A |"TP%Jk United States
^tmriwnmentsi Pr°tecticiri
EPA/690/R-17/002
FINAL
09-13-2017
Provisional Peer-Reviewed Toxicity Values for
?7-Heptanal
(CASRN 111-71-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Lucina E. Lizarraga, 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
Q. Jay Zhao, MPH, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Jeffry L. Dean II, PhD
National Center for Environmental Assessment, Cincinnati, OH
This document was externally peer reviewed under contract to:
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
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).
li
//-Heptanal

-------
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)	5
HUMAN STUDIES	8
ANIMAL STUDIES	8
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	8
Genotoxicity	8
Supporting Animal Toxicity Studies	11
DERIVATION 01 PROVISIONAL VALUES	17
DERIVATION OF ORAL REFERENCE DOSES	17
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	18
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	18
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES	18
APPENDIX A. SCREENING PROVISIONAL VALUES	19
APPENDIX B. REFERENCES	35
in
//-Heptanal

-------
COMMONLY USED ABBREVIATIONS AND ACRONYMS1
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
7V-acetyl-P-D-glucosaminidase
AR
androgen receptor
NCEA
National Center for Environmental
AST
aspartate aminotransferase

Assessment
atm
atmosphere
NCI
National Cancer Institute
ATSDR
Agency for Toxic Substances and
NOAEL
no-observed-adverse-effect level

Disease Registry
NTP
National Toxicology Program
BMD
benchmark dose
NZW
New Zealand White (rabbit breed)
BMDL
benchmark dose lower confidence limit
OCT
ornithine carbamoyl transferase
BMDS
Benchmark Dose Software
ORD
Office of Research and Development
BMR
benchmark response
PBPK
physiologically based pharmacokinetic
BUN
blood urea nitrogen
PCNA
proliferating cell nuclear antigen
BW
body weight
PND
postnatal day
CA
chromosomal aberration
POD
point of departure
CAS
Chemical Abstracts Service
PODadj
duration-adjusted POD
CASRN
Chemical Abstracts Service registry
QSAR
quantitative structure-activity

number

relationship
CBI
covalent binding index
RBC
red blood cell
CHO
Chinese hamster ovary (cell line cells)
RDS
replicative DNA synthesis
CL
confidence limit
RfC
inhalation reference concentration
CNS
central nervous system
RfD
oral reference dose
CPN
chronic progressive nephropathy
RGDR
regional gas dose ratio
CYP450
cytochrome P450
RNA
ribonucleic acid
DAF
dosimetric adjustment factor
SAR
structure activity relationship
DEN
diethylnitrosamine
SCE
sister chromatid exchange
DMSO
dimethylsulfoxide
SD
standard deviation
DNA
deoxyribonucleic acid
SDH
sorbitol dehydrogenase
EPA
Environmental Protection Agency
SE
standard error
ER
estrogen receptor
SGOT
serum glutamic oxaloacetic
FDA
Food and Drug Administration

transaminase, also known as AST
FEVi
forced expiratory volume of 1 second
SGPT
serum glutamic pyruvic transaminase,
GD
gestation day

also known as ALT
GDH
glutamate dehydrogenase
SSD
systemic scleroderma
GGT
y-glutamyl transferase
TCA
trichloroacetic acid
GSH
glutathione
TCE
trichloroethylene
GST
glutathione-S-transferase
TWA
time-weighted average
Hb/g-A
animal blood-gas partition coefficient
UF
uncertainty factor
Hb/g-H
human blood-gas partition coefficient
UFa
interspecies uncertainty factor
HEC
human equivalent concentration
UFc
composite uncertainty factor
HED
human equivalent dose
UFd
database uncertainty factor
i.p.
intraperitoneal
UFh
intraspecies uncertainty factor
IRIS
Integrated Risk Information System
UFl
LOAEL-to-NOAEL uncertainty factor
IVF
in vitro fertilization
UFS
subchronic-to-chronic 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


Abbreviations and acronyms not listed on this page are defined upon first use in the PPRTV document.
iv
//-Heptanal

-------
FINAL
09-13-2017
PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
ft-HEPTANAL (CASRN 111-71-7)
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 at least two National Center for
Environment Assessment (NCEA) scientists and an independent external peer review by at least
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.
PPRTV assessments are eligible to be updated on a 5-year cycle to incorporate new data
or methodologies that might impact the toxicity values or characterization of potential for
adverse human-health effects and are revised as appropriate. Questions regarding nomination of
chemicals for update can be sent to the appropriate U.S. Environmental Protection Agency
(EPA) Superfund and Technology Liaison (https://www.epa.gov/research/fact-sheets-regional-
science).
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. 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 (ORD's) NCEA, Superfund Health Risk Technical
Support Center (513-569-7300).
1
//-Heptanal

-------
FINAL
09-13-2017
INTRODUCTION
//-Heptanal, CASRN 111-71-7, is obtained commercially from the pyrolysis or catalytic
dehydration of ricinoleic acid (from castor oil). It also occurs naturally in various fruits,
including cassava, plums, and Bisbee Delicious apples, and in flowers, such as clary sage
(HSI)B- 2014). //-Heptanal is primarily used as a chemical intermediate to make
a-amylcinnamaldehyde and esters of heptanoic acid (HSDB, 2014). Additionally, it has direct
applications as a food additive and a fragrance (HSDB. 2014). The U.S. Food and Drug
Administration and the World Health Organization (WHO) have approved //-heptanal as a
synthetic flavoring agent for human consumption (FDA. 2015; WHO, 2002). According to
estimates from the WHO, oral intake of //-heptanal (3.2 |ig/day) in the United States is below the
human intake threshold for class I substances (1,800 |ig/day); therefore, //-heptanal was
determined to pose no safety concerns from use as a flavoring agent on the basis of its structural
class and low levels of estimated intake (WHO. 1999; IPC'S. 1998).
At room temperature, //-heptanal is a liquid with a penetrating fruity odor (HSDB. 2014).
In the environment, //-heptanal will partition primarily to air where it will exist in the gas phase
(HSDB. 2014). Its atmospheric half-life is approximately 13 hours based on its experimental
rate constant for reaction with hydroxyl radicals. If released to dry soil, it will readily volatilize
due to its high vapor pressure. Based on its measured Henry's law constant, //-heptanal will also
exhibit moderate volatility from moist soil and water surfaces. In addition, //-heptanal deposited
on soil may leach to groundwater or undergo runoff after a rain event based on its high water
solubility and moderate soil absorption coefficient. Removal of //-heptanal from soil by leaching
with water will likely compete with volatilization and biodegradation, depending on the local
conditions (wet, dry, etc.). The empirical formula for //-heptanal is C7H14O (see Figure 1). A
table of physicochemical properties for //-heptanal is provided below (see Table 1).
O
H
H
Figure 1. ft-Heptanal Structure
2
//-Heptanal

-------
FINAL
09-13-2017
Table 1. Physicochemical Properties of «-Heptanal (CASRN lll-71-7)a
Property (unit)
Value
Physical state
Colorless liquidb
Boiling point (°C)
152.8
Melting point (°C)
-43.3
Density (g/cm3)
0.82162b
Vapor pressure (mm Hg at 25°C)
3.52
pH (unitless)
NA
Solubility in water (g/L at 25°C)
1.25
Octanol-water partition constant (log Kow)
2.8°
Henry's law constant (atm-m3/mol at 25°C)
2.7 x 10-4
Soil adsorption coefficient Koc (mL/g) (estimated)
176 (estimated)
Relative vapor density (air = 1)
3.9b
Molecular weight (g/mol)
114.19
"Data was gathered from the PHYSPROP database unless otherwise noted (U.S. EPA. 2012b').
bHSDB (2014).
CU.S. EPA (2015).
NA = not applicable.
A summary of available toxicity values for //-heptanal from U.S. EPA and other
agencies/organizations is provided in Table 2.
3
//-Heptanal

-------
FINAL
09-13-2017
Table 2. Summary of Available Toxicity Values for «-Heptanal (CASRN 111-71-7)
Source (parameter)3'b
Value (applicability)
Notes
Reference
Noncancer
IRIS
NV
NA
U.S. EPA (2017)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
ATSDR
NV
NA
ATSDR (2017)
WHO (ADI)
Acceptable
No safety concern at current levels of intake
when used as a flavoring agent; secondary
components do not raise a safety concern.
WHO (2002)
Cal/EPA
NV
NA
Cal/EPA (2014):
Cal/EPA (2017a):
Cal/EPA (2017b)
OSHA
NV
NA
OSHA (2006);
OSHA (2011)
NIOSH
NV
NA
NIOSH (2016)
ACGIH
NV
NA
ACGIH (2016)
Cancer
IRIS
NV
NA
U.S. EPA (2017)
HEAST
NV
NA
U.S. EPA (2011)
DWSHA
NV
NA
U.S. EPA (2012a)
NTP
NV
NA
NTP (2014)
IARC
NV
NA
IARC (2017)
Cal/EPA
NV
NA
Cal/EPA (2011);
Cal/EPA (2017a):
Cal/EPA (2017b)
ACGIH
NV
NA
ACGIH (2016)
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; 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: ADI = acceptable daily intake.
NA = not applicable; NV = not available.
4
//-Heptanal

-------
FINAL
09-13-2017
Non-date-limited literature searches were conducted in May 2015 and updated in
June 2017 for studies relevant to the derivation of provisional toxicity values for //-heptanal
(CASRN 111-71-7). 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 (WOS). The following
databases were searched outside of HERO for health-related data: American Conference of
Governmental Industrial Hygienists (ACGIH), Agency for Toxic Substances and Disease
Registry (ATSDR), California Environmental Protection Agency (Cal/EPA), U.S. EPA
Integrated Risk Information System (IRIS), U.S. EPA Health Effects Assessment Summary
Tables (HEAST), U.S. EPA Office of Water (OW), U.S. EPA TSCATS2/TSCATS8e, National
Institute for Occupational Safety and Health (NIOSH), National Toxicology Program (NTP), and
Occupational Safety and Health Administration (OSHA).
REVIEW OF POTENTIALLY RELEVANT DATA
(NONCANCER AND CANCER)
As shown in Tables 3 A and 3B, there are no potentially relevant and repeated
short-term-, subchronic-, or chronic-duration studies, or developmental or reproductive toxicity
studies in humans or animals.
5
//-Heptanal

-------
FINAL
09-13-2017
Table 3A. Summary of Potentially Relevant Noncancer Data for «-Heptanal (CASRN 111-71-7)
Number of Male/Female, Strain, Species, Study
Category	Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
NOAEL
LOAEL
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
LOAEL = lowest-observed-adverse-effect level; ND = no data; NOAEL = no-observed-adverse-effect level.
6
//-Heptanal

