreatment of the urine by acid
hydrolysis and/or glucuronidase.
Table 4. Metabolites Excreted over 24 Hours in Urine of Male S-D Rats Exposed by
Inhalation to «-Heptane (CASRN 142-82-5) at 1,800 ppm for 6 Hours3
Metabolite
Mass Excreted, jig/24 hrb
Percent of Total
2-Heptanol
264
46.3%
3-Heptanol
201
35.2%
y-Valerolactone
65.4
11.5%
2-Heptanone
20
3.5%
3-Heptanone
8.4
1.5%
4-Heptanone
7.3
1.2%
2,5-Heptanedione
4.4
0.8%
aPerbe11im eta! (1986)
bAcid-hydrolyzed urine.
S-D = Sprague-Dawley.
Table 5. Metabolite Concentration in Urine of Female Wistar Rats Exposed by Inhalation
to n-Heptane (CASRN 142-82-5) at 2,000 ppm for 6 Hours"
Metabolite
Concentration, jig/mLb
Percent of Total
6-Hydroxy-2-heptanone
63.2
30%
2-Heptanol
60.7
29%
3-Heptanol
46.1
22%
y-Valerolactone
21.2
10%
2,6-Heptanediol
10.5
5%
5-Hydroxy-2-heptanone
9.4
4%
2,5-Heptanediol
1.3
0.1%
aBahima et al. (1984).
bUrine pretreated with acid hydrolysis and /^-glucuronidase.
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Table 6. Metabolites Excreted in Urine of Female Wistar Rats Exposed by Inhalation to
ft-Heptane (CASRN 142-82-5) at 2,000 ppm for 6 Hours/Day, 5 Days/Week, for
12 Weeks"
Metabolite
Mean Daily Excretion, jig/ratb
Percent of Total Daily Mass Excreted
2-Heptanol
561.0
29.9%
6-Hy dro xy-2-heptano ne
433.6
23.1%
3-Heptanol
381.9
20.3%
y-Valerolactone
190.9
10.2%
2,6-Heptanediol
141.9
7.6%
5-Hydroxy-2-heptanone
74.3
4.0%
1-Heptanol
29.0
1.5%
4-Heptanol
17.2
0.9%
2,5-Heptanediol
14.1
0.8%
6-Hydroxy-3 -heptanone
13.6
0.7%
2-Heptanone
10.6
0.6%
2,6-Heptanedione
7.4
0.4%
2,5-Heptanedione
2.4
0.1%
"Bahima et al. (1984).
bUrine pretreated with acid hydrolysis and /^-glucuronidase.
Mode-of-Action/Mechanistic Studies
CNS effects and irritation at the sites of contact could directly result from //-heptane due
to its lipophilic properties [reviewed by MAK Commission (2012)1. Neurotoxicity could also
result from the formation of the }'-di ketone metabolite, 2,5-heptanedione. In particular,
reactions with primary amino groups in neurofilamentary proteins to form pyrroles have been
implicated in the mechanism of peripheral neuropathy of }'-di ketone compounds [reviewed by
MAK Commission (2012)1. However, in vivo studies suggest that 2,5-heptanedione is a minor
metabolite of //-heptane (Miser et al, 1996; Perbellini et al, 1986; Bahima et al.. 1984).
Limited information is available regarding biochemical changes that may underlie
neurological changes observed following exposure to //-heptane. In a short-term-duration
inhalation study, groups of male Wistar rats exposed to //-heptane vapor at concentrations of
100, 500, or 1,500 ppm 6 hours/day, 5 days/week for 2 weeks showed statistically significant
increases in acid proteinase activity in the brain, compared with controls; however, increases
were small and not concentration related (increased 15, 7, and 9% at 100, 500, and 1,500 ppm,
respectively, compared with controls) (Savolainen and Pfaflli. 1980). Rats exposed to
1,500 ppm also showed a significant 6% decrease in brain glutathione content after 1-2 weeks
of exposure, compared with control (Savolainen and Pfaflli. 1980). These biochemical changes
were not accompanied by clinical signs of neurotoxicity (no other neurological endpoints were
assessed). In vitro, //-heptane has been shown to increase the production of reactive oxygen
species and reactive nitrogen species in cultured rat brain synaptosome fractions (Myhre and
Fonnum. 2001).
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DERIVATION OF PROVISIONAL VALUES
Tables 7 and 8 present summaries of noncancer and cancer references values,
respectively.
Table 7. Summary of Noncancer Reference Values for «-Heptane (CASRN 142-82-5)
Toxicity Type
(units)
Species/
Sex
Critical
Effect
p-Reference
Value
POD Method
POD
UFc
Principal Study
Screening
subchronic p-RfD
(mg/kg-d)
Mouse/M
Forestomach
lesions
3 x 1(T3
BMDLio
3.13
(based on
surrogate
POD)
1,000
Dodd et al.
(2003) as cited in
U.S. EPA
(2009b)
Screening
chronic p-RfD
(mg/kg-d)
Mouse/M
Forestomach
lesions
3 x 1(T4
BMDLio
3.13
(based on
surrogate
POD)
10,000
Dodd et al.
(2003) as cited in
U.S. EPA
(2009b)
Subchronic
p-RfC (mg/m3)
Rat/M
Loss of
hearing
sensitivity
4
BMCLisd
(HEC)
1,170
300
Sitnottscn and
Lund (1995)
Chronic p-RfC
(mg/m3)
Rat/M
Loss of
hearing
sensitivity
4 x KT1
BMCLisd
(HEC)
1,170
3,000
Sitnottscn and
Lund (1995)
BMCLisd (HEC) = benchmark concentration lower confidence limit estimated at a default benchmark response of
one standard deviation and reported in human equivalent concentration; BMDLio = benchmark dose lower
confidence limit estimated at a default benchmark response of 10%; M = male(s); p-RfC = provisional reference
concentration; p-RfD = provisional reference dose; POD = point of departure; UFC = composite uncertainty factor.
Table 8. Summary of Cancer Reference Values for «-Heptane (CASRN 142-82-5)
Toxicity Type
Species/Sex
Tumor Type
Cancer Value
Principal Study
p-OSF (mg/kg-d) 1
NDr
p-IUR (mg/m3)-1
NDr
NDr = not determined; p-IUR = provisional inhalation unit risk; p-OSF = provisional oral slope factor.
DERIVATION OF ORAL REFERENCE DOSES
No information was located regarding effects of orally ingested //-heptane in humans.
Animal studies were limited to a 3-week range-finding study and a 13-week
subchronic-duration study (both from the same laboratory) that dosed male CD COBS rats via
gavage. The range-finding study reported hyperplasia of the gastric nonglandular epithelium in
rats at doses >714 mg/kg-day (Eastman Kodak. 1979). Elevations in serum LDH, a general
marker of tissue or cellular damage, were also observed in exposed rats, but were not
accompanied by changes in organ-specific serum markers (i.e., ALP, AST, and ALT).
Additionally, increases in absolute and relative liver and kidney weights (>10%) occurred in
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exposed rats but histopathological findings in these organs were unremarkable. Overall, the
short-term duration, small group sizes (n = 3), and failure to report either statistical analyses or
any measure of variability within groups, limits the use of this study for quantitative assessment.
Evidence for chemical-related effects on the nonglandular gastric mucosa were also
found in the 13-week study, most prominently hyperkeratosis with pseudoepitheliomatous
hyperplasia occurred in 7/8 rats exposed to a dose of 2,860 mg/kg-day (Eastman Kodak. 1980).
Furthermore, effects were noted in the liver, kidney and adrenal glands of rats with subchronic
//-heptane treatment. Statistically significant increases in relative liver (+17%), kidney (+16%),
and adrenal gland (+36%) weights were reported in the three exposed rats surviving until
sacrifice. No statistically or biologically relevant changes were observed in the absolute
weights of these organs, although animals that died by gavage error exhibited grossly enlarged
livers. Histopathological lesions in the liver, kidney, and adrenal glands of exposed rats were
for the most part minimal or minor and only slightly elevated from controls. Although
statistically significant decreases in absolute heart weight were found in treated animals, these
changes are not supported by significant pathological findings and could be secondary to
reductions in mean body weight (>10%). Mean body weights were significantly reduced in
exposed rats compared to controls during the first week of treatment, which could be in part
related to concomitant decreases in food consumption. However, body weights in treated
animals did not appear to recover, remaining depressed (8—15%) throughout the study.
Ultimately, the 13-week study is also considered unsuitable for deriving provisional toxicity
values due to the inclusion of a single dose level along with high gavage-related mortality
(5/8 rats) in the treated group (Eastman Kodak. 1980).
In summary, the short-term- and subchronic-duration rat studies provide support for the
relevance of forestomach toxicity following gavage administration of //-heptane. Other
potential treatment-related effects were found in the liver, kidney and adrenal glands, although
the significance of such effects are not entirely understood due to the limitations in the available
data. As a result of the uncertainties in the oral toxicity database for //-heptane, subchronic and
chronic provisional reference doses (p-RfDs) were not derived. Instead, screening p-RfDs are
derived in Appendix A using an established tiered surrogate approach (Wang et ai. 2012).
Please refer to Appendix A for further details on the derivation of screening oral values.
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Information on the effects of //-heptane exposure via the inhalation route in humans is
limited but provides support for potential nervous system effects. Male and female volunteers
exposed to //-heptane vapor at concentrations >4,000 mg/m3 (1,000 ppm) for up to 15 minutes
reported vertigo and were observed to experience hilarity, incoordination, and inability to walk
straight at a dose of 20,000 mg/m3 (5,000 ppm) (Patty and Yant, 1929). However, the duration
of this study is insufficient for consideration in the derivation of inhalation reference values.
Occupational exposure to unknown concentrations of a solvent containing //-heptane
(>95% purity) for 1-9 years produced minimal peripheral nerve damage in tire factory workers,
evidenced by increased AD of the evoked MAP along the peroneal nerve and a correlation
between length of exposure and decreased MNCV (Crespi et ai. 1979). Residual amounts of
other hydrocarbons were present in the solvent at very small quantities; therefore, it is unlikely
that these impurities had a major impact in the observed neurophysiological effects. Ultimately,
the lack of exposure estimates limits the use of this study for quantitative risk assessment.
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Several animal studies have been performed to investigate potential neurotoxicity of
inhaled //-heptane. Acute-duration studies have reported neurological effects at concentrations
of //-heptane >2,740 ppm in rats and >4,740 ppm in mice (Gonczi et aL 2000; Frantik et aL
1994; Glowa, 1991). Similarly, a 28-day inhalation study identified possible neurotoxic effects
of //-heptane based on a NOAEL (HEC) of 821 mg/m3 (801 ppm) and a LOAEL (HEC) of
4,105 mg/m3 (4,006 ppm) for abnormal auditory brainstem responses and increased auditory
threshold in male Long-Evans rats 2 months after treatment, which indicate a loss of hearing
sensitivity (Simonsen and Lund. 1995). Compounds that cause hearing damage by altering the
brainstem or central auditory pathways are considered both ototoxic and neurotoxic, as it
appears to be the case for //-heptane (Johnson and Morata. 2010). Longer-duration
neurotoxicity studies in male rats found no effects at exposures up to HEC of 6,066 mg/m3
(2,960 ppm) for 16-30 weeks; however, these studies focused primarily on the assessment of
peripheral nerve damage (MNCV, mixed nerve conduction velocity, neurobehavioral
parameters, and neurohistopathology); thus, measurements of central auditory function were not
conducted (Frontal i et aL 1981; Takeuchi et aL 1981; Bio Dynamics. 1980; Yeshiva
University. 1980).
Chronic systemic toxicity was evaluated in a 26-week study in male and female S-D rats
that reported no adverse effects on physical assessment, body weight, hematology, serum
chemistry, and urinalysis related to inhalation of //-heptane at an HEC of up to 2,174 mg/m3
(2,970 ppm) (Bio Dynamics, 1980). The study noted significant increases in serum ALP levels
in females at the highest exposure group (2,970 ppm) after 26 weeks of treatment. The
biological relevance of elevated ALP levels is uncertain given that the effect appeared minor
(1.6-fold change from controls) and no corresponding changes occurred in male rats or at the
intermediate time-point (Week 13) in females. Additionally, short-term- and
subchronic-duration gavage studies reported no significant changes in ALP levels in rats
exposed to doses that caused significant forestomach toxicity (2,860 mg/kg-day) (Eastman
Kodak. 1980. 1979). A comprehensive neurohistological evaluation of central and peripheral
tissues was also conducted under the current study and results were summarized by Yeshiva
University (1980). Neurological lesions presumed to be associated with advancing age rather
than treatment were observed in control and exposed rats, most notably an increased incidence
of myelin bubbles in the dorsal roots of treated animals. However, histological data were not
provided for independent review, precluding the determination of the significance of these
neurological observations. Overall, the study is considered of limited use for deriving
provisional toxicity values as it failed to provide incidence data for the neurohistological
findings and to include organ-weight measurements and pathology of non-nervous system
tissues.
Altogether, human and animal data indicate that the nervous system is a critical target
organ of toxicity for continuous exposure to //-heptane via inhalation. Although
subchronic- and chronic-duration inhalation studies in rats suggest that //-heptane does not
induce peripheral nerve damage up to HEC of 6,066 mg/m3, the central auditory deficits in male
rats exposed for 28 days at an HEC of 4,105 mg/m3 demonstrate potential neurotoxic responses
for //-heptane. Systemic toxicity has not been rigorously tested in animals following inhalation
exposure to //-heptane, but a 26-week study in rats showed no adverse effects on limited
systemic endpoints, including physical assessment, body weight, hematology, serum chemistry,
and urinalysis at an HEC of up to 2,174 mg/m3. Evidence of neurological effects in
experimental animals from acute inhalation studies (Gonczi et aL 2000; Frantik et aL 1994;
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Glowa, 1991) and in tire factory workers with long-term exposure (Crespi et aL 1979) provide
further support for the neurotoxicity of //-heptane.
Derivation of a Subchronic Provisional Reference Concentration (p-RfC)
The Simonsen and Lund (1995) study is selected as a principal study for the derivation
of the subchronic p-RfC. Although the study is of short-term duration (28 days), it is adequate
in design and in assessing the dose-response relationship of central auditory function in rats
exposed to //-heptane via inhalation. It identified both a NOAEL (HEC) of 821 mg/m3
(801 ppm) and a LOAEL (HEC) of 4,105 mg/m3 (4,006 ppm) based on evidence for loss
hearing sensitivity, a relevant endpoint of toxicity for organic solvents. //-Hexane, an aliphatic
solvent and structural analog of //-heptane, caused abnormalities in the auditory brainstem
response in rats at similar inhalation concentrations (4,000 ppm, 14 hours/day, 7 days/week for
9 weeks) as those reported with //-heptane treatment (Pryor and Rebert, 1992). The effects of
//-hexane and //-heptane on the auditory system are primarily attributed to their neurotoxic
potential (Johnson and Morata, 2010), although //-hexane appears to be a more potent
neurotoxicant (see Appendix A for further details).
Benchmark dose (BMD) analyses were performed to model central auditory effects in
rats exposed to //-heptane in the Simonsen and Lund (1995) study. The reduction in peak
amplitude of auditory brainstem responses reflected a similar increase (8-10 dB) in the auditory
threshold across frequencies 4-32 kHz. As a result, continuous data for auditory threshold at all
frequencies tested were considered for BMD modeling, although statistical significance was
only achieved at 8 and 16 kHz (see Table B-5). Appendix C provides details on the BMD
modeling procedures and results for the selected data. The data sets at frequencies 4 and 8 kHz
were unsuitable for BMD analyses (see Table C-2). The estimated benchmark concentration
lower confidence limits (BMCLs) for the remaining endpoints were very similar (1,170 and
1,440 mg/m3 at frequencies 16 and 32 kHz, respectively). Thus, the lowest BMCLisd (HEC)
of 1,170 mg/m3 identified for loss of hearing sensitivity in rats from the 28-day inhalation
study is selected as a point of departure (POD) for the derivation of the subchronic p-RfC.
Subchronic p-RfC = BMCLisd (HEC) - UFC
1,170 mg/m3-300
= 4 mg/m3
The composite uncertainty (UFc) for the subchronic p-RfC for //-heptane is 300, as
summarized in Table 9.
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Table 9. Uncertainty Factors for the Subchronic p-RfC for w-Heptane (CASRN 142-82-5)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for remaining uncertainty (e.g., the toxicodynamic
differences between rats and humans) following inhaled //-heptane exposure. The toxicokinetic
uncertainty has been accounted for bv calculation of an HEC as previously described (U.S. EPA.
1994a).
UFh
10
A UFh of 10 is applied to account for intraspecies variability in susceptibility in the absence of
quantitative information to assess the toxicokinetics and toxicodynamics of //-heptane in humans.
UFd
10
UFd of 10 is applied in the absence of acceptable studies that inform of potential systemic,
developmental, and multi-generational reproductive effects that may potentially be more sensitive
than the central auditory effects identified in the 28-d rat study. Although systemic toxicity has not
been rigorously studied in animals exposed by inhalation (lack of organ-weight measurements and
histopathology of non-nervous system tissues), information available from a 26-wk study in rats
suggest a lack of significant effect on (limited) systemic endpoints (e.g., physical assessment, body
weight, hematology, serum chemistry, and urinalysis).
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMCL.
UFS
1
A UFs for subchronic-to-chronic extrapolation is not relevant for the derivation of the subchronic
RfC; thus, a 1 is applied.
UFC
300
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; UF = uncertainty factor.
The confidence in the subchronic p-RfC for //-heptane is low as explained in Table 10.
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Table 10. Confidence Descriptors for the Subchronic p-RfC for n-Heptane
(CASRN 142-82-5)
Confidence Categories
Designation
Discussion
Confidence in study
M
Confidence in the orincioal study (Simonsen and Lund. 1995) is
medium. The study is peer-reviewed and its methodology was
adequate for the examination of central auditory effects in rats.
Furthermore, the study identified both a NOAEL and LOAEL on
the basis of abnormal auditory brainstem responses, a relevant
endpoint of toxicity for solvents. However, confidence is reduced
because it is a short-term-duration study (28 d), only male rats
were tested, and limited endpoints were analyzed.
Confidence in database
L
There are no acceptable developmental or multi-generational
reproductive studies. Systemic toxicity via the inhalation route
was examined in only one chronic-duration study that lacked
organ-weight measurements and histopathology of a
comprehensive set of tissues.
Confidence in subchronic p-RfCa
L
The overall confidence in the subchronic p-RfC is low.
aThe overall confidence cannot be greater than the lowest entry in the table (low).
L = low; LOAEL = lowest-observed-adverse-effect level; M = medium; NOAEL = no-observed-adverse-effect
level; p-RfC = provisional reference concentration.
Derivation of a Chronic Provisional Reference Concentration (p-RfC)
As previously discussed, two chronic-duration studies in rats are available in the
database for inhalation of //-heptane. One is a neurotoxicity study that examined only a few
endpoints related to peripheral neuropathy (hind limb spread on landing and tibial nerve
histology) and identified a NOAEL (HEC) of 1,647 mg/m3 (1,500 ppm) for the absence of
effects in male S-D rats exposed for up to 30 weeks (Frontali et aL 1981). Similarly, another
study in male and female S-D rats reported no adverse effects on a limited number of systemic
endpoints at an HEC of 2,174 mg/m3 (2,970 ppm) (Bio Dynamics. 1980); however, the study is
considered inadequate because it lacked complete data reporting for neurohistology results,
while also excluding organ-weight measurements and pathology of non-nervous system tissues.
Due to the failure to identify any critical effects that are more sensitive than the loss of hearing
sensitivity reported in male rats with short-term exposure to //-heptane (Simonsen and Lund.
1995), the two aforementioned studies are not considered appropriate for the derivation of the
chronic p-RfC. Although the Simonsen and Lund (1995) study is only 28 days, it reported the
lowest NOAEL (HEC) of 821 mg/m3 (801 ppm) in the inhalation database for //-heptane. These
findings are consistent with studies from acute exposure in rodents (Gonczi et aL 2000; Frantik
et al. 1994; Glowa. 1991) and long-term occupational exposure in humans that suggest the
nervous system is a target organ of //-heptane toxicity (Crespi et al.. 1979). Thus, the
BMCLisd (HEC) of 1,170 mg/m3 previously identified for loss of hearing sensitivity in rats
is selected as a POD for the derivation of the chronic p-RfC.
Chronic p-RfC = BMCLisd (HEC) - UFC
1,170 mg/m3-3,000
= 4 x 10"1 mg/m3
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Table 11 summarizes the UFc for the chronic p-RfC for //-heptane.
Table 11. Uncertainty Factors for the Chronic p-RfC for «-Heptane (CASRN 142-82-5)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for remaining uncertainty (e.g., the toxicodynamic
differences between rats and humans) following inhaled //-heptane exposure. The toxicokinetic
uncertainty has been accounted for bv calculation of an HEC as previously described (U.S. EPA.