-------
FINAL
09-13-2017
Table 3B. Summary of Potentially Relevant Cancer Data for w-Heptanal (CASRN 111-71-7)
Number of Male/Female, Strain, Species, Study
Category	Type, Reported Doses, Study Duration
Dosimetry
Critical Effects
Reference
Notes
Human
1. Oral (mg/kg-d)
ND
2. Inhalation (mg/m3)
ND
Animal
1. Oral (mg/kg-d)
ND
ND
2. Inhalation (mg/m3)
ND = no data.
//-Heptanal

-------
FINAL
09-13-2017
HUMAN STUDIES
The literature search revealed no studies of humans exposed to //-heptanal via oral or
inhalation routes. Human volunteers were exposed dermally to //-heptanal (4% concentration in
petrolatum) in a 48-hour patch test (Rlf'M, 1974). No evidence of irritation or sensitization were
observed in the subjects. Lawson et al. (1956) briefly reported experiments in which //-heptanal
was injected intramuscularly into breast cancer patients to explore //-heptanal's possible
therapeutic function and/or use for early diagnosis. The experiments were not rigorously
performed or documented, and provide no information on potential health effects.
ANIMAL STUDIES
The literature search did not reveal any studies of animals exposed to //-heptanal via oral
administration or inhalation apart from acute lethality studies; the latter are discussed in the
"Other Data" section below.
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Tables 4A and 4B provide overviews of genotoxicity and other supporting studies of
//-heptanal, respectively. Table 4B includes:
•	Acute oral and inhalation studies,
•	Intraperitoneal (i.p.) injection studies (gestational and acute exposure),
•	Acute and short-term-duration dermal studies, and
•	Acute ocular irritation studies.
Genotoxicity
The genotoxicity of //-heptanal was evaluated in several in vitro studies (see Table 4A).
The findings suggest that //-heptanal is not mutagenic or clastogenic. All available studies of
//-heptanal using strains of Salmonella typhimurium and Escherichia coli were negative for
mutagenicity with or without metabolic activation (Zeiger et al.. 1992; Shell Oil Co. 1982; Florin
et al.. 1980; Litton Bionetics. 1980). //-Heptanal did not induce chromosomal aberrations (CAs)
in rat liver (RL4) cells or mitotic gene conversion in strain JD1 of the yeast Saccharomyces
cerevisiae (Shell Oil Co. 1982).
8
//-Heptanal

-------
FINAL
09-13-2017
Table 4A. Summary of ft-Heptanal (CASRN 111-71-7) Genotoxicity
Endpoint
Test System
Dose/Concentration3
Results
without
Activationb
Results
with
Activationb
Comments
References
Genotoxicity studies in prokaryotic organisms
Mutation
Salmonella typhimurium TA97,
TA98, TA100, TA1535, and
TA1537
0, 1, 3, 10, 33, 100, 166,
333, 1,000, 1,666, or
3,333 ng/plate


Preincubation assay. Cytotoxicity
was observed at doses
>1,666 ng/plate.
Zeieeretal. (1992)

Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537, and TA1538
0, 15.6,31.3,62.5, 125,250,
500, 1,000, 2,000, or
4,000 ng/mL


Preincubation assay. Positive results
in TA1535 and TA1538 without S9
were not reproduced in replicate
assays.
Shell Oil Co (1982)
Mutation
Escherichia coli WP2 and
\VP2uvrA
0, 15.6,31.3,62.5, 125,250,
500, 1,000, 2,000, or
4,000 ng/mL


Preincubation assay.
Shell Oil Co (1982)
Mutation
S. typhimurium TA98, TA100,
TA1535, and TA1537
0, 3 |imol/platc
—
—
Spot test.
Florin etal. (1980)
Mutation
S. typhimurium TA98, TA100,
TA1535, TA1537, and TA1538
0.0001-0.01 nL/plate
—
—
Cytotoxicity occurred at
0.01 |iL/platc.
Litton Bionetics (1980)
Genotoxicity studies in nonmammalian eukaryotic organisms
Gene
conversion
Saccharomyces cerevisiae JD1
0, 1.25,2.5, 5, 12.5, or
25 iig/mL (without S9), and
5, 12.5, 25, 50, or
125 |ig/mL (with S9)


Equivocal result at histidine locus
was considered to result from
instability and volatility of test
compound.
Shell Oil Co (1982)
Genotoxicity studies in mammalian cells—in vitro
CAs
RL4 cells
0, 2.5, 5, 10, or 12.5 ng/mL
-
-
NA
Shell Oil Co (1982)
9
//-Heptanal

-------
FINAL
09-13-2017
Table 4A. Summary of ft-Heptanal (CASRN 111-71-7) Genotoxicity
Endpoint
Test System
Dose/Concentration3
Results
without
Activationb
Results
with
Activationb
Comments
References
Genotoxicity studies—in vivo
ND
Genotoxicity studies in subcellular systems
ND
'Concentrations tested in the assay.
b+ = positive; ± = weakly positive; - = negative.
CA = chromosomal aberration; NA = not applicable; ND = no data; RL4 = rat liver cell.
10
//-Heptanal

-------
FINAL
09-13-2017
Supporting Animal Toxicity Studies
A number of supporting animal toxicity studies were identified (see Table 4B for
additional details), including:
•	Four acute inhalation studies in rats, with lethality observed only in a single study
conducted at vapor saturation (concentration not reported) (Dow Chemical Co. 1958).
The estimated median lethal concentration (LC50) values were >520 mg/m3 (Bio
Dynamics, 1981), >4,700 mg/m3 (Bio Dynamics, 1989), and >18,400 mg/m3 (Shell
Oil Co. 1982).
•	An acute oral lethality study that reported an approximate median lethal dose (LD50)
of 3,200 mg/kg in both rats and mice (Eastman Kodak. 1985), and two other acute
oral studies in rats reported no lethality at doses of 2,000 mg/kg (Dow Chemical Co,
1958) and 5,000 mg/kg (MB Research Laboratories Inc. 1974).
•	A gestational exposure study using i.p. injection that reported resorption at all doses
(>700 mg/kg-day) (Carruthers and Stowell. 1941) and an acute i.p. injection study
that reported approximate LD50 values of 1,600 mg/kg for rats and 400-800 mg/kg
for mice (Eastman Kodak. 1985).
•	A 2-week dermal study in rabbits (500 mg/kg) that demonstrated histopathological
changes restricted to the application site (no treatment-related effects were observed
in the brain, heart, kidneys, liver, or lungs) (Bio Dynamics. 1991).
•	Three acute dermal studies that reported skin irritation (Eastman Kodak, 1985; MB
Research Laboratories Inc. 1974; Dow Chemical Co, 1958) and two acute ocular
studies that reported eye irritation (Bio Dynamics, 1980; Dow Chemical Co. 1958).
11
//-Heptanal

-------
FINAL
09-13-2017
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute oral and inhalation studies
Acute oral (lethality)
2 rats (sex and strain not
reported) received 2,000 mg/kg
//-heptanal as a 10% solution in
corn oil. Evaluations were not
detailed.
Neither rat died. The study report indicated that diuresis
was observed after dosing; pathology findings were
negative.
This study was reported in
tabular form with limited
information.
Dow Chemical Co
(1958)
Acute oral (lethality)
10 rats and 10 mice (sex and
strain not reported) were given
//-heptanal via oral
administration at doses between
200-3,200 mg/kg. Clinical
signs and body weight were
recorded, and animals were
observed for at least 14 d after
exposure.
Numbers of deaths were not reported, but time of death
was reported to be 1 hr in rats and 7 d in mice. The study
reported slight or moderate muscle weakness as the only
symptoms. The animals all gained weight during the
observation period.
The approximate LD5o for
both rats and mice was
estimated as 3,200 mg/kg.
This study was reported in
tabular form with limited
information.
Eastman Kodak
(1985)
Acute oral (lethality)
10 rats were given //-heptanal
orally at a dose of 5,000 mg/kg
and observed for 14 d.
No rats died. Clinical signs included lethargy and
piloerection. No other information was presented.
This study was reported in
tabular form with limited
information.
MB Research
Laboratories Inc
(1974)
Acute inhalation
(lethality)
M and F Wistar rats (5/sex)
were exposed (whole body) for
4 hr, to 0 or 18,400 mg/m3
//-heptanal vapor (near
saturation). The animals were
observed for signs of toxicity
daily over the 14-d observation
period; body weights were
recorded after 7 and 14 d.
1 male rat died within 5 min after the end of exposure.
Autopsy of this animal revealed dark liver, hemorrhagic
lung (considered a postmortem change), and hemolysis
and Hb crystals in the renal cortical tubules, suggesting
pre-exposure hemolysis. Clinical signs in surviving
animals included rapid respiration, eye and nose
irritation, salivation, and agitation. Body weights were
not affected by exposure. Signs in female rats resolved
within 48 hr, but males continued to exhibit some signs
throughout the 14-d follow-up.
The study authors did not
consider the single death to
be treatment-related. The
LC50 for //-heptanal was
estimated to be
>18,400 mg/m3. Exposure
was associated with
respiratory and ocular
irritation.
Shell Oil Co (1982)
12
//-Heptanal

-------
FINAL
09-13-2017
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute inhalation
(lethality)
M and F S-D CD rats (5/sex)
were exposed (whole body) for
4 hr to 230 or 520 mg/m3
//-heptanal vapor. The animals
were observed for signs of
toxicity daily over the 14-d
observation period; body
weights were recorded on D 0,
1, 2, 4, 7, and 14 (exposure was
on D 1). All animals were
subjected to gross necropsy.
No animals died during or after exposure. Clinical signs
of toxicity during exposure included matted fur, reduced
activity, closed eyes, labored breathing/gasping, mucoid
nasal discharge, and chromodacryorrhea in most animals
of both exposure groups. The high-exposure group (but
not the low) exhibited lacrimation, salivation, dried red
nasal discharge, and dried material around the eyes and
face. During the first 4 hr postexposure, neurological
signs including body tremors, tiptoeing, and
hyper-sensitivity to touch were seen in the high-exposure
group, and lacrimation, ocular abnormalities, and labored
or rapid breathing were seen in both groups. During the
14-d observation period, ocular abnormalities, signs of
respiratory dysfunction, and body-weight loss were seen
in both groups, but were more severe or at higher
incidence in the high-exposure group. Necropsy findings
at the low exposure included: dilated renal pelvis in
2 females, and lung and kidney discoloration in 1 male.
At the high exposure, 1 male exhibited dilated renal
pelvis and 1 exhibited lung discoloration; no necropsy
findings in females were reported.
LC50 for //-heptanal was
estimated to be
>520 mg/m3. Exposure
was associated with
respiratory, ocular,
neurological, body weight,
kidney, and lung effects.
Bio Dynamics (1981)