19943).
UFh
10
A UFh of 10 is applied to account for intraspecies variability in susceptibility in the absence of
quantitative information to assess the toxicokinetics and toxicodynamics of //-heptane in humans.
UFd
10
UFd of 10 is applied in the absence of acceptable studies that inform of potential systemic,
developmental, and multi-generational reproductive effects that may potentially be more sensitive
than the central auditory effects identified in the 28-day rat study. Although systemic toxicity has
not been rigorously studied in animals exposed by inhalation (lack of organ-weight measurements
and histopathology of non-nervous system tissues), information available from a 26-week study in
rats suggest a lack of significant effect on (limited) systemic endpoints (e.g., physical assessment,
body weight, hematology, serum chemistry, and urinalysis).
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMCL.
UFS
10
A UFS of 10 is applied to account for the chronic extrapolation from a 28-day study used in the
derivation of the chronic p-RfC.
UFC
3,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMCL = benchmark concentration lower confidence limit; HEC = human equivalent concentration;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfC = provisional reference concentration; UF = uncertainty factor.
The confidence in the chronic p-RfC for n-heptane is low as explained in Table 12.
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Table 12. Confidence Descriptors for the Chronic p-RfC for «-Heptane (CASRN 142-82-5)
Confidence Categories
Designation
Discussion
Confidence in study
M
Confidence in the orincroal studv (Simonsen and Lund. 1995) is
medium. The study is peer-reviewed and its methodology was
adequate for the examination of central auditory effects in rats.
Furthermore, the study identified both a NOAEL and LOAEL on
the basis of abnormal auditory brainstem responses, a relevant
endpoint of toxicity for solvents. However, confidence is reduced
because it is a short-term-duration study (28 d), only male rats
were tested, and limited endpoints were analyzed.
Confidence in database
L
There are no acceptable developmental or multi-generational
reproductive studies and systemic toxicity via the inhalation route
was examined in a single chronic-duration study that lacked
organ-weight measurements and histopathology of a
comprehensive set of tissues.
Confidence in subchronic p-RfCa
L
The overall confidence in the subchronic p-RfC is low.
aThe overall confidence cannot be greater than the lowest entry in the table (low).
L = low; LOAEL = lowest-observed-adverse-effect level; M = medium; NOAEL = no-observed-adverse-effect
level; p-RfC = provisional reference concentration.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 13 identifies the cancer weight-of-evidence (WOE) descriptor for n-heptane.
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Table 13. Cancer WOE Descriptor for «-Heptane (CASRN 142-82-5)
Possible WOE Descriptor
Designation
Route of Entry
(oral, inhalation,
or both)
Comments
"Carcinogenic to Humans"
NS
NA
There are no human carcinogenicity data identified
to support this descriptor.
"Likely to Be Carcinogenic
to Humans "
NS
NA
There are no animal carcinogenicity studies
identified to support this descriptor.
"Suggestive Evidence of
Carcinogenic Potential"
NS
NA
There are no animal carcinogenicity studies
identified to support this descriptor.
"Inadequate Information to
Assess Carcinogenic
Potential"
Selected
Both
This descriptor is selected due to the lack of
adequate information for an assessment of
human carcinogenic potential. No data in
humans are available to assess carcinogenicity
of w-heptane. The only chronic-duration study
in experimental animals that evaluated systemic
toxicity after inhalation exposure to w-heptane
failed to report pathological findings from
non-nervous svstem tissues (Bio Dynamics.
1980; Yeshiva University, 1980). Limited data
indicate that this chemical is not genotoxic
(Brooks et a I.. 1988).
"Not Likely to Be
Carcinogenic to Humans"
NS
NA
No evidence of noncarcinogenicity is available.
NA = not applicable; NS = not selected.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
Derivation of quantitative estimates of cancer risk for //-heptane is precluded by the
absence of carcinogenicity data for //-heptane.
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APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main provisional peer-reviewed toxicity value (PPRTV)
document, the database for continuous exposure to //-heptane is inappropriate for the derivation
of provisional oral toxicity values. However, information is available for this chemical, which,
although insufficient to support derivation of a provisional toxicity value, under current
guidelines, may be of limited use to risk assessors. In such cases, the Superfund Health Risk
Technical Support Center summarizes available information in an appendix and develops a
"screening value." Appendices receive the same level of internal and external scientific peer
review as the PPRTV documents to ensure their appropriateness within the limitations detailed in
the document. Users of screening toxicity values in an appendix to a PPRTV assessment should
understand that there is considerably more uncertainty associated with the derivation of an
appendix screening toxicity value than for a value presented in the body of the assessment.
Questions or concerns about the appropriate use of screening values should be directed to the
Superfund Health Risk Technical Support Center.
APPLICATION OF AN ALTERNATIVE SURROGATE APPROACH
The surrogate approach allows for the use of data from related compounds to calculate
screening values when data for the compound of interest are limited or unavailable. Details
regarding searches and methods for surrogate analysis are presented in Wang et al. (2012).
Three types of potential surrogates (structural, metabolic, and toxicity-like) are identified to
facilitate the final surrogate chemical selection. The surrogate approach may or may not be
route-specific or applicable to multiple routes of exposure. In this particular case, the search for
surrogate chemicals was limited to oral noncancer effects based on the available toxicity data.
All information was considered together as part of the final weight-of-evidence (WOE) approach
to select the most suitable surrogate both toxicologically and chemically.
Structural Surrogates (Structural Analogs)
An initial surrogate search focused on the identification of structurally similar chemicals
with toxicity values from Integrated Risk Information System (IRIS), PPRTV, Agency for Toxic
Substances and Disease Registry (ATSDR), or California Environmental Protection Agency
(Cal/EPA) databases to take advantage of the well-characterized chemical-class information.
This was accomplished by searching the U.S. EPA's DSSTox database and the National Library
of Medicine's (NLM's) ChemlDplus database at a similarity level >60%. Two structural analogs
to //-heptane were identified that have oral toxicity values: //-hexane (U.S. EPA, 2009a, 2008)
and //-nonane (U.S. EPA, 2009b). Table A-l summarizes their physicochemical properties and
similarity scores. //-Heptane and the identified analogs are straight-chain alkanes that share
comparable physicochemical properties. In addition, the ChemlDplus and DSSTox similarity
scores for the analogs were relatively high (>83% for ChemlDplus and >86% for DSSTox).
Thus, the two compounds are considered to be appropriate structural surrogate candidates for
//-heptane.
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Table A-l. Physicochemical Properties of «-Heptane (CASRN 142-82-5) and Structural Analogs"
Chemical
rt-Heptane
/i-Hexane
w-Nonane
Structure
CASRN
142-82-5
110-54-3
111-84-2
Molecular weight
100.21
86.18
128.26
DSSTox similarity score (%)b
100
85.7
87.5
ChemlDplus similarity score (%)°
100
82.7
84.6
Melting point (°C)
-90.6
-95.3
-53.5
Boiling point (°C)
98.5
68.7
150.8
Vapor pressure (mm Hg at 25°C)
46
151.3
4.45
Henry's law constant (atm-m3/mole at 25°C)
2.27 (estimated)3
1.71 (estimated)3
4 (estimated)3
Water solubility (mg/L)
3.4
9.5
0.22
Log Kow
4.66
3.9
5.65
pKa
NA
NA
NA
'Data was gathered from PHYSPROP database for each respective compound unless otherwise specified (U.S. EPA. 2012b').
bDSSTox (2015).
°ChemIDplus Advanced, similarity scores (ChemlDplus. 20161.
NA = not applicable.
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Metabolic Surrogates
The primary route of exposure for //-heptane and structurally related alkanes in humans
occurs via inhalation; thus, toxicokinetics data following oral administration of these compounds
is largely unavailable. Pulmonary retention in humans is similar for //-heptane and //-hexane,
25 and 22-24%, respectively, indicating that these compounds are well-absorbed by inhalation
(EC, 1996; Yen 1 em an s et aL, 1982). Absorption of //-hexane and n-nonane via the oral route can
be inferred from the recovery of primary metabolic products of the parent chemicals in urine
(Baelum et aL 1998; Serve et aL 1995; Krasavage et aL 1980). Information regarding the
distribution of orally ingested //-heptane and its two structural analogs is currently lacking;
however, inhalation exposure to rats revealed that these compounds are widely distributed
throughout the body, with a tendency to concentrate in nervous system and adipose tissues.
Indeed, linear relationships between exposure levels and solvent concentrations in the brain and
perirenal fat were found in rats after inhalation of //-heptane (100-1,500 ppm, 12 hours/day) for
1 week, and during the second week of treatment, accumulation was noted in the brain
(Savolainen and Pfaffli. 1980). High concentrations of //-hexane were detected in the sciatic
nerve of rats relative to blood, liver, and kidney following a single or repeated exposure to this
alkane (1,000 ppm, 6 hours/day) (Bus et aL. 1981). Similarly, //-nonane concentrations in the
brain exceeded those of blood, and accumulation was observed in adipose tissue following
continuous exposure in rats (100 ppm, 12 hours/day for up to 3 days) (Zahlsen et aL 1992).
In general, metabolism pathways are similar for //-heptane, //-hexane, and //-nonane,
although routes of exposure from available rat disposition studies differ among chemicals
(see Table A-2 in Appendix A and Tables 4, 5, and 6 under the "Absorption, Distribution,
Metabolism, and Excretion [ADME] Studies" section in the main document). Each compound
undergoes hydroxylation to one or more alcohols (1-, 2-, 3-, or 4-heptanol for //-heptane; 1-, 2-,
or 3-hexanol for //-hexane; and 2-, 3-, or 4-nonanol for //-nonane). The alcohols are then
subjected to further hydroxylation and/or dehydrogenation, leading to monohydroxy, dihydroxy,
hydroxyketo, and diketo derivatives.
Of particular importance with respect to the metabolism of these compounds is the degree
to which each forms a }'-diketone metabolite. Studies with //-hexane, the most well-studied
compound of the group, have shown that 2,5-hexanedione, a principal metabolite of //-hexane
(see Table A-2), is the compound primarily responsible for the axonopathy and peripheral
neuropathy that is characteristic of //-hexane exposure, and represents the critical effect of both
the inhalation and oral routes (U.S. EPA. 2009a. 2008). Metabolism of //-hexane after inhalation
in rats yields relatively high quantities of the }'-di ketone metabolite (2,5-hexanedione) (33%;
see Table A-2) and a number of studies have confirmed formation of urinary 2,5-hexanedione in
humans with oral and inhalation exposure to //-hexane (Prieto et aL. 2003; dos Santos et aL.