Acute inhalation
(lethality)
M and F S-D CD rats (3/sex)
were exposed (whole body) for
4 hr to 4,700 mg/m3 n-heptanal
vapor. The animals were
observed for signs of toxicity
daily over the 7-d observation
period; body weights were
recorded on D 1 and 8.
Necropsy was not performed.
No animals died during exposure or the observation
period. Irritation of the respiratory tract (evidenced by
labored breathing, gasping, salivation, and decreased
activity) was observed during exposure, but not after
exposure ended or during the observation period. During
the first 2 hr after exposure, yellow anogenital staining
was noted in exposed animals. During the week-long
observation period, some animals exhibited diy rales and
nasal discharge. Body weight was not affected.
LC50 for //-heptanal is
>4,700 mg/m3. Rats
exposed to //-heptanal at
this concentration
exhibited signs of
respiratory irritation.
Bio Dynamics (1989)

13
//-Heptanal

-------
FINAL
09-13-2017
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute inhalation
(lethality)
3 rats/group (sex and strain not
reported) were exposed for
6-15 minto a saturated
atmosphere of //-heptanal
(concentration not specified).
Mortality, signs of toxicity, and
necropsy were evaluated. The
postexposure observation period
was not reported.
None of the rats exposed for 6 min died, but all 3 died
shortly after 15 min of exposure. Respiratory and ocular
irritation were seen in both exposure groups.
This study was reported in
tabular form with limited
information. //-Heptanal
treatment was associated
with respiratory and ocular
irritation.
Dow Chemical Co
(1958)

Other route studies
Gestational i.p.
injection (reproduction)
Pregnant rats (Wistar, piebald,
and stock; 1-9/group) were
injected with //-heptanal (in lard
or acetone, with
methyl salicylate at
concentrations of 0.1-1% as a
stabilizer) daily throughout
pregnancy. Doses ranged from
700-12,000 mg/kg-d (assuming
an average body weight of
0.25 kg). Dams were sacrificed
and examined for resorptions at
2-d intervals from GD 6-18 or
at the first appearance of bloody
discharge. Body weights were
measured daily.
All dose levels produced resorption (acetone and lard
vehicles) in some, but not all, dams (incidence and
severity data were not provided). Rats given injections
with lard showed varying degrees of ascites, whitish
exudates coating the liver and spleen, and adhesions
(liver to diaphragm and intestine, ovaries to intestine) and
pulmonary hemorrhage (associated with lipoid
pneumonitis). In rats treated with heptanal in acetone,
lung hemorrhages were not observed and ascites and
related peritoneal changes were less severe.
Administered doses varied
within each group;
incidence and severity data
were not provided.
Carruthers and
Stowell (1941)
Acute i.p. injection
(lethality)
10 rats and 10 mice (sex and
strain not reported) were given
//-heptanal via i.p. injection at
doses between
200-3,200 mg/kg. Clinical
signs and body weight were
recorded, and animals were
observed for at least 14 d after
exposure.
Numbers of deaths were not reported, but time of death
was reported to be 2 hr-3 d in rats, and 1-7 d in mice.
The study reported moderate weakness with diarrhea in
rats, and slight-to-significant weakness with rough coat
and prostration in mice. The animals all gained weight
during the observation period.
The approximate LD5o was
1,600 mg/kg for rats and
400-800 mg/kg for mice.
This study was reported in
tabular form with limited
information.
Eastman Kodak
(1985)
14
//-Heptanal

-------
FINAL
09-13-2017
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Short-term dermal
Rabbits (5/sex/group) were
treated with dermal application
(uncovered) of n-heptanal
(25% w/w in mineral oil) for
2	wk at a dose of 0 or
500 mg/kg-d on 5 d/wk. Prior
to treatment, the skin was
abraded for half of the animals
in each group. The animals
were observed daily, and body
weights were recorded weekly.
3	animals/sex were sacrificed at
the end of exposure, and the
remaining animals were
sacrificed 2 wk after exposure
ended. All animals received
gross necropsy, and the brain,
heart, kidneys, liver, lungs, and
skin were subjected to
microscopic examination.
No rabbits died prior to scheduled sacrifice. Body-weight
loss was noted in most animals after 1-2 wk of exposure.
Signs of dermal irritation and injury in treated rabbits
included slight or moderate erythema with minimal
edema during Wk 1 and necrosis, eschar formation,
atonia, Assuring, desquamation, and exfoliation in all
animals during Wk 2; 1 rabbit showed alopecia.
Decreased food consumption was also noted in the
second wk of exposure. The study authors noted that the
skin changes "subsided" in the animals observed for 2 wk
following exposure. Histopathology changes consisted of
epidermal necrosis at the application site, accompanied
by epidermal hyperplasia and hyperkeratosis, in animals
exposed to n-heptanal.
Histopathological changes
were restricted to the
application site. No
treatment-related effects
were observed in the brain,
heart, kidneys, liver, or
lungs.
Bio Dynamics (1991)

Acute dermal
(irritation)
10 rabbits were treated dermally
with n-heptanal at a dose of
5,000 mg/kg and observed for
14 d.
No rabbits died. Signs of dermal irritation included
moderate to marked redness and edema. No other
information was presented.
This study was reported in
tabular form with limited
information.
MB Research
Laboratories Inc
(1974)

Acute dermal
(irritation)
Rabbits (number, sex, and strain
not reported) were exposed to
undiluted or diluted (10% in
Dowanol DPM) //-heptanal by
dermal application to intact or
abraded skin, of the ear or belly.
Evaluations were not detailed.
Slight-to-moderate hyperemia, with slight edema and
necrosis, and in some cases, a raw ulcer resulted from
exposure to undiluted n-heptanal. With diluted
//-heptanal, slight exfoliation, resolving within 18 d, was
seen.
Undiluted //-heptanal was
irritating to the skin of
rabbits. This study was
reported in tabular form
with limited information.
Dow Chemical Co
(1958)

15
//-Heptanal

-------
FINAL
09-13-2017
Table 4B. Other Studies
Test
Materials and Methods
Results
Conclusions
References
Acute dermal
(irritation)
A guinea pig (sex and strain not
reported) was exposed dermally
to 0.6 mL undiluted //-heptanal.
Dermal examinations and body
weight were recorded for 14 d
after exposure.
The guinea pig survived treatment. Signs of dermal
irritation and injury included moderate edema and
necrosis, with hemorrhage at the treatment site boundary
within 24 hr; eschar loss leaving raw area in 1 wk; and
scarring with alopecia in the treatment area after 2 wks.
The guinea pig gained weight during the observation
period.
Undiluted //-heptanal was
irritating to the skin of a
guinea pig. This study was
reported in tabular form
with limited information.
Eastman Kodak
(1985)

Acute ocular
(irritation)
Rabbits (number, sex, and strain
not reported) were exposed to
undiluted or diluted (in
10% propylene glycol)
//-heptanal applied to the eyes.
Evaluations were not detailed.
Exposure to undiluted //-heptanal yielded slight pain and
conjunctivitis that resolved in 48 hr. Exposure to diluted
//-heptanal resulted in immediate slight conjunctivitis
(later becoming extensive) accompanied by moderate
corneal damage and iritis; with postexposure washing
(but not without washing), these effects resolved in 1 wk.
In rabbits, direct contact
with //-heptanal was
irritating to the eyes, and
moderately to severely
injurious to the eyes in a
solution with propylene
glycol. This study was
reported in tabular form
with limited information.
Dow Chemical Co
(1958)

Acute ocular
(irritation)
9 adult NZW rabbits (sex not
reported) were exposed to
undiluted //-heptanal (0.1 mL)
applied to the conjunctival sac
of 1 eye. Eyes of 3 rabbits were
washed 20 sec after treatment,
and the eyes of the remaining
6	rabbits were not. Eye
irritation was evaluated for up to
7	d after exposure.
Exposure to undiluted //-heptanal resulted in conjunctival
redness, swelling, and necrosis in all rabbits. Corneal
opacity and ulceration and iridial irritation were observed
in some animals of both groups.
Undiluted //-heptanal was
irritating to the eyes of
rabbits after direct contact.
Bio Dynamics (1980)

F = female(s); GD = gestation day; Hb = hemoglobin; i.p. = intraperitoneal; LC50 = median lethal concentration; LD50 = median lethal dose; M = male(s); NZW = New
Zealand White; S-D = Sprague-Dawley.
16
//-Heptanal

-------
FINAL
09-13-2017
DERIVATION OF PROVISIONAL VALUES
Tables 5 and 6 present summaries of noncancer and cancer references values,
respectively.
Table 5. Summary of Noncancer Reference Values for «-Heptanal (CASRN 111-71-7)
Toxicity Type
(units)
Species/Sex
Critical
Effect
p-Reference
Value
POD Method
POD (HED)
UFc
Principal
Study
Subchronic p-RfD
(mg/kg-d)
NDr
Chronic p-RfD
(mg/kg-d)
NDr
Screening
subchronic p-RfC
(mg/m3)
Rat/M
Atrophy of
the olfactory
epithelium
3 x 10-2
BMCLio
(HEC)
8
(based on
surrogate
POD [HEC])
300
Union
Carbide
(1993) as
cited in U.S.
EPA (2008b)
Screening chronic
p-RfC (mg/m3)
Rat/M
Atrophy of
the olfactory
epithelium
3 x 1(T3
BMCLio
(HEC)
8
(based on
surrogate
POD [HEC])
3,000
Union
Carbide
(1993) as
cited in U.S.
EPA (2008b)
BMCLio = 10% benchmark concentration lower confidence limit; HEC = human equivalent concentration;
HED = human equivalent dose; M = male(s); NDr = not determined; POD = point of departure;
p-RfC = provisional reference concentration; p-RfD = provisional reference dose; UFC = composite uncertainty
factor.
Table 6. Summary of Cancer Reference Values for «-Heptanal (CASRN 111-71-7)
Toxicity Type (units)
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
Available data on oral exposure to //-heptanal consists of acute-duration lethality studies
in rodents that are inadequate in terms of scope and length of exposure for the development of
provisional reference doses (p-RfDs) (Eastman Kodak. 1985; MB Research Laboratories Inc.
1974; Dow Chemical Co. 1958). The European Chemical Agency (ECHA) registered substances
database has summarized 3- and 13-week toxicity studies in rats exposed to //-heptanal via
gavage (ECHA, 2017). The EPA was not able to obtain copies of the original studies or verify
the primary source(s) and validity of the study reports. Therefore, the information is considered
17
//-Heptanal