2002; Mavan et aL. 2002; Baelum et aL. 1998). In contrast, studies in rats suggest that, while
metabolism of inhaled //-heptane may yield a 7-di ketone metabolite (2,5-heptanedione), the
quantity of this metabolite formed in vivo is low (<1%; see Table A-2 in Appendix A and
Tables 4, 5, and 6 under the "Absorption, Distribution, Metabolism, and Excretion [ADME]
Studies" section in the main document). Moreover, F'ilser et al. (1996) showed that excretion of
the corresponding 7-di ketone metabolites in urine was seven times lower in rats and four times
lower in humans after inhalation exposure to //-heptane (500 ppm) in comparison to //-hexane
(50 ppm). No disposition studies that can inform on the metabolism and elimination of
//-heptane following oral ingestion have been found.
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Available data on urinary metabolites of //-nonane are limited to an oral exposure study.
Serve et al. (1995) reported the relative abundance of metabolites from the urine of rats given
//-nonane by gavage; 2,5-hexanedione, the only 7-di ketone metabolite detected, was present at
the smallest relative abundance of 1.0 (see Table A-2).
Table A-2. Summary of Metabolites for «-Heptane (CASRN 142-82-5) and
Structural Analogs
Chemical
Route
Species
Metabolites in Urine
References
//-Heptane
Inhalation
(1,800 ppm
for 6 h)
Rat/M
2-heptanol (46.3), 3-heptanol (35.2), y-valerolactone
(11.5), 2-heptanone (3.5), 3-heptanone (1.5), and
4-heptanone (1.2), 2,5-heptanedione (0.8) over 24 ha
Perbellini et
al. (1986)
n-Hexane
Inhalation
(1,000 ppm
for 8 h)
Rat/M
2-hexanol (57), 2,5-hexanedione (33), 3-hexanol (6), and
1-hexanol (3), 2-hexanone (1) over 24 lv'
Fedtke and
Bolt (1986)
//-Nonane
Oral
(800 mg/kg-d)
Rat/M
y-valerolactone (38.6), 2-nonanol (17.9), 3-nonanol (10.7),
4-nonanone (6.8), 5-heptanolactone (6.5), 1-heptanol (5.7),
4-nonanol (3.5), 5-methyl-2-(3-oxobutyl) furan (3.2),
5-hexanolactone (2.8), 2,5-hexanedione (1) over 48 hb
Serve et al.
(1995)
Percentage of total metabolites in urine.
bRelative abundance of metabolites in urine.
M = male(s).
In summary, the pattern of metabolic disposition in rats for //-nonane is similar to
//-heptane with high relative amounts of the 2- and 3-alcohols and y-valerolactone metabolites
and low production of the }'-di ketone compound (see Table A-2), although routes of exposure
from available studies are different. In contrast to //-heptane, metabolism of //-hexane appears to
favor the formation of the neurotoxic }'-di ketone metabolite by inhalation exposure
[see Table A-2 and F'ilser et al. (1996)1. //-Nonane is, therefore, considered to be the most
appropriate metabolic surrogate for //-heptane.
Toxicity-Like Surrogates
Table A-3 summarizes available oral toxicity data for //-heptane and the structural
analogs identified. Consistent findings of chemical-related irritative and hyperplastic effects in
the nonglandular gastric mucosa of rats were observed after gavage //-heptane treatment for 3 or
13 weeks, providing evidence of forestomach toxicity following oral exposure to this chemical
(Eastman Kodak. 1980. 1979). These studies also found potential effects in the liver, kidney,
and adrenal glands with //-heptane treatment. Therefore, information from structurally related
analogs of //-heptane was analyzed, anticipating similar toxicities in rodent studies.
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Table A-3. Comparison of Available Repeated-Dose Oral Toxicity Data for «-Heptane (CASRN 142-82-5) and Structural Analogs
Chemical
M-Heptane
w-Hexane
w-Nonane
Structure
CASRN
142-82-5
110-54-3
111-84-2
Repeat-dose toxicity—oral, subchronic
POD (mg/kg-d)
NA
785
3.13
POD type
NA
LOAEL
BMDLio
Subchronic UFC
NA
3,000
1,000
Subchronic p-RfD
(mg/kg-d)
NA
3 x 10-1
3 x 10-3
Critical effects
Irritative and proliferative forestomach
lesions and potential effects in the liver,
kidney, and adrenal glands at a dose of
2,860 mg/kg-d. Lack of neurotoxicity at
doses up to 2,860 mg/kg-d based on
histological evaluation (13-wk rat study).
Decreased MNCV associated with peripheral
neuropathy
Proliferative forestomach lesions with varying
degrees of hyperplasia and hyperkeratosis of the
squamous epithelium
Other effects
Hind-limb paralysis accompanied by evidence of
peripheral neuropathy and testicular effects based
on histopathology at a dose of 2,843 mg/kg-d
(90-d rat study)
Additional effects in principal study:
histopathological lesions in the duodenum (rats)
and rectum (rats and mice) at doses
>1,000 mg/kg-d; nasal and pulmonary lesions,
possibly due to aspiration (rats and mice).
Increases in liver and lung weights at a dose of
5,000 mg/kg-d and dose-related increases in
adrenal gland and ovary weights at doses
>1,000 mg/kg-d. No significant
neurohistopathology or neurobehavioral
abnormalities reported in rats or mice at doses up
to 5,000 mg/kg-d
Species
NA
Rat (M)
Mouse (M) and Rat (F)
Duration
NA
8 wk
90 d
Route (method)
NA
Oral (gavage)
Oral (gavage)
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Table A-3. Comparison of Available Repeated-Dose Oral Toxicity Data for «-Heptane (CASRN 142-82-5) and Structural Analogs
Chemical
M-Heptane
w-Hexane
/i-Nonane
Notes
NA
Available oral studies did not examine histology of
the gastrointestinal tract or a comprehensive battery
of systemic endpoints.
Quantitation is based on male mice, but the same
types of lesions were observed in female rats.
Source
U.S. EPA (2016b)
U.S. EPA (2009a)
U.S. EPA (2009b)
Repeat-dose toxicity—oral, chronic
POD (mg/kg-d)
NA
NA
3.13
POD type
NA
NA
BMDLio
Chronic UFC
NA
NA
10,000
Chronic p-RfD
(mg/kg-d)
NA
NA
3 x 10 4 (screening)
Critical effects
NA
NA
Proliferative forestomach lesions with varying
degrees of hyperplasia and hyperkeratosis of the
squamous epithelium
Other effects
NA
NA
NA
Species
NA
NA
Mouse (M)
Duration
NA
NA
90 d
Route
NA
NA
Oral (gavage)
Notes
NA
NA
No oral chronic-duration studies are available.
Source
U.S. EPA (2016b)
U.S. EPA (2009a)
U.S. EPA (2009b)
BMDL = benchmark dose lower confidence limit (subscripts denote benchmark response: i.e., 10 = exposure concentration associated with 10% extra risk);
F = female(s); LOAEL = lowest-observed-adverse-effect level; M = male(s); MNCV = motor nerve conduction velocity; NA = not applicable; p-RfD = provisional
reference dose; POD = point of departure; UFC = composite uncertainty factor.
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The critical effect for //-hexane following oral exposure is peripheral neuropathy
(measured as decreased motor nerve conduction velocity [MNCV]), identified in rats gavaged
with 785 mg/kg-day for 8 weeks and presumably related to the formation of the toxic metabolite,
2,5-hexanedione (U.S. EPA. 2009a. 2008). At higher doses (2,843 mg/kg-day), //-hexane
induced testicular toxicity concomitantly with peripheral neuropathy in a 90-day rat study. The
available database for oral exposure to //-hexane is limited to the evaluation of putative
neurotoxic and testicular effects; information on the gastrointestinal tract or other major systemic
organs is lacking. On the other hand, no evidence of neurotoxicity was found in rats with
short-term or subchronic oral exposure to //-heptane at doses up to 2,860 mg/kg-day, based on
histological evaluation of central and peripheral nervous system tissues (Eastman Kodak. 1980.
1979). Comparative inhalation studies in rats exposed to //-heptane or //-hexane for 16 weeks
(3,000 ppm, 12 hours/day, 7 days/week) revealed a decrease in MNCV and morphological
impairments in the peripheral nerves, muscle, and neuromuscular junction for //-hexane only
(Takenchi et ai. 1981. 1980). suggesting that //-hexane is a more potent neurotoxicant than
//-heptane via the inhalation route. These findings are in agreement with toxicokinetic data that
demonstrate an enhanced formation of the neurotoxic }'-di ketone metabolite from the metabolism
of //-hexane in rats and humans compared to that of //-heptane (Filser et ai. 1996). Altogether,
//-hexane is not considered to be an appropriate toxicity-like surrogate for //-heptane via the oral
route based on apparent differences in target organs and the absence of comprehensive data on
potential gastrointestinal effects.
Gastric lesions were observed in a 90-day gavage study of n-nonane (neat) in rats and
mice (U.S. EPA. 2009b) that were similar to the histopathological findings in the forestomach of
rats exposed to 2,860 mg/kg-day of //-heptane for 13 weeks (Eastman Kodak. 1980. 1979).
Specifically, hyperplasia and hyperkeratosis of the forestomach epithelium with occasional
erosion or ulceration of the mucosa occurred with //-nonane at doses >100 mg/kg-day in the two
species, although only female rats and male mice were tested based on concerns of possible
alpha 2u-globulin (a2u-g) nephropathy in male rats. Higher //-nonane doses produced mild
inflammation of the proximal duodenum in rats only (5,000-mg/kg-day treatment group) and
perianal hyperplasia, hyperkeratosis, and inflammation of the rectum in both rats and mice
(1,000- and 5,000-mg/kg-day treatment groups). Irritative nasal lesions in exposed animals were
consistent with evidence of aspiration of //-nonane into the rat lung and do not appear to be
chemical-specific effects targeting the nasal mucosa. Statistically significant increases in liver
weights were reported in rats and mice at a dose of 5,000 mg/kg-day. Other significant
organ-weight effects occurring only in rats included increased lung weights at a dose of
5,000 mg/kg-day and dose-related changes in adrenal gland weights (increased) and ovary
(decreased) weights at doses >1,000 mg/kg-day. No treatment-related histopathological changes
were noted in these organs. Examinations of neurobehavioral activity and histology of central
and peripheral nervous system tissues were unremarkable, except for a pattern of reduced
locomotor activity in mice and rats with no clear dose-response relationship. In summary, the
gastrointestinal tract, in particular the nonglandular epithelium, appears to be a critical target
organ in rodents for both //-heptane and //-nonane via the oral route.
Despite the lack of evidence for significant neurotoxicity from gavage treatment with
//-nonane or //-heptane, these chemicals appear to target the central nervous system (CNS) by
inhalation exposure. Acute inhalation studies reported neurological effects at //-heptane
concentrations >2,740 ppm in rats and >4,740 ppm in mice (Gonczi et al. 2000; Frantik et al.
1994; Glowa, 1991). Similarly, //-nonane induced neurobehavioral changes in rats exposed to
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concentrations >3,580 ppm for 8 hours and severe histopathological damage was observed in
cerebellar neurons after a 14-day observation period at an exposure of 4,438 ppm (Nilsen et al..
1988). In a 28-day study, abnormal auditory brainstem responses were identified in rats treated
with //-heptane at concentrations of 4,006 ppm (Simonsen and Lund. 1995) and used as critical
effects in the derivation of inhalation toxicity values for //-heptane (see the "Derivation of
Inhalation Reference Concentrations" section). Although repeat-exposure studies that
adequately address the neurotoxic potential of inhaled n-nonane are currently unavailable,
Carpenter et al. (1978) noted behavioral symptoms (mild coordination loss and fine tremors) in
rats during the first 4 days of //-nonane treatment. These symptoms were accompanied by
clinical signs of toxicity (salivation and lacrimation) and marginally depressed body weights
(-7%) that persisted throughout the 13-week study at an inhalation exposure of 1,600 ppm (U.S.
EPA, 2009b).
Due to the aforementioned similarities in the toxicity profile of //-heptane and //-nonane,
primarily the induction of gastrointestinal effects following gavage treatment in experimental
animals, //-nonane is identified as a toxicity-like surrogate for //-heptane by the oral route.
Weight-of-Evidence Approach
A weight-of-evidence (WOE) approach is used to evaluate information from potential
candidate surrogates as described by Wane et al. (2012). Commonalities in
structural/physicochemical properties, toxicokinetics, metabolism, toxicity, or mode of action
between potential surrogates and chemical(s) of concern are identified. Emphasis is given to
toxicological and/or toxicokinetic similarity over structural similarity. Surrogate candidates are
excluded if they do not have commonality or demonstrate significantly different
physicochemical properties and toxicokinetic profiles that set them apart from the pool of
potential surrogates and/or chemical(s) of concern. From the remaining potential surrogates, the
most appropriate surrogate (most biologically or toxicologically relevant analog chemical) with
the highest structural similarity and/or most conservative toxicity value is selected.
Overall, //-nonane was selected as an appropriate surrogate chemical for //-heptane oral
toxicity based on the following WOE:
1) The critical effect identified for //-nonane is "proliferative forestomach lesions with
varying degrees of hyperplasia and hyperkeratosis of the squamous epithelium (U.S.
EPA, 2009b)." This effect is similar to the gastrointestinal lesions observed after
gavage //-heptane treatment.
2) //-Nonane is metabolized in vivo similarly to //-heptane, resulting in the formation of
higher relative amounts of the 2- and 3-alcohol and y-valerolactone metabolites
compared to the neurotoxic }'-diketone compounds.
3) //-Nonane displays a high structural similarity of 84.6 and 87.5% to //-heptane, using
the National Library of Medicine's (NLM's) ChemlDplus database (ChemlDplus,
2016) and the EPA DSSTox database, respectively.
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4) //-Hexane, the other structural analog, is not considered to be a metabolic or a
toxicity-like surrogate for //-heptane. The principal metabolite of //-hexane is the
}'-diketone derivative, 2,5-hexanedione, which is primarily responsible for the
axonopathy and peripheral neuropathy (measured as decreased MNCV) observed
with oral and inhalation exposure to //-hexane. The quantity of 2,5-heptanedione
formed from //-heptane metabolism is very low (<1%), and decreased MNCV has
been reported for inhalation exposure to //-hexane, but not //-heptane.
5) A lack of significant adverse effects on neurological endpoints were reported from
gavage studies in rodents at exposures up to 2,860 mg/kg-day for //-heptane and up to
5,000 mg/kg-day for //-nonane, although findings from acute and short-term-duration
studies indicate that these alkanes are capable of targeting the CNS via the inhalation
route.
ORAL TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Dose (p-RfD)
Based on the overall surrogate approach presented in this PPRTV assessment, //-nonane
is selected as an acceptable surrogate for //-heptane for the derivation of oral toxicity values. The
study used for the p-RfD for //-nonane is a 13-week gavage study in male C57BL/6 mice and
female Fischer 344 rats [Dodd et al. (2003) as cited in U.S. EPA (2009bYl. A summary of the
study design and main histopathological findings described in the PPRTV report for //-nonane
are provided below [for further details refer to U.S. EPA ("2009bYl:
Dodd et al. (2003) treated groups of 10 male C57BL/6 mice and 10 female
Fischer 344 rats with doses (neat) of0, 100, 1000, or 5000 mg/kg-day of
n-nonane (99% purity) by gavage 7 days/week for 90 days. The test protocol
required two rodent species and both male andfemale animals. Because of a
concern for the development of a-2u-globulin nephropathy in male rats, only
female rats were dosed. The study authors dosed only male mice. The dosages
were established based on a 7-day range-finding study conducted by the same
researchers, which are discussed in further detail below. Dodd et al. (2003)
randomly assigned mice and rats to dose groups (10/group). Due to unexpected
mortality in the high-dose rats during the first 4 days of dosing, two additional
rats were assigned to this group. Animals were allowedfree access to food and
water and were housed individually in plastic cages. Body weights were
determined and recorded immediately prior to the initiation of the study. Body
weights andfood consumption were determined and recorded weekly thereafter.
Animals were fasted at least 12 hours prior to sacrifice following the 90-day
exposure period.
Effects on general toxicity, neurobehavioral activity (grip strength and
locomotor activity), hematology (hematocrit [HCT], hemoglobin [HGB]
concentration, erythrocyte count [RBC], mean corpuscular volume [MCV], mean
corpuscular hemoglobin [MCH], mean corpuscular hemoglobin concentration
[MCHC], total and differential leukocyte count [WBC], and platelet count),
clinical chemistry (calcium, phosphorus, chloride, sodium, potassium, glucose,
alanine aminotransferase [ALT], aspartate aminotransferase [AST],
y-glutamyl transpeptidase, alkaline phosphatase [ALP], blood urea nitrogen
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[BUN], albumin, globulin, total protein, creatinine, and total bilirubin), and
organ weights (liver, kidneys, adrenals, gonads, spleen, lungs, and brain) were
evaluated in all animals (Dodd et al., 2003). In addition, a few additional serum
chemistry measurements of cholesterol, triglycerides, and magnesium were made
only in rats. Gross necropsy, including examination of the external surface of the
body, all the orifices, and the cranial, thoracic, and the abdominal cavities and
their contents, were conducted on each animal. Histopathologic examination of
32 tissues and organs, including any gross lesions identified at necropsy, were
conducted on all control and high-dose animals and on "target" tissues from
low- and mid-dose animals.
(...)
Table 5 summarizes the tissue lesion incidence reported by Dodd et al.
(2003) in exposed animals. Lesions occurred primarily along the alimentary
tract. Varying degrees of hyperplasia and hyperkeratosis of the squamous
epithelium were found in the nonglandular stomach (forestomach) of mice and
rats from all dose groups. Occasionally, erosion and ulceration of the mucosa
were also present. No lesions were observed in the glandular stomach of any
treated animal. Other lesions observed were mild inflammation in the proximal
duodenum mucosa (high-dose rats), perianal hyperplasia accompanied by
hyperkeratosis often with mild inflammation (mid- and high-dose mice and rats),
and multifocal minimal-to-mild necrosis and suppurative inflammation of the
nasal turbinates (high-dose mice; low-, mid-, and high-dose rats). In rats, the
nasal lesions were often accompanied by pulmonary lesions (incidence not
reported) consistent with aspiration offoreign material, ranging from
peribronchial histiocytic infiltrates to necrohemorrhagic bronchopneumonia.
Based on the pathology of these lesions and the pulmonary foreign body response
observed in rats, Dodd et al. (2003) suggest that the lesions in the nasal
turbinates resultedfrom direct contact with the gavaged test agent—rather than
from specific xenobiotic targeting of nasal mucosa. Based on the lesions
observed in the forestomachs of both rats and mice at all dose levels, the lowest
dose tested of 100 mg/kg-day is identified as a LOAEL for the purposes of this
review. A NOAEL is not identified in this study.
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Table 5. Incidence of Tissue Lesionsa
Lesion
Dose (mg/kg-day)
0
100
1000
5000
Mice
Rats
Mice
Rats
Mice
Rats
Mice
Rats
Stomach (nonglandular)—
squamous epithelial
hyperplasia/hyperkeratosis
0/9
0/10
6/10
8/10
7/8
10/10
8/8
10/11
Proximal Duodenum—
inflammation (mild)
0/7
0/10
0/10
0/10
0/10
0/10
0/10
2/10
Rectum—perianal
hyperplasia,
hyperkeratosis and
inflammation
0/9
0/10
0/10
0/10
2/10
5/10
8/10
9/11
Nasal Turbinates—rhinitis
0/9
0/10
0/10
1/9
0/10
7/10
4/10
9/10
"Dodd et al., 2003; C57BL/6 mice; Fischer 344 rats
The critical effect for the derivation of oral reference values for //-nonane identified in the
Dodd et al. (2003) study is forestomach lesions, including squamous epithelial hyperplasia and
hyperkeratosis. Proliferative lesions in the forestomach mucosa, occasionally accompanied by
suppuration and necrosis were also detected following gavage //-heptane treatment (Eastman
Kodak. 1980). These portal-of-entry effects are reflective of the strong irritating properties of
//-heptane and //-nonane and provide support for the relevance of gastrointestinal toxicity after
oral exposure to these alkanes. Similar to //-heptane, effects were found in the liver and adrenal
glands with exposure to //-nonane, but at doses 10-50 times higher than those inducing
forestomach toxicity. U.S. EPA (2009b) performed BMD analyses of forestomach incidence
data from animals treated with //-nonane. A 10% benchmark dose lower confidence limit
(BMDLio) of 3.13 mg/kg-day derived from male mice was identified as the most sensitive
endpoint and the point of departure (POD) for //-nonane (U.S. EPA. 2009b); this value is adopted
as the POD for the screening subchronic provisional reference dose (p-RfD) for //-heptane.