-------
FINAL
09-13-2017
insufficient for the derivation of oral reference values. In the absence of any suitable studies, the
derivation of p-RfDs for //-heptanal is precluded. A tiered read-across approach yielded no
potential surrogates with oral toxicity data for the development of screening p-RfDs
(see Appendix A).
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
The database for inhalation exposure to //-heptanal includes acute-duration lethality
studies (Bio Dynamics. 1989; Shell Oil Co. 1982; Bio Dynamics. 1981; Dow Chemical Co.
1958) that are inadequate for the derivation of provisional reference concentrations (p-RfCs).
However, a screening subchronic p-RfC value was derived applying a tiered surrogate approach
(see Appendix A).
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
Table 7 identifies the cancer weight-of-evidence (WOE) descriptor for //-heptanal.
Table 7. Cancer WOE Descriptor for «-Heptanal (CASRN 111-71-7)
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
absence of suitable data in humans or
animals for an assessment of
carcinogenicity.
"Not Likely to Be
Carcinogenic to Humans "
NS
NA
No evidence of noncarcinogenicity is
available.
NA = not applicable; NS = not selected; WOE = weight of evidence.
DERIVATION OF PROVISIONAL CANCER POTENCY VALUES
The absence of suitable data precludes development of cancer potency values.
18
//-Heptanal

-------
FINAL
09-13-2017
APPENDIX A. SCREENING PROVISIONAL VALUES
For reasons noted in the main Provisional Peer-Reviewed Toxicity Value (PPRTV)
document, it is inappropriate to derive provisional toxicity values for //-heptanal. 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. 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 the 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 U.S. EPA's DSSTox database (DSSTox.
2016)	and the National Library of Medicine's (NLM's) ChemlDplus database (ChemlDplus.
2017).	The Organisation for Economic Co-operation and Development (OECD) quantitative
structure-activity relationship (QSAR) toolbox was also used to calculate structural similarity
using the Tanimoto method (a similar quantitative method used by ChemlDplus and DSSTox)
(OECD, 2017). Three structural analogs to //-heptanal were identified that have inhalation
toxicity values: acetaldehyde (U.S. EPA. 1998). propionaldehyde (U.S. EPA. 2008a. b), and
glutaraldehyde (Cal/EPA. 2000). No potential candidates with oral toxicity values were found;
therefore, the current analysis is limited to the identification of surrogate chemicals for the
derivation of inhalation noncancer reference values for //-heptanal.
Table A-l summarizes the physicochemical properties and similarity scores for
//-heptanal and the structural analogs. All four compounds are straight chain, saturated
aldehydes with physicochemical properties that are consistent with related aldehydes. An effect
of carbon chain length on the physicochemical properties of the monoaldehyde compounds
(i.e., acetaldehyde, propionaldehyde, and //-heptanal) is apparent. Indeed, an increasing trend in
19
//-Heptanal

-------
FINAL
09-13-2017
melting point, boiling point, Henry's law constant, and lipophilicity (Log Kow) is observed with
the increase in carbon number, meanwhile, water solubility and vapor pressure decrease as
carbon number increases. The DSSTox and OCED QSAR toolbox similarity scores for the
analogs were relatively low (10-36% for OECD, 33-69% for DSSTox). Similarity estimates for
the candidate analogs were not obtained from ChemlDplus, given the >50% cut-off threshold for
similarity search within the database. A review of the similarity search output suggests that the
low similarity scores are strongly biased by the descriptor for the carbon chain length (the
analogs are C2-C5, and the target chemical is CI). Structural similarity metrics use a variety of
structural descriptors to calculate similarity (although the nature of the descriptors may vary
across different tools). Similarity scores calculated for compounds with few structural
descriptors will be disproportionately influenced by changes in, or absence of, a single
descriptor, while these same changes have relatively lower impact on similarity scores for
compounds with many descriptors. Thus, similarity scores may be of limited use when
comparing surrogates with relatively simple structures such as those evaluated in this
assessment. However, more importantly, these compounds share a reactive aldehyde moiety,
which has been associated with the mode of action (MOA) for the inhalation toxicity of
aldehydes (U.S. EPA. 2008b). The presence of two aldehyde functional groups on
glutaraldehyde is anticipated to enhance chemical reactivity in relation to the monoaldehyde
analogs; therefore, acetaldehyde and propionaldehyde are considered more appropriate structural
surrogates for //-heptanal over glutaraldehyde.
20
//-Heptanal

-------
FINAL
09-13-2017
Table A-l. Structural and Physicochemical Properties of «-Heptanal (CASRN 111-71-7) and Candidate Analogs"

«-Heptanal
Acetaldehyde
Propionaldehyde
Glutaraldehyde

(heptaldehyde)
(ethanal)
(propanal)
(pentanedial)
Structure
O'
o
o
O O'

x^ ^ ,
A
X /
X ^ J

H ^
H
H " ' ^ H
CASRN
111-71-7
75-07-0
123-38-6
111-30-8
Molecular weight
114.19
44.05
58.08
100.12
DSSTox similarity score (%)b
100
33
47
69
OECD QSAR Toolbox similarity score (%)°
100
10
33
36
Melting point (°C)
-43.3
-123.37
-80
-29.86 (estimated)3
Boiling point (°C)
153
20.1
48
o
00
00
Vapor pressure (mm Hg at 25°C)
3.52
902
317
0.6
Henry's law constant (atm-m3/mole at 25°C)
2.7 x 10-4
6.7 x 10-5
7.3 x 10-5
3.3 x 10-8
Water solubility (mg/L)
1,250
1,000,000
306,000
167,200 (estimated)3
Log Iv
2.8d
-0.34
0.59
-0.33
pKa
NV
13.57
NV
NV
'Data was gathered from the PHYSPROP database for each respective compound unless otherwise specified (U.S. EPA. 2012b').
bDSSTox (2016).
°OECD (2017).
dU.S. EPA (2015).
NV = not available.
21
//-Heptanal

-------
FINAL
09-13-2017
Metabolic Surrogates
Toxicokinetic information on //-heptanal and the structural analogs is largely unavailable.
No specific studies that inform on the absorption or distribution, of //-heptanal or glutaraldehyde
via relevant routes of exposure (i.e., inhalation or oral) could be identified. Kinetic studies
demonstrated significant uptake in the upper respiratory tract following inhalation of
acetaldehyde (1-1,500 ppm) or propionaldehyde (0.4-0.6 |ig/mL or -950-1,400 ppm) in
experimental animals (Stanek and Morris. 1999; Morris and Blanchard. 1992; Egle. 1972).
Upon absorption, systemic distribution of inhaled aldehydes is expected to be reduced by the
reactivity of the aldehyde moiety and the potential for metabolism in the respiratory tract (U.S.
EPA. 2008a. b, 1998). although data examining the tissue distribution of //-heptanal and the
structural analogs after inhalation exposure is currently lacking.
Metabolism and elimination pathways for //-heptanal, acetaldehyde, propionaldehyde,
and glutaraldehyde (see Table A-2) are similar, as expected for most saturated aliphatic
aldehydes (WHO, 1999). All four compounds appear to be substrates for aldehyde
dehydrogenase (ALDH), a primary enzyme responsible for the initial oxidation to their
corresponding carboxylic acids (heptanoic acid for //-heptanal; acetic acid for acetaldehyde;
propionic acid for propionaldehyde; glutaric acid for glutaraldehyde). Glutaraldehyde is a poor
substrate for certain human and rat isoforms of ALDH in relation to other aldehydes, suggesting
that additional enzymes could be involved in its metabolism (Beauchamp et al. 1992). Further
oxidation of the carboxylic acid analogs occurs via /^-oxidation pathways as in the metabolism of
fatty acids. Briefly, carboxylic acids condense with coenzyme A (CoA) to form thioesters that
are subject to /;-cleavage, yielding acetyl-CoA and/or propionyl-CoA. Propionyl-CoA is further
metabolized to succinyl-CoA; both acetyl-CoA and succinyl-CoA enter the Krebs cycle and are
eventually excreted as carbon dioxide (CO2) and water.
The role of metabolism in the detoxification of reactive aldehydes can be inferred by the
correlation between low levels of ALDH activity and increased severity of lesions in the
olfactory epithelium of rats exposed to acetaldehyde (Bogdanffy et al.. 1986). Additionally,
mice devoid of ALDH2 activity display susceptibility to acetaldehyde-mediated histopathology
in the respiratory tract (Ovama et al.. 2007). Wang et al. (2002) examined metabolic ALDH2
activity for different aldehydes, including //-heptanal and its monoaldehyde analogs, in human
liver samples from individuals heterozygous (ALDH2*l/*2) for the ALDH2 487G/A
polymorphism, and individuals with a homozygous genotype (ALDH2*1/*1) for the wildtype
allele. Metabolic rates for acetaldehyde, propionaldehyde, and //-heptanal were comparable
(35.01-59.07 nmol/min/mg protein) in the homozygous wildtype group, providing further
support for the metabolic similarity between the target chemical and these analogs. More
pronounced differences were reported in subjects heterozygous for the mutant allele
(2.72-36.99 nmol/min/mg protein). The study authors concluded that ALDH2 genetic
polymorphisms could influence the metabolism and presumably the toxicity of short chain
aliphatic aldehydes.
As their metabolism and excretory pathways are similar to those of //-heptanal,
acetaldehyde, propionaldehyde, and glutaraldehyde are considered potential metabolic surrogates
for //-heptanal.
22
//-Heptanal

-------
FINAL
09-13-2017
Table A-2. Available Metabolism and Excretion Data for «-Heptanal (CASRN 111-71-7)
and Candidate Analogs
Compound
Metabolism and Excretion
Reference
//-Heptanal
•	Oxidation to heptanoic acid.
•	Heptanoic acid undergoes //-oxidation, yielding acetyl-CoA and
propionyl-CoA.
•	Propionyl-CoA is converted to succinyl-CoA.
•	Acetyl-CoA and succinyl-CoA are used by Krebs cycle and ultimately
exhaled as CO2.
WHO (1999):
RIFM (1979)
Acetaldehyde
•	Oxidation to acetic acid.
•	Acetic acid condenses with CoA to form acetyl-CoA.
•	Acetyl-CoA is used by the Krebs cycle and ultimately exhaled as CO2.
U.S. EPA (2008b):
WHO (1999)
Propionaldehyde
•	Oxidation to propanoic acid.
•	Propanoic acid condenses with CoA to form propionyl-CoA.
•	Propionyl-CoA is converted to succinyl-CoA.
•	Succinyl-CoA is an intermediate in the Krebs cycle and is ultimately
exhaled as CO2.
U.S. EPA (2008b):
WHO (1999)
Glutaraldehyde
•	Oxidation to glutaric acid.
•	Glutaric acid reacts with CoA to form glutaconyl-CoA.
•	Glutaconyl-CoA is decarboxylated to crotonyl-CoA, followed by
hydration to //-hydroxybutyrl-Co A.
•	//-hydroxybutyrl-Co A condenses to form acetyl-CoA, which is used by
the Krebs cycle and ultimately exhaled as CO2.
Beauchanro et al.
(1992); NTP (1999)
Co A = coenzyme A; CO2 = carbon dioxide.
Toxicity-Like Surrogates
Table A-3 summarizes available toxicity data for //-heptanal and the structurally similar
analogs. //-Heptanal lacks repeated-dose toxicity data in experimental animals. Inhalation
reference concentrations (RfCs) for acetaldehyde and propionaldehyde are available on IRIS
(U.S. EPA. 2008a. b, 1998) and chronic inhalation reference levels (REL) were derived for
glutaraldehyde by Cal/EPA (2000). The critical effect for the three structural analogs to
//-heptanal are based on upper respiratory tract lesions in rodents. Nevertheless, differences in
the potency of these analogs with respect to repeated-dose toxicity in the airway are apparent.
The points of departure (PODs) for degenerative changes in the nasal cavity of rats treated with
acetaldehyde or propionaldehyde are very similar (no-observed-adverse-effect level [NOAEL]
human equivalent concentration [HEC] of 8.7 mg/m3 for acetaldehyde and 10% benchmark
concentration lower confidence limit [BMCL10] [HEC] of 8 mg/m3 for propionaldehyde),
meanwhile the POD for glutaraldehyde identified for noncancer nasal lesions in mice is
three orders of magnitude lower (5% benchmark concentration [BMC05] [HEC] of 0.002 mg/m3).
Indirect systemic effects following inhalation exposure to acetaldehyde, propionaldehyde, and
glutaraldehyde were only observed at concentrations considerably higher than those associated
with portal-of-entry (airway) toxicity (see Table A-3).
Acute lethality studies in rodents are available for //-heptanal and the structural analogs
via multiple routes of exposure, providing an opportunity for comparison of acute toxicity
23
//-Heptanal

-------
FINAL
09-13-2017
potencies. Study results are presented in Table A-3. Further details on study design and protocol
were not found (ChemlDplus. 2017). Oral median lethal doses (LDsos) in rats suggest that
//-heptanal (LD50 = 3,200 mg/kg) is less acutely toxic than propionaldehyde (rat
LD50 = 1,410 mg/kg), acetaldehyde (rat LD50 = 661 mg/kg), and glutaraldehyde (rat
LD50 = 134 mg/kg). Intraperitoneal (i.p.) LD50S are similar for acetaldehyde, propionaldehyde,
and //-heptanal in mice (LD50 = 200-400 mg/kg), and in rats, acute lethality values for
propionaldehyde (LD50 = 200 mg/kg) are lower compared to //-heptanal (LD50 = 1,600 mg/kg).
Notably, i.p. LD50S for glutaraldehyde are approximately one to two orders of magnitude lower
(13.9 and 17.9 mg/kg in mice and rats, respectively) in relation to the monoaldehyde compounds.
Acute inhalation toxicity in rodents is comparable for acetaldehyde, propionaldehyde, and
//-heptanal (median lethal concentration [LC50] = >18,400 - 24,000 mg/m3), whereas
glutaraldehyde is distinctly more potent (LC50 = 480 mg/m3). Finally, //-heptanal, acetaldehyde,
and propionaldehyde showed analogous acute target organ effects, including neurological and
respiratory tract toxicity.
In general, the acute lethality information described above suggests the rank order of
potency to be glutaraldehyde » acetaldehyde ~ propionaldehyde > //-heptanal. Likewise,
median reference irritation dose (RD50) values (concentration producing a 50% respiratory rate
decrease), which represent a measure of respiratory irritation potential, are similar for
acetaldehyde and propionaldehyde, but remarkably lower for glutaraldehyde (see Table A-3). In
summary, data from repeated-dose exposure, acute lethality, and respiratory irritation (RD50)
indicate that glutaraldehyde exhibits enhanced chemical reactivity and inhalation toxicity
compared to //-heptanal and the monoaldehyde analogs; therefore, glutaraldehyde is not
considered an appropriate toxicity-like surrogate for //-heptanal.
Comparative studies of low molecular-weight aldehydes (C1-C4) note a reduction in
potency with increasing carbon chain length based on measurements of in vitro cytotoxicity and
acute lethality (Bombick and Doolittle. 1995; Koerker et al.. 1976; Skog. 1950). which is
consistent with the above findings that indicate //-heptanal is slightly less acutely toxic than
acetaldehyde and propionaldehyde. Structure-activity relationship analyses of aldehydes reveal
that carbon chain length can have a modest effect on respiratory irritating potency; however,
major differences are most prominently observed across different aldehyde groups (Alarie et al.
1998; Babiuk et al.. 1985; Steinhagen and Barrow. 1984). Indeed, mouse RD50 values for
C2-C6 saturated aliphatic aldehydes, including acetaldehyde and propionaldehyde, were similar
(1,014-5,689 ppm), and approximately three orders of magnitude higher than for unsaturated
aliphatic aldehydes (RD50 = 1.03-4.88 ppm) and formaldehyde (RD50 = 3.2-4.9 ppm). Cyclic
aldehydes displayed moderate irritating potency with RD50 values in the range of 59-186 ppm.
RD50 values for //-heptanal are not available; nonetheless, acute studies in rodents demonstrate
similarly low inhalation potency for //-heptanal, acetaldehyde, and propionaldehyde
(see Table A-3). The MOA for nasal toxicity relates to the reactivity of the aldehyde moiety
(U.S. EPA. 2008b) and is expected to be similar for //-heptanal as for the shorter-chain
monoaldehydes. Indeed, respiratory irritation was consistently reported in acute inhalation
studies with rats exposed to concentrations of //-heptanal >520 mg/m3, supporting the relevance
of the respiratory tract as a potential target organ of toxicity for this chemical (Bio Dynamics.
1989; Shell Oil Co. 1982; Bio Dynamics. 1981; Dow Chemical Co. 1958). In summary, both
24
//-Heptanal

-------
FINAL
09-13-2017
acetaldehyde and propionaldehyde are considered potential toxicity-like surrogates for
/7-heptanal.
25
//-Heptanal

-------
FINAL
09-13-2017
Table A-3. Comparison of Available Toxicity Data for «-Heptanal (CASRN 111-71-7) and Candidate Analogs

rt-Heptanal
(heptaldehyde)
Acet aldehyde
(ethanal)
Propionaldehyde
(propanal)
Glutaraldehyde
(pentanedial)
Structure
0
II
0
II
O
II
O O
II II

A -x. ^
H' ^
.11
t-r
H

CASRN
111-71-7
75-07-0
123-38-6
111-30-8
Repeated-dose toxicity (inhalation)
POD (mg/m3)
NV
8.7
8
0.002
POD type
NV
NOAEL (HEC)
BMCLio (HEC)
BMCos (HEC)
UFC
NV
1,000
1,000
30
RfC or REL (mg/m3)
NV
9 x 10-3
8 x 10-3
8 x 10-5
Critical effects
NV
Degeneration of olfactory epithelium
at concentrations >400 ppm.
Atrophy of the olfactory epithelium
in rats at concentrations >150 ppm.
Squamous metaplasia of the
respiratory epithelium at
concentrations >62.5 ppb.
26
//-Heptanal

-------
FINAL
09-13-2017
Table A-3. Comparison of Available Toxicity Data for «-Heptanal (CASRN 111-71-7) and Candidate Analogs

rt-Heptanal
(heptaldehyde)
Acet aldehyde
(ethanal)
Propionaldehyde
(propanal)
Glutaraldehyde
(pentanedial)
Other effects in
principal study
NV
Effects at higher exposures: severe
degenerative hyperplastic and
metaplastic changes of the nasal,
laryngeal, and tracheal epithelium at
>1,000 ppm; growth retardation at
>1,000 ppm and mortality at
>2,200 ppm; decreased percent of
lymphocytes and increased percent
of neutrophils in the blood at
5,000 ppm; organ-weight changes at
5,000 ppm.
Additional effects reported include:
vacuolization of olfactory epithelium
and rhinitis in the respiratory
epithelium at >150 ppm; squamous
metaplasia of the respiratory
epithelium in males only at
>750 ppm. Maternal (decreased
body weight and food consumption
during GD 0-21) and developmental
(reduced pup body-weight gain at
birth and PND 4) effects were noted
at 1,500 ppm. No effects on
reproductive parameters up to
1,500 ppm.
Additional lesions found at
concentrations >62.5 ppb in
female mice only included:
increased incidence of nose
inflammation and hyaline
degeneration of the respiratory
epithelium; mean body weight in
female mice was lower compared
to controls at 250 ppb.
In an accompanying rat study,
non-neoplastic nasal lesions
(hyperplasia and inflammation of
the squamous and respiratory
epithelia, and squamous
metaplasia of the respiratory
epithelium) occurred at
>250 ppb; decreased body weight
at >250 ppb and increased
mortality in females at >500 ppb.
Species
NV
Rat (males)
Rats (males)
Mice (females)
Duration
NV
4 wk
7 wk
104 wk
Route
NV
Inhalation
Inhalation
Inhalation
27
//-Heptanal

-------
FINAL
09-13-2017
Table A-3. Comparison of Available Toxicity Data for «-Heptanal (CASRN 111-71-7) and Candidate Analogs

rt-Heptanal
(heptaldehyde)
Acet aldehyde
(ethanal)
Propionaldehyde
(propanal)
Glutaraldehyde
(pentanedial)
Notes

The same types of lesions appear at
longer exposure times and higher
exposure levels in chronic-duration
studies.
Liver cell vacuolation was observed
in rats exposed to 1,300 ppm for 6 d.
Cardiovascular effects (blood
pressure and heart rate) reported in
rats with acute inhalation exposures
>10 |ig/mL (-24,000 ppm).
Respiratory tract toxicity was
also reported in acute,
short-term- and
subchronic-duration studies in
rats and mice with inhalation
exposure.
Effects described in humans with
occupational exposure include
asthma, skin sensitivity, and
irritation of the eyes and nose
with accompanying rhinitis.
Source
NV
U.S. EPA (1998)
U.S. EPA (2008a): U.S. EPA
(2008b)
Cal/EPA (2000)
Acute toxicity
Rat oral LD5o (mg/kg)
3,200
661
1,410
134
Toxicity target
Behavioral
Peripheral nervous system;
behavioral; respiratory tract
NS
NS
Mouse oral LD5o
(mg/kg)
3,200
900
NV
100
Toxicity target
Behavioral
NS
NV
NS
Rat inhalation LC50
(mg/m3)
>18,400
24,000
NV
480
Toxicity target
Respiratory tract;
Behavioral; GI tract
Respiratory tract; behavioral
NV
NS
Mouse inhalation LC50
(mg/m3)
NV
23,000
21,800
NV
Toxicity target
NV
NS
NS
NV
Rat i.p. LD50 (mg/kg)
1,600
NV
200
17.9
28
//-Heptanal