The //-nonane BMDLio of 3.13 mg/kg-day was not adjusted for molecular-weight
differences in the derivation of the //-heptane provisional toxicity value because the
molecular-weight difference between //-heptane and //-nonane is less than twofold (Wang et al,
2012). EPA endorses body-weight scaling to the 3/4 power (i.e., BW3/4) as a default to
extrapolate toxicologically equivalent doses of orally administered agents from all laboratory
animals to humans for the purpose of deriving an RfD under certain exposure. For oral
portal-of-entry effects occurring in laboratory animal studies in which the agent is administered
via food, direct application of the BW3/4 approach is recommended (U.S. EPA. 2011b). The
forestomach lesions induced by //-nonane or //-heptane treatment represent portal-of-entry effects
likely resulting from direct contact between the chemical agents and the nonglandular gastric
mucosa; however, the use of the BW3/4 scaling for dose extrapolation is precluded because the
test chemicals were administered via gavage treatment.
The subchronic p-RfD value for //-nonane was derived using a composite uncertainty
factor (UFc) of 1,000, reflecting 10-fold uncertainty factor values for interspecies extrapolation
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(UFa), intraspecies variability (UFh), and database uncertainties (UFd, primarily reflecting the
absence of data evaluating neurotoxic, reproductive, and developmental toxicity, including a
multi-generation study) (U.S. EPA. 2009b). Wang et al. (2012) indicated that the uncertainty
factors typically applied in deriving a toxicity value for the chemical of concern are the same as
those applied to the surrogate unless additional information is available. In deriving a screening
subchronic p-RfD for //-heptane, the same UFc of 1,000 is applied to the surrogate POD of
3.13 mg/kg-day based on forestomach lesions in male mice. The screening subchronic p-RfD for
w-heptane is derived as follows:
Screening Subchronic p-RfD = Surrogate POD ^ UFc
= 3.13 mg/kg-day ^ 1,000
= 3 x 10"3 mg/kg-day
Table A-4 summarizes the uncertainty factors for the screening subchronic p-RfD for
//-heptane.
Table A-4. Uncertainty Factors for the Screening Subchronic p-RfD for n-Heptane
(CASRN 142-82-5)
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty, including toxicokinetic and toxicodynamic
differences, between rats and humans following n-heptane ingestion. A DAF was not applied
because the critical effect was a portal-of-entry effect (i.e., forestomach lesions), and the principal
studv dosed animals via gavage CU.S. EPA. 20lib).
UFh
10
A UFh of 10 is applied for intraspecies variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of //-heptane in humans.
UFd
10
A UFd of 10 is applied due to the absence of reliable studies evaluating systemic, nervous system,
reproductive, and developmental toxicity of //-heptane via the oral route.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDLio.
UFS
1
A UFs for subchronic-to-chronic extrapolation is not relevant for the derivation of the screening
subchronic RfD; thus, a 1 is applied.
UFC
1,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMDL = benchmark dose lower confidence limit; DAF = dosimetric adjustment factor;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfD = provisional reference dose; UF = uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Dose (p-RfD)
No chronic-duration oral studies are available for either //-heptane or its surrogate
chemical, //-nonane. A screening chronic p-RfD value for n-nonane was derived using the same
POD as the subchronic p-RfD (3.13 mg/kg-day) and applying a UFc of 10,000 (U.S. EPA.
2009b). The UFc included a UFs of 10 to account for increased uncertainty associated with
extrapolating to a longer //-nonane exposure duration, and 10-fold uncertainty factor values for
interspecies extrapolation (UFa), intraspecies variability (UFh), and database uncertainties (UFd,
primarily reflecting the absence of oral data evaluating chronic duration systemic, neurotoxic,
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reproductive, and developmental toxicity, including a multi-generation study). The screening
chronic p-RfD for //-heptane is derived as follows:
Screening Chronic p-RfD = Surrogate POD ^ UFc
= 3.13 mg/kg-day ^ 10,000
= 3 x 10"4 mg/kg-day
Table A-5 summarizes the uncertainty factors for the screening chronic p-RfD for
//-heptane.
Table A-5. Uncertainty Factors for the Screening Chronic p-RfD for «-Heptane
(CASRN 142-82-5)
UF
Value
Justification
UFa
10
A UFa of 10 is applied to account for uncertainty, including toxicokinetic and toxicodynamic
differences, between rats and humans following «-heptane ingestion. A DAF was not applied
because the critical effect was a portal-of-entry effect (i.e., forestomach lesions), and the principal
studv dosed animals via gavage (U.S. EPA. 201 lb).
UFh
10
A UFh of 10 is applied for inter-individual variability to account for human-to-human variability in
susceptibility in the absence of quantitative information to assess the toxicokinetics and
toxicodynamics of n-heptane in humans.
UFd
10
A UFd of 10 is applied due to the absence of reliable studies, evaluating systemic, nervous system,
reproductive, and developmental toxicity of //-heptane via the oral route.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMDLio.
UFS
10
A UFS of 10 is applied due to increased uncertainty associated with longer exposure to n-heptane.
UFC
10,000
Composite UF = UFA x UFH x UFD x UFL x UFS.
BMDL = benchmark dose lower confidence limit; DAF = dosimetric adjustment factor;
LOAEL = lowest-observed-adverse-effect level; NOAEL = no-observed-adverse-effect level; POD = point of
departure; p-RfD = provisional oral reference dose; UF = uncertainty factor.
41
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APPENDIX B. DATA TABLES
Table B-l. Treatment-Related Effects in Male CD COBS Rats Exposed to «-Heptane
(CASRN 142-82-5) 5 Days/Week for 3 Weeks via Gavage"
Dose (ADD in mg/kg-d)b
0
1,000 (714)
2,000 (1,430)
4,000 (2,860)
LDH (IU/L)°
326
502 (1.5-fold)
788 (2.4-fold)
771 (2.4-fold)
Absolute liver weight (g)0
9.79
13.61 (+39%)
11.99 (+22%)
11.13 (+14%)
Relative liver weight (% B W)0
3.06
4.21 (+38%)
3.86 (+26%)
3.64 (+19%)
Absolute kidney weight (g)0
2.51
2.72 (+8%)
2.67 (+6%)
2.87 (+14%)
Relative kidney weight (% BW)0
0.78
0.84 (+8%)
0.86 (+10%)
0.94 (+21%)
Hyperplasia of the nonglandular
(forestomach) gastric epitheliumd
0/9
1/3 (moderate)
2/3 (minor)
1/3 (moderate)
"Eastman Kodak (1979).
bAdministered doses in mg/kg-day (as reported by study authors) were converted to an ADD (mg/kg-day) by
multiplying the administered gavage dose by (5/7) days per week.
°Values represent group means (fold change from control or percent change from control); fold change = treatment
mean + control mean; percent change control = [(treatment mean - control mean) + control mean] x 100. The
study authors did not report any measure of variability within treatment groups or statistical analyses.
dValues represent incidence data for the forestomach epithelium.
ADD = adjusted daily dose; COBS = cesarean-obtained barrier-sustained; BW = body weight; LDH = lactate
dehydrogenase.
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Table B-2. Treatment-Related Effects in Male CD COBS Rats Exposed to w-Heptane
(CASRN 142-82-5) 5 Days/Week for 13 Weeks via Gavagea b
Dose (ADD in mg/kg-d)c
0
4,000 (2,860)
Body weight (g)
WkO
295 ± 17.3
282 ± 45.4 (-4%)
1
320 ± 16.0
282 ±33.7* (-12%)
2
351 ± 17.1
324 ± 37.2 (-8%)
3
369 ±23.5
328 ±27.8 (-11%)
4
397 ±20.2
359 ± 29.6* (-10%)
5
410 ± 33.1
348 ± 47.9* (-15%)
6
434 ±26.7
384 ± 20.8* (-12%)
7
452 ±30.9
403 ±20.1* (-11%)
8
455 ±36.1
411 ±22.0 (-10%)
9
479 ±30.4
428 ±20.2* (-11%)
10
494 ±34.3
427 ±31.2* (-14%)
11
504 ±35.5
443 ± 28.7* (-12%)
12
512 ±39.9
450 ± 28.5* (-12%)
13
516 ±45.4
468 ± 32.1 (-9%)
Terminal
495 ±40.3
429 ± 37.5* (-13%)
Glucosed
137 ± 12.5
110 ± 10.0* (-20%)
Absolute heart weightd
1.74 ±0.427
1.26 ±0.237* (-28%)
Relative heart weightd
0.35 ±0.071
0.29 ± 0.033 (-17%)
Absolute liver weightd
13.38 ± 1.336
13.31 ±2.444 (-0.5%)
Relative liver weightd
2.70 ±0.126
3.16 ±0.319* (+17%)
Absolute kidney weightd
3.10 ±0.276
3.13 ±0.631 (+1%)
Relative kidney weightd
0.63 ±0.030
0.73 ±0.853* (+16%)
Absolute adrenal gland weightd
0.053 ±0.0054
0.063 ± 0.0053 (+19%)
Relative adrenal gland weightd
0.011 ±0.0009
0.015 ±0.0026* (+36%)
"Eastman Kodak (1980).
bValues are mean ± standard deviation (percent change compared with control); percent change
control = [(treatment mean - control mean) + control mean] x 100.
Administered doses in mg/kg-day (as reported by study authors) were converted to an ADD (mg/kg-day) by
multiplying the administered gavage dose by (5/7) days per week.
dUnits of measurement were not specified in the report.
*Significant difference from control atp< 0.05, as calculated by the study authors.
ADD = adjusted daily dose; COBS = cesarean-obtained barrier-sustained.