-------
FINAL
09-13-2017
Table A-3. Comparison of Available Toxicity Data for «-Heptanal (CASRN 111-71-7) and Candidate Analogs

rt-Heptanal
(heptaldehyde)
Acet aldehyde
(ethanal)
Propionaldehyde
(propanal)
Glutaraldehyde
(pentanedial)
Toxicity target
Behavioral; GI tract
NV
Behavioral
NS
Mouse i.p. LD5o
(mg/kg)
400
500
200
13.9
Toxicity target
Behavioral; skin and
appendages
NS
Respiratory tract; behavioral
NS
Source
GiemlDplus (2016)
GiemlDplus (2016)
ChemlDplus (2016)
ChemlDplus (2016)
Respiratory irritation
Mouse RD5o (ppm)
NV
3,900a
5,700a
NV
Swiss-Webster mouse
RD50 (ppm)
NV
2,845b
2,052b
13.9°
B6C3Fi mouse RD50
(ppm)
NV
2,932b
2,073b
NV
aAlarie et al. (1998).
bSteinhagen and Barrow (1984).
°Werlev et al. (1995).
BMCos = 5% benchmark concentration; BMCLio = 10% benchmark concentration lower confidence limit; GD = gestation day; GI = gastrointestinal;
HEC = human equivalent concentration; i.p. = intraperitoneal; LCso = median lethal concentration; LD5o = median lethal dose;
NOAEL = no-observed-adverse-effect level; NS = not specified; NV = not available; PND = postnatal day; POD = point of departure; RDso = median reference
dose; REL = reference level; RfC = reference concentration; UFC = composite uncertainty factor.
29
//-Heptanal

-------
FINAL
09-13-2017
Weight-of-Evidence Approach
A WOE approach is used to evaluate information from potential candidate surrogates as
described by Wang et al. (2012). Commonalities in structural/physicochemical properties,
toxicokinetics/metabolism, toxicity, or MOA 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 target chemical. 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.
Based on a WOE analysis, acetaldehyde and propionaldehyde are considered appropriate
chemical surrogates for //-heptanal via the inhalation route. No surrogate candidates were
identified with available oral toxicity values; therefore, the development of screening provisional
reference doses (p-RfDs) is precluded. Acetaldehyde and propionaldehyde are shorter chain
analogs of //-heptanal that share a key functional group (i.e., aldehyde moiety). Indeed, the
reactive mechanism for the aldehyde moiety of acetaldehyde and propionaldehyde has been
associated with the critical effect for inhalation exposure, (i.e., nasal toxicity) and is anticipated
to be analogous to that of //-heptanal. Similarities in metabolism and excretion pathways
indicate acetaldehyde and propionaldehyde are also metabolic surrogates for //-heptanal.
Moreover, acute lethality studies in rodents showed comparable LD50 values and target-organ
effects (neurological and respiratory tract toxicity) for //-heptanal, acetaldehyde, and
propionaldehyde. Conversely, glutaraldehyde is not considered an appropriate surrogate based
on the presence of an additional aldehyde moiety in the molecule that is anticipated to result in
substantially greater airway reactivity and inhalation toxicity for this chemical in relation to
//-heptanal.
Consistency in functional group properties, metabolism and excretion pathways, critical
endpoints, and PODs for repeated-dose toxicity for propionaldehyde and acetaldehyde provide
additional support for the use of the surrogate approach and suggest that either compound could
be considered a suitable surrogate for //-heptanal. However, given the perceived effect of carbon
chain length on the physicochemical properties and acute toxicity of these monoaldehyde
compounds, propionaldehyde is selected as the final surrogate chemical because it is the closest
analog to //-heptanal (heptanal is C7, propinaldehyde is C3, and acetaldehyde is C2).
Furthermore, the POD value for propionaldehyde is based on a study of slightly longer exposure
duration (7 weeks) than that of acetaldehyde (4 weeks), thus, increasing confidence in the
principal study as the basis for a screening subchronic and chronic provisional reference
concentration.
INHALATION TOXICITY VALUES
Derivation of a Screening Subchronic Provisional Reference Concentration
Based on the overall surrogate approach presented in this PPRTV assessment,
propionaldehyde is selected as the surrogate for //-heptanal. The study used in deriving the IRIS
RfC for propionaldehyde is a 7-week inhalation study in male CD rats [Union Carbide (1993) as
cited in U.S. EPA (2008b)1. The IRIS toxicological review for propionaldehyde described the
study as follows (U.S. EPA. 2008b):
30
//-Heptanal

-------
FINAL
09-13-2017
Young adult male andfemale CD rats (15/sex/group) were exposed to 0, 150, 750,
or 1,500 ppm (0, 357, 1,785, or 3,570 mg/m3) propionaldehyde for 6 hours/day,
7 days/week via whole-body inhalation, during a 2-weekprematingperiod and a
14-day (maximum) mating phase (Union Carbide, 1993). The matedfemales
were exposed daily through Gestation Day (GD 20 only for a minimum of 35 days
and a maximum of 48 days depending upon when they mated (average exposure
period ~38 days). The females were then allowed to deliver their litters naturally
and raise their offspring until postnatal day (PND) 4 both free of exposure to
propionaldehyde. The males continued to be exposedfor a total of 52 exposures
until sacrifice in week 7. Clinical observations were made daily, following
exposure, and body weight andfood consumption were measured at regular
intervals throughout the study. Offspring body weight, viability, and disposition
were monitoredfrom birth until PND 4. Following the last exposure, males were
fasted and blood samples were obtainedfor clinical pathology analyses prior to
necropsy. On PND 4, necropsies were performed on adult females, and a number
of organs and tissues, including at least two sections of the nasal cavity
(sectioning details not provided), were examined histologically. The offspring
were examined externally and sacrificed without pathologic evaluation.
No exposure-related clinical signs were noted in the adult females. During the
first week of exposure to 750 and 1,500 ppm, body weight gains were decreased
to approximately 60 and 71% (p < 0.01), respectively, of controls, andfood
consumption was decreased by approximately 7% (p < 0.05) of controls at both
concentrations. No differences were observed during the second week of
exposure. During gestation, body weight (over GDs 0-14) andfood consumption
(over GDs 0-21) were decreased in the high exposure group compared with
controls, but no significant differences in body weight gain were observed. At
sacrifice, no gross lesions attributable to propionaldehyde exposure were found.
However, microscopic examination of the nasal cavity revealed
propionaldehyde-induced vacuolization of the olfactory epithelium in the 150 and
750 ppm exposure groups and atrophy of the olfactory epithelium in the 750 and
1,500ppm exposure groups. These effects were noted to be localized to the
dorsal anterior two sections of the nasal cavity. The incidence of atrophy was
0/15, 0/15, 2/15, and 15/15 at 0, 150, 750, and 1,500 ppm, respectively (see Table
4-1). The severity of this nasal lesion increased with exposure concentration
being minimal to mild at 750 ppm and moderate to marked at 1,500 ppm. No
evidence of squamous metaplasia was found in olfactory or respiratory
epithelium. Low incidences of minimal to mild rhinitis involving the respiratory
epithelium were also noted at 150, 750, and 1,500 ppm. No significant effects of
exposure on any of the reproductive parameters assessed were found. Litter size
and viability were similar among the groups. Pup body weights on the day of
birth and PND 4 were not affected by exposure, although at the high
concentration only body weight gain for that period was significantly depressed
(p < 0.05, -0.8 g) compared with controls. The biological significance of this
finding is difficult to assess since changes in absolute body weight were not
demonstrated and the time period of observation was relatively short.
31
//-Heptanal

-------
FINAL
09-13-2017
The adult males did not display any overt signs of toxicity at any time during the
study. Body weight, weight gain, clinical observation, andfood consumption
were similar among all exposure groups and controls. Hematology and clinical
chemistry analyses revealed elevated erythrocyte counts, with a corresponding
increase in hemoglobin and hematocrit values and an increase in monocytes in
the males exposed to 1,500 ppm. These effects were considered to be consistent
with and indicative of dehydration. At necropsy (examination performed as per
the 10 adult females), no gross lesions were found that could be attributable to
propionaldehyde exposure. However, similar to effects in the females,
microscopic examination revealed exposure-related effects in the olfactory
epithelium of the nasal cavity that consisted of vacuolization and atrophy in the
low, intermediate, and high exposure groups. These effects were also noted to be
localized to the dorsal anterior two sections of the nasal cavity. The incidence of
atrophy was 0/15, 2/15, 10/15, and 15/15 at 0, 150, 750, and 1,500 ppm,
respectively (see Table 4-1).
The severity of this nasal lesion increased with exposure concentration being
minimal at 150 ppm, minimal to moderate at 750 ppm, and mild to marked at
1,500 ppm. Squamous metaplasia of the respiratory epithelium was reported in
one male from the 750 ppm group and two males from the 1,500 ppm group. An
increased incidence of minimal to moderate rhinitis involving the respiratory
epithelium was also noted at 750 and 1,500 ppm. The results of this study
indicate a lowest-observed-adverse-effect level (LOAEL) for portal-of-entry
toxicity of 150 ppm as a result of olfactory atrophy graded by Union Carbide
(1993) as being of minimal severity by the study authors and supported by the
presence of vacuolization.
The critical effect identified for propionaldehyde in the Union Carbide (1993) study was
nasal olfactory atrophy (U.S. EPA. 2008b). Benchmark Dose Software (BMDS) was used to
model incidence of atrophy in the olfactory epithelium of male rats using a benchmark response
(BMR) of 10% extra risk (U.S. EPA. 2008b). A BMC Lin of 32 mg/m3 was derived from BMDS
and converted to a HEC by applying a regional gas dose ratio (RGDR) of 0.26 for extrathoracic
respiratory effects in accordance to U.S. EPA (1994) guidelines. The resulting BMCLin (HEC)
of 8 mg/m3 was used as a POD in the RfC for propionaldehyde and is, therefore, adopted as the
surrogate POD for the derivation of a screening subchronic p-RfC for n-heptanal. The BMCLio
(HEC) of 8 mg/m3 was not adjusted for molecular-weight differences in the derivation of the
//-heptanal provisional toxicity value because the molecular-weight difference between
//-heptanal and propionaldehyde is less than twofold (Wang et at.. 2012).
In deriving a screening subchronic p-RfC for //-heptanal, a composite uncertainty factor
(UFc) of 300 is applied, based on a 3-fold uncertainty factor value for interspecies extrapolation
(interspecies uncertainty factor [UFa], reflecting use of a dosimetric adjustment) and 10-fold
uncertainty factor values for both intraspecies variability (UFh) and database deficiencies
(database uncertainty factor [UFd], reflecting lack of any repeated-exposure toxicity information
for //-heptanal). The screening subchronic p-RfC for //-heptanal is derived as follows:
32
//-Heptanal

-------
FINAL
09-13-2017
Screening Subchronic p-RfC = Surrogate POD (HEC) ^ UFc
= 8 mg/m3 ^ 300
= 3 x 10"2 mg/m3
Table A-4 summarizes the uncertainty factors for the screening subchronic p-RfC for
//-heptanal.
Table A-4. Uncertainty Factors for the Screening Subchronic p-RfC for
ft-Heptanal (CASRN 111-71-7)
UF
Value
Justification
UFa
3
A UFa of 3 (10°5) is applied to account for residual uncertainty, including toxicodynamic differences,
between rats and humans following //-heptanal inhalation. The toxicokinetic uncertainty has been
accounted for by calculation of a HEC through application of a RGDR in extrapolating from animals
to humans CU.S. EPA. 2008b) according to the procedures in the RfC methodoloev CU.S. EPA. 1994).
UFd
10
A UFd of 10 is applied due to the absence of repeated-dose toxicity studies for //-heptanal and the use
of a surrogate approach to derive the screening p-RfC.
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 //-heptanal in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMCLio.
UFS
1
A UFS of 1 is applied because a 7-wk study was selected as the principal study.
UFC
300
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCLio = 10% 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; RfC = reference concentration; RGDR = regional gas dose
ratio; UF = uncertainty factor; UFA = interspecies uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
Derivation of a Screening Chronic Provisional Reference Concentration
The IRIS assessment for propionaldehyde derived a chronic RfC using the critical effect
(atrophy of the olfactory epithelium) and POD (BMCLio [HEC] of 8 mg/m3) identified in the
7-week inhalation study in rats (U.S. EPA. 2008b). The database for propionaldehyde lacks
longer duration studies; however, the pattern and progression of the nasal lesions (atrophy
accompanied by vacuolization, necrosis, and squamous metaplasia) observed in the 7-week rat
study are consistent with those reported from chronic-duration studies with other aldehydes,
including acetaldehyde (U.S. EPA. 2008a. b, 1998). Importantly, no adverse systemic effects
occurred in chronic-duration studies with acetaldehyde or short-term-duration studies with
propionaldehyde at concentrations that caused significant portal-of-entry toxicity
(see Table A-3). Therefore, a screening chronic p-RfC for //-heptanal is derived using the POD
(BMCLio [HEC] of 8 mg/m3) from the 7-week inhalation study with propionaldehyde and
applying an additional uncertainty factors of 10 to account for increased uncertainty associated
with longer exposure. A total UFc of 3,000 was derived, reflecting a 3-fold uncertainty factor
value for UFa, and 10-fold uncertainty factor values for UFh, sub chronic-to-chronic
33
//-Heptanal

-------
FINAL
09-13-2017
extrapolation (UFs), and UFd. Finally, the screening chronic p-RfC for n-heptanal is derived as
follows:
Screening Chronic p-RfC = Surrogate POD (HEC) ^ UFc
= 8 mg/m3 ^ 3,000
= 3 x 10"3 mg/m3
Table A-5 summarizes the uncertainty factors for the screening chronic p-RfC for
//-heptanal.
Table A-5. Uncertainty Factors for the Screening Chronic p-RfC for
w-Heptanal (CASRN 111-71-7)
UF
Value
Justification
UFa
3
A UFa of 3 (100 5) is applied to account for residual uncertainty, including toxicodynamic
differences, between rats and humans following //-heptanal inhalation. The toxicokinetic
uncertainty has been accounted for by calculation of a HEC through application of a RGDR in
extraoolatine from animals to humans CU.S. EPA. 2008b) according to the procedures in the RfC
methodology CU.S. EPA. 1994).
UFd
10
A UFd of 10 is applied due to the absence of repeated-dose toxicity studies for //-heptanal and the
use of a surrogate approach to derive the screening p-RfC.
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 //-heptanal in humans.
UFl
1
A UFl of 1 is applied for LOAEL-to-NOAEL extrapolation because the POD is a BMCLio.
UFS
10
A UFS of 10 is applied due to increased uncertainty associated with extrapolating from a
subchronic-duration study (7-wk) to a chronic exposure.
UFC
3,000
Composite UF = UFA x UFD x UFH x UFL x UFS.
BMCLio = 10% 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; RfC = reference concentration; RGDR = regional gas dose
ratio; UF = uncertainty factor; UFa = interspecies uncertainty factor; UFD = database uncertainty factor;
UFh = intraspecies uncertainty factor; UFL = LOAEL-to-NOAEL uncertainty factor; UFS = subchronic-to-chronic
uncertainty factor.
34
//-Heptanal

-------
FINAL
09-13-2017
APPENDIX B. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). (2016). 2016 TLVs and
BEIs: Based on documentation of the threshold limit values for chemical substances and
physical agents and biological exposure indices. Cincinnati, OH.
https://www.acgih.ore/forms/store/ProductFormPublic/20164lvs-and-beis
Alarie. A; Schaper. M; Nielson. GD; Abraham. MH. (1998). Structure-activity relationships of
volatile organic chemicals as sensory irritants. Arch Toxicol 72: 125-140.
http://dx.doi.org/10.1007/s00204005Q479
AT SDR (Agency for Toxic Substances and Disease Registry). (2017). Minimal risk levels
(MRLs). June 2017. Atlanta, GA: Agency for Toxic Substances and Disease Registry
(ATSDR). Retrieved from http://www.atsdr.cdc.gov/mrls/index.asp
Babiuk. C; Steinhagen. WH; Barrow. CS. (1985). Sensory irritation response to inhaled
aldehydes after formaldehyde pretreatment. Toxicol Appl Pharmacol 79: 143-149.
http://dx.doi.org/10.1016/0041-008x(85)90376-x
Beauchamp. RQ; St Clair. MBG; Fennelt, TR; Clarke. DO; Morgan. KT; Kari. FW. (1992). A
critical review of the toxicology of glutaraldehyde [Review], Crit Rev Toxicol 22: 143-
174. http://dx.doi.org/10.3109/104084492Q9145322
Bio Dynamics (Bio/dynamics Inc.). (1980). Eye irritation study in rabbits (final report) on
heptanal with attachment and cover letter dated 112291. (TSCATS/420312.
OTS0534460. Doc I.D. 86-920000403). Dallas, TX: Hoecht Celanese Corporation.
Bio Dynamics (Bio/dynamics Inc.). (1981). An acute inhalation toxicity study of C-191 in the rat
(Final report) with cover letter dated 112291. (TSCATS/420318. OTS0534466. EPA I.D.
86-920000409). Washington, DC: Hoechst Celanese Chemical Group, Inc.; U.S.
Environmental Protection Agency.
https://ntrl.ntis.gov/NTRL/dashboard/searchResults.xhtml?searchQuery=OTS0534466
Bio Dynamics (Bio/dynamics Inc.). (1989). Letter concerning enclosed acute inhalation toxicity
study and air quality dispersion modeling report with attachments. (TSCATS/420351.
OTS0534499. Doc I.D. 86-920000443). Dallas, TX: Hoecht Celanese.
Bio Dynamics (Bio/dynamics Inc.). (1991). A 28-day dermal toxicity study in rabbits (final
report) on heptanal with attachments and cover letter dated 112291. (TSCATS/420311.
OTS0534459. EPA I.D. 86-920000402). Dallas, TX: Hoechst Celanese.
Bogdanfl'v. MS; Randall. HW; Morgan. KT. (1986). Histochemical localization of aldehyde
dehydrogenase in the respiratory tract of the Fischer-344 rat. Toxicol Appl Pharmacol 82:
560-567. http://dx.doi.org/10.1016/0041 -Q08X(86)9Q291 -7
Bombick. DW; Doolittle. DJ. (1995). The role of chemical structure and cell type in the
cytotoxicity of low-molecular-weight aldehydes and pyridines. In Vitro Toxicol 8: 349-
356.
Cal/EPA (California Environmental Protection Agency). (2000). Chronic toxicity study.
Glutaraldehyde.
Cal/EPA (California Environmental Protection Agency). (201 1). Hot spots unit risk and cancer
potency values. Appendix A. Sacramento, CA: Office of Environmental Health Hazard
Assessment.
http://standards.nsf.org/apps/group public/download.php?document id= 19121
Cal/EPA (California Environmental Protection Agency). (2014). All OEHHA acute, 8-hour and
chronic reference exposure levels (chRELs) as of June 2014. Sacramento, CA: Office of
Health Hazard Assessment, http://www.oehha.ca.gov/air/allrels.html
35
//-Heptanal

-------
FINAL
09-13-2017
Cal/EPA (California Environmental Protection Agency). (2017a). Chemicals known to the state
to cause cancer or reproductive toxicity January 27, 2017. (Proposition 65 list).
Sacramento, CA: Office of Environmental Health Hazard Assessment.
http://oehha.ca.eov/proposition-65/proposition-65-list
Cal/EPA (California Environmental Protection Agency). (2017b). OEHHA toxicity criteria
database [Database]: Office of Environmental Health Assessment. Retrieved from
http://www.oehha.ca.gov/tcdb/index.asp
Carruthers- C; Stowell. RE. (1941). Influence of heptaldehyde on the pregnancy in rats. Cancer
Res 1: 724-728.
ChemlDplus. (2016). ChemlDplus - a TOXNET database. Bethesda, MD: National Institutes of
Health, U.S. Library of Medicine. Retrieved from
http: //chem. si s. nlm. nih. gov/chemi dplus/
ChemlDplus. (2017). ChemlDplus a TOXNET database. Bethesda, MD: National Institutes of
Health, U.S. Library of Medicine. Retrieved from
http: //chem. si s. nlm. nih. gov/chemi dplus/
Dow Chemical Co (Dow Chemical Company). (1958). Results of range finding toxicological
tests on heptyl aldehyde (isomeric primary mixture). In Letter submitting multiple studies
on multiple chemicals required for docket opts-82036 with attachments (sanitized).
(TSCATS/422419. OTS0535413.).
DSSTox (Distributed Structure-Searchable Toxicity). (2016). DSSTox database [Database],
Research Triangle Park, NC: U.S. Environmental Protection Agency, National Center for
Computational Toxicology. Retrieved from http://www.epa.gov/ncct/dsstox/
Eastman Kodak (Eastman Kodak Company). (1985). Letter from Eastman Kodak Company to
USEPA submitting enclosed toxicity and health hazard summary and toxicity report on
heptanal with attachments. (TSCATS/421039. OTS0533620. EPA Doc I.D. 86-
920000054). Rochester, NY.
EC HA (European Chemicals Agency). (2017). Registered substances [Database], Helsinki,
Finland. Retrieved from https://echa.europa.eu/information-on-chemicals/registered-
substances
Egle, JL, Jr. (1972). Retention of inhaled formaldehyde, propionaldehyde, and acrolein in the
dog. Arch Environ Occup Health 25: 119-124.
FDA (U.S. Food and Drug Administration). (2015). Code of Federal Regulations Title 21
(21CFR172.515). Silver Spring, MD: U.S. FDA.
https://www.accessdata.fda. gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch. cfm?fr=172.515&S
earchT erm heptanal
Florin, I; Rutberg, L; Curvall, M; Enzell, CR. (1980). Screening of tobacco smoke constituents
for mutagenicity using the Ames' test. Toxicology 15: 219-232.
http://dx.doi.org/10.1016/0300-483X(80)90055-4
HSDB (Hazardous Substances Data Bank). (2014). N-Heptanal. Bethesda, MD: National Library
of Medicine, National Toxicology Program.
I ARC (International Agency for Research on Cancer). (2017). I ARC Monographs on the
evaluation of carcinogenic risk to humans. Geneva, Switzerland: International Agency for
Research on Cancer, WHO. http://monographs.iarc.fr/ENG/Monographs/PDFs/index.php
36
//-Heptanal