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Table B-3. Histopathological Findings for Male CD COBS Rats Exposed to n-Heptane
(CASRN 142-82-5) 5 Days/Week for 13 Weeks via Gavage"
Dose (ADD in mg/kg-d)b
0
4,000 (2,860)
No. of animals examined
8
8°
Nonglandular (forestomach) gastric mucosa
Acute suppurative gastritisd
0
2 (2/5 dead rats)
Acute necrotizing gastritisd
0
1 (1/5 dead rats)
Superficial necrosis'1
0
1 (1/3 surviving rats)
Hyperkeratosis with
pseudoepithelimatous hyperplasia6
0
7 (4/5 dead rats and 3/3 surviving rats)
Liver
Vacuolated hepatocytesf
0
1 (1/3 surviving rats)
Serosal adhesions®
0
1 (1/3 surviving rats)
Congestionf
0
1 (1/5 dead rats)
Kidney
Regenerating tubular epitheliumf
2
5 (4/5 dead rats and 1/3 surviving rats)
Tubular dilation with castsf
1
3 (2/5 dead rats and 1/3 surviving rats)
Hyaline dropletsf
0
2 (2/5 dead rats)
Hemorrhage11
0
2 (2/5 dead rats)
Congestion11
0
3 (3/5 dead rats)
Adrenal glands
Cortical hemorrhage11
0
5 (5/5 dead rats)
Congestion11
0
2 (2/5 dead rats)
"Eastman Kodak (1980).
bAdministered doses in mg/kg-day (as reported by study authors) were converted to an ADD (mg/kg-day) by
multiplying the administered gavage dose by (5/7) days per week.
°Five of the eight rats in the exposed group died from acute chemically-induced pneumonitis associated with
gavage treatment at different time points throughout the study. The remaining three rats that survived were
euthanized after 13 weeks of treatment.
dModerate to severe.
"Mostly moderate.
fMinimal or minor.
gPresent.
hMinor or moderate.
ADD = adjusted daily dose; COBS = cesarean-obtained barrier-sustained.
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Table B-4. Amplitude of Component IV of the Auditory Brainstem Responses in Male
Long-Evans Rats Exposed to n-Heptane (CASRN 142-82-5) for 28 Days via Inhalationa'b
Exposure Group, ppm w-Heptane (HEC
in mg/m3)c
Parameter
0
801 (821)
4,006 (4,105)
4 kHz of frequency:
95 dB
18.1 ± 3.1
19.8 ±3.5 (+9%)
14.9 + 4.0 (-18%)
85 dB
14.9 ±2.5
15.3 ± 2.3 (+3%)
10.9 + 3.1* (-27%)
75 dB
9.2 ± 1.9
9.3 ± 2.3 (+1%)
7.2 + 2.1 (-22%)
65 dB
7.5 ±2.0
7.9 ±2.1 (+5%)
5.8 + 2.5 (-23%)
55 dB
5.3 ±2.5
6.5 ± 1.9 (+23%)
5.0 + 2.0 (-6%)
45 dB
3.3 ± 1.4
4.6 ± 1.9 (+39%)
3.2+1.3 (-3%)
35 dB
1.8 ±0.5
2.6 ± 1.2 (+44%)
2.7 + 0 (+50%)
25 dB
-
-
-
8 kHz of frequency:
95 dB
22.9 ±4.4
24.5 ± 4.3 (+7%)
18.0 + 5.8 (-21%)
85 dB
20.2 ±3.5
21.0 ±3.8 (+4%)
14.8 + 5.6* (-27%)
75 dB
13.8 ±2.5
13.3 ± 3.2 (+4%)
10.3 + 4.2 (-25%)
65 dB
8.4 ± 1.5
8.9 ± 1.9 (+6%)
6.8 + 2.0 (-19%)
55 dB
6.3 ± 1.6
6.7 ± 1.6 (+6%)
5.1+ 1.9 (-19%)
45 dB
5.1 ± 1.6
5.1 ± 1.5(0%)
4.4+1.3 (-14%)
35 dB
3.3 ± 1.0
3.8±1.2 (+15%)
3.0+ 1.2 (-9%)
25 dB
2.1 ±0.6
3.2+ 0.9 (+52%)
2.2 + 0.5 (-5%)
16 kHz of frequency:
95 dB
18.7 ±3.1
20.1 ±3.7 (+7%)
14.5 + 5.0* (-22%)
85 dB
18.5 ±3.5
19.6 ±3.8 (+6%)
14.3 + 4.8* (-23%)
75 dB
14.5 ±3.0
15.0 + 3.5 (+3%)
10.4+ 3.7* (-28%)
65 dB
10.4 ±2.4
10.4 + 2.6 (0%)
7.8 + 2.9 (-25%)
55 dB
7.5 ± 1.7
7.6 + 2.0 (+1%)
5.7 + 2.0 (-24%)
45 dB
5.7 ± 1.2
5.4+1.5 (-5%)
4.1 + 1.8 (-28%)
35 dB
4.3 ± 1.3
3.9+1.1 (-9%)
3.4+1.2 (-21%)
25 dB
3.1 ± 1.0
3.1 + 1.2(0%)
2.6+1.2 (-16%)
45
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Table B-4. Amplitude of Component IV of the Auditory Brainstem Responses in Male
Long-Evans Rats Exposed to n-Heptane (CASRN 142-82-5) for 28 Days via Inhalationa'b
Parameter
Exposure Group, ppm w-Heptane (HEC
in mg/m3)'
0
Sill (821)
4,006 (4,105)
32 kHz of frequency:
95 dB
12.4 ±2.1
13.7 ± 1.9 (+10%)
11.3 ±3.1 (-9%)
85 dB
15.2 ±3.7
15.5 ± 2.8 (+2%)
11.2 ±3.6* (-26%)
75 dB
14.8 ±3.0
15.6 ±3.2 (+5%)
10.8 ±3.8* (-27%)
65 dB
12.3 ±2.9
12.6 ± 2.7 (+2%)
8.7 ±3.4* (-29%)
55 dB
9.8 ±3.1
10.1 ±2.3 (+3%)
7.4 ± 2.4 (-24%)
45 dB
7.4 ±2.1
7.42 ± 1.7 (0%)
5.7 ±2.1 (-22%)
35 dB
4.7 ± 1.5
5.2 ± 1.4 (+11%)
4.3 ± 1.3 (-9%)
25 dB
-
"Simonsen and Lund (1995).
bAmplitude is reported in |iV at different kHz and dB. Values are mean ± standard deviation (percent change
compared with control); percent change control = [(treatment mean - control mean) + control mean] x 100.
°Mean exposure concentrations in ppm (as reported by study authors) were adjusted for continuous exposure and
converted to HECs (mg/m3) for extrarespiratory effects by applying the following formula:
HECexresp = (ppm x MW + 24.45) x (hours per day exposed + 24) x (days per week exposed + 7) x blood-gas
partition coefficient.
*Significant difference from control at p< 0.05, as calculated by the study authors.
-Indicates a lack of detection of Peak IV.
kHz = frequencies; HEC = human equivalent concentration; |iV = microvolts; MW = molecular weight;
dB = sound intensities.
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Table B-5. Auditory Threshold in Male Long-Evans Rats Exposed to ft-Heptane
(CASRN 142-82-5) for 28 Days via Inhalationa'b
Parameter
Exposure Group, ppm w-Heptane (HEC in mg/m3)c
0
801 (821)
4,006 (4,105)
Frequency:
4 kHz
46.1 ± 1.2
42.2 ± 2.0 (-4%)
53.9 ±3.5 (8%)
8 kHz
36.2 ± 1.0
32.3 ± 2.0 (-4%)
47.0 ±4.4* (11%)
16 kHz
31.7 ± 1.7
33.4 ± 1.6 (2%)
42.0 ±3.9* (10%)
32 kHz
29.5 ± 1.5
28.7 ± 1.4 (-1%)
37.9 ±3.9 (8%)
"Simoiisen and Lund (1995).
bAuditory threshold is defined as the lowest sound pressure level in 10 dB steps at which Component I of the
auditory brain stem responses could be detected. Values are mean ± SEM (percent change compared with
control); percent change control = [(treatment mean - control mean) control mean] x 100. Values were
calculated for this review based on graphically reported sound pressure levels (data was digitally extracted using
Grablt! Software).
°Mean exposure concentrations in ppm (as reported by study authors) were adjusted for continuous exposure and
converted to HECs (mg/m3) for extrarespiratory effects by applying the following formula:
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood-gas
partition coefficient.
*Significant difference from control at p< 0.05, as calculated by the study authors.
HEC = human equivalent concentration; MW = molecular weight; SEM = standard error of the mean.
Table B-6. Serum Alkaline Phosphatase Levels in S-D Rats Exposed to n-Heptane
(CASRN 142-82-5) for 26 Weeks via Inhalationa b
Parameter
Exposure Group, ppm w-Heptane (HEC in mg/m3)c
0
398 (291)
2,970 (2,174)
Males
ALP (IU)
Wk 13
26
98 ±4
92 ±3
115 ± 10 (1.2-fold)
83 ± 3 (0.9-fold)
108 ±9 (1.1-fold)
86 ± 8 (0.9-fold)
Females
ALP (IU)
Wk 13
26
40 ±5
25 ± 1
42 ±4 (1.1-fold)
30 ± 4 (1-fold)
40 ± 3 (1.2-fold)
39 ±3* (1.6-fold)
"Bio Dynamics (1980).
bValues are mean ± SEM (fold change from control); fold change = treatment mean control mean.
°Mean exposure concentrations in ppm (as reported by study authors) were adjusted for continuous exposure and
converted to HECs (mg/m3) for extrarespiratory effects by applying the following formula:
HECexresp = (ppm x MW ^ 24.45) x (hours per day exposed ^ 24) x (days per week exposed ^ 7) x blood-gas
partition coefficient.
*Significant difference from control at p< 0.05, as calculated by the study authors.
ALP = alkaline phosphatase level; HEC = human equivalent concentration; IU = international unit;
MW = molecular weight; S-D = Sprague-Dawley; SEM = standard error of the mean.
47
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APPENDIX C. BENCHMARK DOSE MODELING RESULTS
MODEL-FITTING PROCEDURE FOR CONTINUOUS DATA
The benchmark dose (BMD) modeling of continuous data was conducted with the EPA's
Benchmark Dose Software (BMDS, Version 2.6). For these data, all continuous models
available within the software were fit using a default benchmark response (BMR) of 1 standard
deviation (SD) relative risk. An adequate fit was judged based on the %2 goodness-of-fit />value
(p > 0.1), magnitude of the scaled residuals in the vicinity of the BMR, and visual inspection of
the model fit. In addition to these three criteria forjudging adequacy of model fit, a
determination was made as to whether the variance across dose groups was homogeneous. If a
homogeneous variance model was deemed appropriate based on the statistical test provided in
BMDS (i.e., Test 2), the final BMD results were estimated from a homogeneous variance model.
If the test for homogeneity of variance was rejected (p< 0.1), the model was run again while
modeling the variance as a power function of the mean to account for this nonhomogeneous
variance. If this nonhomogeneous variance model did not adequately fit the data (i.e., Test 3;
p-value < 0.1), the data set was considered unsuitable for BMD modeling. Among all models
providing adequate fit, the lowest benchmark concentration lower confidence limit (BMCL) was
selected if the BMCLs estimated from different models varied greater than threefold; otherwise,
the BMCL from the model with the lowest Akaike's Information Criterion (AIC) was selected as
a potential point of departure (POD) from which to derive the provisional reference
concentration (p-RfC).