-------
FINAL
09-13-2017
IPC'S (International Programme on Chemical Safety). (1998). Safety evaluation of certain food
additives and contaminants. Saturated aliphatic acyclic linear primary alcohols,
aldehydes, and acids. WHO food additive series 40. Prepared by the forty ninth meeting
of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). Geneva,
Switzerland: World Health Organization.
http://www.inchem.org/documents/iecfa/iecmono/v040iel0.htm
Koerker. RL; Berlin. AJ; Schneider. FH. (1976). The cytotoxicity of short-chain alcohols and
aldehydes in cultured neuroblastoma cells. Toxicol Appl Pharmacol 37: 281-288.
Lawson. RN; Saunders. AL; Cowen. RD. (1956). Breast cancer and heptaldehyde; preliminary
report. Can Med Assoc J 75: 486-488.
Litton Bionetics. (1980). Mutagenicity evaluation of c-191 sn 2213-1 in the ames
salmonella/microsome plate test (final report) with cover letter dated 112291. (86-
920000404). Kensington, MD: Litton Bionetics, Inc.
MB Research Laboratories Inc. (1974). Acute oral toxicity in rats/dermal toxicity in rabbits (final
report) on heptanal with cover letter dated 112291. (TSCATS/420317. OTS0534465. Doc
I.D. 86-920000408). Dallas, TX: Hoescht Celanese Labroatories.
Morris. IB; Blanchard. KT. (1992). Upper respiratory tract deposition of inspired acetaldehyde.
Toxicol Appl Pharmacol 1 14: 140-146. http://dx.doi.org/10.1016/0041 -008X(92)90106-3
NIOSH (National Institute for Occupational Safety and Health). (2016). NIOSH pocket guide to
chemical hazards. Index of chemical abstracts service registry numbers (CAS No.).
Atlanta, GA: Center for Disease Control and Prevention, U.S. Department of Health,
Education and Welfare, http://www.cdc.gov/niosh/npg/npgdcas.html
NTP (National Toxicology Program). (1999). Toxicology and carcinogenesis studies of
glutaraldehyde (CAS NO. 111-30-8) in F344/N rats and B6C3F1 mice (inhalation
studies). (NTP TR 490). Research Triangle Park, NC: U.S. Department of Health and
Human Services, Public Health Service, National Institutes of Health.
https://ntp.niehs.nih.gov/ntp/htdocs/lt rpts/tr490.pdf
NTP (National Toxicology Program). (2014). Report on carcinogens. Thirteenth edition.
Research Triangle Park, NC: U.S. Department of Health and Human Services, Public
Health Service.
OECD (Organisation for Economic Co-operation and Development). (2017). The OECD QSAR
toolbox. Retrieved from http://www.oecd.org/chemicalsafety/risk-
assessment/theoecdqsartoolbox.htm
OSHA (Occupational Safety & Health Administration). (2006). Table Z-l: Limits for air
contaminants. Occupational safety and health standards, subpart Z, toxic and hazardous
substances. (OSHA standard 1910.1000, 29 CFR). Washington, DC: U.S. Department of
Labor.
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p
id=9992
OSHA (Occupational Safety & Health Administration). (201 1). Air contaminants: Occupational
safety and health standards for shipyard employment, subpart Z, toxic and hazardous
substances. (OSHA Standard 1915.1000). Washington, DC: U.S. Department of Labor.
https://www.osha.gov/pls/oshaweb/owadisp.show document?p table STANDARDS&P
id=10286
Ovama. T; Isse. T; Ogawa. M; Muto. M; Uchiyama. I; Kawamoto. T. (2007). Susceptibility to
inhalation toxicity of acetaldehyde in Aldh2 knockout mice. Front Biosci 12: 1927-1934.
37
//-Heptanal

-------
FINAL
09-13-2017
RIFM (Research Institute for Fragrance Materials). (1974). Synopsis of maximization test using
25 human volunteers with cover letter dated 112291. (TSCATS/420316. OTS0534464.
Doc I.D. 86-920000407). Dallas, TX: Hoechst Celanese Corporation.
RIFM (Research Institute for Fragrance Materials). (1979). Aldehyde C-7. In DLJ Opdyke (Ed.),
Monographs on Fragrance Raw Materials (pp. 48-49). Oxford: Pergamon Press.
Shell Oil Co (Shell Oil Company). (1982). Toxicology of polymer intermediates: The 4 h acute
inhalation toxicity of heptanal in rats (Final report) with attachments and cover letter
dated 120291. (TSCATS/420353. OTS0534501. EPA/OTS; Doc I.D. 86-920000445).
Houston, TX.
Skog. E. (1950). A toxicological investigation of lower aliphatic aldehydes I Toxicity of
formaldehyde, acetaldehyde, propionaldehyde and butyraldehyde; as well as of acrolein
and crotonaldehyde. Acta Pharmacol Sin 6: 299-3 18. http://dx.doi.org/10.1111/j .1600-
0773.1950.tb03477.x
Stanek. II; Morris. IB. (1999). The effect of inhibition of aldehyde dehydrogenase on nasal
uptake of inspired acetaldehyde. Toxicol Sci 49: 225-231.
http://dx.doi.Org/10.1093/toxsci/49.2.225
Steinhagen, WH; Barrow. CS. (1984). Sensory irritation structure-activity study of inhaled
aldehydes in B6C3F1 and Swiss-Webster mice. Toxicol Appl Pharmacol 72: 495-503.
http://dx.doi .org/10.1016/0041 -008Xf84)90126-1
U.S. EPA (U.S. Environmental Protection Agency). (1994). Methods for derivation of inhalation
reference concentrations and application of inhalation dosimetry [EPA Report] (pp. 1-
409). (EPA/600/8-90/066F). Research Triangle Park, NC: U.S. Environmental Protection
Agency, Office of Research and Development, Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office.
https://cfpub. epa.gov/ncea/risk/recordisplav. cfm?deid=71993&CFID=51174829&CFTO
KEN 25006317
U.S. EPA (U.S. Environmental Protection Agency). (1998). IRIS summary for acetaldehyde
(CASRN 75-07-0). Washington, DC: U.S. Environmental Protection Agency, Integrated
Risk Information System, http://www.epa.gov/iris/subst/0290.htm
U.S. EPA (U.S. Environmental Protection Agency). (2008a). IRIS summary for
propionaldehyde; CASRN 123-38-6. Washington, DC: U.S. Environmental Protection
Agency, Integrated Risk Information System, http://www.epa.gov/iris/subst/1011 .htm
U.S. EPA (U.S. Environmental Protection Agency). (2008b). Toxicological review for
propionaldehyde. Washington, DC: U.S. Enviornmental Protection Agency, IRIS.
http://cfpub.epa.gov/ncea/cfm/recordisplav.cfm?deid=188165
U.S. EPA (U.S. Environmental Protection Agency). (201 1). Health effects assessment summary
tables (HEAST). Washington, DC: U.S. Environmental Protection Agency, Office of
Emergency and Remedial Response, http://epa-heast.ornl.gov/heast.php
U.S. EPA (U.S. Environmental Protection Agency). (2012a). 2012 Edition of the drinking water
standards and health advisories [EPA Report], (EPA/822/S-12/001). Washington, DC:
U.S. Environmental Protection Agency, Office of Water.
http://www.epa.gov/sites/production/files/2015-09/documents/dwstandards2Q12.pdf
U.S. EPA (U.S. Environmental Protection Agency). (2012b). Distributed Structure-Searchable
Toxicity (DSSTox) Database Network. n-Heptanal, CASRN 111-71-7. Available online
at https://\v\v\v.epa.gov/chemical-research/distributed-structure-searchable-toxicitv-
dsstox-databa.se
38
//-Heptanal

-------
FINAL
09-13-2017
U.S. EPA (U.S. Environmental Protection Agency). (2015). High Production Volume
Information System (HPVIS). Partition Coefficient. (111-71-7) Heptanal.
http://ofmpub.epa.gov/oppthpv/Public Search.PublicTabs?SECTION=l&epcount=2&v
rs list=25056639.25056615
U.S. EPA (U.S. Environmental Protection Agency). (2017). Integrated risk information system.
IRIS assessments [Database], Washington, DC: Integrated Risk Information 'System.
Retrieved from http://www.epa.eov/iris/
Wane. NC; Zhao. OJ; Wesselkamper. SC; Lambert, JC; Petersen. D; Hess-Wilson. JK. (2012).
Application of computational toxicological approaches in human health risk assessment.
I. A tiered surrogate approach. Regul Toxicol Pharmacol 63: 10-19.
http://dx.doi.Org/10.1016/i.vrtph.2012.02.006
Wane, RS; Nakajima. T; Kawamoto, T; Hon ma. T. (2002). Effects of aldehyde dehydrogenase-2
genetic polymorphisms on metabolism of structurally different aldehydes in human liver.
Drug Metab Dispos 30: 69-73.
Werlev. MS; Burleieh-f'laver. HP; Ballantvne. B. (1995). Respiratory peripheral sensory
irritation and hypersensitivity studies with glutaraldehyde vapor. Toxicol Ind Health 11:
489-501.
WHO (World Health Organization). (1999). Evaluation of certain food additives and
contaminants: Forty-ninth report of the Joint FAO/WHO Expert Committee on Food
Additives. (WHO Technical Report Series 884). Geneva, Switzerland.
http://whqlibdoc.who.int/trs/WHO TRS 884.pdf
WHO (World Health Organization). (2002). Evaluations of the Joint FAO/WHO Expert
Committee on Food Additives (JECFA). Heptanal. Geneva, Switzerland: FAO/WHO.
http://apps.who.int/food-additives-contaminants-i ecfa-
database/chemical. aspx?chemID=4346
Zeieer. E; Anderson. B; Haworth. S; Lawlor. T; Mortelmans. K. (1992). Salmonella
mutagenicity tests: V Results from the testing of 311 chemicals. Environ Mol Mutagen
19: 2-141. http://dx.doi.org/10.1002/em.28501906Q3
39
//-Heptanal

-------