BMD Modeling for Loss of Hearing Sensitivity in Male Long-Evans Rats Exposed to
«-Heptane (CASRN 142-82-5) via Inhalation for 28 Days (Simonsen and Lund, 1995)
Table C-l. Selected Continuous Data for Effects of n-Heptane (CASRN 142-82-5) on
Auditory Threshold across Different Frequencies"
Number of animals
9
11
10
HEC, mg/m3
0
821
4,105
Increased auditory threshold at 4 kHz
46.1 ± 1.2
42.2 ±2.0
53.9 ±3.5
Increased auditory threshold at 8 kHz
36.2 ± 1.0
32.3 ±2.0
47.0 ±4.4*
Increased auditory threshold at 16 kHz
31.7 ± 1.7
33.4 ± 1.6
42.0 ±3.9*
Increased auditory threshold at 32 kHz
29.5 ± 1.5
28.7 ± 1.4
37.9 ±3.9
'Auditory threshold is defined as the lowest sound pressure level in 10 dB steps at which Components I of the
auditory brain stem responses could be detected. Values are mean ± SEM, as calculated for this review based on
graphically reported sound pressure levels (data was digitally extracted using Grablt! Software).
*Significant difference from control at p< 0.05, as calculated by the study authors.
HEC = human equivalent concentration; SEM = standard error of the mean.
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Table C-2. Summary of Benchmark Concentration Modeling of Data from the 28-Day
Inhalation Study with Rats Exposed to ft-Heptane (CASRN 142-82-5)
Endpoint
Model
/j-Value11
AIC for
Fitted Model
Scaled
Residual
BMCisd
(HEC in mg/m3)
BMCLisd
(HEC in mg/m3)
Increased auditory
threshold at 4 kHzb
No fit
Increased auditory
threshold at 8 kHzb
No fit
Increased auditory
threshold at 16 kHz
Exponential
(2-degree)
0.757
151.2442
-0.0476
1,940
1,170
Increased auditory
threshold at 32 kHz
Polynomial
(3-degree)
0.7584
145.8827
0.00669
3,230
1,440
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bFor increased auditory thresholds at frequencies 4 and 16 kHz, both the homogenous and nonhomogeneous
variance models failed to provide an appropriate fit (Tests 2 and 3;/? 0.1), scaled residuals (<2.0), and visual inspection of the model fit. The
BMCLisds from adequate models were within two to threefold difference; therefore, the model
with the lowest AIC was selected (Exponential, 2-degree).
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Table C-3. Modeling Results for Increased Auditory Threshold at 16 kHz in Male
Long-Evans Rats Treated with «-Heptane (CASRN 142-82-5) via Inhalation
Model
Variance
/j-Valuc11
Means
/j-Valuc11
AIC
Scaled
Residualsb
BMCisd
(HEC in mg/m3)
BMCLisd
(HEC in mg/m3)
Constant variance
Exponential (Model 2)c
0.7487
0.757
151.2442
-0.0476
1,943.69
1,171.45
Exponential (Model 3)°
0.7487
NA
153.1484
0.1384
2,258.29
1,180.77
Exponential (Model 4)°
0.7487
NA
153.341
-0.1266
1,806
1,010.17
Hillc
No Fit
Linear"1
0.7487
0.6608
151.340905
-0.127
1,806.07
1,010.24
Polynomial (2-degree)d
0.7487
NA
153.148404
0.138
2,316.1
1,029.12
Polynomial (3-degree)d
0.7487
NA
153.148404
0.138
2,456.23
1,029.13
Power0
0.7487
NA
153.148404
0.138
2,209.52
1,029.12
aValues <0.10 fail to meet conventional goodness-of-fit criteria.
bScaled residuals for dose group near the BMC.
Tower restricted to >1.
Coefficients restricted to be negative.
AIC = Akaike's information criterion; BMC = benchmark concentration; BMCL = lower confidence limit (95%) on
the benchmark concentration; HEC = human equivalent concentration; NA = not applicable.
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Exponential 2 Model, with BMR of 1 Std. Dev. for the BMD and 0.95 Lower Confidence Limit for the BMDL
Exponential 2
BMDL
500
1000
1500
2000
dose
2500
3000
3500
4000
11:14 07/06 2016
Exponential Model. (Version: 1.10; Date: 01/12/2015)
Input Data File: C:/Users/llizarra/Desktop/BMDS2601/Data/exp_Simonsen
1995_auditthreshold_16khz_Opt.(d)
Gnuplot Plotting File:
Wed Jul 06 11:14:09 2016
BMDS Model Run
The form of the response function by Model:
Model 2
Model 3
Model 4
Model 5
Y[dose] = a * exp{sign * b * dose}
Y[dose] = a * exp{sign * (b * dose)Ad}
Y[dose] = a * [c-(c-l) * exp{-b * dose}]
Y[dose] = a * [c-(c-l) * exp{-(b * dose)Ad}]
Note: Y[dose] is the median response for exposure
sign = +1 for increasing trend in data;
sign = -1 for decreasing trend.
Model 2 is nested within Models 3 and 4.
Model 3 is nested within Model 5.
Model 4 is nested within Model 5.
dose;
Dependent variable = Mean
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Independent variable = Dose
Data are assumed to be distributed: normally
Variance Model: exp(lnalpha +rho *ln(Y[dose]))
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 5 00
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
MLE solution provided: Exact
Initial Parameter Values
Variable
Model 5
NC
NC
NC
NC
NC
NC
lnalpha
rho
a
b
c
d
Model 2
-19.6284
6.58707
31.6317
6.8 94 66e-005
0
1
Model 3
-19. 6284
6.58707
31.6317
6.8 94 66e-005
0
1
Model 4
-19.6284
6.58707
30.115
6.13142e-005
2.78931
1
* Indicates that this parameter has been specified
Parameter Estimates by Model
Variable
Model 5
NC
NC
NC
NC
NC
d
lnalpha
rho
a
b
Model 2
-19.9154
6.6376
31.6444
6.8 6114e-005
Model 3
-19.7896
6.60048
31.8845
8.4 6574e-005
Model 4
-20.1873
6.71594
31.5749
3 . 99086e-008
1969.01
1.20885
NC = No Convergence
-- Indicates that this parameter does not appear in model
NC
Variable
Std. Err. Estimates by Model
Model 2 Model 3 Model 4
Model 5
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lnalpha
4 . 60651e-157
10.9882
11.4246
rho
3.14984
3.10239
3.22657
a
1.21472
1.46257
1.24629
b
2.4 07 68e-005 6.
09515e-005
4 . 8527e-006
c
NA
NA
239282
d
NA
0. 81223
NA
NA -
Indicates
that this parameter was
specified (by
the user or becaus
form)
or has hit
a bound implied by some ineguality constraint and thus !
error.
Table of Stats From Input
Data
Dose
N Obs Mean
Obs Std Dev
0
9 31.7
5.1
821
11 33.4
5.3
4105
10 42
12 .3
Estimated Values
of Interest
Model
Dose Est Mean
Est Std
Scaled Residual
2
0 31.64
4.514
0.03694
821 33.48
5.442
-0.0476
4105 41.94
11.5
0.01683
3
0 31.88
4. 623
-0.1197
821 33.18
5.272
0.1384
4105 42.13
11.6
-0.03595
4
0 31.57
4.479
0.08377
821 33.61
5.524
-0.1266
4105 41.75
11.45
0.06792
NC
NC
NC
NC
NC
NC
Other models for which likelihoods are calculated:
Model A1: Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2 : Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)^2
Model A3: Yij = Mu(i) + e(ij)
Var{e(ij)} = exp(lalpha + log(mean(i)) * rho)
Model R: Yij = Mu + e(i)
Var{e(ij)} = Sigma^2
Likelihoods of Interest
Model
A1
A2
A3
R
2
3
4
Log(likelihood) DF
-76.83094 4
-71.5229 6
-71.5742 5
-81.03714 2
-71.62209 4
-71.5742 5
-71.67049 5
AIC
161.6619
155.0458
153.1484
166.0743
151.2442
153.1484
153.341
53
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Additive constant for all log-likelihoods = -27.57. This constant added to the
above values gives the log-likelihood including the term that does not
depend on the model parameters.
Explanation of Tests
Test
1:
Test
2 :
Test
3:
Test
4 :
Does response and/or variances differ among Dose levels? (A2 vs. R)
Are Variances Homogeneous? (A2 vs. Al)
Are variances adeguately modeled? (A2 vs. A3)
Does Model 2 fit the data? (A3 vs. 2)
Test 5a: Does Model 3 fit the data? (A3 vs 3)
Test 5b: Is Model 3 better than Model 2? (3 vs. 2)
Test 6a: Does Model 4 fit the data? (A3 vs 4)
Test 6b: Is Model 4 better than Model 2? (4 vs. 2)
Test
Test 1
Test 2
Test 3
Test 4
Test 5a
Test 5b
Test 6a
Test 6b
Tests of Interest
-2*log(Likelihood Ratio)
19. 03
10. 62
0.1026
0.09578
-1.27 6e-011
0.09578
0.1926
-0.09679
D. F.
4
2
1
1
0
1
0
1
p-value
0.0007759
0.004952
0.7487
0.757
N/A
0.757
N/A
N/A
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose
levels, it seems appropriate to model the data.
The p-value for Test 2 is less than .1. A non-homogeneous
variance model appears to be appropriate.
The p-value for Test 3 is greater than .1. The modeled
variance appears to be appropriate here.
The p-value for Test 4 is greater than .1. Model 2 seems
to adeguately describe the data.
Degrees of freedom for Test 5a are less than or egual to 0.
The Chi-Sguare test for fit is not valid.
The p-value for Test 5b is greater than .05. Model 3 does
not seem to fit the data better than Model 2.
Degrees of freedom for Test 6a are less than or egual to 0.
The Chi-Sguare test for fit is not valid.
The p-value for Test 6b is less than .05. Model 4 appears
to fit the data better than Model 2.
Benchmark Dose Computations:
Specified Effect = 1.000000
54
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Risk Type = Estimated standard deviations from control
Confidence Level = 0.950000
Model
2
3
4
5
BMD and BMDL by Model
BMD
1943.69
2259.29
1806
-0
BMDL
1171.45
1180.77
1010.17
-0
Not computed
55
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